Clinical Review

CASE Patient-centered counseling for contraception

A 19-year-old woman (G0) with moderately well-controlled seizure disorder while taking levetiracetam, who reports migraines, and has a BMI of 32 kg/m² presents to your office seeking contraception. She is currently sexually active with her second lifetime partner and uses condoms inconsistently. She is otherwise healthy and has no problems to report. Her last menstrual period (LMP) was 1 week ago, and a pregnancy test today is negative. How do you approach counseling for this patient?

The modern contraceptive patient

Our patients are becoming increasingly medically and socially complicated. Meeting the contraceptive needs of patients with multiple comorbidities can be a daunting task. Doing so in a patient-centered way that also recognizes the social contexts and intimacy inherent to contraceptive care can feel overwhelming. However, by employing a systematic approach to each patient, we can provide safe, effective, individualized care to our medically complex patients. Having a few “go-to tools” can streamline the process.

Medically complex patients are often told that they need to avoid pregnancy or optimize their health conditions prior to becoming pregnant, but they may not receive medically-appropriate contraception.^1-3 Additionally, obesity rates in women of reproductive age in the United States are increasing, along with related medical complexities.⁴ Disparities in contraceptive access and use of particular methods exist by socioeconomic status, body mass index (BMI), age, and geography. ^5,6 Evidence-based, shared decision making can improve contraceptive satisfaction.⁷

Clinicians need to stay attuned to all options. Staying current on available contraceptive methods can broaden clinicians’ thinking and allow patients more choices that are compatible with their medical needs. In the last 2 years alone, a 1-year combined estrogen-progestin vaginal ring, a drospirinone-only pill, and a nonhormonal spermicide have become available for prescription.^8-10 Both 52 mg levonorgestrel-containing intrauterine devices (IUDs) are now US Food and Drug Administration (FDA)-approved for 6 years, and there is excellent data for off-label use to 7 years.¹¹

Tools are available for use. To ensure patient safety, we must evaluate the relative risks of each method given their specific medical history. The Centers for Disease Control and Prevention (CDC) Medical Eligibility Criteria (MEC) provides a comprehensive reference for using each contraceptive method category with preexisting medical conditions on a scale from 1 (no restrictions) to 4 (unacceptable health risk) (TABLE 1).¹² It is important to remember that pregnancy often poses a larger risk even than category 4 methods. With proper counseling and documentation, a category 3 method may be appropriate in some circumstances. The CDC MEC can serve as an excellent counseling tool and is available as a free smartphone app. The app can be downloaded via https://www.cdc.gov/reproductivehealth/contraception/mmwr/mec/summary.html (TABLE 2).

In a shared decision-making model, we contribute our medical knowledge, and the patient provides expertise on her own values and social context.¹³ By starting the contraceptive conversation with open-ended questions, we invite the patient to lead the discussion. We partner with them in finding a safe, effective method that is compatible with both the medical history and stated preferences. Bedsider.org has an interactive tool that allows patients to explore different contraceptive methods and compare their various characteristics. While tiered efficacy models may help us to organize our thinking as clinicians, it is important to recognize that patients may consider side effect profiles, nonreliance on clinicians for discontinuation, or other priorities above effectiveness.

Continue to: How to craft your approach...

How to craft your approach

Developing a systematic approach to the medically complex patient seeking contraception can help to change an initially daunting task into a fulfilling experience (FIGURE 1). Begin by eliciting patient priorities. Then frame the discussion around them, rather than around efficacy. Although anecdotal reasoning can initially be frustrating (“My best friend’s IUD was really painful and I don’t want anything like that inside me!”), learning about these experiences prior to counseling can be incredibly informative. Ask detailed questions about medical comorbidities, as these subtleties may change the relative safety of each method. Finally, engage the patient in a frank discussion of the relative merits, safety, and use of all medically appropriate contraceptive methods. The right method is the method that the patient will use.

CASE Continued: Applying our counseling method

Upon open-ended questioning, the patient tells you that she absolutely cannot be on a contraceptive method that will make her gain weight. She has several friends who told her that they gained weight on “the shot” and “the implant.” She wants to avoid these at all costs and thinks she might want to take “the pill.” She also tells you that she is in college and that her daily routine varies significantly between weekdays and weekends. She definitely does not want to get pregnant until she has completed her education, which will be at least 3 years from now.

To best counsel this patient and arrive at the most appropriate contraceptive option for her, clarify her medical history and employ shared decision-making for her chosen method.

Probe her seizure history

She tells you that she has had seizures since she was a child, and the last one occurred 4 months ago when she ran out of her anticonvulsant medication. Her seizures have never been associated with her menses. This is an important piece of information. The frequency of catamenial seizures can be decreased with use of any method that suppresses ovulation, such as depot-medroxyprogesterone (DMPA) injections, continuous combined hormonal contraceptive (CHC) pills or ring, or the implant. Noncatamenial seizures also can be suppressed by DMPA, which increases the seizure threshold.¹⁴ Many anticonvulsants are metabolized through cytochrome P450 in the liver and, therefore, interact with all oral contraceptive formulations. However, levetiracetam is not among them and may be safely taken with progestin-only pills. At this point, all contraceptive methods remain CDC MEC category 1 (FIGURE 2).¹²

Ask migraine specifics

It is important to clarify whether or not the patient experiences aura with her migraines. She says that she always knows when a migraine is coming on because she sees floaters in her vision for about 30 minutes prior to the onset of excruciating headache. One tool that may aid in the diagnosis of aura is the Visual Aura Rating Scale (VARS).¹⁵ The presence of aura renders all CHCs category 4 by the CDC MEC.¹² (See FIGURE 2.)

Discuss contraceptive pros and cons

Have a frank discussion about the relative risks and benefits of each method. For instance, although DMPA may improve the patient’s seizures, she has expressed a desire to avoid weight gain, and DMPA is the only method consistently shown in studies to do so.¹⁶ Her seizures are not associated with menses, so menstrual suppression is neither beneficial nor deleterious. Although her current medication levetiracetam does not influence the metabolism of contraceptive methods, many anticonvulsants do. Offer anticipatory guidance around seeking gynecologic consultation with any future seizure medication changes.

Allow for shared decision-making on a final choice

The patient indicated that she had been considering “the pill” when she made this appointment, but you have explained that CHCs are contraindicated for her. She is concerned that she will not be able to stick to the strict dosing schedule of a progestin-only pill. Although you inform her that the drospirinone-only pill has a more forgiving window, the patient decides that she wants a “set it and forget it” method and opts for an IUD. 

CASE Resolved

Following recommendations from the American College of Obstetricians and Gynecologists (ACOG), you provide for same-day insertion of a 52-mg levonorgestrel IUD.¹⁷ You use a paracervical block in addition to ibuprofen for pain control.¹⁸ The patient undergoes same-day testing for gonorrhea and chlamydia, and she understands that if a test is found to be positive, she can be treated without removing the IUD. You provide instruction on the importance of dual contraceptive use with barrier methods for the prevention of STIs. The patient is instructed on self-string checks, and she acknowledges that she will call if she has any concerns; no routine follow-up is required. She leaves her visit satisfied with her preferred, safe, effective contraceptive method in situ. ●

CASE Patient-centered counseling for contraception

A 19-year-old woman (G0) with moderately well-controlled seizure disorder while taking levetiracetam, who reports migraines, and has a BMI of 32 kg/m² presents to your office seeking contraception. She is currently sexually active with her second lifetime partner and uses condoms inconsistently. She is otherwise healthy and has no problems to report. Her last menstrual period (LMP) was 1 week ago, and a pregnancy test today is negative. How do you approach counseling for this patient?

The modern contraceptive patient

Our patients are becoming increasingly medically and socially complicated. Meeting the contraceptive needs of patients with multiple comorbidities can be a daunting task. Doing so in a patient-centered way that also recognizes the social contexts and intimacy inherent to contraceptive care can feel overwhelming. However, by employing a systematic approach to each patient, we can provide safe, effective, individualized care to our medically complex patients. Having a few “go-to tools” can streamline the process.

Medically complex patients are often told that they need to avoid pregnancy or optimize their health conditions prior to becoming pregnant, but they may not receive medically-appropriate contraception.^1-3 Additionally, obesity rates in women of reproductive age in the United States are increasing, along with related medical complexities.⁴ Disparities in contraceptive access and use of particular methods exist by socioeconomic status, body mass index (BMI), age, and geography. ^5,6 Evidence-based, shared decision making can improve contraceptive satisfaction.⁷

Clinicians need to stay attuned to all options. Staying current on available contraceptive methods can broaden clinicians’ thinking and allow patients more choices that are compatible with their medical needs. In the last 2 years alone, a 1-year combined estrogen-progestin vaginal ring, a drospirinone-only pill, and a nonhormonal spermicide have become available for prescription.^8-10 Both 52 mg levonorgestrel-containing intrauterine devices (IUDs) are now US Food and Drug Administration (FDA)-approved for 6 years, and there is excellent data for off-label use to 7 years.¹¹

Tools are available for use. To ensure patient safety, we must evaluate the relative risks of each method given their specific medical history. The Centers for Disease Control and Prevention (CDC) Medical Eligibility Criteria (MEC) provides a comprehensive reference for using each contraceptive method category with preexisting medical conditions on a scale from 1 (no restrictions) to 4 (unacceptable health risk) (TABLE 1).¹² It is important to remember that pregnancy often poses a larger risk even than category 4 methods. With proper counseling and documentation, a category 3 method may be appropriate in some circumstances. The CDC MEC can serve as an excellent counseling tool and is available as a free smartphone app. The app can be downloaded via https://www.cdc.gov/reproductivehealth/contraception/mmwr/mec/summary.html (TABLE 2).

In a shared decision-making model, we contribute our medical knowledge, and the patient provides expertise on her own values and social context.¹³ By starting the contraceptive conversation with open-ended questions, we invite the patient to lead the discussion. We partner with them in finding a safe, effective method that is compatible with both the medical history and stated preferences. Bedsider.org has an interactive tool that allows patients to explore different contraceptive methods and compare their various characteristics. While tiered efficacy models may help us to organize our thinking as clinicians, it is important to recognize that patients may consider side effect profiles, nonreliance on clinicians for discontinuation, or other priorities above effectiveness.

Continue to: How to craft your approach...

How to craft your approach

Developing a systematic approach to the medically complex patient seeking contraception can help to change an initially daunting task into a fulfilling experience (FIGURE 1). Begin by eliciting patient priorities. Then frame the discussion around them, rather than around efficacy. Although anecdotal reasoning can initially be frustrating (“My best friend’s IUD was really painful and I don’t want anything like that inside me!”), learning about these experiences prior to counseling can be incredibly informative. Ask detailed questions about medical comorbidities, as these subtleties may change the relative safety of each method. Finally, engage the patient in a frank discussion of the relative merits, safety, and use of all medically appropriate contraceptive methods. The right method is the method that the patient will use.

CASE Continued: Applying our counseling method

Upon open-ended questioning, the patient tells you that she absolutely cannot be on a contraceptive method that will make her gain weight. She has several friends who told her that they gained weight on “the shot” and “the implant.” She wants to avoid these at all costs and thinks she might want to take “the pill.” She also tells you that she is in college and that her daily routine varies significantly between weekdays and weekends. She definitely does not want to get pregnant until she has completed her education, which will be at least 3 years from now.

To best counsel this patient and arrive at the most appropriate contraceptive option for her, clarify her medical history and employ shared decision-making for her chosen method.

Probe her seizure history

She tells you that she has had seizures since she was a child, and the last one occurred 4 months ago when she ran out of her anticonvulsant medication. Her seizures have never been associated with her menses. This is an important piece of information. The frequency of catamenial seizures can be decreased with use of any method that suppresses ovulation, such as depot-medroxyprogesterone (DMPA) injections, continuous combined hormonal contraceptive (CHC) pills or ring, or the implant. Noncatamenial seizures also can be suppressed by DMPA, which increases the seizure threshold.¹⁴ Many anticonvulsants are metabolized through cytochrome P450 in the liver and, therefore, interact with all oral contraceptive formulations. However, levetiracetam is not among them and may be safely taken with progestin-only pills. At this point, all contraceptive methods remain CDC MEC category 1 (FIGURE 2).¹²

Ask migraine specifics

It is important to clarify whether or not the patient experiences aura with her migraines. She says that she always knows when a migraine is coming on because she sees floaters in her vision for about 30 minutes prior to the onset of excruciating headache. One tool that may aid in the diagnosis of aura is the Visual Aura Rating Scale (VARS).¹⁵ The presence of aura renders all CHCs category 4 by the CDC MEC.¹² (See FIGURE 2.)

Discuss contraceptive pros and cons

Have a frank discussion about the relative risks and benefits of each method. For instance, although DMPA may improve the patient’s seizures, she has expressed a desire to avoid weight gain, and DMPA is the only method consistently shown in studies to do so.¹⁶ Her seizures are not associated with menses, so menstrual suppression is neither beneficial nor deleterious. Although her current medication levetiracetam does not influence the metabolism of contraceptive methods, many anticonvulsants do. Offer anticipatory guidance around seeking gynecologic consultation with any future seizure medication changes.

Allow for shared decision-making on a final choice

The patient indicated that she had been considering “the pill” when she made this appointment, but you have explained that CHCs are contraindicated for her. She is concerned that she will not be able to stick to the strict dosing schedule of a progestin-only pill. Although you inform her that the drospirinone-only pill has a more forgiving window, the patient decides that she wants a “set it and forget it” method and opts for an IUD. 

CASE Resolved

Following recommendations from the American College of Obstetricians and Gynecologists (ACOG), you provide for same-day insertion of a 52-mg levonorgestrel IUD.¹⁷ You use a paracervical block in addition to ibuprofen for pain control.¹⁸ The patient undergoes same-day testing for gonorrhea and chlamydia, and she understands that if a test is found to be positive, she can be treated without removing the IUD. You provide instruction on the importance of dual contraceptive use with barrier methods for the prevention of STIs. The patient is instructed on self-string checks, and she acknowledges that she will call if she has any concerns; no routine follow-up is required. She leaves her visit satisfied with her preferred, safe, effective contraceptive method in situ. ●

CASE Patient-centered counseling for contraception

A 19-year-old woman (G0) with moderately well-controlled seizure disorder while taking levetiracetam, who reports migraines, and has a BMI of 32 kg/m² presents to your office seeking contraception. She is currently sexually active with her second lifetime partner and uses condoms inconsistently. She is otherwise healthy and has no problems to report. Her last menstrual period (LMP) was 1 week ago, and a pregnancy test today is negative. How do you approach counseling for this patient?

The modern contraceptive patient

Our patients are becoming increasingly medically and socially complicated. Meeting the contraceptive needs of patients with multiple comorbidities can be a daunting task. Doing so in a patient-centered way that also recognizes the social contexts and intimacy inherent to contraceptive care can feel overwhelming. However, by employing a systematic approach to each patient, we can provide safe, effective, individualized care to our medically complex patients. Having a few “go-to tools” can streamline the process.

Medically complex patients are often told that they need to avoid pregnancy or optimize their health conditions prior to becoming pregnant, but they may not receive medically-appropriate contraception.^1-3 Additionally, obesity rates in women of reproductive age in the United States are increasing, along with related medical complexities.⁴ Disparities in contraceptive access and use of particular methods exist by socioeconomic status, body mass index (BMI), age, and geography. ^5,6 Evidence-based, shared decision making can improve contraceptive satisfaction.⁷

Clinicians need to stay attuned to all options. Staying current on available contraceptive methods can broaden clinicians’ thinking and allow patients more choices that are compatible with their medical needs. In the last 2 years alone, a 1-year combined estrogen-progestin vaginal ring, a drospirinone-only pill, and a nonhormonal spermicide have become available for prescription.^8-10 Both 52 mg levonorgestrel-containing intrauterine devices (IUDs) are now US Food and Drug Administration (FDA)-approved for 6 years, and there is excellent data for off-label use to 7 years.¹¹

Tools are available for use. To ensure patient safety, we must evaluate the relative risks of each method given their specific medical history. The Centers for Disease Control and Prevention (CDC) Medical Eligibility Criteria (MEC) provides a comprehensive reference for using each contraceptive method category with preexisting medical conditions on a scale from 1 (no restrictions) to 4 (unacceptable health risk) (TABLE 1).¹² It is important to remember that pregnancy often poses a larger risk even than category 4 methods. With proper counseling and documentation, a category 3 method may be appropriate in some circumstances. The CDC MEC can serve as an excellent counseling tool and is available as a free smartphone app. The app can be downloaded via https://www.cdc.gov/reproductivehealth/contraception/mmwr/mec/summary.html (TABLE 2).

In a shared decision-making model, we contribute our medical knowledge, and the patient provides expertise on her own values and social context.¹³ By starting the contraceptive conversation with open-ended questions, we invite the patient to lead the discussion. We partner with them in finding a safe, effective method that is compatible with both the medical history and stated preferences. Bedsider.org has an interactive tool that allows patients to explore different contraceptive methods and compare their various characteristics. While tiered efficacy models may help us to organize our thinking as clinicians, it is important to recognize that patients may consider side effect profiles, nonreliance on clinicians for discontinuation, or other priorities above effectiveness.

Continue to: How to craft your approach...

How to craft your approach

Developing a systematic approach to the medically complex patient seeking contraception can help to change an initially daunting task into a fulfilling experience (FIGURE 1). Begin by eliciting patient priorities. Then frame the discussion around them, rather than around efficacy. Although anecdotal reasoning can initially be frustrating (“My best friend’s IUD was really painful and I don’t want anything like that inside me!”), learning about these experiences prior to counseling can be incredibly informative. Ask detailed questions about medical comorbidities, as these subtleties may change the relative safety of each method. Finally, engage the patient in a frank discussion of the relative merits, safety, and use of all medically appropriate contraceptive methods. The right method is the method that the patient will use.

CASE Continued: Applying our counseling method

Upon open-ended questioning, the patient tells you that she absolutely cannot be on a contraceptive method that will make her gain weight. She has several friends who told her that they gained weight on “the shot” and “the implant.” She wants to avoid these at all costs and thinks she might want to take “the pill.” She also tells you that she is in college and that her daily routine varies significantly between weekdays and weekends. She definitely does not want to get pregnant until she has completed her education, which will be at least 3 years from now.

To best counsel this patient and arrive at the most appropriate contraceptive option for her, clarify her medical history and employ shared decision-making for her chosen method.

Probe her seizure history

She tells you that she has had seizures since she was a child, and the last one occurred 4 months ago when she ran out of her anticonvulsant medication. Her seizures have never been associated with her menses. This is an important piece of information. The frequency of catamenial seizures can be decreased with use of any method that suppresses ovulation, such as depot-medroxyprogesterone (DMPA) injections, continuous combined hormonal contraceptive (CHC) pills or ring, or the implant. Noncatamenial seizures also can be suppressed by DMPA, which increases the seizure threshold.¹⁴ Many anticonvulsants are metabolized through cytochrome P450 in the liver and, therefore, interact with all oral contraceptive formulations. However, levetiracetam is not among them and may be safely taken with progestin-only pills. At this point, all contraceptive methods remain CDC MEC category 1 (FIGURE 2).¹²

Ask migraine specifics

It is important to clarify whether or not the patient experiences aura with her migraines. She says that she always knows when a migraine is coming on because she sees floaters in her vision for about 30 minutes prior to the onset of excruciating headache. One tool that may aid in the diagnosis of aura is the Visual Aura Rating Scale (VARS).¹⁵ The presence of aura renders all CHCs category 4 by the CDC MEC.¹² (See FIGURE 2.)

Discuss contraceptive pros and cons

Have a frank discussion about the relative risks and benefits of each method. For instance, although DMPA may improve the patient’s seizures, she has expressed a desire to avoid weight gain, and DMPA is the only method consistently shown in studies to do so.¹⁶ Her seizures are not associated with menses, so menstrual suppression is neither beneficial nor deleterious. Although her current medication levetiracetam does not influence the metabolism of contraceptive methods, many anticonvulsants do. Offer anticipatory guidance around seeking gynecologic consultation with any future seizure medication changes.

Allow for shared decision-making on a final choice

The patient indicated that she had been considering “the pill” when she made this appointment, but you have explained that CHCs are contraindicated for her. She is concerned that she will not be able to stick to the strict dosing schedule of a progestin-only pill. Although you inform her that the drospirinone-only pill has a more forgiving window, the patient decides that she wants a “set it and forget it” method and opts for an IUD. 

CASE Resolved

Following recommendations from the American College of Obstetricians and Gynecologists (ACOG), you provide for same-day insertion of a 52-mg levonorgestrel IUD.¹⁷ You use a paracervical block in addition to ibuprofen for pain control.¹⁸ The patient undergoes same-day testing for gonorrhea and chlamydia, and she understands that if a test is found to be positive, she can be treated without removing the IUD. You provide instruction on the importance of dual contraceptive use with barrier methods for the prevention of STIs. The patient is instructed on self-string checks, and she acknowledges that she will call if she has any concerns; no routine follow-up is required. She leaves her visit satisfied with her preferred, safe, effective contraceptive method in situ. ●

CASE Woman in second stage with prolonged pushing

Ms. J. is an 18-year-old woman (G1P0) at 39 weeks’ gestation whose cervix is completely dilated; she has been actively pushing for 60 minutes. The estimated fetal weight is 8 lb, and electronic fetal monitoring shows a Category I fetal heart rate (FHR) tracing. The presenting part remains at 0 station and occiput transverse despite great pushing effort.

After another hour of active pushing, the FHR becomes Category II with repetitive variable decelerations. During the third hour of the second stage, Ms. J. is diagnosed with chorioamnionitis and the fetus remains at 0 station. She undergoes a primary cesarean delivery (CD) complicated by bilateral lower uterine extensions and postpartum hemorrhage. The birth weight was 4,100 g, and 5- and 10-minute Apgar scores were 4 and 8, respectively. The umbilical cord arterial pH was 7.03.

Ms. J. and her baby were discharged home on postoperative day 4.

In 2014, the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine jointly released a document, “Safe prevention of the primary cesarean delivery,” in response to the sharp rise in cesarean births from 1996 to 2011.¹ It described management strategies to safely reduce the most common indications for a primary CD in nulliparous women. Specifically, it recommended that the second stage of labor—defined as the interval from complete cervical dilation through delivery of the neonate—may be prolonged, as “longer durations may be appropriate on an individualized basis (eg, with the use of epidural analgesia or with fetal malposition) as long as progress is being documented.”¹

A prolonged second stage was defined as 3 hours of pushing in nulliparous women and 2 hours in multiparous women, with 1 additional hour (or longer) in those receiving epidural analgesia. Indeed, the primary CD rate decreased slightly to 21.7% in 2018, down from 21.9% in 2017.² More recent evidence, however, has shown an increase in maternal and neonatal morbidity with prolonged second stage.^3-8

Efforts to manage the second stage from an evidence-based perspective are critical to balance the desired outcome of a safe vaginal delivery against the risks of prolonged second stage and operative vaginal delivery or CD.

Perspectives on the “ideal” labor duration

It is important to consider the historical context that led to the 2014 change in recommendations for duration of the second stage.⁹ In 1955, Dr. Emanuel Friedman published a prospective observational study of 622 consecutive primigravid parturients at term, of which 500 were included in the analysis that led to the graphicostatistical labor curve, or the well-known “Friedman’s curve.”¹⁰ The mean duration of the second stage was 0.95 hour. The statistical maximum for “ideal labor” for the second stage was set at 2 hours, with an additional hour allotted for patients receiving epidural analgesia.

In 2010, Zhang and colleagues published contemporary labor curves using data from the Consortium on Safe Labor, a multicenter retrospective observational study of 62,415 parturients.¹¹ Among more than 25,000 nulliparous women, the median duration (95th percentile) of the second stage in hours was 1.1 (3.6), respectively. Notably, this analysis included only women with a spontaneous vaginal delivery and normal neonatal outcome.

Prior to the publication of the “Safe prevention of primary cesarean delivery,” multiple investigations examined the relationship between the duration of the second stage and adverse maternal and neonatal outcomes, and the findings have been inconsistent.^12-15

For example, Cheng and colleagues noted increased maternal complications that included postpartum hemorrhage, third- and fourth-degree perineal lacerations, and chorioamnionitis, but not neonatal morbidity, with each increasing hour within the second stage.¹² By contrast, a large, population-based cohort study among low-risk women showed an increase in low 5-minute Apgar scores, admission to the neonatal intensive care unit (NICU), and composite perinatal morbidity with prolonged second stage.¹⁵ Furthermore, a secondary analysis of the Pushing Early or Pushing Late with Epidural (PEOPLE) trial showed that the chances of a vaginal delivery with a newborn without signs of asphyxia decreased significantly every hour after the first hour, and the risk of postpartum hemorrhage and intrapartum fever increased significantly after 2 hours of pushing.¹⁴

While these findings may represent the risks inherent with the intervention of operative delivery and not the duration of second stage of labor per se, one could posit that if the intervention were initiated earlier, could it prevent or at least reduce maternal and neonatal morbidity?

Continue to: Factors to assess and monitor in the second stage...

Factors to assess and monitor in the second stage

When assessing progress in the second stage of labor, consider:

• maternal factors
• fetal/neonatal factors, and
• modifiable factors.

Maternal factors that influence the second stage of labor include parity, body mass index (BMI), age, and clinical pelvimetry.^11,16-19 Fetal/neonatal factors that impact the second stage include the estimated fetal weight, fetal presentation (cephalic, face, and so on), position, and station, as well as the FHR Category.^{20, 21} Factors that can be modified in the second stage include the effect of epidural analgesia (turning it down to reduce motor blockade while maintaining sensory pain relief so that patients feel the “urge” to push), maternal pushing position and technique, the presence of maternal support person(s), manual rotation for a fetal position that is not optimal, immediate versus delayed pushing, and prevention of perineal tears.^22-32 Interestingly, epidural analgesia, parity, birth weight, and station at complete dilation predicted second stage duration but accounted for only 25% of the variability in second stage length, leaving 75% of the variance unexplained.¹⁶

A specific absolute maximum length of time spent in the second stage of labor beyond which all women should undergo operative delivery has not been identified.¹ Therefore, maternal, fetal/neonatal, and modifiable factors need to be critically assessed and continually monitored to determine whether a prolonged second stage or an operative delivery is warranted to prevent or minimize adverse maternal and neonatal outcomes.

Maternal factors

Maternal age correlates directly with the length of the second stage. That is, the length of the second stage increases with increasing age.¹⁷

Multiparous women have a shorter length of the second stage, regardless of epidural analgesia, compared with nulliparous women.¹¹ In the Consortium for Safe Labor, multiparous women had a significantly shorter median second stage compared with nulliparous women.¹¹

In adjusted analyses, maternal obesity was associated with an increased risk for CD, with the risk of CD more than 3 times greater in women with a BMI higher than 40 kg/m² compared with those who had a BMI less than 25 kg/m².¹⁸ There were no significant differences in the length of the second stage of labor by BMI catgeories.¹⁹

Fetal factors

Birth weight greater than 4,000 g was associated with an increased risk for arrest of descent during the second stage.³³

Persistent fetal occiput posterior or transverse position may impact the duration of the second stage. A retrospective cohort study in women who underwent a trial of manual rotation compared with expectant management during the second stage of labor with the fetus in occiput posterior or occiput transverse position found that women with manual rotation were less likely to have a CD, severe perineal laceration, postpartum hemorrhage, and chorioamnionitis. However, an increased risk of cervical laceration was associated with manual rotation.²⁰

Regarding FHR status, FHR abnormalities occurred in 91% of second stage labor patterns, with Category II being the most common.²¹ The fetal status should remain reassuring to allow for continuation of the second stage.

Continue to: Epidural analgesia...

Epidural analgesia

About 60% of women receive neuraxial analgesia in the United States,²² although rates vary widely across different populations. A Cochrane review showed no difference in the duration of the second stage among women who had early versus late initiation of epidural analgesia in labor.²³ Epidural analgesia has no impact on the risk of CD; however, women with epidural analgesia experienced more hypotension, motor blockade, fever, and urinary retention.²⁴

One management practice has been to discontinue epidural analgesia to allow resumption of sensory and motor nerve function. Another Cochrane systematic review found no difference in mode of delivery or neonatal outcomes.²⁵ Rather than discontinuing epidural analgesia, which results in a profound increase in inadequate pain relief, one may consider titrating the dose with joint patient decision-making to allow for greater motor capability while maintaining adequate analgesia.³⁴

Immediate vs delayed pushing

The 2 most common approaches to managing the second stage were either to initiate pushing with contractions once complete dilation occurred (immediate pushing) or to allow for a rest period in which the fetus passively rotated and descended while conserving a woman’s energy for pushing efforts (delayed pushing, laboring down, or passive descent). Since the publication of “Safe prevention of primary cesarean delivery,” however, studies have shown a concerning association between maternal and neonatal complications and prolonged second stage (which may occur with delayed pushing).^3-8,35 An observational study of nearly 44,000 nulliparous women without epidural analgesia found that prolonged second stage was associated with increased chorioamnionitis, third- and fourth-degree lacerations, neonatal sepsis, neonatal asphyxia, and perinatal mortality.³⁵

A pragmatic multicenter randomized clinical trial on the optimal management of second stage of labor across the United States recently was conducted.⁷ More than 2,000 nulliparous women at term in spontaneous or induced labor with epidural analgesia were randomly assigned at complete dilation to immediate pushing or delayed pushing (1 hour after complete dilation). There was no difference in the rate of vaginal delivery. The rate of postpartum hemorrhage was significantly lower among women in the immediate-pushing group compared with the delayed-pushing group (2.3% vs 4.0%, respectively; relative risk [RR], 0.6; 95% confidence interval [CI], 0.3–0.9; P = .03). Furthermore, rates of chorioamnionitis were significantly lower among women in the immediate-pushing group compared with the delayed-pushing group (6.7% vs 9.1%, respectively; RR, 0.70; 95% CI, 0.66–0.90; P = .005). No significant difference occurred in the composite outcome of neonatal morbidity between the groups. However neonatal acidemia (umbilical cord arterial pH <7.1) and confirmed or suspected sepsis were significantly increased in the delayed-pushing group.

The evidence supports active pushing at the start of the second stage. Women who consider delayed pushing should be informed that delayed pushing has not been shown to increase the likelihood of vaginal birth and that it is associated with increased risks of infection, hemorrhage, and neonatal acidemia.³⁶

Maternal pushing position and technique

Spontaneous pushing (in which women are free to follow their instincts and generally push 3 to 5 times per contraction) versus directed pushing (women are encouraged to take a deep breath at the beginning of a contraction then hold it and bear down throughout the contraction) demonstrated no clear difference in duration of the second stage, perineal laceration, episiotomy, time spent pushing, or number of women with spontaneous vaginal birth. There was no difference in 5-minute Apgar score less than 7 or admission to the NICU.²⁶

With regard to maternal positioning during the second stage, a Cochrane systematic review found benefits for upright posture, including a very small reduction in the duration of the second stage, reduction in episiotomy rates, and reduction in assisted deliveries.³⁷ There was an increased risk of blood loss greater than 500 mL and possibly an increased risk in second-degree tears.³⁷ Compared with women allocated to lying down, women in the upright position during the second stage with epidural analgesia had significantly fewer spontaneous vaginal births. There was no difference in operative vaginal delivery, obstetric anal sphincter injury (OASI), infant Apgar score of less than 4 at 5 minutes, and maternal fecal incontinence at 1 year.²⁸

Continue to: Maternal support person...

 

 

Maternal support person

Continuous support during labor may improve outcomes for women and infants, including increased spontaneous vaginal birth, shorter duration of labor, and decreased cesarean birth.²⁹ In a randomized trial of 412 healthy nulliparous women, women in labor were assigned to either a support group that received continuous support from a doula or an observed group that was monitored by an inconspicuous observer. Continuous labor support significantly reduced the rate of CDs and forceps deliveries.^30,36 Indeed, during the COVID-19 pandemic, doulas have found innovative ways to continue to provide this essential support through virtual health.³⁸

Prevention of perineal tears

Evidence suggests that warm compresses, and massage, may reduce third- and fourth-degree perineal tears.³¹ A meta-analysis of observational studies showed a significant reduction in the risk of OASI.³²

Second stage steps: Recap

Throughout the second stage of labor, the decision to continue with expectant management or intervene with either an operative vaginal delivery or a CD is complex and requires consistent assessment and integration of multiple factors. An evidence-based approach to second stage labor management includes active pushing that is either Valsalva pushing or spontaneous, coached or uncoached, but most importantly, at the start of the second stage when a patient reaches complete dilation. Reassessment should occur at regular intervals to determine progress, after ensuring maternal and fetal well-being.

If there has been no advancement in station, an attempt at manual rotation or titration of epidural analgesia should be considered. Importantly, fetal descent with adequate pushing should be demonstrated throughout the second stage.

Additional considerations that improve outcomes include warm compresses or perineal massage to prevent third- and fourth-degree tears and the presence of a continuous support person to reduce the risk for an operative delivery.

Delivery should be expected within 2 hours for multiparous women and 3 hours for nulliparous women in the second stage. Prolonging the second stage beyond these thresholds should be individualized and occur only in the setting of assured maternal and fetal well-being.

CASE An alternative management strategy

Despite Ms. J.’s great active pushing effort for 60 minutes, the presenting part remains at 0 station and occiput transverse. Ms. J. is counseled regarding the risks and benefits of an attempt at manual rotation of the fetal head, and she wishes to proceed. The fetal position remains occiput transverse.

After another hour of active pushing, the FHR becomes Category II with repetitive variable decelerations. At this time, Ms. J. is informed that there has been no descent, and she is counseled on the risks and benefits of continued pushing versus CD. Through shared decision-making, she consents to a CD. She undergoes a primary CD without complication. The birth weight was 4,100 g, and 5- and 10-minute Apgar scores were 8 and 9, respectively. The umbilical cord arterial pH was 7.13. 

Ms. J. and her baby were discharged home on postoperative day 4. ●

CASE Woman in second stage with prolonged pushing

Ms. J. is an 18-year-old woman (G1P0) at 39 weeks’ gestation whose cervix is completely dilated; she has been actively pushing for 60 minutes. The estimated fetal weight is 8 lb, and electronic fetal monitoring shows a Category I fetal heart rate (FHR) tracing. The presenting part remains at 0 station and occiput transverse despite great pushing effort.

After another hour of active pushing, the FHR becomes Category II with repetitive variable decelerations. During the third hour of the second stage, Ms. J. is diagnosed with chorioamnionitis and the fetus remains at 0 station. She undergoes a primary cesarean delivery (CD) complicated by bilateral lower uterine extensions and postpartum hemorrhage. The birth weight was 4,100 g, and 5- and 10-minute Apgar scores were 4 and 8, respectively. The umbilical cord arterial pH was 7.03.

Ms. J. and her baby were discharged home on postoperative day 4.

In 2014, the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine jointly released a document, “Safe prevention of the primary cesarean delivery,” in response to the sharp rise in cesarean births from 1996 to 2011.¹ It described management strategies to safely reduce the most common indications for a primary CD in nulliparous women. Specifically, it recommended that the second stage of labor—defined as the interval from complete cervical dilation through delivery of the neonate—may be prolonged, as “longer durations may be appropriate on an individualized basis (eg, with the use of epidural analgesia or with fetal malposition) as long as progress is being documented.”¹

A prolonged second stage was defined as 3 hours of pushing in nulliparous women and 2 hours in multiparous women, with 1 additional hour (or longer) in those receiving epidural analgesia. Indeed, the primary CD rate decreased slightly to 21.7% in 2018, down from 21.9% in 2017.² More recent evidence, however, has shown an increase in maternal and neonatal morbidity with prolonged second stage.^3-8

Efforts to manage the second stage from an evidence-based perspective are critical to balance the desired outcome of a safe vaginal delivery against the risks of prolonged second stage and operative vaginal delivery or CD.

Perspectives on the “ideal” labor duration

It is important to consider the historical context that led to the 2014 change in recommendations for duration of the second stage.⁹ In 1955, Dr. Emanuel Friedman published a prospective observational study of 622 consecutive primigravid parturients at term, of which 500 were included in the analysis that led to the graphicostatistical labor curve, or the well-known “Friedman’s curve.”¹⁰ The mean duration of the second stage was 0.95 hour. The statistical maximum for “ideal labor” for the second stage was set at 2 hours, with an additional hour allotted for patients receiving epidural analgesia.

In 2010, Zhang and colleagues published contemporary labor curves using data from the Consortium on Safe Labor, a multicenter retrospective observational study of 62,415 parturients.¹¹ Among more than 25,000 nulliparous women, the median duration (95th percentile) of the second stage in hours was 1.1 (3.6), respectively. Notably, this analysis included only women with a spontaneous vaginal delivery and normal neonatal outcome.

Prior to the publication of the “Safe prevention of primary cesarean delivery,” multiple investigations examined the relationship between the duration of the second stage and adverse maternal and neonatal outcomes, and the findings have been inconsistent.^12-15

For example, Cheng and colleagues noted increased maternal complications that included postpartum hemorrhage, third- and fourth-degree perineal lacerations, and chorioamnionitis, but not neonatal morbidity, with each increasing hour within the second stage.¹² By contrast, a large, population-based cohort study among low-risk women showed an increase in low 5-minute Apgar scores, admission to the neonatal intensive care unit (NICU), and composite perinatal morbidity with prolonged second stage.¹⁵ Furthermore, a secondary analysis of the Pushing Early or Pushing Late with Epidural (PEOPLE) trial showed that the chances of a vaginal delivery with a newborn without signs of asphyxia decreased significantly every hour after the first hour, and the risk of postpartum hemorrhage and intrapartum fever increased significantly after 2 hours of pushing.¹⁴

While these findings may represent the risks inherent with the intervention of operative delivery and not the duration of second stage of labor per se, one could posit that if the intervention were initiated earlier, could it prevent or at least reduce maternal and neonatal morbidity?

Continue to: Factors to assess and monitor in the second stage...

Factors to assess and monitor in the second stage

When assessing progress in the second stage of labor, consider:

• maternal factors
• fetal/neonatal factors, and
• modifiable factors.

Maternal factors that influence the second stage of labor include parity, body mass index (BMI), age, and clinical pelvimetry.^11,16-19 Fetal/neonatal factors that impact the second stage include the estimated fetal weight, fetal presentation (cephalic, face, and so on), position, and station, as well as the FHR Category.^{20, 21} Factors that can be modified in the second stage include the effect of epidural analgesia (turning it down to reduce motor blockade while maintaining sensory pain relief so that patients feel the “urge” to push), maternal pushing position and technique, the presence of maternal support person(s), manual rotation for a fetal position that is not optimal, immediate versus delayed pushing, and prevention of perineal tears.^22-32 Interestingly, epidural analgesia, parity, birth weight, and station at complete dilation predicted second stage duration but accounted for only 25% of the variability in second stage length, leaving 75% of the variance unexplained.¹⁶

A specific absolute maximum length of time spent in the second stage of labor beyond which all women should undergo operative delivery has not been identified.¹ Therefore, maternal, fetal/neonatal, and modifiable factors need to be critically assessed and continually monitored to determine whether a prolonged second stage or an operative delivery is warranted to prevent or minimize adverse maternal and neonatal outcomes.

Maternal factors

Maternal age correlates directly with the length of the second stage. That is, the length of the second stage increases with increasing age.¹⁷

Multiparous women have a shorter length of the second stage, regardless of epidural analgesia, compared with nulliparous women.¹¹ In the Consortium for Safe Labor, multiparous women had a significantly shorter median second stage compared with nulliparous women.¹¹

In adjusted analyses, maternal obesity was associated with an increased risk for CD, with the risk of CD more than 3 times greater in women with a BMI higher than 40 kg/m² compared with those who had a BMI less than 25 kg/m².¹⁸ There were no significant differences in the length of the second stage of labor by BMI catgeories.¹⁹

Fetal factors

Birth weight greater than 4,000 g was associated with an increased risk for arrest of descent during the second stage.³³

Persistent fetal occiput posterior or transverse position may impact the duration of the second stage. A retrospective cohort study in women who underwent a trial of manual rotation compared with expectant management during the second stage of labor with the fetus in occiput posterior or occiput transverse position found that women with manual rotation were less likely to have a CD, severe perineal laceration, postpartum hemorrhage, and chorioamnionitis. However, an increased risk of cervical laceration was associated with manual rotation.²⁰

Regarding FHR status, FHR abnormalities occurred in 91% of second stage labor patterns, with Category II being the most common.²¹ The fetal status should remain reassuring to allow for continuation of the second stage.

Continue to: Epidural analgesia...

Epidural analgesia

About 60% of women receive neuraxial analgesia in the United States,²² although rates vary widely across different populations. A Cochrane review showed no difference in the duration of the second stage among women who had early versus late initiation of epidural analgesia in labor.²³ Epidural analgesia has no impact on the risk of CD; however, women with epidural analgesia experienced more hypotension, motor blockade, fever, and urinary retention.²⁴

One management practice has been to discontinue epidural analgesia to allow resumption of sensory and motor nerve function. Another Cochrane systematic review found no difference in mode of delivery or neonatal outcomes.²⁵ Rather than discontinuing epidural analgesia, which results in a profound increase in inadequate pain relief, one may consider titrating the dose with joint patient decision-making to allow for greater motor capability while maintaining adequate analgesia.³⁴

Immediate vs delayed pushing

The 2 most common approaches to managing the second stage were either to initiate pushing with contractions once complete dilation occurred (immediate pushing) or to allow for a rest period in which the fetus passively rotated and descended while conserving a woman’s energy for pushing efforts (delayed pushing, laboring down, or passive descent). Since the publication of “Safe prevention of primary cesarean delivery,” however, studies have shown a concerning association between maternal and neonatal complications and prolonged second stage (which may occur with delayed pushing).^3-8,35 An observational study of nearly 44,000 nulliparous women without epidural analgesia found that prolonged second stage was associated with increased chorioamnionitis, third- and fourth-degree lacerations, neonatal sepsis, neonatal asphyxia, and perinatal mortality.³⁵

A pragmatic multicenter randomized clinical trial on the optimal management of second stage of labor across the United States recently was conducted.⁷ More than 2,000 nulliparous women at term in spontaneous or induced labor with epidural analgesia were randomly assigned at complete dilation to immediate pushing or delayed pushing (1 hour after complete dilation). There was no difference in the rate of vaginal delivery. The rate of postpartum hemorrhage was significantly lower among women in the immediate-pushing group compared with the delayed-pushing group (2.3% vs 4.0%, respectively; relative risk [RR], 0.6; 95% confidence interval [CI], 0.3–0.9; P = .03). Furthermore, rates of chorioamnionitis were significantly lower among women in the immediate-pushing group compared with the delayed-pushing group (6.7% vs 9.1%, respectively; RR, 0.70; 95% CI, 0.66–0.90; P = .005). No significant difference occurred in the composite outcome of neonatal morbidity between the groups. However neonatal acidemia (umbilical cord arterial pH <7.1) and confirmed or suspected sepsis were significantly increased in the delayed-pushing group.

The evidence supports active pushing at the start of the second stage. Women who consider delayed pushing should be informed that delayed pushing has not been shown to increase the likelihood of vaginal birth and that it is associated with increased risks of infection, hemorrhage, and neonatal acidemia.³⁶

Maternal pushing position and technique

Spontaneous pushing (in which women are free to follow their instincts and generally push 3 to 5 times per contraction) versus directed pushing (women are encouraged to take a deep breath at the beginning of a contraction then hold it and bear down throughout the contraction) demonstrated no clear difference in duration of the second stage, perineal laceration, episiotomy, time spent pushing, or number of women with spontaneous vaginal birth. There was no difference in 5-minute Apgar score less than 7 or admission to the NICU.²⁶

With regard to maternal positioning during the second stage, a Cochrane systematic review found benefits for upright posture, including a very small reduction in the duration of the second stage, reduction in episiotomy rates, and reduction in assisted deliveries.³⁷ There was an increased risk of blood loss greater than 500 mL and possibly an increased risk in second-degree tears.³⁷ Compared with women allocated to lying down, women in the upright position during the second stage with epidural analgesia had significantly fewer spontaneous vaginal births. There was no difference in operative vaginal delivery, obstetric anal sphincter injury (OASI), infant Apgar score of less than 4 at 5 minutes, and maternal fecal incontinence at 1 year.²⁸

Continue to: Maternal support person...

 

 

Maternal support person

Continuous support during labor may improve outcomes for women and infants, including increased spontaneous vaginal birth, shorter duration of labor, and decreased cesarean birth.²⁹ In a randomized trial of 412 healthy nulliparous women, women in labor were assigned to either a support group that received continuous support from a doula or an observed group that was monitored by an inconspicuous observer. Continuous labor support significantly reduced the rate of CDs and forceps deliveries.^30,36 Indeed, during the COVID-19 pandemic, doulas have found innovative ways to continue to provide this essential support through virtual health.³⁸

Prevention of perineal tears

Evidence suggests that warm compresses, and massage, may reduce third- and fourth-degree perineal tears.³¹ A meta-analysis of observational studies showed a significant reduction in the risk of OASI.³²

Second stage steps: Recap

Throughout the second stage of labor, the decision to continue with expectant management or intervene with either an operative vaginal delivery or a CD is complex and requires consistent assessment and integration of multiple factors. An evidence-based approach to second stage labor management includes active pushing that is either Valsalva pushing or spontaneous, coached or uncoached, but most importantly, at the start of the second stage when a patient reaches complete dilation. Reassessment should occur at regular intervals to determine progress, after ensuring maternal and fetal well-being.

If there has been no advancement in station, an attempt at manual rotation or titration of epidural analgesia should be considered. Importantly, fetal descent with adequate pushing should be demonstrated throughout the second stage.

Additional considerations that improve outcomes include warm compresses or perineal massage to prevent third- and fourth-degree tears and the presence of a continuous support person to reduce the risk for an operative delivery.

Delivery should be expected within 2 hours for multiparous women and 3 hours for nulliparous women in the second stage. Prolonging the second stage beyond these thresholds should be individualized and occur only in the setting of assured maternal and fetal well-being.

CASE An alternative management strategy

Despite Ms. J.’s great active pushing effort for 60 minutes, the presenting part remains at 0 station and occiput transverse. Ms. J. is counseled regarding the risks and benefits of an attempt at manual rotation of the fetal head, and she wishes to proceed. The fetal position remains occiput transverse.

After another hour of active pushing, the FHR becomes Category II with repetitive variable decelerations. At this time, Ms. J. is informed that there has been no descent, and she is counseled on the risks and benefits of continued pushing versus CD. Through shared decision-making, she consents to a CD. She undergoes a primary CD without complication. The birth weight was 4,100 g, and 5- and 10-minute Apgar scores were 8 and 9, respectively. The umbilical cord arterial pH was 7.13. 

Ms. J. and her baby were discharged home on postoperative day 4. ●

CASE Woman in second stage with prolonged pushing

Ms. J. is an 18-year-old woman (G1P0) at 39 weeks’ gestation whose cervix is completely dilated; she has been actively pushing for 60 minutes. The estimated fetal weight is 8 lb, and electronic fetal monitoring shows a Category I fetal heart rate (FHR) tracing. The presenting part remains at 0 station and occiput transverse despite great pushing effort.

After another hour of active pushing, the FHR becomes Category II with repetitive variable decelerations. During the third hour of the second stage, Ms. J. is diagnosed with chorioamnionitis and the fetus remains at 0 station. She undergoes a primary cesarean delivery (CD) complicated by bilateral lower uterine extensions and postpartum hemorrhage. The birth weight was 4,100 g, and 5- and 10-minute Apgar scores were 4 and 8, respectively. The umbilical cord arterial pH was 7.03.

Ms. J. and her baby were discharged home on postoperative day 4.

In 2014, the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine jointly released a document, “Safe prevention of the primary cesarean delivery,” in response to the sharp rise in cesarean births from 1996 to 2011.¹ It described management strategies to safely reduce the most common indications for a primary CD in nulliparous women. Specifically, it recommended that the second stage of labor—defined as the interval from complete cervical dilation through delivery of the neonate—may be prolonged, as “longer durations may be appropriate on an individualized basis (eg, with the use of epidural analgesia or with fetal malposition) as long as progress is being documented.”¹

A prolonged second stage was defined as 3 hours of pushing in nulliparous women and 2 hours in multiparous women, with 1 additional hour (or longer) in those receiving epidural analgesia. Indeed, the primary CD rate decreased slightly to 21.7% in 2018, down from 21.9% in 2017.² More recent evidence, however, has shown an increase in maternal and neonatal morbidity with prolonged second stage.^3-8

Efforts to manage the second stage from an evidence-based perspective are critical to balance the desired outcome of a safe vaginal delivery against the risks of prolonged second stage and operative vaginal delivery or CD.

Perspectives on the “ideal” labor duration

It is important to consider the historical context that led to the 2014 change in recommendations for duration of the second stage.⁹ In 1955, Dr. Emanuel Friedman published a prospective observational study of 622 consecutive primigravid parturients at term, of which 500 were included in the analysis that led to the graphicostatistical labor curve, or the well-known “Friedman’s curve.”¹⁰ The mean duration of the second stage was 0.95 hour. The statistical maximum for “ideal labor” for the second stage was set at 2 hours, with an additional hour allotted for patients receiving epidural analgesia.

In 2010, Zhang and colleagues published contemporary labor curves using data from the Consortium on Safe Labor, a multicenter retrospective observational study of 62,415 parturients.¹¹ Among more than 25,000 nulliparous women, the median duration (95th percentile) of the second stage in hours was 1.1 (3.6), respectively. Notably, this analysis included only women with a spontaneous vaginal delivery and normal neonatal outcome.

Prior to the publication of the “Safe prevention of primary cesarean delivery,” multiple investigations examined the relationship between the duration of the second stage and adverse maternal and neonatal outcomes, and the findings have been inconsistent.^12-15

For example, Cheng and colleagues noted increased maternal complications that included postpartum hemorrhage, third- and fourth-degree perineal lacerations, and chorioamnionitis, but not neonatal morbidity, with each increasing hour within the second stage.¹² By contrast, a large, population-based cohort study among low-risk women showed an increase in low 5-minute Apgar scores, admission to the neonatal intensive care unit (NICU), and composite perinatal morbidity with prolonged second stage.¹⁵ Furthermore, a secondary analysis of the Pushing Early or Pushing Late with Epidural (PEOPLE) trial showed that the chances of a vaginal delivery with a newborn without signs of asphyxia decreased significantly every hour after the first hour, and the risk of postpartum hemorrhage and intrapartum fever increased significantly after 2 hours of pushing.¹⁴

While these findings may represent the risks inherent with the intervention of operative delivery and not the duration of second stage of labor per se, one could posit that if the intervention were initiated earlier, could it prevent or at least reduce maternal and neonatal morbidity?

Continue to: Factors to assess and monitor in the second stage...

Factors to assess and monitor in the second stage

When assessing progress in the second stage of labor, consider:

• maternal factors
• fetal/neonatal factors, and
• modifiable factors.

Maternal factors that influence the second stage of labor include parity, body mass index (BMI), age, and clinical pelvimetry.^11,16-19 Fetal/neonatal factors that impact the second stage include the estimated fetal weight, fetal presentation (cephalic, face, and so on), position, and station, as well as the FHR Category.^{20, 21} Factors that can be modified in the second stage include the effect of epidural analgesia (turning it down to reduce motor blockade while maintaining sensory pain relief so that patients feel the “urge” to push), maternal pushing position and technique, the presence of maternal support person(s), manual rotation for a fetal position that is not optimal, immediate versus delayed pushing, and prevention of perineal tears.^22-32 Interestingly, epidural analgesia, parity, birth weight, and station at complete dilation predicted second stage duration but accounted for only 25% of the variability in second stage length, leaving 75% of the variance unexplained.¹⁶

A specific absolute maximum length of time spent in the second stage of labor beyond which all women should undergo operative delivery has not been identified.¹ Therefore, maternal, fetal/neonatal, and modifiable factors need to be critically assessed and continually monitored to determine whether a prolonged second stage or an operative delivery is warranted to prevent or minimize adverse maternal and neonatal outcomes.

Maternal factors

Maternal age correlates directly with the length of the second stage. That is, the length of the second stage increases with increasing age.¹⁷

Multiparous women have a shorter length of the second stage, regardless of epidural analgesia, compared with nulliparous women.¹¹ In the Consortium for Safe Labor, multiparous women had a significantly shorter median second stage compared with nulliparous women.¹¹

In adjusted analyses, maternal obesity was associated with an increased risk for CD, with the risk of CD more than 3 times greater in women with a BMI higher than 40 kg/m² compared with those who had a BMI less than 25 kg/m².¹⁸ There were no significant differences in the length of the second stage of labor by BMI catgeories.¹⁹

Fetal factors

Birth weight greater than 4,000 g was associated with an increased risk for arrest of descent during the second stage.³³

Persistent fetal occiput posterior or transverse position may impact the duration of the second stage. A retrospective cohort study in women who underwent a trial of manual rotation compared with expectant management during the second stage of labor with the fetus in occiput posterior or occiput transverse position found that women with manual rotation were less likely to have a CD, severe perineal laceration, postpartum hemorrhage, and chorioamnionitis. However, an increased risk of cervical laceration was associated with manual rotation.²⁰

Regarding FHR status, FHR abnormalities occurred in 91% of second stage labor patterns, with Category II being the most common.²¹ The fetal status should remain reassuring to allow for continuation of the second stage.

Continue to: Epidural analgesia...

Epidural analgesia

About 60% of women receive neuraxial analgesia in the United States,²² although rates vary widely across different populations. A Cochrane review showed no difference in the duration of the second stage among women who had early versus late initiation of epidural analgesia in labor.²³ Epidural analgesia has no impact on the risk of CD; however, women with epidural analgesia experienced more hypotension, motor blockade, fever, and urinary retention.²⁴

One management practice has been to discontinue epidural analgesia to allow resumption of sensory and motor nerve function. Another Cochrane systematic review found no difference in mode of delivery or neonatal outcomes.²⁵ Rather than discontinuing epidural analgesia, which results in a profound increase in inadequate pain relief, one may consider titrating the dose with joint patient decision-making to allow for greater motor capability while maintaining adequate analgesia.³⁴

Immediate vs delayed pushing

The 2 most common approaches to managing the second stage were either to initiate pushing with contractions once complete dilation occurred (immediate pushing) or to allow for a rest period in which the fetus passively rotated and descended while conserving a woman’s energy for pushing efforts (delayed pushing, laboring down, or passive descent). Since the publication of “Safe prevention of primary cesarean delivery,” however, studies have shown a concerning association between maternal and neonatal complications and prolonged second stage (which may occur with delayed pushing).^3-8,35 An observational study of nearly 44,000 nulliparous women without epidural analgesia found that prolonged second stage was associated with increased chorioamnionitis, third- and fourth-degree lacerations, neonatal sepsis, neonatal asphyxia, and perinatal mortality.³⁵

A pragmatic multicenter randomized clinical trial on the optimal management of second stage of labor across the United States recently was conducted.⁷ More than 2,000 nulliparous women at term in spontaneous or induced labor with epidural analgesia were randomly assigned at complete dilation to immediate pushing or delayed pushing (1 hour after complete dilation). There was no difference in the rate of vaginal delivery. The rate of postpartum hemorrhage was significantly lower among women in the immediate-pushing group compared with the delayed-pushing group (2.3% vs 4.0%, respectively; relative risk [RR], 0.6; 95% confidence interval [CI], 0.3–0.9; P = .03). Furthermore, rates of chorioamnionitis were significantly lower among women in the immediate-pushing group compared with the delayed-pushing group (6.7% vs 9.1%, respectively; RR, 0.70; 95% CI, 0.66–0.90; P = .005). No significant difference occurred in the composite outcome of neonatal morbidity between the groups. However neonatal acidemia (umbilical cord arterial pH <7.1) and confirmed or suspected sepsis were significantly increased in the delayed-pushing group.

The evidence supports active pushing at the start of the second stage. Women who consider delayed pushing should be informed that delayed pushing has not been shown to increase the likelihood of vaginal birth and that it is associated with increased risks of infection, hemorrhage, and neonatal acidemia.³⁶

Maternal pushing position and technique

Spontaneous pushing (in which women are free to follow their instincts and generally push 3 to 5 times per contraction) versus directed pushing (women are encouraged to take a deep breath at the beginning of a contraction then hold it and bear down throughout the contraction) demonstrated no clear difference in duration of the second stage, perineal laceration, episiotomy, time spent pushing, or number of women with spontaneous vaginal birth. There was no difference in 5-minute Apgar score less than 7 or admission to the NICU.²⁶

With regard to maternal positioning during the second stage, a Cochrane systematic review found benefits for upright posture, including a very small reduction in the duration of the second stage, reduction in episiotomy rates, and reduction in assisted deliveries.³⁷ There was an increased risk of blood loss greater than 500 mL and possibly an increased risk in second-degree tears.³⁷ Compared with women allocated to lying down, women in the upright position during the second stage with epidural analgesia had significantly fewer spontaneous vaginal births. There was no difference in operative vaginal delivery, obstetric anal sphincter injury (OASI), infant Apgar score of less than 4 at 5 minutes, and maternal fecal incontinence at 1 year.²⁸

Continue to: Maternal support person...

 

 

Maternal support person

Continuous support during labor may improve outcomes for women and infants, including increased spontaneous vaginal birth, shorter duration of labor, and decreased cesarean birth.²⁹ In a randomized trial of 412 healthy nulliparous women, women in labor were assigned to either a support group that received continuous support from a doula or an observed group that was monitored by an inconspicuous observer. Continuous labor support significantly reduced the rate of CDs and forceps deliveries.^30,36 Indeed, during the COVID-19 pandemic, doulas have found innovative ways to continue to provide this essential support through virtual health.³⁸

Prevention of perineal tears

Evidence suggests that warm compresses, and massage, may reduce third- and fourth-degree perineal tears.³¹ A meta-analysis of observational studies showed a significant reduction in the risk of OASI.³²

Second stage steps: Recap

Throughout the second stage of labor, the decision to continue with expectant management or intervene with either an operative vaginal delivery or a CD is complex and requires consistent assessment and integration of multiple factors. An evidence-based approach to second stage labor management includes active pushing that is either Valsalva pushing or spontaneous, coached or uncoached, but most importantly, at the start of the second stage when a patient reaches complete dilation. Reassessment should occur at regular intervals to determine progress, after ensuring maternal and fetal well-being.

If there has been no advancement in station, an attempt at manual rotation or titration of epidural analgesia should be considered. Importantly, fetal descent with adequate pushing should be demonstrated throughout the second stage.

Additional considerations that improve outcomes include warm compresses or perineal massage to prevent third- and fourth-degree tears and the presence of a continuous support person to reduce the risk for an operative delivery.

Delivery should be expected within 2 hours for multiparous women and 3 hours for nulliparous women in the second stage. Prolonging the second stage beyond these thresholds should be individualized and occur only in the setting of assured maternal and fetal well-being.

CASE An alternative management strategy

Despite Ms. J.’s great active pushing effort for 60 minutes, the presenting part remains at 0 station and occiput transverse. Ms. J. is counseled regarding the risks and benefits of an attempt at manual rotation of the fetal head, and she wishes to proceed. The fetal position remains occiput transverse.

After another hour of active pushing, the FHR becomes Category II with repetitive variable decelerations. At this time, Ms. J. is informed that there has been no descent, and she is counseled on the risks and benefits of continued pushing versus CD. Through shared decision-making, she consents to a CD. She undergoes a primary CD without complication. The birth weight was 4,100 g, and 5- and 10-minute Apgar scores were 8 and 9, respectively. The umbilical cord arterial pH was 7.13. 

Ms. J. and her baby were discharged home on postoperative day 4. ●

Parkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease.¹ Age-standardized incidence rates of PD in population-based studies in Europe and the United States range from 8.6 to 19.0 per 100,000 individuals, using a strict diagnostic criterion for PD.² The negative impact of PD on health-related quality of life imposes a heavy burden on veterans. According to the US Department of Veterans Affairs (VA) National Parkinson’s Disease Consortium, the VA has as many as 50,000 patients with PD under its care. Because of this demand, the VA has strived to revolutionize available services for veterans with PD and related movement disorders.³

The classic motor symptoms of resting tremors, bradykinesia, postural instability, and rigidity of this progressive neurodegenerative disorder is a significant cause of functional limitations that lead to increased falls and inability to perform activities of daily living that challenges the individual and caregiver. ⁴ Rehabilitation has been considered as an adjuvant to surgical and medical treatments for PD to maximize function and minimize complications. High-intensity multimodal exercise boot camps and therapy that focuses on intensely exercising high-amplitude movements, have been shown to improve motor performance in PD.^5,6 Available evidence has shown that exercise-dependent plasticity is the main mechanism underlying the effects of physiotherapy because it increases synaptic strength and affects neurotransmission.⁷ Although there is no consensus on the optimal approach for rehabilitation, innovative techniques have been proposed and studied. One such approach involves virtual reality (VR), which has begun to attract attention for its potential use during rehabilitation.⁸

VR is a simulated experience created by computer-based technology that grants users access to a virtual environment. There are 2 categories of VR: immersive and nonimmersive. Immersive VR is the most direct experience of virtual environments and usually is implemented through a head-mounted display. These displays have monitors in front of each eye, which can provide monocular or biocular imaging with the most common display being small liquid crystal display (LCD) panels.

Nonimmersive VR typically allows a participant to view a virtual environment by using standard high-resolution monitors rather than a headset or an immersive screen room. Many systems are readily available to the general public as electronic interactive entertainment (ie, video games). Interaction with the virtual world happens through interfaces such as keyboards and controllers while viewing a television or computer monitor. These systems often are more accessible and affordable when compared with immersive VR, although this is changing rapidly.

VR therapy is a noninvasive therapeutic alternative modality for PD. This review aims to study the use of VR to treat PD from a rehabilitative standpoint. Although not the only review on the topic, this systematic review is the first to examine the differences between immersive and nonimmersive VR rehabilitation for PD. VR technology is evolving rapidly and the research behind its clinical applications is steadily growing, especially as accessibility improves. This review also is an updated summary of the current literature on the effectiveness of VR therapy during PD rehabilitation.

Methods

Starting in July 2019, the authors searched several databases (PubMed, Google Scholar, Cochrane, and the Physiotherapy Evidence Database [PEDro]) for articles by using the keyword “Parkinson’s disease” combined with either “virtual reality” or “video games.” To find studies specific to rehabilitation, searches included the additional keyword: “rehabilitation.” After compiling an initial set of 89 articles, titles were reviewed to eliminate duplicates. The authors then read the abstracts to exclude study protocols, systematic reviews, and studies that used VR but did not focus on PD or any therapeutic outcome.

Articles were sorted into immersive or nonimmersive virtual reality categories. To be included as immersive VR, studies had to use any type of VR headset or full-scale VR room. Anything less immersive or similar to a traditional video game was included in the nonimmersive VR category. Articles that met inclusion criteria were selected for the systematic review. Criteria for inclusion in this review were: (1) English language; (2) included a study population focused on PD; (3) used some form of VR therapy; and (4) assessed potential rehabilitation by quantitative outcome measures. Only articles published in peer-reviewed journals were included.

Data were extracted into 2 tables specifically modified for this review: immersive and nonimmersive VR. Extracted data included study author name and publication date, study design, methodologic quality, sample size and group allocation, symptom progression via the Hoehn and Yahr Scale (1 to 5), VR modality, presence of control groups, primary outcomes, and primary findings.

Results

This review is reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA).¹⁰ After screening and assessment, 28 articles met inclusion criteria for this review: 7 using immersive VR and 21 using nonimmersive VR (Figure). The immersive studies included 2 RCTs (both with PEDro scores of 5), 1 controlled study with a PEDro score of 5, 1 pre-post pilot study, and 3 cohort studies (Table 2). The nonimmersive studies included 13 RCTs with an average PEDro score of 5.8; 2 pre-post pilot studies, 1 repeated measures study with a historic control, 1 non-RCT, 2 pre-post prospective studies, and 2 cohort studies (1 retrospective and 1 prospective) (Table 3).

Several outcome and assessment tools were used; the most common measures were related to gait, balance, kinematics, and VR feasibility. Studies varied in VR modalities and protocol, ranging from 21 sessions of Nintendo Wii Fit gaming for 7 weeks to 1 session of VR headset use.

Immersive VR

There were fewer immersive VR studies and these studies had lower mean PEDro scores when compared with nonimmersive VR studies. The VR modalities in the immersive studies used a VR headset or a multisensory immersive system that included polarized glasses. All the studies showed positive improvement in primary outcomes with the exception of Ma and colleagues,which showed no difference in success rates or kinematics with moving balls, and only showed improvement in reaching for stationary balls.¹¹ The mean number of participants in the studies was 18.4.

All 7 studies had each participant complete tasks without VR then with the VR therapy. None of the studies compared immersive VR therapy with more conventional therapies. Robles-Garcia and colleagues compared 2 VR groups where the experimental group imitated an avatar’s finger tapping in the VR system while the control group lacked this imitation.¹² The authors found that adding that imitation to the VR group lead to an increase in movement amplitude.

Among the immersive VR studies, only Janeh and colleagues commented on possible adverse effects (AEs) and found that VR was a safe method without AEs of discomfort or simulator sickness.¹³ The other 6 studies did not make any mention or discussion of AEs related to the training.

Nonimmersive VR

VR modalities used in nonimmersive studies included consumer video gaming systems. Nintendo Wii and Microsoft Xbox Kinect were most commonly used. Among the 21 studies, 14 compared VR therapy with a type of traditional exercise (eg, treadmill training, stretching exercises, balance training). The mean number of participants of the studies was 28.3.

Five studies showed a difference between the VR and traditional training groups.^14-18 However, 9 studies showed positive improvement in both groups and found no between-group differences.^19-25 Among the remaining 7 studies, all showed improvement in primary outcomes after adding VR interventional therapy. In 1 RCT, 3 groups were compared (no intervention, Nintendo Wii, and Xbox Kinect) for gait tests, anxiety levels, memory, and attention.²⁶ The authors found that only the Nintendo Wii group showed improvement in outcomes. A prospective cohort study was the only one to compare different doses of VR therapy (10 sessions vs 15 sessions of Nintendo Wii Fit).²⁷ The authors found that both groups demonstrated the same amount of improvement on balance performances with no group effect.

Ten studiesreported no AEs during the training, but also did not define what was considered an AE.^{15,16,19,22-25,27-29} Eight studies did not make any mention of AEs.^{14,17,21,26,27,30-32} Yen and colleagues reported no AEs during training except for the patients’ tendency to fall.²⁰ However, therapists supervised the patients to avoid falls and no falls occurred. Nuic and colleaguesreported 3 serious AEs, unrelated to the training: severe pneumonia (n = 1) and deep-brain stimulation generator replacement (n = 2).³³ During the video game training sessions no specific AEs occurred. Only Pompeu and colleagues defined an AE as any untoward medical occurrence such as convulsion, syncope, dizziness, vertigo, falls, or any medical condition that required hospitalization or disability.³⁴ One researcher registered the occurrence of any AE; however, none occurred during the study period.

Discussion

This systematic review demonstrates that VR therapy is a promising addition to rehabilitation for PD. Evidence supporting VR therapy is limited, but is continually expanding, and current evidence has shown improvement in assessments and rehabilitative outcomes involving PD. Most nonimmersive studies have shown that VR therapy does not lead to better outcomes when compared with traditional therapy but also is not harmful and does provide similar improvement. Immersive VR studies, on the other hand, have not compared therapy with conventional training extensively, and tend to focus more on time for task completion or movement.

There were fewer immersive VR studies than nonimmersive VR studies. This could be because of the increased technological difficulty and demand to correctly execute immersive VR modalities, as well as the—until recently—substantial expense. This might be another reason why the mean PEDro scores for immersive VR RCTs were lower than the mean scores found in nonimmersive RCTs.

Limitations

This review was limited by several factors related to the included studies. A variety of rating scales were used in the immersive and nonimmersive VR studies. Although there was some general overlap with common measurements such as gait, balance, kinematics, and VR feasibility, no studies had the same primary and secondary outcomes. Such heterogeneity in protocols and outcomes limited our ability to draw conclusions from these differing studies. Additionally, the average number of participants of both immersive and nonimmersive studies were small and the statistical significance of findings should be interpreted with caution. Finally, VR devices and systems differed between studies, further limiting comparisons. Although these factors limit this systematic review, we can still identify treatment and research implications. Adequately powered future studies with standardized protocols would further improve the available evidence and support for VR as an intervention.

Conclusions

VR therapy is a promising rehabilitation modality for PD. Additional investigations of VR therapy and PD should include direct comparisons between immersive and nonimmersive VR therapies. It could be hypothesized that the greater immersion and engagement potential of immersive VR would demonstrate greater functional improvement compared with nonimmersive VR, but there is no data to support this for PD. VR therapy for PD appears to be a relatively safe alternative or adjunct to traditional therapy with a potentially positive impact on a variety of symptoms and is growing as an innovative therapeutic approach for PD patients.

Parkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease.¹ Age-standardized incidence rates of PD in population-based studies in Europe and the United States range from 8.6 to 19.0 per 100,000 individuals, using a strict diagnostic criterion for PD.² The negative impact of PD on health-related quality of life imposes a heavy burden on veterans. According to the US Department of Veterans Affairs (VA) National Parkinson’s Disease Consortium, the VA has as many as 50,000 patients with PD under its care. Because of this demand, the VA has strived to revolutionize available services for veterans with PD and related movement disorders.³

The classic motor symptoms of resting tremors, bradykinesia, postural instability, and rigidity of this progressive neurodegenerative disorder is a significant cause of functional limitations that lead to increased falls and inability to perform activities of daily living that challenges the individual and caregiver. ⁴ Rehabilitation has been considered as an adjuvant to surgical and medical treatments for PD to maximize function and minimize complications. High-intensity multimodal exercise boot camps and therapy that focuses on intensely exercising high-amplitude movements, have been shown to improve motor performance in PD.^5,6 Available evidence has shown that exercise-dependent plasticity is the main mechanism underlying the effects of physiotherapy because it increases synaptic strength and affects neurotransmission.⁷ Although there is no consensus on the optimal approach for rehabilitation, innovative techniques have been proposed and studied. One such approach involves virtual reality (VR), which has begun to attract attention for its potential use during rehabilitation.⁸

VR is a simulated experience created by computer-based technology that grants users access to a virtual environment. There are 2 categories of VR: immersive and nonimmersive. Immersive VR is the most direct experience of virtual environments and usually is implemented through a head-mounted display. These displays have monitors in front of each eye, which can provide monocular or biocular imaging with the most common display being small liquid crystal display (LCD) panels.

Nonimmersive VR typically allows a participant to view a virtual environment by using standard high-resolution monitors rather than a headset or an immersive screen room. Many systems are readily available to the general public as electronic interactive entertainment (ie, video games). Interaction with the virtual world happens through interfaces such as keyboards and controllers while viewing a television or computer monitor. These systems often are more accessible and affordable when compared with immersive VR, although this is changing rapidly.

VR therapy is a noninvasive therapeutic alternative modality for PD. This review aims to study the use of VR to treat PD from a rehabilitative standpoint. Although not the only review on the topic, this systematic review is the first to examine the differences between immersive and nonimmersive VR rehabilitation for PD. VR technology is evolving rapidly and the research behind its clinical applications is steadily growing, especially as accessibility improves. This review also is an updated summary of the current literature on the effectiveness of VR therapy during PD rehabilitation.

Methods

Starting in July 2019, the authors searched several databases (PubMed, Google Scholar, Cochrane, and the Physiotherapy Evidence Database [PEDro]) for articles by using the keyword “Parkinson’s disease” combined with either “virtual reality” or “video games.” To find studies specific to rehabilitation, searches included the additional keyword: “rehabilitation.” After compiling an initial set of 89 articles, titles were reviewed to eliminate duplicates. The authors then read the abstracts to exclude study protocols, systematic reviews, and studies that used VR but did not focus on PD or any therapeutic outcome.

Articles were sorted into immersive or nonimmersive virtual reality categories. To be included as immersive VR, studies had to use any type of VR headset or full-scale VR room. Anything less immersive or similar to a traditional video game was included in the nonimmersive VR category. Articles that met inclusion criteria were selected for the systematic review. Criteria for inclusion in this review were: (1) English language; (2) included a study population focused on PD; (3) used some form of VR therapy; and (4) assessed potential rehabilitation by quantitative outcome measures. Only articles published in peer-reviewed journals were included.

Data were extracted into 2 tables specifically modified for this review: immersive and nonimmersive VR. Extracted data included study author name and publication date, study design, methodologic quality, sample size and group allocation, symptom progression via the Hoehn and Yahr Scale (1 to 5), VR modality, presence of control groups, primary outcomes, and primary findings.

Results

This review is reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA).¹⁰ After screening and assessment, 28 articles met inclusion criteria for this review: 7 using immersive VR and 21 using nonimmersive VR (Figure). The immersive studies included 2 RCTs (both with PEDro scores of 5), 1 controlled study with a PEDro score of 5, 1 pre-post pilot study, and 3 cohort studies (Table 2). The nonimmersive studies included 13 RCTs with an average PEDro score of 5.8; 2 pre-post pilot studies, 1 repeated measures study with a historic control, 1 non-RCT, 2 pre-post prospective studies, and 2 cohort studies (1 retrospective and 1 prospective) (Table 3).

Several outcome and assessment tools were used; the most common measures were related to gait, balance, kinematics, and VR feasibility. Studies varied in VR modalities and protocol, ranging from 21 sessions of Nintendo Wii Fit gaming for 7 weeks to 1 session of VR headset use.

Immersive VR

There were fewer immersive VR studies and these studies had lower mean PEDro scores when compared with nonimmersive VR studies. The VR modalities in the immersive studies used a VR headset or a multisensory immersive system that included polarized glasses. All the studies showed positive improvement in primary outcomes with the exception of Ma and colleagues,which showed no difference in success rates or kinematics with moving balls, and only showed improvement in reaching for stationary balls.¹¹ The mean number of participants in the studies was 18.4.

All 7 studies had each participant complete tasks without VR then with the VR therapy. None of the studies compared immersive VR therapy with more conventional therapies. Robles-Garcia and colleagues compared 2 VR groups where the experimental group imitated an avatar’s finger tapping in the VR system while the control group lacked this imitation.¹² The authors found that adding that imitation to the VR group lead to an increase in movement amplitude.

Among the immersive VR studies, only Janeh and colleagues commented on possible adverse effects (AEs) and found that VR was a safe method without AEs of discomfort or simulator sickness.¹³ The other 6 studies did not make any mention or discussion of AEs related to the training.

Nonimmersive VR

VR modalities used in nonimmersive studies included consumer video gaming systems. Nintendo Wii and Microsoft Xbox Kinect were most commonly used. Among the 21 studies, 14 compared VR therapy with a type of traditional exercise (eg, treadmill training, stretching exercises, balance training). The mean number of participants of the studies was 28.3.

Five studies showed a difference between the VR and traditional training groups.^14-18 However, 9 studies showed positive improvement in both groups and found no between-group differences.^19-25 Among the remaining 7 studies, all showed improvement in primary outcomes after adding VR interventional therapy. In 1 RCT, 3 groups were compared (no intervention, Nintendo Wii, and Xbox Kinect) for gait tests, anxiety levels, memory, and attention.²⁶ The authors found that only the Nintendo Wii group showed improvement in outcomes. A prospective cohort study was the only one to compare different doses of VR therapy (10 sessions vs 15 sessions of Nintendo Wii Fit).²⁷ The authors found that both groups demonstrated the same amount of improvement on balance performances with no group effect.

Ten studiesreported no AEs during the training, but also did not define what was considered an AE.^{15,16,19,22-25,27-29} Eight studies did not make any mention of AEs.^{14,17,21,26,27,30-32} Yen and colleagues reported no AEs during training except for the patients’ tendency to fall.²⁰ However, therapists supervised the patients to avoid falls and no falls occurred. Nuic and colleaguesreported 3 serious AEs, unrelated to the training: severe pneumonia (n = 1) and deep-brain stimulation generator replacement (n = 2).³³ During the video game training sessions no specific AEs occurred. Only Pompeu and colleagues defined an AE as any untoward medical occurrence such as convulsion, syncope, dizziness, vertigo, falls, or any medical condition that required hospitalization or disability.³⁴ One researcher registered the occurrence of any AE; however, none occurred during the study period.

Discussion

This systematic review demonstrates that VR therapy is a promising addition to rehabilitation for PD. Evidence supporting VR therapy is limited, but is continually expanding, and current evidence has shown improvement in assessments and rehabilitative outcomes involving PD. Most nonimmersive studies have shown that VR therapy does not lead to better outcomes when compared with traditional therapy but also is not harmful and does provide similar improvement. Immersive VR studies, on the other hand, have not compared therapy with conventional training extensively, and tend to focus more on time for task completion or movement.

There were fewer immersive VR studies than nonimmersive VR studies. This could be because of the increased technological difficulty and demand to correctly execute immersive VR modalities, as well as the—until recently—substantial expense. This might be another reason why the mean PEDro scores for immersive VR RCTs were lower than the mean scores found in nonimmersive RCTs.

Limitations

This review was limited by several factors related to the included studies. A variety of rating scales were used in the immersive and nonimmersive VR studies. Although there was some general overlap with common measurements such as gait, balance, kinematics, and VR feasibility, no studies had the same primary and secondary outcomes. Such heterogeneity in protocols and outcomes limited our ability to draw conclusions from these differing studies. Additionally, the average number of participants of both immersive and nonimmersive studies were small and the statistical significance of findings should be interpreted with caution. Finally, VR devices and systems differed between studies, further limiting comparisons. Although these factors limit this systematic review, we can still identify treatment and research implications. Adequately powered future studies with standardized protocols would further improve the available evidence and support for VR as an intervention.

Conclusions

VR therapy is a promising rehabilitation modality for PD. Additional investigations of VR therapy and PD should include direct comparisons between immersive and nonimmersive VR therapies. It could be hypothesized that the greater immersion and engagement potential of immersive VR would demonstrate greater functional improvement compared with nonimmersive VR, but there is no data to support this for PD. VR therapy for PD appears to be a relatively safe alternative or adjunct to traditional therapy with a potentially positive impact on a variety of symptoms and is growing as an innovative therapeutic approach for PD patients.

Parkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease.¹ Age-standardized incidence rates of PD in population-based studies in Europe and the United States range from 8.6 to 19.0 per 100,000 individuals, using a strict diagnostic criterion for PD.² The negative impact of PD on health-related quality of life imposes a heavy burden on veterans. According to the US Department of Veterans Affairs (VA) National Parkinson’s Disease Consortium, the VA has as many as 50,000 patients with PD under its care. Because of this demand, the VA has strived to revolutionize available services for veterans with PD and related movement disorders.³

The classic motor symptoms of resting tremors, bradykinesia, postural instability, and rigidity of this progressive neurodegenerative disorder is a significant cause of functional limitations that lead to increased falls and inability to perform activities of daily living that challenges the individual and caregiver. ⁴ Rehabilitation has been considered as an adjuvant to surgical and medical treatments for PD to maximize function and minimize complications. High-intensity multimodal exercise boot camps and therapy that focuses on intensely exercising high-amplitude movements, have been shown to improve motor performance in PD.^5,6 Available evidence has shown that exercise-dependent plasticity is the main mechanism underlying the effects of physiotherapy because it increases synaptic strength and affects neurotransmission.⁷ Although there is no consensus on the optimal approach for rehabilitation, innovative techniques have been proposed and studied. One such approach involves virtual reality (VR), which has begun to attract attention for its potential use during rehabilitation.⁸

VR is a simulated experience created by computer-based technology that grants users access to a virtual environment. There are 2 categories of VR: immersive and nonimmersive. Immersive VR is the most direct experience of virtual environments and usually is implemented through a head-mounted display. These displays have monitors in front of each eye, which can provide monocular or biocular imaging with the most common display being small liquid crystal display (LCD) panels.

Nonimmersive VR typically allows a participant to view a virtual environment by using standard high-resolution monitors rather than a headset or an immersive screen room. Many systems are readily available to the general public as electronic interactive entertainment (ie, video games). Interaction with the virtual world happens through interfaces such as keyboards and controllers while viewing a television or computer monitor. These systems often are more accessible and affordable when compared with immersive VR, although this is changing rapidly.

VR therapy is a noninvasive therapeutic alternative modality for PD. This review aims to study the use of VR to treat PD from a rehabilitative standpoint. Although not the only review on the topic, this systematic review is the first to examine the differences between immersive and nonimmersive VR rehabilitation for PD. VR technology is evolving rapidly and the research behind its clinical applications is steadily growing, especially as accessibility improves. This review also is an updated summary of the current literature on the effectiveness of VR therapy during PD rehabilitation.

Methods

Starting in July 2019, the authors searched several databases (PubMed, Google Scholar, Cochrane, and the Physiotherapy Evidence Database [PEDro]) for articles by using the keyword “Parkinson’s disease” combined with either “virtual reality” or “video games.” To find studies specific to rehabilitation, searches included the additional keyword: “rehabilitation.” After compiling an initial set of 89 articles, titles were reviewed to eliminate duplicates. The authors then read the abstracts to exclude study protocols, systematic reviews, and studies that used VR but did not focus on PD or any therapeutic outcome.

Articles were sorted into immersive or nonimmersive virtual reality categories. To be included as immersive VR, studies had to use any type of VR headset or full-scale VR room. Anything less immersive or similar to a traditional video game was included in the nonimmersive VR category. Articles that met inclusion criteria were selected for the systematic review. Criteria for inclusion in this review were: (1) English language; (2) included a study population focused on PD; (3) used some form of VR therapy; and (4) assessed potential rehabilitation by quantitative outcome measures. Only articles published in peer-reviewed journals were included.

Data were extracted into 2 tables specifically modified for this review: immersive and nonimmersive VR. Extracted data included study author name and publication date, study design, methodologic quality, sample size and group allocation, symptom progression via the Hoehn and Yahr Scale (1 to 5), VR modality, presence of control groups, primary outcomes, and primary findings.

Results

This review is reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA).¹⁰ After screening and assessment, 28 articles met inclusion criteria for this review: 7 using immersive VR and 21 using nonimmersive VR (Figure). The immersive studies included 2 RCTs (both with PEDro scores of 5), 1 controlled study with a PEDro score of 5, 1 pre-post pilot study, and 3 cohort studies (Table 2). The nonimmersive studies included 13 RCTs with an average PEDro score of 5.8; 2 pre-post pilot studies, 1 repeated measures study with a historic control, 1 non-RCT, 2 pre-post prospective studies, and 2 cohort studies (1 retrospective and 1 prospective) (Table 3).

Several outcome and assessment tools were used; the most common measures were related to gait, balance, kinematics, and VR feasibility. Studies varied in VR modalities and protocol, ranging from 21 sessions of Nintendo Wii Fit gaming for 7 weeks to 1 session of VR headset use.

Immersive VR

There were fewer immersive VR studies and these studies had lower mean PEDro scores when compared with nonimmersive VR studies. The VR modalities in the immersive studies used a VR headset or a multisensory immersive system that included polarized glasses. All the studies showed positive improvement in primary outcomes with the exception of Ma and colleagues,which showed no difference in success rates or kinematics with moving balls, and only showed improvement in reaching for stationary balls.¹¹ The mean number of participants in the studies was 18.4.

All 7 studies had each participant complete tasks without VR then with the VR therapy. None of the studies compared immersive VR therapy with more conventional therapies. Robles-Garcia and colleagues compared 2 VR groups where the experimental group imitated an avatar’s finger tapping in the VR system while the control group lacked this imitation.¹² The authors found that adding that imitation to the VR group lead to an increase in movement amplitude.

Among the immersive VR studies, only Janeh and colleagues commented on possible adverse effects (AEs) and found that VR was a safe method without AEs of discomfort or simulator sickness.¹³ The other 6 studies did not make any mention or discussion of AEs related to the training.

Nonimmersive VR

VR modalities used in nonimmersive studies included consumer video gaming systems. Nintendo Wii and Microsoft Xbox Kinect were most commonly used. Among the 21 studies, 14 compared VR therapy with a type of traditional exercise (eg, treadmill training, stretching exercises, balance training). The mean number of participants of the studies was 28.3.

Five studies showed a difference between the VR and traditional training groups.^14-18 However, 9 studies showed positive improvement in both groups and found no between-group differences.^19-25 Among the remaining 7 studies, all showed improvement in primary outcomes after adding VR interventional therapy. In 1 RCT, 3 groups were compared (no intervention, Nintendo Wii, and Xbox Kinect) for gait tests, anxiety levels, memory, and attention.²⁶ The authors found that only the Nintendo Wii group showed improvement in outcomes. A prospective cohort study was the only one to compare different doses of VR therapy (10 sessions vs 15 sessions of Nintendo Wii Fit).²⁷ The authors found that both groups demonstrated the same amount of improvement on balance performances with no group effect.

Ten studiesreported no AEs during the training, but also did not define what was considered an AE.^{15,16,19,22-25,27-29} Eight studies did not make any mention of AEs.^{14,17,21,26,27,30-32} Yen and colleagues reported no AEs during training except for the patients’ tendency to fall.²⁰ However, therapists supervised the patients to avoid falls and no falls occurred. Nuic and colleaguesreported 3 serious AEs, unrelated to the training: severe pneumonia (n = 1) and deep-brain stimulation generator replacement (n = 2).³³ During the video game training sessions no specific AEs occurred. Only Pompeu and colleagues defined an AE as any untoward medical occurrence such as convulsion, syncope, dizziness, vertigo, falls, or any medical condition that required hospitalization or disability.³⁴ One researcher registered the occurrence of any AE; however, none occurred during the study period.

Discussion

This systematic review demonstrates that VR therapy is a promising addition to rehabilitation for PD. Evidence supporting VR therapy is limited, but is continually expanding, and current evidence has shown improvement in assessments and rehabilitative outcomes involving PD. Most nonimmersive studies have shown that VR therapy does not lead to better outcomes when compared with traditional therapy but also is not harmful and does provide similar improvement. Immersive VR studies, on the other hand, have not compared therapy with conventional training extensively, and tend to focus more on time for task completion or movement.

There were fewer immersive VR studies than nonimmersive VR studies. This could be because of the increased technological difficulty and demand to correctly execute immersive VR modalities, as well as the—until recently—substantial expense. This might be another reason why the mean PEDro scores for immersive VR RCTs were lower than the mean scores found in nonimmersive RCTs.

Limitations

This review was limited by several factors related to the included studies. A variety of rating scales were used in the immersive and nonimmersive VR studies. Although there was some general overlap with common measurements such as gait, balance, kinematics, and VR feasibility, no studies had the same primary and secondary outcomes. Such heterogeneity in protocols and outcomes limited our ability to draw conclusions from these differing studies. Additionally, the average number of participants of both immersive and nonimmersive studies were small and the statistical significance of findings should be interpreted with caution. Finally, VR devices and systems differed between studies, further limiting comparisons. Although these factors limit this systematic review, we can still identify treatment and research implications. Adequately powered future studies with standardized protocols would further improve the available evidence and support for VR as an intervention.

Conclusions

VR therapy is a promising rehabilitation modality for PD. Additional investigations of VR therapy and PD should include direct comparisons between immersive and nonimmersive VR therapies. It could be hypothesized that the greater immersion and engagement potential of immersive VR would demonstrate greater functional improvement compared with nonimmersive VR, but there is no data to support this for PD. VR therapy for PD appears to be a relatively safe alternative or adjunct to traditional therapy with a potentially positive impact on a variety of symptoms and is growing as an innovative therapeutic approach for PD patients.

Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system, with recent estimates of around 1 million people living with MS in the US.¹ In many countries, MS is a leading cause of disability among young adults, second only to trauma.² Clinically, neurologic worsening (ie, disability) in MS can occur in the relapsing-remitting (RRMS) phase of disease due to incomplete recovery from neuroinflammatory relapses. However, in the 15% of patients with a progressive course from onset (PPMS), and in those with RRMS who transition to a secondary progressive phenotype (SPMS), neurologic worsening follows a slowly progressive pattern.³ A progressive disease course—either PPMS at onset or transitioning to SPMS—is the dominant factor affecting MS-related neurologic disability accumulation. In particular, epidemiologic studies have shown that, in the absence of transitioning to a progressive disease course, < 5% of individuals with MS will accumulate sufficient disability to necessitate use of a cane for ambulation.^4-6 Therefore, developing disease modifying therapies (DMTs) that are highly effective at slowing or stopping the gradual accumulation of neurologic disability in progressive MS represent a critical unmet need.

Research into the development of DMTs for progressive MS has been hindered by a number of factors. In particular, the clinical definition and diagnosis of progressive MS has been an evolving concept. Diagnostic criteria for MS, which help facilitate the enrollment of appropriate subjects into clinical trials, have only recently clarified the current consensus definition for progressive MS—steadily increasing neurologic disability independent of clinical relapses. Looking back to the Schumacher criteria in 1965 and Poser criteria in 1983, it was acknowledged that neurologic symptoms in MS may follow a relapsing-remitting or progressive pattern, but little attempt was made to define progressive MS.^7,8 The original McDonald criteria in 2001 defined diagnostic criteria for progressive MS.⁹ These criteria continued to evolve through subsequent revisions (eg, cerebrospinal fluid [CSF] specific oligoclonal bands no longer are an absolute requirement), and only in the 2017 revision was it emphasized that disability progression must occur independent of clinical relapses, concordant with similar emphasis in the 2013 revision of MS clinical course definitions.^3,10

The interpretation of prior clinical trials of DMT for progressive MS must consider this evolving clinical definition. The US Food and Drug Administration (FDA) approved mitoxantrone in 2000—making it the first DMT to carry an approved label for SPMS. While achieving significant clinical efficacy, it is clear from the details of the trial that the enrolled subjects had a high degree of inflammatory disease activity, which suggests that mitoxantrone treats neuroinflammation and not relapse-independent worsening. More recently, disparate results were seen in the anti-CD20 (rituximab, ocrelizumab) and S1P receptor modulator (fingolimod, siponimod) trials targeted at patients with primary and secondary progressive MS.^11-14 Although there are differences between these therapies, they are more similar than not within the same therapeutic class. Taken together, these trials illustrate the critical impact the narrower inclusion/exclusion criteria (namely age and extent of inflammatory activity) had on attaining positive outcomes. Other considerations, such as confounding illness, also may impact trial recruitment and generalizability of findings.

The lack of known biological targets in progressive MS, which is a complex disease with an incompletely understood and heterogeneous pathology, also hinders DMT development. Decades of research has characterized multifocal central nervous system (CNS) lesions that exhibit features of demyelination, inflammation, reactive gliosis, axonal loss, and neuronal damage. Until recently, however, much of this research focused on the relapsing phase of disease, and so the understanding of the pathologic underpinnings of progressive disease has remained limited. Current areas of investigation encompass a broad range of pathological processes, such as microglial activation, meningeal lymphoid follicles, remyelination failure, vulnerability of chronically demyelinated axons, oxidative injury, iron accumulation, mitochondrial damage, and others. There is the added complication that the pathologic processes underlying progressive MS are superimposed on the CNS aging process. In particular, the transition to progressive MS and the rate of disability accumulation during progressive MS show strong correlation with age.^6,15-17

Finally, DMT development for progressive MS also is hindered by the lack of specific surrogate and clinical outcome measures. Trials for relapsing MS have benefited greatly from the relatively straightforward assessment of clinical relapses and inflammatory disease activity on magnetic resonance imaging (MRI). With the goal of developing DMTs that are highly effective at slowing or stopping the gradual accumulation of neurologic disability in progressive MS, which by definition occurs independent of clinical relapses, these measures are not directly relevant. The longitudinal clinical disability outcome measures change at a slower rate than in early, relapsing disease. The use of standardized scales (eg, the Expanded Disability Status Scale [EDSS]), lower limb function, upper limb function, cognition, or a combination is a subject of ongoing debate. For example, the ASCEND and IMPACT trials (placebo-controlled trials for SPMS with natalizumab and interferon β-1a, respectively) showed no significant impact in EDSS progression—but in both of these trials, the 9-hole peg test (9-HPT), a performance measure for upper limb function, showed significant improvement.^10,18 Particularly in those with an EDSS of > 6.5, who are unlikely to have measurable EDSS progression, functional tests such as the 9-HPT or timed 25-foot walk may be more sensitive as measures for disability progression.¹¹ MRI measures of brain atrophy is the current gold standard surrogate outcome for clinical trials in progressive MS, but others that may warrant consideration include optical coherence tomography (OCT) or CSF markers of axonal degeneration.

DMT for Progressive MS

Current diagnostic nomenclature separates patients with active (superimposed clinical and/or radiographic relapses) from those with inactive disease.^3,12 Relapsing forms of MS include all RRMS and those with SPMS with superimposed relapses (ie, active SPMS). Following this paradigm shift, the FDA changed the indication for already approved DMT from RRMS to relapsing forms of MS. Below is a discussion of DMT that specifically use the term SPMS and PPMS in the indication, where phase 3 trial data for progressive MS is available.

In 2019, the FDA approved the first oral medication (siponimod) for active SPMS. Subsequently, updates to the labels of the older DMT expanded to include active SPMS. Until 2019, the only FDA approved medication for SPMS was mitoxantrone, and use of this medication was limited due to unfavorable adverse effects (AEs). No medications had obtained FDA approval for inactive SPMS to this point, which represented an unmet need for a considerable number of patients.

Mitoxantrone became the first DMT approved for use in SPMS in 2000 following early trials that showed reductions in EDSS worsening, change in ambulation index, reduced number of treated relapses, and prolonged time to first treated relapse. However, as with some of the other positive trials in progressive MS, it is difficult to discern the impact of suppression of relapses as opposed to direct impact on progressive pathophysiology. Within the placebo arm, for example, there were 129 relapses among the 64 subjects, which suggests that these cases had particularly active disease or were in the early stages of SPMS.¹³ Furthermore, the use of this medication was limited due to concerns of cardiotoxicity and hematologic malignancy as serious AEs.

The trials of interferon β-1b illustrate the same difficulty of isolating possible benefits in disease progression from disability accumulated from relapses. The first interferon β-1b trial for SPMS, was conducted in Europe using fingolimod and showed a delay in confirmed disability progression compared to placebo as measured with the EDSS.¹⁴ However, a North American trial that followed in 2004 was unable to replicate this finding.¹⁵ The patients in the European trial appeared to be in an earlier phase of SPMS with more active disease, and a post-hoc pooled analysis suggested that patients with active disease and those with more pronounced disability progression were more likely to benefit from treatment.¹⁶ Overall, interferons do not appear to appreciably alter disability in the long-term for patients with SPMS, though they may modify short-term, relapse-related disability.

Perhaps the most encouraging data for SPMS was found in the EXPAND trial, which investigated siponimod, an S1P receptor modulator that is more selective than fingolimod. The trial identified a 21% reduction in 3-month confirmed disability progression for SPMS patients taking siponimod compared with those taking a placebo.¹⁷ Although the patients in EXPAND did seem to have relatively less disease activity at baseline than those who participated in other SPMS trials, those who benefitted from siponimod were primarily patients who had clinical and/or radiographic relapses over the prior 2 years. Based on this, the FDA approved siponimod for active SPMS. The extent to which siponimod exerts a true neuroprotective effect beyond reducing inflammation has not been clearly established.

B-cell depleting therapies rituximab and ocrelizumab have been evaluated in both primary and secondary progressive MS populations. Early investigations of the chimeric rituximab in PPMS did not show benefits on disability (EDSS) progression; however, benefits were seen in analysis of some subgroups.¹⁸ With this in mind, the ORATORIO trial for the humanized version, ocreluzimab, included PPMS patients that were younger (aged < 55 years) and had cutoffs for disease duration (< 15 years for those with EDSS more than 5 years, < 10 years for those with EDSS less than 5 years). The study showed statistically significant changes on disability progression, which led to ocrelizumab receiving the first FDA indication for PPMS.¹¹ There are substantial pathophysiologic similarities between PPMS and SPMS in the progressive phase.¹⁹ While these medications may have similar effects across these disease processes, these benefits have not yet been demonstrated in a prospective trial for the SPMS population. Regardless, B-cell depleting therapy is a reasonable consideration for select patients with active SPMS, consistent with a relapsing form of MS.

Therapies in Development 

DMT development for progressive MS is a high priority area. Current immunomodulatory therapies for RRMS have consistently been ineffective in the inactive forms of MS, with the possible exceptions of ocrelizumab and siponimod. Therefore, instead of immunosuppression, many agents currently in phase 2 and 3 clinical trials target alternative pathophysiological processes in order to provide neuroprotection, and/or promote remyelination and neurogenesis. These targets include oxidative stress (OS), non-T cell mediated inflammation, and mitochondrial/energy failure.²⁰ Below we review a selection of clinical trials testing agents following these approaches. Many agents have more than one potential mechanism of action (MOA) that could benefit progressive MS.

Lipoic acid (LA), also known as α-lipoic acid and thiotic acid, is one such agent targeting alternative pathophysiology in SPMS. LA is an endogenous agent synthesized de novo from fatty acids and cysteine as well as obtained in small amounts from foods.²¹ It has antioxidant (AO) properties including direct radical scavenging, regeneration of glutathione, and upregulation of AO enzymes via the NrF2 pathway.²² It supports mitochondria as a key cofactor for pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, and it also aids mitochondrial DNA synthesis.^21,22 Studies in experimental autoimmune encephalomyelitis, a widely used experimental mouse model of inflammatory demyelinating disease, also indicate a reduction in excessive microglial activation.²³ A phase 2 pilot randomized controlled trial (RCT) of 1200 mg LA in SPMS (n = 51) resulted in significantly less whole brain atrophy by SIENA (Structural Image Evaluation, Using Normalization, of Atrophy) at 2 years.²⁴ A follow-up multicenter trial is ongoing.

Simvastatin also targets alternative pathophysiology in SPMS. It has anti-inflammatory effects, improves vascular function, and promotes neuroprotection by reducing excitotoxicity. A phase 2 RCT demonstrated a reduction in whole brain atrophy in SPMS (n = 140), and a phase 3 trial is underway.²⁵ Ibudilast is another repurposed drug that targets alternative inflammation by inhibiting several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor and toll-like receptor 4. A phase 2 trial (n = 225) in both SPMS and PPMS also demonstrated a reduction in brain atrophy, but participants had high rates of AEs.²⁶

Lithium and riluzole promote neuroprotection by reducing excitotoxicity. Lithium is a pharmacologic active cation used as a mood stabilizer and causes inhibition of glycogen synthase kinase-3β. Animal models also indicate that lithium may decrease inflammation and positively impact neurogenesis.²⁷ A crossover pilot trial demonstrated tolerability with trends toward stabilization of EDSS and reductions in brain atrophy.²⁸ Three neuroprotective agents, riluzole (reduces glutamate excitotoxicity), fluoxetine (stimulates glycogenolysis and improves mitochondrial energy production), and amiloride (an acid-sensing ion channel blocker that opens in response to inflammation) were tested in a phase 2b multi-arm, multi-site parallel group RCT in SPMS (n = 445). The study failed to yield differences from placebo for any agent in reduction of brain volume loss.²⁹ A prior study of lamotrigine, a sodium channel blocker, also failed to find changes in brain volume loss.³⁰ These studies highlight the large sample sizes and/or long study durations needed to test agents using brain atrophy as primary outcome. In the future, precise surrogate markers of neuroprotection will be a great need for earlier phase trials. These results also suggest that targeting > 1 MOA may be necessary to treat SPMS effectively.

Efforts to promote remyelination target one hallmark of MS damage. High dose biotin (about 10,000× usual dose) may promote myelin repair as a cofactor for fatty acid synthesis and support mitochondrial oxidative phosphorylation. While a RCT yielded a greater proportion of participants with either PPMS or SPMS with improvement in disability than placebo at 12 months, an open label trial suggested otherwise indicating a need for a more definitive trial.^31,32

Anti-LINGO-1 (opicinumab) is a monoclonal antibody that targets LINGO, a potent negative regulator of oligodendrocyte differentiation and myelination.³³ Although this agent failed in a phase 2 trial in relapsing MS, and is thus unlikely to be tested in progressive forms, the innovative approach to stimulating oligodendrocytes is ongoing. One such effort is to use thyroid hormone, crucial to myelin formation during development, as a repair agent in MS.³⁴ A dose-finding study of thyroid hormone was completed and efforts to develop a thyromimetic agent are ongoing.

Finally, efforts to promote neurogenesis remain a goal for many neurodegenerative diseases. Exercise appears to prevent age-related atrophy of the hippocampus in animals and humans and help maintain neuronal health.³⁵ In patients with RRMS, cortical thickness is impacted positively by resistance training, which suggests a neuroprotective effect.³⁶ A multi-center trial of exercise in patients with progressive MS investigating cognitive outcomes is ongoing.

Discontinuing DMT

In the early 1990s, the successful development of immune modulating therapies that reliably reduced disease activity in RRMS led to widespread initiation in patients with relapsing disease. However, guidance on when or if to discontinue DMT, even in those who have transitioned to SPMS, remains largely absent at this time. Requests to discontinue DMT may come from patients weary of taking medication (especially injections), bothered by AEs, or those who no longer perceive efficacy from their treatments. Clinicians also may question the benefit of immune modulation in patients with longstanding freedom from relapses or changes in MRI lesion burden.

To inform discussion centered on treatment discontinuation, a clinical trial is currently underway to better answer the question of when and how to withdraw MS therapy. Discontinuation of Disease Modifying Therapies in Multiple Sclerosis (DISCO-MS) is a prospective, placebo-controlled RCT and its primary endpoint is recurrence of disease activity over a 2 year follow-up period.³⁷ Eligibility requirements for the trial include age > 55 years, 5-year freedom from relapses, and 3-year freedom from new MRI lesions (criteria informed by progressive MS cohort studies).³¹ In addition to demonstrating the active disease recurrence rates in this patient population, the trial also aims to identify risk factors for recurrent disease activity among treated MS patients.³⁷ DISCO-MS builds upon a series of retrospective and observational studies that partially answered these questions, albeit in the context of biases inherent in retrospective or observational studies.

A Minneapolis MS Treatment and Research Center single-center study identified 77 SPMS patients with no acute CNS inflammatory events over 2 to 20 years and advised these patients to stop taking DMT.³² In this group, 11.7% of subjects experienced recurrent active disease. Age was the primary discriminating factor. The mean age of those who experienced disease activity was 56 years vs 61 years those who did not. A second observational study from France found that among 100 SPMS patients treated either with interferon β or glatiramer acetate for at least 6 months, 35% experienced some form of inflammatory disease upon discontinuation.³⁸ Sixteen patients relapsed and 19 developed gadolinium-enhancing MR lesions after DMT discontinuation. However, the age of the cohort was younger than the Minneapolis study (47.2 years vs 61 years), and reasons for discontinuation (eg, AEs or lack of disease activity) were not considered in the analysis.

Other studies examining the safety of DMT discontinuation have not considered MS subtype or excluded patients with progressive subtypes of MS. The largest studies to date on DMT discontinuation utilized the international MSBase global patient registry, which identified nearly 5,000 patients who discontinued interferons (73%), glatiramer acetate (18%), natalizumab (6%), or fingolimod (3%), without specifying the reasons for discontinuation.³⁹ Despite these shortcomings, data reveal trends that are helpful in predicting how MS tends to behave in patients who have discontinued therapy. Not surprisingly, disability progression was most likely among patients already characterized as having a progressive phenotype, while relapses were less likely to occur among older, progressive patients.

Although clinicians may be increasingly willing to discuss DMT discontinuation with their patients, at least 1 study exploring patient perspectives on stopping treatment suggests widespread reluctance to stop treatment. A survey conducted with participants in the North American Research Committee on Multiple Sclerosis patient-report registry found that among survey respondents, only 11.9% would discontinue their MS medication if deemed stable, while 66.3% stated they were unlikely to stop treatment.⁴⁰

These results suggest that before clinicians incorporate DMT discontinuation into the normal course of discussion with patients, they should be prepared to provide both education (on the wisdom of stopping under the right circumstances) and evidence to support when and how to make the recommendation. Based on existing evidence, criteria for recommending treatment discontinuation might include prolonged freedom from disease activity (≥ 5 years), age > 55 years or 60 years, and a progressive disease course. Thus far, no combination of factors has been shown to completely predict an event-free transition off of medicine. Since no fixed algorithm yet exists to guide DMT stoppage in MS, reasonable suggestions for monitoring patients might include surveillance MRIs, more frequent clinic visits, and possible transitional treatment for patients coming off of natalizumab or fingolimod, since these drugs have been associated with rebound disease activity when discontinued.^41,42

Clinicians wishing to maximize function and quality of life for their patients at any age or stage of disease should look to nonpharmacologic interventions to lessen disability and maximize quality of life. While beyond the scope of this discussion, preliminary evidence suggests multimodal (aerobic, resistance, balance) exercise may enhance endurance and cognitive processing speed, and that treatment of comorbid diseases affecting vascular health benefits MS. ⁴³

Conclusions

The development of numerous treatments for RRMS has established an entirely new landscape and disease course for those with MS. While this benefit has not entirely extended to those with progressive MS, those with active disease with superimposed relapses may receive limited benefit from these medications. New insights into the pathophysiology of progressive MS may lead us to new treatments through multiple alternative pathophysiologic pathways. Some early studies using this strategy show promise in slowing the progressive phase. Medication development for progressive MS faces multiple challenges due to lack of a single animal model demonstrating both pathology and clinical effects, absence of phase 1 surrogate biomarkers, and later phase trial endpoints that require large sample sizes and extended study durations. Nevertheless, the increase in number of trials and diversity of therapeutic approaches for progressive MS provides hope for effective therapy. Currently, the heterogeneity of the population with progressive MS requires an individualized treatment approach, and in some of these patients, stopping therapy may be a reasonable consideration. Symptomatic management remains critical for all patients with progressive MS as well as non-pharmacologic approaches that maximize quality of life.

Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system, with recent estimates of around 1 million people living with MS in the US.¹ In many countries, MS is a leading cause of disability among young adults, second only to trauma.² Clinically, neurologic worsening (ie, disability) in MS can occur in the relapsing-remitting (RRMS) phase of disease due to incomplete recovery from neuroinflammatory relapses. However, in the 15% of patients with a progressive course from onset (PPMS), and in those with RRMS who transition to a secondary progressive phenotype (SPMS), neurologic worsening follows a slowly progressive pattern.³ A progressive disease course—either PPMS at onset or transitioning to SPMS—is the dominant factor affecting MS-related neurologic disability accumulation. In particular, epidemiologic studies have shown that, in the absence of transitioning to a progressive disease course, < 5% of individuals with MS will accumulate sufficient disability to necessitate use of a cane for ambulation.^4-6 Therefore, developing disease modifying therapies (DMTs) that are highly effective at slowing or stopping the gradual accumulation of neurologic disability in progressive MS represent a critical unmet need.

Research into the development of DMTs for progressive MS has been hindered by a number of factors. In particular, the clinical definition and diagnosis of progressive MS has been an evolving concept. Diagnostic criteria for MS, which help facilitate the enrollment of appropriate subjects into clinical trials, have only recently clarified the current consensus definition for progressive MS—steadily increasing neurologic disability independent of clinical relapses. Looking back to the Schumacher criteria in 1965 and Poser criteria in 1983, it was acknowledged that neurologic symptoms in MS may follow a relapsing-remitting or progressive pattern, but little attempt was made to define progressive MS.^7,8 The original McDonald criteria in 2001 defined diagnostic criteria for progressive MS.⁹ These criteria continued to evolve through subsequent revisions (eg, cerebrospinal fluid [CSF] specific oligoclonal bands no longer are an absolute requirement), and only in the 2017 revision was it emphasized that disability progression must occur independent of clinical relapses, concordant with similar emphasis in the 2013 revision of MS clinical course definitions.^3,10

The interpretation of prior clinical trials of DMT for progressive MS must consider this evolving clinical definition. The US Food and Drug Administration (FDA) approved mitoxantrone in 2000—making it the first DMT to carry an approved label for SPMS. While achieving significant clinical efficacy, it is clear from the details of the trial that the enrolled subjects had a high degree of inflammatory disease activity, which suggests that mitoxantrone treats neuroinflammation and not relapse-independent worsening. More recently, disparate results were seen in the anti-CD20 (rituximab, ocrelizumab) and S1P receptor modulator (fingolimod, siponimod) trials targeted at patients with primary and secondary progressive MS.^11-14 Although there are differences between these therapies, they are more similar than not within the same therapeutic class. Taken together, these trials illustrate the critical impact the narrower inclusion/exclusion criteria (namely age and extent of inflammatory activity) had on attaining positive outcomes. Other considerations, such as confounding illness, also may impact trial recruitment and generalizability of findings.

The lack of known biological targets in progressive MS, which is a complex disease with an incompletely understood and heterogeneous pathology, also hinders DMT development. Decades of research has characterized multifocal central nervous system (CNS) lesions that exhibit features of demyelination, inflammation, reactive gliosis, axonal loss, and neuronal damage. Until recently, however, much of this research focused on the relapsing phase of disease, and so the understanding of the pathologic underpinnings of progressive disease has remained limited. Current areas of investigation encompass a broad range of pathological processes, such as microglial activation, meningeal lymphoid follicles, remyelination failure, vulnerability of chronically demyelinated axons, oxidative injury, iron accumulation, mitochondrial damage, and others. There is the added complication that the pathologic processes underlying progressive MS are superimposed on the CNS aging process. In particular, the transition to progressive MS and the rate of disability accumulation during progressive MS show strong correlation with age.^6,15-17

Finally, DMT development for progressive MS also is hindered by the lack of specific surrogate and clinical outcome measures. Trials for relapsing MS have benefited greatly from the relatively straightforward assessment of clinical relapses and inflammatory disease activity on magnetic resonance imaging (MRI). With the goal of developing DMTs that are highly effective at slowing or stopping the gradual accumulation of neurologic disability in progressive MS, which by definition occurs independent of clinical relapses, these measures are not directly relevant. The longitudinal clinical disability outcome measures change at a slower rate than in early, relapsing disease. The use of standardized scales (eg, the Expanded Disability Status Scale [EDSS]), lower limb function, upper limb function, cognition, or a combination is a subject of ongoing debate. For example, the ASCEND and IMPACT trials (placebo-controlled trials for SPMS with natalizumab and interferon β-1a, respectively) showed no significant impact in EDSS progression—but in both of these trials, the 9-hole peg test (9-HPT), a performance measure for upper limb function, showed significant improvement.^10,18 Particularly in those with an EDSS of > 6.5, who are unlikely to have measurable EDSS progression, functional tests such as the 9-HPT or timed 25-foot walk may be more sensitive as measures for disability progression.¹¹ MRI measures of brain atrophy is the current gold standard surrogate outcome for clinical trials in progressive MS, but others that may warrant consideration include optical coherence tomography (OCT) or CSF markers of axonal degeneration.

DMT for Progressive MS

Current diagnostic nomenclature separates patients with active (superimposed clinical and/or radiographic relapses) from those with inactive disease.^3,12 Relapsing forms of MS include all RRMS and those with SPMS with superimposed relapses (ie, active SPMS). Following this paradigm shift, the FDA changed the indication for already approved DMT from RRMS to relapsing forms of MS. Below is a discussion of DMT that specifically use the term SPMS and PPMS in the indication, where phase 3 trial data for progressive MS is available.

In 2019, the FDA approved the first oral medication (siponimod) for active SPMS. Subsequently, updates to the labels of the older DMT expanded to include active SPMS. Until 2019, the only FDA approved medication for SPMS was mitoxantrone, and use of this medication was limited due to unfavorable adverse effects (AEs). No medications had obtained FDA approval for inactive SPMS to this point, which represented an unmet need for a considerable number of patients.

Mitoxantrone became the first DMT approved for use in SPMS in 2000 following early trials that showed reductions in EDSS worsening, change in ambulation index, reduced number of treated relapses, and prolonged time to first treated relapse. However, as with some of the other positive trials in progressive MS, it is difficult to discern the impact of suppression of relapses as opposed to direct impact on progressive pathophysiology. Within the placebo arm, for example, there were 129 relapses among the 64 subjects, which suggests that these cases had particularly active disease or were in the early stages of SPMS.¹³ Furthermore, the use of this medication was limited due to concerns of cardiotoxicity and hematologic malignancy as serious AEs.

The trials of interferon β-1b illustrate the same difficulty of isolating possible benefits in disease progression from disability accumulated from relapses. The first interferon β-1b trial for SPMS, was conducted in Europe using fingolimod and showed a delay in confirmed disability progression compared to placebo as measured with the EDSS.¹⁴ However, a North American trial that followed in 2004 was unable to replicate this finding.¹⁵ The patients in the European trial appeared to be in an earlier phase of SPMS with more active disease, and a post-hoc pooled analysis suggested that patients with active disease and those with more pronounced disability progression were more likely to benefit from treatment.¹⁶ Overall, interferons do not appear to appreciably alter disability in the long-term for patients with SPMS, though they may modify short-term, relapse-related disability.

Perhaps the most encouraging data for SPMS was found in the EXPAND trial, which investigated siponimod, an S1P receptor modulator that is more selective than fingolimod. The trial identified a 21% reduction in 3-month confirmed disability progression for SPMS patients taking siponimod compared with those taking a placebo.¹⁷ Although the patients in EXPAND did seem to have relatively less disease activity at baseline than those who participated in other SPMS trials, those who benefitted from siponimod were primarily patients who had clinical and/or radiographic relapses over the prior 2 years. Based on this, the FDA approved siponimod for active SPMS. The extent to which siponimod exerts a true neuroprotective effect beyond reducing inflammation has not been clearly established.

B-cell depleting therapies rituximab and ocrelizumab have been evaluated in both primary and secondary progressive MS populations. Early investigations of the chimeric rituximab in PPMS did not show benefits on disability (EDSS) progression; however, benefits were seen in analysis of some subgroups.¹⁸ With this in mind, the ORATORIO trial for the humanized version, ocreluzimab, included PPMS patients that were younger (aged < 55 years) and had cutoffs for disease duration (< 15 years for those with EDSS more than 5 years, < 10 years for those with EDSS less than 5 years). The study showed statistically significant changes on disability progression, which led to ocrelizumab receiving the first FDA indication for PPMS.¹¹ There are substantial pathophysiologic similarities between PPMS and SPMS in the progressive phase.¹⁹ While these medications may have similar effects across these disease processes, these benefits have not yet been demonstrated in a prospective trial for the SPMS population. Regardless, B-cell depleting therapy is a reasonable consideration for select patients with active SPMS, consistent with a relapsing form of MS.

Therapies in Development 

DMT development for progressive MS is a high priority area. Current immunomodulatory therapies for RRMS have consistently been ineffective in the inactive forms of MS, with the possible exceptions of ocrelizumab and siponimod. Therefore, instead of immunosuppression, many agents currently in phase 2 and 3 clinical trials target alternative pathophysiological processes in order to provide neuroprotection, and/or promote remyelination and neurogenesis. These targets include oxidative stress (OS), non-T cell mediated inflammation, and mitochondrial/energy failure.²⁰ Below we review a selection of clinical trials testing agents following these approaches. Many agents have more than one potential mechanism of action (MOA) that could benefit progressive MS.

Lipoic acid (LA), also known as α-lipoic acid and thiotic acid, is one such agent targeting alternative pathophysiology in SPMS. LA is an endogenous agent synthesized de novo from fatty acids and cysteine as well as obtained in small amounts from foods.²¹ It has antioxidant (AO) properties including direct radical scavenging, regeneration of glutathione, and upregulation of AO enzymes via the NrF2 pathway.²² It supports mitochondria as a key cofactor for pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, and it also aids mitochondrial DNA synthesis.^21,22 Studies in experimental autoimmune encephalomyelitis, a widely used experimental mouse model of inflammatory demyelinating disease, also indicate a reduction in excessive microglial activation.²³ A phase 2 pilot randomized controlled trial (RCT) of 1200 mg LA in SPMS (n = 51) resulted in significantly less whole brain atrophy by SIENA (Structural Image Evaluation, Using Normalization, of Atrophy) at 2 years.²⁴ A follow-up multicenter trial is ongoing.

Simvastatin also targets alternative pathophysiology in SPMS. It has anti-inflammatory effects, improves vascular function, and promotes neuroprotection by reducing excitotoxicity. A phase 2 RCT demonstrated a reduction in whole brain atrophy in SPMS (n = 140), and a phase 3 trial is underway.²⁵ Ibudilast is another repurposed drug that targets alternative inflammation by inhibiting several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor and toll-like receptor 4. A phase 2 trial (n = 225) in both SPMS and PPMS also demonstrated a reduction in brain atrophy, but participants had high rates of AEs.²⁶

Lithium and riluzole promote neuroprotection by reducing excitotoxicity. Lithium is a pharmacologic active cation used as a mood stabilizer and causes inhibition of glycogen synthase kinase-3β. Animal models also indicate that lithium may decrease inflammation and positively impact neurogenesis.²⁷ A crossover pilot trial demonstrated tolerability with trends toward stabilization of EDSS and reductions in brain atrophy.²⁸ Three neuroprotective agents, riluzole (reduces glutamate excitotoxicity), fluoxetine (stimulates glycogenolysis and improves mitochondrial energy production), and amiloride (an acid-sensing ion channel blocker that opens in response to inflammation) were tested in a phase 2b multi-arm, multi-site parallel group RCT in SPMS (n = 445). The study failed to yield differences from placebo for any agent in reduction of brain volume loss.²⁹ A prior study of lamotrigine, a sodium channel blocker, also failed to find changes in brain volume loss.³⁰ These studies highlight the large sample sizes and/or long study durations needed to test agents using brain atrophy as primary outcome. In the future, precise surrogate markers of neuroprotection will be a great need for earlier phase trials. These results also suggest that targeting > 1 MOA may be necessary to treat SPMS effectively.

Efforts to promote remyelination target one hallmark of MS damage. High dose biotin (about 10,000× usual dose) may promote myelin repair as a cofactor for fatty acid synthesis and support mitochondrial oxidative phosphorylation. While a RCT yielded a greater proportion of participants with either PPMS or SPMS with improvement in disability than placebo at 12 months, an open label trial suggested otherwise indicating a need for a more definitive trial.^31,32

Anti-LINGO-1 (opicinumab) is a monoclonal antibody that targets LINGO, a potent negative regulator of oligodendrocyte differentiation and myelination.³³ Although this agent failed in a phase 2 trial in relapsing MS, and is thus unlikely to be tested in progressive forms, the innovative approach to stimulating oligodendrocytes is ongoing. One such effort is to use thyroid hormone, crucial to myelin formation during development, as a repair agent in MS.³⁴ A dose-finding study of thyroid hormone was completed and efforts to develop a thyromimetic agent are ongoing.

Finally, efforts to promote neurogenesis remain a goal for many neurodegenerative diseases. Exercise appears to prevent age-related atrophy of the hippocampus in animals and humans and help maintain neuronal health.³⁵ In patients with RRMS, cortical thickness is impacted positively by resistance training, which suggests a neuroprotective effect.³⁶ A multi-center trial of exercise in patients with progressive MS investigating cognitive outcomes is ongoing.

Discontinuing DMT

In the early 1990s, the successful development of immune modulating therapies that reliably reduced disease activity in RRMS led to widespread initiation in patients with relapsing disease. However, guidance on when or if to discontinue DMT, even in those who have transitioned to SPMS, remains largely absent at this time. Requests to discontinue DMT may come from patients weary of taking medication (especially injections), bothered by AEs, or those who no longer perceive efficacy from their treatments. Clinicians also may question the benefit of immune modulation in patients with longstanding freedom from relapses or changes in MRI lesion burden.

To inform discussion centered on treatment discontinuation, a clinical trial is currently underway to better answer the question of when and how to withdraw MS therapy. Discontinuation of Disease Modifying Therapies in Multiple Sclerosis (DISCO-MS) is a prospective, placebo-controlled RCT and its primary endpoint is recurrence of disease activity over a 2 year follow-up period.³⁷ Eligibility requirements for the trial include age > 55 years, 5-year freedom from relapses, and 3-year freedom from new MRI lesions (criteria informed by progressive MS cohort studies).³¹ In addition to demonstrating the active disease recurrence rates in this patient population, the trial also aims to identify risk factors for recurrent disease activity among treated MS patients.³⁷ DISCO-MS builds upon a series of retrospective and observational studies that partially answered these questions, albeit in the context of biases inherent in retrospective or observational studies.

A Minneapolis MS Treatment and Research Center single-center study identified 77 SPMS patients with no acute CNS inflammatory events over 2 to 20 years and advised these patients to stop taking DMT.³² In this group, 11.7% of subjects experienced recurrent active disease. Age was the primary discriminating factor. The mean age of those who experienced disease activity was 56 years vs 61 years those who did not. A second observational study from France found that among 100 SPMS patients treated either with interferon β or glatiramer acetate for at least 6 months, 35% experienced some form of inflammatory disease upon discontinuation.³⁸ Sixteen patients relapsed and 19 developed gadolinium-enhancing MR lesions after DMT discontinuation. However, the age of the cohort was younger than the Minneapolis study (47.2 years vs 61 years), and reasons for discontinuation (eg, AEs or lack of disease activity) were not considered in the analysis.

Other studies examining the safety of DMT discontinuation have not considered MS subtype or excluded patients with progressive subtypes of MS. The largest studies to date on DMT discontinuation utilized the international MSBase global patient registry, which identified nearly 5,000 patients who discontinued interferons (73%), glatiramer acetate (18%), natalizumab (6%), or fingolimod (3%), without specifying the reasons for discontinuation.³⁹ Despite these shortcomings, data reveal trends that are helpful in predicting how MS tends to behave in patients who have discontinued therapy. Not surprisingly, disability progression was most likely among patients already characterized as having a progressive phenotype, while relapses were less likely to occur among older, progressive patients.

Although clinicians may be increasingly willing to discuss DMT discontinuation with their patients, at least 1 study exploring patient perspectives on stopping treatment suggests widespread reluctance to stop treatment. A survey conducted with participants in the North American Research Committee on Multiple Sclerosis patient-report registry found that among survey respondents, only 11.9% would discontinue their MS medication if deemed stable, while 66.3% stated they were unlikely to stop treatment.⁴⁰

These results suggest that before clinicians incorporate DMT discontinuation into the normal course of discussion with patients, they should be prepared to provide both education (on the wisdom of stopping under the right circumstances) and evidence to support when and how to make the recommendation. Based on existing evidence, criteria for recommending treatment discontinuation might include prolonged freedom from disease activity (≥ 5 years), age > 55 years or 60 years, and a progressive disease course. Thus far, no combination of factors has been shown to completely predict an event-free transition off of medicine. Since no fixed algorithm yet exists to guide DMT stoppage in MS, reasonable suggestions for monitoring patients might include surveillance MRIs, more frequent clinic visits, and possible transitional treatment for patients coming off of natalizumab or fingolimod, since these drugs have been associated with rebound disease activity when discontinued.^41,42

Clinicians wishing to maximize function and quality of life for their patients at any age or stage of disease should look to nonpharmacologic interventions to lessen disability and maximize quality of life. While beyond the scope of this discussion, preliminary evidence suggests multimodal (aerobic, resistance, balance) exercise may enhance endurance and cognitive processing speed, and that treatment of comorbid diseases affecting vascular health benefits MS. ⁴³

Conclusions

The development of numerous treatments for RRMS has established an entirely new landscape and disease course for those with MS. While this benefit has not entirely extended to those with progressive MS, those with active disease with superimposed relapses may receive limited benefit from these medications. New insights into the pathophysiology of progressive MS may lead us to new treatments through multiple alternative pathophysiologic pathways. Some early studies using this strategy show promise in slowing the progressive phase. Medication development for progressive MS faces multiple challenges due to lack of a single animal model demonstrating both pathology and clinical effects, absence of phase 1 surrogate biomarkers, and later phase trial endpoints that require large sample sizes and extended study durations. Nevertheless, the increase in number of trials and diversity of therapeutic approaches for progressive MS provides hope for effective therapy. Currently, the heterogeneity of the population with progressive MS requires an individualized treatment approach, and in some of these patients, stopping therapy may be a reasonable consideration. Symptomatic management remains critical for all patients with progressive MS as well as non-pharmacologic approaches that maximize quality of life.

Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system, with recent estimates of around 1 million people living with MS in the US.¹ In many countries, MS is a leading cause of disability among young adults, second only to trauma.² Clinically, neurologic worsening (ie, disability) in MS can occur in the relapsing-remitting (RRMS) phase of disease due to incomplete recovery from neuroinflammatory relapses. However, in the 15% of patients with a progressive course from onset (PPMS), and in those with RRMS who transition to a secondary progressive phenotype (SPMS), neurologic worsening follows a slowly progressive pattern.³ A progressive disease course—either PPMS at onset or transitioning to SPMS—is the dominant factor affecting MS-related neurologic disability accumulation. In particular, epidemiologic studies have shown that, in the absence of transitioning to a progressive disease course, < 5% of individuals with MS will accumulate sufficient disability to necessitate use of a cane for ambulation.^4-6 Therefore, developing disease modifying therapies (DMTs) that are highly effective at slowing or stopping the gradual accumulation of neurologic disability in progressive MS represent a critical unmet need.

Research into the development of DMTs for progressive MS has been hindered by a number of factors. In particular, the clinical definition and diagnosis of progressive MS has been an evolving concept. Diagnostic criteria for MS, which help facilitate the enrollment of appropriate subjects into clinical trials, have only recently clarified the current consensus definition for progressive MS—steadily increasing neurologic disability independent of clinical relapses. Looking back to the Schumacher criteria in 1965 and Poser criteria in 1983, it was acknowledged that neurologic symptoms in MS may follow a relapsing-remitting or progressive pattern, but little attempt was made to define progressive MS.^7,8 The original McDonald criteria in 2001 defined diagnostic criteria for progressive MS.⁹ These criteria continued to evolve through subsequent revisions (eg, cerebrospinal fluid [CSF] specific oligoclonal bands no longer are an absolute requirement), and only in the 2017 revision was it emphasized that disability progression must occur independent of clinical relapses, concordant with similar emphasis in the 2013 revision of MS clinical course definitions.^3,10

The interpretation of prior clinical trials of DMT for progressive MS must consider this evolving clinical definition. The US Food and Drug Administration (FDA) approved mitoxantrone in 2000—making it the first DMT to carry an approved label for SPMS. While achieving significant clinical efficacy, it is clear from the details of the trial that the enrolled subjects had a high degree of inflammatory disease activity, which suggests that mitoxantrone treats neuroinflammation and not relapse-independent worsening. More recently, disparate results were seen in the anti-CD20 (rituximab, ocrelizumab) and S1P receptor modulator (fingolimod, siponimod) trials targeted at patients with primary and secondary progressive MS.^11-14 Although there are differences between these therapies, they are more similar than not within the same therapeutic class. Taken together, these trials illustrate the critical impact the narrower inclusion/exclusion criteria (namely age and extent of inflammatory activity) had on attaining positive outcomes. Other considerations, such as confounding illness, also may impact trial recruitment and generalizability of findings.

The lack of known biological targets in progressive MS, which is a complex disease with an incompletely understood and heterogeneous pathology, also hinders DMT development. Decades of research has characterized multifocal central nervous system (CNS) lesions that exhibit features of demyelination, inflammation, reactive gliosis, axonal loss, and neuronal damage. Until recently, however, much of this research focused on the relapsing phase of disease, and so the understanding of the pathologic underpinnings of progressive disease has remained limited. Current areas of investigation encompass a broad range of pathological processes, such as microglial activation, meningeal lymphoid follicles, remyelination failure, vulnerability of chronically demyelinated axons, oxidative injury, iron accumulation, mitochondrial damage, and others. There is the added complication that the pathologic processes underlying progressive MS are superimposed on the CNS aging process. In particular, the transition to progressive MS and the rate of disability accumulation during progressive MS show strong correlation with age.^6,15-17

Finally, DMT development for progressive MS also is hindered by the lack of specific surrogate and clinical outcome measures. Trials for relapsing MS have benefited greatly from the relatively straightforward assessment of clinical relapses and inflammatory disease activity on magnetic resonance imaging (MRI). With the goal of developing DMTs that are highly effective at slowing or stopping the gradual accumulation of neurologic disability in progressive MS, which by definition occurs independent of clinical relapses, these measures are not directly relevant. The longitudinal clinical disability outcome measures change at a slower rate than in early, relapsing disease. The use of standardized scales (eg, the Expanded Disability Status Scale [EDSS]), lower limb function, upper limb function, cognition, or a combination is a subject of ongoing debate. For example, the ASCEND and IMPACT trials (placebo-controlled trials for SPMS with natalizumab and interferon β-1a, respectively) showed no significant impact in EDSS progression—but in both of these trials, the 9-hole peg test (9-HPT), a performance measure for upper limb function, showed significant improvement.^10,18 Particularly in those with an EDSS of > 6.5, who are unlikely to have measurable EDSS progression, functional tests such as the 9-HPT or timed 25-foot walk may be more sensitive as measures for disability progression.¹¹ MRI measures of brain atrophy is the current gold standard surrogate outcome for clinical trials in progressive MS, but others that may warrant consideration include optical coherence tomography (OCT) or CSF markers of axonal degeneration.

DMT for Progressive MS

Current diagnostic nomenclature separates patients with active (superimposed clinical and/or radiographic relapses) from those with inactive disease.^3,12 Relapsing forms of MS include all RRMS and those with SPMS with superimposed relapses (ie, active SPMS). Following this paradigm shift, the FDA changed the indication for already approved DMT from RRMS to relapsing forms of MS. Below is a discussion of DMT that specifically use the term SPMS and PPMS in the indication, where phase 3 trial data for progressive MS is available.

In 2019, the FDA approved the first oral medication (siponimod) for active SPMS. Subsequently, updates to the labels of the older DMT expanded to include active SPMS. Until 2019, the only FDA approved medication for SPMS was mitoxantrone, and use of this medication was limited due to unfavorable adverse effects (AEs). No medications had obtained FDA approval for inactive SPMS to this point, which represented an unmet need for a considerable number of patients.

Mitoxantrone became the first DMT approved for use in SPMS in 2000 following early trials that showed reductions in EDSS worsening, change in ambulation index, reduced number of treated relapses, and prolonged time to first treated relapse. However, as with some of the other positive trials in progressive MS, it is difficult to discern the impact of suppression of relapses as opposed to direct impact on progressive pathophysiology. Within the placebo arm, for example, there were 129 relapses among the 64 subjects, which suggests that these cases had particularly active disease or were in the early stages of SPMS.¹³ Furthermore, the use of this medication was limited due to concerns of cardiotoxicity and hematologic malignancy as serious AEs.

The trials of interferon β-1b illustrate the same difficulty of isolating possible benefits in disease progression from disability accumulated from relapses. The first interferon β-1b trial for SPMS, was conducted in Europe using fingolimod and showed a delay in confirmed disability progression compared to placebo as measured with the EDSS.¹⁴ However, a North American trial that followed in 2004 was unable to replicate this finding.¹⁵ The patients in the European trial appeared to be in an earlier phase of SPMS with more active disease, and a post-hoc pooled analysis suggested that patients with active disease and those with more pronounced disability progression were more likely to benefit from treatment.¹⁶ Overall, interferons do not appear to appreciably alter disability in the long-term for patients with SPMS, though they may modify short-term, relapse-related disability.

Perhaps the most encouraging data for SPMS was found in the EXPAND trial, which investigated siponimod, an S1P receptor modulator that is more selective than fingolimod. The trial identified a 21% reduction in 3-month confirmed disability progression for SPMS patients taking siponimod compared with those taking a placebo.¹⁷ Although the patients in EXPAND did seem to have relatively less disease activity at baseline than those who participated in other SPMS trials, those who benefitted from siponimod were primarily patients who had clinical and/or radiographic relapses over the prior 2 years. Based on this, the FDA approved siponimod for active SPMS. The extent to which siponimod exerts a true neuroprotective effect beyond reducing inflammation has not been clearly established.

B-cell depleting therapies rituximab and ocrelizumab have been evaluated in both primary and secondary progressive MS populations. Early investigations of the chimeric rituximab in PPMS did not show benefits on disability (EDSS) progression; however, benefits were seen in analysis of some subgroups.¹⁸ With this in mind, the ORATORIO trial for the humanized version, ocreluzimab, included PPMS patients that were younger (aged < 55 years) and had cutoffs for disease duration (< 15 years for those with EDSS more than 5 years, < 10 years for those with EDSS less than 5 years). The study showed statistically significant changes on disability progression, which led to ocrelizumab receiving the first FDA indication for PPMS.¹¹ There are substantial pathophysiologic similarities between PPMS and SPMS in the progressive phase.¹⁹ While these medications may have similar effects across these disease processes, these benefits have not yet been demonstrated in a prospective trial for the SPMS population. Regardless, B-cell depleting therapy is a reasonable consideration for select patients with active SPMS, consistent with a relapsing form of MS.

Therapies in Development 

DMT development for progressive MS is a high priority area. Current immunomodulatory therapies for RRMS have consistently been ineffective in the inactive forms of MS, with the possible exceptions of ocrelizumab and siponimod. Therefore, instead of immunosuppression, many agents currently in phase 2 and 3 clinical trials target alternative pathophysiological processes in order to provide neuroprotection, and/or promote remyelination and neurogenesis. These targets include oxidative stress (OS), non-T cell mediated inflammation, and mitochondrial/energy failure.²⁰ Below we review a selection of clinical trials testing agents following these approaches. Many agents have more than one potential mechanism of action (MOA) that could benefit progressive MS.

Lipoic acid (LA), also known as α-lipoic acid and thiotic acid, is one such agent targeting alternative pathophysiology in SPMS. LA is an endogenous agent synthesized de novo from fatty acids and cysteine as well as obtained in small amounts from foods.²¹ It has antioxidant (AO) properties including direct radical scavenging, regeneration of glutathione, and upregulation of AO enzymes via the NrF2 pathway.²² It supports mitochondria as a key cofactor for pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, and it also aids mitochondrial DNA synthesis.^21,22 Studies in experimental autoimmune encephalomyelitis, a widely used experimental mouse model of inflammatory demyelinating disease, also indicate a reduction in excessive microglial activation.²³ A phase 2 pilot randomized controlled trial (RCT) of 1200 mg LA in SPMS (n = 51) resulted in significantly less whole brain atrophy by SIENA (Structural Image Evaluation, Using Normalization, of Atrophy) at 2 years.²⁴ A follow-up multicenter trial is ongoing.

Simvastatin also targets alternative pathophysiology in SPMS. It has anti-inflammatory effects, improves vascular function, and promotes neuroprotection by reducing excitotoxicity. A phase 2 RCT demonstrated a reduction in whole brain atrophy in SPMS (n = 140), and a phase 3 trial is underway.²⁵ Ibudilast is another repurposed drug that targets alternative inflammation by inhibiting several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor and toll-like receptor 4. A phase 2 trial (n = 225) in both SPMS and PPMS also demonstrated a reduction in brain atrophy, but participants had high rates of AEs.²⁶

Lithium and riluzole promote neuroprotection by reducing excitotoxicity. Lithium is a pharmacologic active cation used as a mood stabilizer and causes inhibition of glycogen synthase kinase-3β. Animal models also indicate that lithium may decrease inflammation and positively impact neurogenesis.²⁷ A crossover pilot trial demonstrated tolerability with trends toward stabilization of EDSS and reductions in brain atrophy.²⁸ Three neuroprotective agents, riluzole (reduces glutamate excitotoxicity), fluoxetine (stimulates glycogenolysis and improves mitochondrial energy production), and amiloride (an acid-sensing ion channel blocker that opens in response to inflammation) were tested in a phase 2b multi-arm, multi-site parallel group RCT in SPMS (n = 445). The study failed to yield differences from placebo for any agent in reduction of brain volume loss.²⁹ A prior study of lamotrigine, a sodium channel blocker, also failed to find changes in brain volume loss.³⁰ These studies highlight the large sample sizes and/or long study durations needed to test agents using brain atrophy as primary outcome. In the future, precise surrogate markers of neuroprotection will be a great need for earlier phase trials. These results also suggest that targeting > 1 MOA may be necessary to treat SPMS effectively.

Efforts to promote remyelination target one hallmark of MS damage. High dose biotin (about 10,000× usual dose) may promote myelin repair as a cofactor for fatty acid synthesis and support mitochondrial oxidative phosphorylation. While a RCT yielded a greater proportion of participants with either PPMS or SPMS with improvement in disability than placebo at 12 months, an open label trial suggested otherwise indicating a need for a more definitive trial.^31,32

Anti-LINGO-1 (opicinumab) is a monoclonal antibody that targets LINGO, a potent negative regulator of oligodendrocyte differentiation and myelination.³³ Although this agent failed in a phase 2 trial in relapsing MS, and is thus unlikely to be tested in progressive forms, the innovative approach to stimulating oligodendrocytes is ongoing. One such effort is to use thyroid hormone, crucial to myelin formation during development, as a repair agent in MS.³⁴ A dose-finding study of thyroid hormone was completed and efforts to develop a thyromimetic agent are ongoing.

Finally, efforts to promote neurogenesis remain a goal for many neurodegenerative diseases. Exercise appears to prevent age-related atrophy of the hippocampus in animals and humans and help maintain neuronal health.³⁵ In patients with RRMS, cortical thickness is impacted positively by resistance training, which suggests a neuroprotective effect.³⁶ A multi-center trial of exercise in patients with progressive MS investigating cognitive outcomes is ongoing.

Discontinuing DMT

In the early 1990s, the successful development of immune modulating therapies that reliably reduced disease activity in RRMS led to widespread initiation in patients with relapsing disease. However, guidance on when or if to discontinue DMT, even in those who have transitioned to SPMS, remains largely absent at this time. Requests to discontinue DMT may come from patients weary of taking medication (especially injections), bothered by AEs, or those who no longer perceive efficacy from their treatments. Clinicians also may question the benefit of immune modulation in patients with longstanding freedom from relapses or changes in MRI lesion burden.

To inform discussion centered on treatment discontinuation, a clinical trial is currently underway to better answer the question of when and how to withdraw MS therapy. Discontinuation of Disease Modifying Therapies in Multiple Sclerosis (DISCO-MS) is a prospective, placebo-controlled RCT and its primary endpoint is recurrence of disease activity over a 2 year follow-up period.³⁷ Eligibility requirements for the trial include age > 55 years, 5-year freedom from relapses, and 3-year freedom from new MRI lesions (criteria informed by progressive MS cohort studies).³¹ In addition to demonstrating the active disease recurrence rates in this patient population, the trial also aims to identify risk factors for recurrent disease activity among treated MS patients.³⁷ DISCO-MS builds upon a series of retrospective and observational studies that partially answered these questions, albeit in the context of biases inherent in retrospective or observational studies.

A Minneapolis MS Treatment and Research Center single-center study identified 77 SPMS patients with no acute CNS inflammatory events over 2 to 20 years and advised these patients to stop taking DMT.³² In this group, 11.7% of subjects experienced recurrent active disease. Age was the primary discriminating factor. The mean age of those who experienced disease activity was 56 years vs 61 years those who did not. A second observational study from France found that among 100 SPMS patients treated either with interferon β or glatiramer acetate for at least 6 months, 35% experienced some form of inflammatory disease upon discontinuation.³⁸ Sixteen patients relapsed and 19 developed gadolinium-enhancing MR lesions after DMT discontinuation. However, the age of the cohort was younger than the Minneapolis study (47.2 years vs 61 years), and reasons for discontinuation (eg, AEs or lack of disease activity) were not considered in the analysis.

Other studies examining the safety of DMT discontinuation have not considered MS subtype or excluded patients with progressive subtypes of MS. The largest studies to date on DMT discontinuation utilized the international MSBase global patient registry, which identified nearly 5,000 patients who discontinued interferons (73%), glatiramer acetate (18%), natalizumab (6%), or fingolimod (3%), without specifying the reasons for discontinuation.³⁹ Despite these shortcomings, data reveal trends that are helpful in predicting how MS tends to behave in patients who have discontinued therapy. Not surprisingly, disability progression was most likely among patients already characterized as having a progressive phenotype, while relapses were less likely to occur among older, progressive patients.

Although clinicians may be increasingly willing to discuss DMT discontinuation with their patients, at least 1 study exploring patient perspectives on stopping treatment suggests widespread reluctance to stop treatment. A survey conducted with participants in the North American Research Committee on Multiple Sclerosis patient-report registry found that among survey respondents, only 11.9% would discontinue their MS medication if deemed stable, while 66.3% stated they were unlikely to stop treatment.⁴⁰

These results suggest that before clinicians incorporate DMT discontinuation into the normal course of discussion with patients, they should be prepared to provide both education (on the wisdom of stopping under the right circumstances) and evidence to support when and how to make the recommendation. Based on existing evidence, criteria for recommending treatment discontinuation might include prolonged freedom from disease activity (≥ 5 years), age > 55 years or 60 years, and a progressive disease course. Thus far, no combination of factors has been shown to completely predict an event-free transition off of medicine. Since no fixed algorithm yet exists to guide DMT stoppage in MS, reasonable suggestions for monitoring patients might include surveillance MRIs, more frequent clinic visits, and possible transitional treatment for patients coming off of natalizumab or fingolimod, since these drugs have been associated with rebound disease activity when discontinued.^41,42

Clinicians wishing to maximize function and quality of life for their patients at any age or stage of disease should look to nonpharmacologic interventions to lessen disability and maximize quality of life. While beyond the scope of this discussion, preliminary evidence suggests multimodal (aerobic, resistance, balance) exercise may enhance endurance and cognitive processing speed, and that treatment of comorbid diseases affecting vascular health benefits MS. ⁴³

Conclusions

The development of numerous treatments for RRMS has established an entirely new landscape and disease course for those with MS. While this benefit has not entirely extended to those with progressive MS, those with active disease with superimposed relapses may receive limited benefit from these medications. New insights into the pathophysiology of progressive MS may lead us to new treatments through multiple alternative pathophysiologic pathways. Some early studies using this strategy show promise in slowing the progressive phase. Medication development for progressive MS faces multiple challenges due to lack of a single animal model demonstrating both pathology and clinical effects, absence of phase 1 surrogate biomarkers, and later phase trial endpoints that require large sample sizes and extended study durations. Nevertheless, the increase in number of trials and diversity of therapeutic approaches for progressive MS provides hope for effective therapy. Currently, the heterogeneity of the population with progressive MS requires an individualized treatment approach, and in some of these patients, stopping therapy may be a reasonable consideration. Symptomatic management remains critical for all patients with progressive MS as well as non-pharmacologic approaches that maximize quality of life.

Prior to the first approved disease modifying therapy (DMT) in the 1990s, treatment approaches for multiple sclerosis (MS) were not well understood. The discovery that MS was an immune mediated inflammatory disease paved the way for the treatments we know today. In 1993, interferon β‐1b became the first DMT for MS approved by the US Food and Drug Administration (FDA). Approvals for interferon β‐1a as well as glatiramer acetate (GA) soon followed. Today, we consider these the mildest immunosuppressant DMTs; however, their success verified that suppressing the immune system had a positive effect on the MS disease process.

Following these approvals, the disease process in MS is now better understood. Recently approved therapies include monoclonal antibodies, which affect other immune pathways. Today, there are 14 approved DMTs (Table 1). Although the advent of these newer DMTs has revolutionized care for patients with MS, it has been accompanied by increasing costs for the agents. Direct medical costs associated with MS management, coupled with indirect costs from lost productivity, have been estimated to be $24.2 billion annually in the US.¹ These increases have been seen across many levels of insurance coverage—private payer, Medicare, and the Veterans Health Administration (VHA).^2,3

The Figure demonstrates the cost increase that have been seen across VHA between 2004 and 2019 for the DMTs identified in Table 1. Indeed, this compound annual growth rate may be an underestimate because infusion therapies (eg, natalizumab, ocrelizumab, and alemtuzumab) are difficult to track as they may be dispensed directly via a Risk Evaluation Medication Strategy (REMS) program. According to the VHA Pharmacy Benefit Management Service (PBM), in September 2019, dimethyl fumarate (DMF) had the 13th highest total outpatient drug cost for the US Department of Veterans Affairs (VA), interferon β‐1a ranked 62nd and 83rd (prefilled pen and syringe, respectively), and GA 40 mg ranked 89th.

Factors Impacting DMT Use

Recent changes to MS typing have impacted utilization of DMTs. Traditionally, there were 4 subtypes of MS: relapsing remitting (RRMS), secondary progressive (SPMS), progressive relapsing (PRMS), and primary progressive (PPMS). These subtypes are now viewed more broadly and grouped as either relapsing or progressive. The traditional subtypes fall under these broader definitions. Additionally, SPMS has been broken into active SPMS, characterized by continued worsening of disability unrelated to acute relapses, superimposed with activity that can be seen on magnetic resonance images (MRIs), and nonactive SPMS, which has the same disability progression as active SPMS but without MRI-visible activity.^4-6 In 2019, these supplementary designations to SPMS made their first appearance in FDA-approved indications. All existing DMTs now include this terminology in their labelling and are indicated in active SPMS. There remain no DMTs that treat nonactive SPMS.

The current landscape of DMTs is highly varied in method of administration, risks, and benefits. As efficacy of these medications often is marked by how well they can prevent the immune system from attacking myelin, an inverse relationship between safety and efficacy results. The standard treatment outcomes in MS have evolved over time. The following are the commonly used primary outcomes in clinical trials: relapse reduction; increased time between relapses; decreased severity of relapses; prevention or extend time to disability milestones as measured by the Expanded Disability Status Scale (EDSS) and other disability measures; prevention or extension of time to onset of secondary progressive disease; prevention or reduction of the number and size of new and enhancing lesions on MRI; and limitation of overall MRI lesion burden in the central nervous system (CNS).

Newer treatment outcomes employed in more recent trials include: measures of axonal damage, CNS atrophy, evidence of microscopic disease via conventional MRI and advanced imaging modalities, biomarkers associated with inflammatory disease activity and neurodegeneration in MS, and the use of no evidence of disease activity (NEDA). These outcomes also must be evaluated by the safety concerns of each agent. Short- and long-term safety are critical factors in the selection of DMTs for MS. The injectable therapies for MS (interferon β‐1a, interferon β‐1b, and GA) have established long-term safety profiles from > 20 years of continuous use. The long-term safety profiles of oral immunomodulatory agents and monoclonal antibodies for these drugs in MS have yet to be determined. Safety concerns associated with some therapies and added requirements for safety monitoring may increase the complexity of a therapeutic selection.

Current cost minimization strategies for DMT include limiting DMT agents on formularies, tier systems that incentivize patients/prescribers to select the lowest priced agents on the formulary, negotiating arrangements with manufacturers to freeze prices or provide discounts in exchange for a priority position in the formulary, and requiring prior authorization to initiate or switch therapy. The use of generic medications and interchange to these agents from a brand name formulation can help reduce expense. Several of these strategies have been implemented in VHA.

Disease-Modifying Therapies

In 2019, 18,645 veterans with MS had either a MS-specific DMT or ≥ 1 annual encounters with a primary diagnosis of MS. Of this population, 4,720 were female and 13,357 were service connected according to VA data. About 50% of veterans with MS take a DMT. This percentage has remained stable over the past decade (Table 2). Although it appears the number of unique veterans prescribed an outpatient DMT is decreasing, this does not include the growing use of infused DMTs or DMTs obtained through the Veterans Choice Program (VCP)/Community Care (CC).

The overall outpatient pharmacy costs for veterans have remained constant despite the reduction in outpatient pharmacy prescription numbers. This may be due to increases in DMT cost to the VHA and the use of more expensive oral agents over the previously used platform injection DMTs.

Generic Conversion

GA is available in 20 mg daily and 40 mg3 times weekly subcutaneous injection dosing. The first evidence of clinical efficacy for a generic formulation for GA was evaluated by the GATE trial.⁷ This trial was a multicenter, randomized, double-blind, active- and placebo-controlled phase 3 trial. Eligible participants were randomized to receive daily SC injection for 9 months of 20 mg generic GA (n = 5,353), 20 mg brand GA (n = 5,357), or placebo (n = 584). The primary endpoint was the mean number of gadolinium (Gd1) lesions visible on MRIs during months 7, 8, and 9, which were significantly reduced in the combined GA-treated group and in each GA group individually when compared with the placebo group, confirming the study sensitivity (ie, GA was effective under the conditions of the study). Tolerability (including injection site reactions) and safety (incidence, spectrum, and severity of adverse events [AEs]) were similar in the generic and brand GA groups. These results demonstrated that generic and brand GA had equivalent efficacy, tolerability, and safety over a 9-month period.⁷

Results of a 15-month extension of the study were presented in 2015 and showed similar efficacy, safety, and tolerability in participants treated with generic GA for 2 years and patients switched from brand to generic GA.⁸ Multiple shifts for GA occurred, most notably the conversion from branded Copaxone (Teva Pharmaceutical Industries) to generic Glatopa (Sandoz). Subsequently, Sandoz released a generic 40 mg 3 times weekly formulation. Additionally, Mylan entered the generic GA market. With 3 competing manufacturers, internal data from the VHA indicated that it was able to negotiate a single source contract for this medication that provided a savings of $32,088,904.69 between September 2016 and May 2019.

The impact of generic conversions is just being realized. Soon, patents will begin to expire for oral DMTs, leading to an expected growth of generic alternatives. Already the FDA has approved 4 generic alternatives for teriflunomide, 3 for fingolimod (with 13 tentative approvals), and 15 generic alternatives for dimethyl fumarate (DMF). Implementation of therapeutic interchanges will be pursued by VHA as clinically supported by evidence.

Criteria for Use

PBM supports utilizing criteria to help guide providers on DMT options and promote safe, effective, and value-based selection of a DMT. The PBM creates monographs and criteria for use (CFU) for new medications. The monograph contains a literature evaluation of all studies available to date that concern both safety and efficacy of the new medication. Therapeutic alternatives also are presented and assessed for key elements that may determine the most safe and effective use. Additional safety areas for the new medications such as look-alike, sound-alike potential, special populations use (ie, those who are pregnant, the elderly, and those with liver or renal dysfunction), and drug-drug interactions are presented. Lastly, and possibly most importantly in an ever-growing growing world of DMTs, the monograph describes a reasonable place in therapy for the new DMT.

CFU are additional guidance for some DMTs. The development of CFU are based on several questions that arise during the monograph development for a DMT. These include, but are not limited to:

• Are there safety concerns that require the drug to receive a review to ensure safe prescribing (eg, agents with REMS programs, or safety concerns in specific populations)?
• Does the drug require a specialty provider type with knowledge and experience in those disease states to ensure appropriate and safe prescribing (eg restricted to infectious diseases)?
• Do VHA or non-VHA guidelines suggest alternative therapy be used prior to the agent?
• Is a review deemed necessary to ensure the preferred agent is used first (eg, second-line therapy)?

The CFU defines parameters of drug use consistent with high quality and evidence-based patient care. CFUs also serve as a basis for monitoring local, regional, and national patterns of pharmacologic care and help guide health care providers (HCPs) on appropriate use of medication.

CFUs are designed to ensure the HCP is safely starting a medication that has evidence for efficacy for their patient. For example, alemtuzumab is a high-risk, high-efficacy DMT. The alemtuzumab CFU acknowledges this by having exclusion criteria that prevent a veteran at high risk (ie, on another immunosuppressant) from being exposed to severe AEs (ie, severe leukopenia) that are associated with the medication. On the other hand, the inclusion criteria recognize the benefits of alemtuzumab and allows those with highly active MS who have failed other DMTs to receive the medication.

The drug monograph and CFU process is an important part of VHA efforts to optimize patient care. After a draft version is developed, HCPs can provide feedback on the exclusion/inclusion criteria and describe how they anticipate using the medication in their practice. This insight can be beneficial for MS treatment as diverse HCPs may have distinct viewpoints on how DMTs should be started. Pharmacists and physicians on a national level then discuss and decide together what to include in the final drafts of the drug monograph and CFU. Final documents are disseminated to all sites, which encourages consistent practices across the VHA.⁹ These documents are reviewed on a regular basis and updated as needed based on available literature evidence.

It is well accepted that early use of DMT correlates with lower accumulated long-term disability.¹⁰ However, discontinuation of DMT should be treated with equal importance. This benefits the patient by reducing their risk of AEs from DMTs and provides cost savings. Age and disease stability are factors to consider for DMT discontinuation. In a study with patients aged > 45 years and another with patients aged > 60 years, discontinuing DMT rarely had a negative impact and improved quality of life.^11,12 A retrospective meta-analysis of age-dependent efficacy of current DMTs predicted that DMT loses efficacy at age 53 years. In addition, higher efficacy DMT only outperforms lower efficacy DMT in patients aged < 40.5 years.¹³ Stability of disease and lack of relapses for ≥ 2 years also may be a positive predictor to safely discontinue DMT.^14,15 The growing literature to support safe discontinuation of DMT makes this a more convincing strategy to avoid unnecessary costs associated with current DMTs. With an average age of 59 years for veterans with MS, this may be one of the largest areas of cost avoidance to consider.

Off-Label Use

Other potential ways to reduce DMT costs is to consider off-label treatments. The OLYMPUS trial studied off-label use of rituximab, an anti-CD20 antibody like ocrelizumab. It did not meet statistical significance for its primary endpoint; however, in a subgroup analysis, off-label use was found to be more effective in a population aged < 51 years.¹⁶ Other case reports and smaller scale studies also describe rituximab’s efficacy in MS.^17,18 In 2018, the FDA approved the first rituximab biosimilar.¹⁹ Further competition from biosimilars likely will make rituximab an even more cost-effective choice when compared with ocrelizumab.

Alternate Dosing Regimens

Extended interval dosing of natalizumab has been studied, extending the standard infusion interval from every 4 weeks to 5- to 8-week intervals. One recent article compared these interval extensions and found that all extended intervals of up to 56 days did not increase new or enhancing lesions on MRI when compared with standard interval dosing.²⁰ Another larger randomized trial is underway to evaluate efficacy and safety of extended interval dosing of natalizumab (NCT03689972). Utilization of this dosing may reduce natalizumab annual costs by up to 50%.

Safety Monitoring

DMF is an oral DMT on the VHA formulary with CFU. Since leukopenia is a known AE, baseline and quarterly monitoring of the complete blood count (CBC) is recommended for patients taking DMF. Additionally, DMF should be held if white blood cell count (WBC) falls below 2,000/mm³.²¹ There have been recent reports of death secondary to progressive multifocal leukoencephalopathy (PML) among European patients taking DMF.^22-24 This has raised concerns about adherence to recommended CBC monitoring in veterans taking DMF. The association of DMF and leukopenia has been evident since early clinical trials.²⁵ Leukopenia in immunocompromised patients increases the risk of PML.

In the long-term extension study ENDORSE, 6% to 7% of patients continuing DMF had WBC counts of 3.0×10⁹/L compared with 7% to 10% in the new to DMF group.²⁶ In addition 6% to 8% of patients continuing DMF had lymphocyte counts of 0.5×10⁹/L, compared with 5% to 9% in the new to DMF group. The cases of PML occurred in patients who had low lymphocyte counts over an extended period with no adjustment to DMF therapy, such as holding the drug until WBC counts returned to normal levels or stopping the drug. Discussion and review within VHA resulted in the recommendation for quarterly WBC monitoring criteria.

PBM and VA Center for Medication Safety (MedSafe) conducted a medication usage evaluation (MUE) on adherence to the WBC monitoring set forth in the CFU. Data collection began in fourth quarter of fiscal year (FY) 2015 with the most recent reporting period of fourth quarter of FY 2017. The Medication Utilization Evaluation Tool tracks patients with no reported WBC in 90 days and WBC < 2,000/mm³. Over the reporting period, 20% to 23% of patients have not received appropriate quarterly monitoring. Additionally, there have been 4 cases where the WBC decreased below the threshold limit. To ensure safe and effective use of DMF, it is important to adhere to the monitoring requirements set forth in the CFU.

Impact of REMS and Special Distribution

As DMTs increase in efficacy, there are often more risks associated with them. Some of these high-risk medications, including natalizumab and alemtuzumab, have REMS programs and/or have special distribution procedures. Although REMS are imperative for patient safety, the complexity of these programs can be difficult to navigate, which can create a barrier to access. The PBM helps to assist all sites with navigating and adhering to required actions to dispense and administer these medications through a national Special Handling Drugs Microsoft SharePoint site, which provides access to REMS forms and procurement information when drugs are dispensed from specialty pharmacies. Easing this process nationwide empowers more sites to be confident they can dispense specialty medications appropriately.

Clinical Pharmacists

The VHA is unique in its utilization of pharmacists in outpatient clinic settings. Utilization of an interdisciplinary team for medication management has been highly used in VHA for areas like primary care; however, pharmacist involvement in specialty areas is on the rise and MS is no exception. Pharmacists stationed in clinics, such as neurology or spinal cord injury, can impact care for veterans with MS. Interdisciplinary teams that include a pharmacist have been shown to increase patient adherence to DMTs.²⁷ However, pharmacists often assist with medication education and monitoring, which adds an additional layer of safety to DMT treatment. At the VHA, pharmacists also can obtain a scope of practice that allows them to prescribe medications and increase access to care for veterans with MS.

Education

The VHA demonstrates how education on a disease state like MS can be distributed on a large, national scale through drug monographs, CFU, and Microsoft SharePoint sites. In addition, VHA has created the MS Centers of Excellence (MSCoE) that serve as a hub of specialized health care providers in all aspects of MS care.

A core function of the MSCoE is to provide education to both HCPs and patients. The MSCoE and its regional hubs support sites that may not have an HCP who specializes in MS by providing advice on DMT selection, how to obtain specialty medications, and monitoring that needs to be completed to ensure veterans’ safety. The MSCoE also has partnered with the National MS Society to hold a lecture series on topics in MS. This free series is available online to all HCPs who interact with patients who have MS and is a way that VA is extending its best practices and expertise beyond its own health care system. There also is a quarterly newsletter for veterans with MS that highlights new information on DMTs that can affect their care.

Conclusion

It is an exciting and challenging period in MS treatment. New DMTs are being approved and entering clinical trials at a rapid pace. These new DMT agents may offer increased efficacy, improvements in AE profiles, and the possibility of increased medication adherence—but often at a higher cost. The utilization of CFU and formulary management provides the ability to ensure the safe and appropriate use of medications by veterans, with a secondary outcome of controlling pharmacy expenditures.

The VHA had expenditures of $142,135,938 for DMT use in FY 2018. As the VHA sees the new contract prices for DMT in January 2020, we are reminded that costs will continue to rise with some pharmaceutical manufacturers implementing prices 8% to 11% higher than 2019 prices, when the consumer price index defines an increase of 1.0% for 2020 and 1.4% in 2021.²⁸ It is imperative that the VHA formulary be managed judiciously and the necessary measures be in place for VHA practitioners to enable effective, safe and value-based care to the veteran population.

Prior to the first approved disease modifying therapy (DMT) in the 1990s, treatment approaches for multiple sclerosis (MS) were not well understood. The discovery that MS was an immune mediated inflammatory disease paved the way for the treatments we know today. In 1993, interferon β‐1b became the first DMT for MS approved by the US Food and Drug Administration (FDA). Approvals for interferon β‐1a as well as glatiramer acetate (GA) soon followed. Today, we consider these the mildest immunosuppressant DMTs; however, their success verified that suppressing the immune system had a positive effect on the MS disease process.

Following these approvals, the disease process in MS is now better understood. Recently approved therapies include monoclonal antibodies, which affect other immune pathways. Today, there are 14 approved DMTs (Table 1). Although the advent of these newer DMTs has revolutionized care for patients with MS, it has been accompanied by increasing costs for the agents. Direct medical costs associated with MS management, coupled with indirect costs from lost productivity, have been estimated to be $24.2 billion annually in the US.¹ These increases have been seen across many levels of insurance coverage—private payer, Medicare, and the Veterans Health Administration (VHA).^2,3

The Figure demonstrates the cost increase that have been seen across VHA between 2004 and 2019 for the DMTs identified in Table 1. Indeed, this compound annual growth rate may be an underestimate because infusion therapies (eg, natalizumab, ocrelizumab, and alemtuzumab) are difficult to track as they may be dispensed directly via a Risk Evaluation Medication Strategy (REMS) program. According to the VHA Pharmacy Benefit Management Service (PBM), in September 2019, dimethyl fumarate (DMF) had the 13th highest total outpatient drug cost for the US Department of Veterans Affairs (VA), interferon β‐1a ranked 62nd and 83rd (prefilled pen and syringe, respectively), and GA 40 mg ranked 89th.

Factors Impacting DMT Use

Recent changes to MS typing have impacted utilization of DMTs. Traditionally, there were 4 subtypes of MS: relapsing remitting (RRMS), secondary progressive (SPMS), progressive relapsing (PRMS), and primary progressive (PPMS). These subtypes are now viewed more broadly and grouped as either relapsing or progressive. The traditional subtypes fall under these broader definitions. Additionally, SPMS has been broken into active SPMS, characterized by continued worsening of disability unrelated to acute relapses, superimposed with activity that can be seen on magnetic resonance images (MRIs), and nonactive SPMS, which has the same disability progression as active SPMS but without MRI-visible activity.^4-6 In 2019, these supplementary designations to SPMS made their first appearance in FDA-approved indications. All existing DMTs now include this terminology in their labelling and are indicated in active SPMS. There remain no DMTs that treat nonactive SPMS.

The current landscape of DMTs is highly varied in method of administration, risks, and benefits. As efficacy of these medications often is marked by how well they can prevent the immune system from attacking myelin, an inverse relationship between safety and efficacy results. The standard treatment outcomes in MS have evolved over time. The following are the commonly used primary outcomes in clinical trials: relapse reduction; increased time between relapses; decreased severity of relapses; prevention or extend time to disability milestones as measured by the Expanded Disability Status Scale (EDSS) and other disability measures; prevention or extension of time to onset of secondary progressive disease; prevention or reduction of the number and size of new and enhancing lesions on MRI; and limitation of overall MRI lesion burden in the central nervous system (CNS).

Newer treatment outcomes employed in more recent trials include: measures of axonal damage, CNS atrophy, evidence of microscopic disease via conventional MRI and advanced imaging modalities, biomarkers associated with inflammatory disease activity and neurodegeneration in MS, and the use of no evidence of disease activity (NEDA). These outcomes also must be evaluated by the safety concerns of each agent. Short- and long-term safety are critical factors in the selection of DMTs for MS. The injectable therapies for MS (interferon β‐1a, interferon β‐1b, and GA) have established long-term safety profiles from > 20 years of continuous use. The long-term safety profiles of oral immunomodulatory agents and monoclonal antibodies for these drugs in MS have yet to be determined. Safety concerns associated with some therapies and added requirements for safety monitoring may increase the complexity of a therapeutic selection.

Current cost minimization strategies for DMT include limiting DMT agents on formularies, tier systems that incentivize patients/prescribers to select the lowest priced agents on the formulary, negotiating arrangements with manufacturers to freeze prices or provide discounts in exchange for a priority position in the formulary, and requiring prior authorization to initiate or switch therapy. The use of generic medications and interchange to these agents from a brand name formulation can help reduce expense. Several of these strategies have been implemented in VHA.

Disease-Modifying Therapies

In 2019, 18,645 veterans with MS had either a MS-specific DMT or ≥ 1 annual encounters with a primary diagnosis of MS. Of this population, 4,720 were female and 13,357 were service connected according to VA data. About 50% of veterans with MS take a DMT. This percentage has remained stable over the past decade (Table 2). Although it appears the number of unique veterans prescribed an outpatient DMT is decreasing, this does not include the growing use of infused DMTs or DMTs obtained through the Veterans Choice Program (VCP)/Community Care (CC).

The overall outpatient pharmacy costs for veterans have remained constant despite the reduction in outpatient pharmacy prescription numbers. This may be due to increases in DMT cost to the VHA and the use of more expensive oral agents over the previously used platform injection DMTs.

Generic Conversion

GA is available in 20 mg daily and 40 mg3 times weekly subcutaneous injection dosing. The first evidence of clinical efficacy for a generic formulation for GA was evaluated by the GATE trial.⁷ This trial was a multicenter, randomized, double-blind, active- and placebo-controlled phase 3 trial. Eligible participants were randomized to receive daily SC injection for 9 months of 20 mg generic GA (n = 5,353), 20 mg brand GA (n = 5,357), or placebo (n = 584). The primary endpoint was the mean number of gadolinium (Gd1) lesions visible on MRIs during months 7, 8, and 9, which were significantly reduced in the combined GA-treated group and in each GA group individually when compared with the placebo group, confirming the study sensitivity (ie, GA was effective under the conditions of the study). Tolerability (including injection site reactions) and safety (incidence, spectrum, and severity of adverse events [AEs]) were similar in the generic and brand GA groups. These results demonstrated that generic and brand GA had equivalent efficacy, tolerability, and safety over a 9-month period.⁷

Results of a 15-month extension of the study were presented in 2015 and showed similar efficacy, safety, and tolerability in participants treated with generic GA for 2 years and patients switched from brand to generic GA.⁸ Multiple shifts for GA occurred, most notably the conversion from branded Copaxone (Teva Pharmaceutical Industries) to generic Glatopa (Sandoz). Subsequently, Sandoz released a generic 40 mg 3 times weekly formulation. Additionally, Mylan entered the generic GA market. With 3 competing manufacturers, internal data from the VHA indicated that it was able to negotiate a single source contract for this medication that provided a savings of $32,088,904.69 between September 2016 and May 2019.

The impact of generic conversions is just being realized. Soon, patents will begin to expire for oral DMTs, leading to an expected growth of generic alternatives. Already the FDA has approved 4 generic alternatives for teriflunomide, 3 for fingolimod (with 13 tentative approvals), and 15 generic alternatives for dimethyl fumarate (DMF). Implementation of therapeutic interchanges will be pursued by VHA as clinically supported by evidence.

Criteria for Use

PBM supports utilizing criteria to help guide providers on DMT options and promote safe, effective, and value-based selection of a DMT. The PBM creates monographs and criteria for use (CFU) for new medications. The monograph contains a literature evaluation of all studies available to date that concern both safety and efficacy of the new medication. Therapeutic alternatives also are presented and assessed for key elements that may determine the most safe and effective use. Additional safety areas for the new medications such as look-alike, sound-alike potential, special populations use (ie, those who are pregnant, the elderly, and those with liver or renal dysfunction), and drug-drug interactions are presented. Lastly, and possibly most importantly in an ever-growing growing world of DMTs, the monograph describes a reasonable place in therapy for the new DMT.

CFU are additional guidance for some DMTs. The development of CFU are based on several questions that arise during the monograph development for a DMT. These include, but are not limited to:

• Are there safety concerns that require the drug to receive a review to ensure safe prescribing (eg, agents with REMS programs, or safety concerns in specific populations)?
• Does the drug require a specialty provider type with knowledge and experience in those disease states to ensure appropriate and safe prescribing (eg restricted to infectious diseases)?
• Do VHA or non-VHA guidelines suggest alternative therapy be used prior to the agent?
• Is a review deemed necessary to ensure the preferred agent is used first (eg, second-line therapy)?

The CFU defines parameters of drug use consistent with high quality and evidence-based patient care. CFUs also serve as a basis for monitoring local, regional, and national patterns of pharmacologic care and help guide health care providers (HCPs) on appropriate use of medication.

CFUs are designed to ensure the HCP is safely starting a medication that has evidence for efficacy for their patient. For example, alemtuzumab is a high-risk, high-efficacy DMT. The alemtuzumab CFU acknowledges this by having exclusion criteria that prevent a veteran at high risk (ie, on another immunosuppressant) from being exposed to severe AEs (ie, severe leukopenia) that are associated with the medication. On the other hand, the inclusion criteria recognize the benefits of alemtuzumab and allows those with highly active MS who have failed other DMTs to receive the medication.

The drug monograph and CFU process is an important part of VHA efforts to optimize patient care. After a draft version is developed, HCPs can provide feedback on the exclusion/inclusion criteria and describe how they anticipate using the medication in their practice. This insight can be beneficial for MS treatment as diverse HCPs may have distinct viewpoints on how DMTs should be started. Pharmacists and physicians on a national level then discuss and decide together what to include in the final drafts of the drug monograph and CFU. Final documents are disseminated to all sites, which encourages consistent practices across the VHA.⁹ These documents are reviewed on a regular basis and updated as needed based on available literature evidence.

It is well accepted that early use of DMT correlates with lower accumulated long-term disability.¹⁰ However, discontinuation of DMT should be treated with equal importance. This benefits the patient by reducing their risk of AEs from DMTs and provides cost savings. Age and disease stability are factors to consider for DMT discontinuation. In a study with patients aged > 45 years and another with patients aged > 60 years, discontinuing DMT rarely had a negative impact and improved quality of life.^11,12 A retrospective meta-analysis of age-dependent efficacy of current DMTs predicted that DMT loses efficacy at age 53 years. In addition, higher efficacy DMT only outperforms lower efficacy DMT in patients aged < 40.5 years.¹³ Stability of disease and lack of relapses for ≥ 2 years also may be a positive predictor to safely discontinue DMT.^14,15 The growing literature to support safe discontinuation of DMT makes this a more convincing strategy to avoid unnecessary costs associated with current DMTs. With an average age of 59 years for veterans with MS, this may be one of the largest areas of cost avoidance to consider.

Off-Label Use

Other potential ways to reduce DMT costs is to consider off-label treatments. The OLYMPUS trial studied off-label use of rituximab, an anti-CD20 antibody like ocrelizumab. It did not meet statistical significance for its primary endpoint; however, in a subgroup analysis, off-label use was found to be more effective in a population aged < 51 years.¹⁶ Other case reports and smaller scale studies also describe rituximab’s efficacy in MS.^17,18 In 2018, the FDA approved the first rituximab biosimilar.¹⁹ Further competition from biosimilars likely will make rituximab an even more cost-effective choice when compared with ocrelizumab.

Alternate Dosing Regimens

Extended interval dosing of natalizumab has been studied, extending the standard infusion interval from every 4 weeks to 5- to 8-week intervals. One recent article compared these interval extensions and found that all extended intervals of up to 56 days did not increase new or enhancing lesions on MRI when compared with standard interval dosing.²⁰ Another larger randomized trial is underway to evaluate efficacy and safety of extended interval dosing of natalizumab (NCT03689972). Utilization of this dosing may reduce natalizumab annual costs by up to 50%.

Safety Monitoring

DMF is an oral DMT on the VHA formulary with CFU. Since leukopenia is a known AE, baseline and quarterly monitoring of the complete blood count (CBC) is recommended for patients taking DMF. Additionally, DMF should be held if white blood cell count (WBC) falls below 2,000/mm³.²¹ There have been recent reports of death secondary to progressive multifocal leukoencephalopathy (PML) among European patients taking DMF.^22-24 This has raised concerns about adherence to recommended CBC monitoring in veterans taking DMF. The association of DMF and leukopenia has been evident since early clinical trials.²⁵ Leukopenia in immunocompromised patients increases the risk of PML.

In the long-term extension study ENDORSE, 6% to 7% of patients continuing DMF had WBC counts of 3.0×10⁹/L compared with 7% to 10% in the new to DMF group.²⁶ In addition 6% to 8% of patients continuing DMF had lymphocyte counts of 0.5×10⁹/L, compared with 5% to 9% in the new to DMF group. The cases of PML occurred in patients who had low lymphocyte counts over an extended period with no adjustment to DMF therapy, such as holding the drug until WBC counts returned to normal levels or stopping the drug. Discussion and review within VHA resulted in the recommendation for quarterly WBC monitoring criteria.

PBM and VA Center for Medication Safety (MedSafe) conducted a medication usage evaluation (MUE) on adherence to the WBC monitoring set forth in the CFU. Data collection began in fourth quarter of fiscal year (FY) 2015 with the most recent reporting period of fourth quarter of FY 2017. The Medication Utilization Evaluation Tool tracks patients with no reported WBC in 90 days and WBC < 2,000/mm³. Over the reporting period, 20% to 23% of patients have not received appropriate quarterly monitoring. Additionally, there have been 4 cases where the WBC decreased below the threshold limit. To ensure safe and effective use of DMF, it is important to adhere to the monitoring requirements set forth in the CFU.

Impact of REMS and Special Distribution

As DMTs increase in efficacy, there are often more risks associated with them. Some of these high-risk medications, including natalizumab and alemtuzumab, have REMS programs and/or have special distribution procedures. Although REMS are imperative for patient safety, the complexity of these programs can be difficult to navigate, which can create a barrier to access. The PBM helps to assist all sites with navigating and adhering to required actions to dispense and administer these medications through a national Special Handling Drugs Microsoft SharePoint site, which provides access to REMS forms and procurement information when drugs are dispensed from specialty pharmacies. Easing this process nationwide empowers more sites to be confident they can dispense specialty medications appropriately.

Clinical Pharmacists

The VHA is unique in its utilization of pharmacists in outpatient clinic settings. Utilization of an interdisciplinary team for medication management has been highly used in VHA for areas like primary care; however, pharmacist involvement in specialty areas is on the rise and MS is no exception. Pharmacists stationed in clinics, such as neurology or spinal cord injury, can impact care for veterans with MS. Interdisciplinary teams that include a pharmacist have been shown to increase patient adherence to DMTs.²⁷ However, pharmacists often assist with medication education and monitoring, which adds an additional layer of safety to DMT treatment. At the VHA, pharmacists also can obtain a scope of practice that allows them to prescribe medications and increase access to care for veterans with MS.

Education

The VHA demonstrates how education on a disease state like MS can be distributed on a large, national scale through drug monographs, CFU, and Microsoft SharePoint sites. In addition, VHA has created the MS Centers of Excellence (MSCoE) that serve as a hub of specialized health care providers in all aspects of MS care.

A core function of the MSCoE is to provide education to both HCPs and patients. The MSCoE and its regional hubs support sites that may not have an HCP who specializes in MS by providing advice on DMT selection, how to obtain specialty medications, and monitoring that needs to be completed to ensure veterans’ safety. The MSCoE also has partnered with the National MS Society to hold a lecture series on topics in MS. This free series is available online to all HCPs who interact with patients who have MS and is a way that VA is extending its best practices and expertise beyond its own health care system. There also is a quarterly newsletter for veterans with MS that highlights new information on DMTs that can affect their care.

Conclusion

It is an exciting and challenging period in MS treatment. New DMTs are being approved and entering clinical trials at a rapid pace. These new DMT agents may offer increased efficacy, improvements in AE profiles, and the possibility of increased medication adherence—but often at a higher cost. The utilization of CFU and formulary management provides the ability to ensure the safe and appropriate use of medications by veterans, with a secondary outcome of controlling pharmacy expenditures.

The VHA had expenditures of $142,135,938 for DMT use in FY 2018. As the VHA sees the new contract prices for DMT in January 2020, we are reminded that costs will continue to rise with some pharmaceutical manufacturers implementing prices 8% to 11% higher than 2019 prices, when the consumer price index defines an increase of 1.0% for 2020 and 1.4% in 2021.²⁸ It is imperative that the VHA formulary be managed judiciously and the necessary measures be in place for VHA practitioners to enable effective, safe and value-based care to the veteran population.

Prior to the first approved disease modifying therapy (DMT) in the 1990s, treatment approaches for multiple sclerosis (MS) were not well understood. The discovery that MS was an immune mediated inflammatory disease paved the way for the treatments we know today. In 1993, interferon β‐1b became the first DMT for MS approved by the US Food and Drug Administration (FDA). Approvals for interferon β‐1a as well as glatiramer acetate (GA) soon followed. Today, we consider these the mildest immunosuppressant DMTs; however, their success verified that suppressing the immune system had a positive effect on the MS disease process.

Following these approvals, the disease process in MS is now better understood. Recently approved therapies include monoclonal antibodies, which affect other immune pathways. Today, there are 14 approved DMTs (Table 1). Although the advent of these newer DMTs has revolutionized care for patients with MS, it has been accompanied by increasing costs for the agents. Direct medical costs associated with MS management, coupled with indirect costs from lost productivity, have been estimated to be $24.2 billion annually in the US.¹ These increases have been seen across many levels of insurance coverage—private payer, Medicare, and the Veterans Health Administration (VHA).^2,3

The Figure demonstrates the cost increase that have been seen across VHA between 2004 and 2019 for the DMTs identified in Table 1. Indeed, this compound annual growth rate may be an underestimate because infusion therapies (eg, natalizumab, ocrelizumab, and alemtuzumab) are difficult to track as they may be dispensed directly via a Risk Evaluation Medication Strategy (REMS) program. According to the VHA Pharmacy Benefit Management Service (PBM), in September 2019, dimethyl fumarate (DMF) had the 13th highest total outpatient drug cost for the US Department of Veterans Affairs (VA), interferon β‐1a ranked 62nd and 83rd (prefilled pen and syringe, respectively), and GA 40 mg ranked 89th.

Factors Impacting DMT Use

Recent changes to MS typing have impacted utilization of DMTs. Traditionally, there were 4 subtypes of MS: relapsing remitting (RRMS), secondary progressive (SPMS), progressive relapsing (PRMS), and primary progressive (PPMS). These subtypes are now viewed more broadly and grouped as either relapsing or progressive. The traditional subtypes fall under these broader definitions. Additionally, SPMS has been broken into active SPMS, characterized by continued worsening of disability unrelated to acute relapses, superimposed with activity that can be seen on magnetic resonance images (MRIs), and nonactive SPMS, which has the same disability progression as active SPMS but without MRI-visible activity.^4-6 In 2019, these supplementary designations to SPMS made their first appearance in FDA-approved indications. All existing DMTs now include this terminology in their labelling and are indicated in active SPMS. There remain no DMTs that treat nonactive SPMS.

The current landscape of DMTs is highly varied in method of administration, risks, and benefits. As efficacy of these medications often is marked by how well they can prevent the immune system from attacking myelin, an inverse relationship between safety and efficacy results. The standard treatment outcomes in MS have evolved over time. The following are the commonly used primary outcomes in clinical trials: relapse reduction; increased time between relapses; decreased severity of relapses; prevention or extend time to disability milestones as measured by the Expanded Disability Status Scale (EDSS) and other disability measures; prevention or extension of time to onset of secondary progressive disease; prevention or reduction of the number and size of new and enhancing lesions on MRI; and limitation of overall MRI lesion burden in the central nervous system (CNS).

Newer treatment outcomes employed in more recent trials include: measures of axonal damage, CNS atrophy, evidence of microscopic disease via conventional MRI and advanced imaging modalities, biomarkers associated with inflammatory disease activity and neurodegeneration in MS, and the use of no evidence of disease activity (NEDA). These outcomes also must be evaluated by the safety concerns of each agent. Short- and long-term safety are critical factors in the selection of DMTs for MS. The injectable therapies for MS (interferon β‐1a, interferon β‐1b, and GA) have established long-term safety profiles from > 20 years of continuous use. The long-term safety profiles of oral immunomodulatory agents and monoclonal antibodies for these drugs in MS have yet to be determined. Safety concerns associated with some therapies and added requirements for safety monitoring may increase the complexity of a therapeutic selection.

Current cost minimization strategies for DMT include limiting DMT agents on formularies, tier systems that incentivize patients/prescribers to select the lowest priced agents on the formulary, negotiating arrangements with manufacturers to freeze prices or provide discounts in exchange for a priority position in the formulary, and requiring prior authorization to initiate or switch therapy. The use of generic medications and interchange to these agents from a brand name formulation can help reduce expense. Several of these strategies have been implemented in VHA.

Disease-Modifying Therapies

In 2019, 18,645 veterans with MS had either a MS-specific DMT or ≥ 1 annual encounters with a primary diagnosis of MS. Of this population, 4,720 were female and 13,357 were service connected according to VA data. About 50% of veterans with MS take a DMT. This percentage has remained stable over the past decade (Table 2). Although it appears the number of unique veterans prescribed an outpatient DMT is decreasing, this does not include the growing use of infused DMTs or DMTs obtained through the Veterans Choice Program (VCP)/Community Care (CC).

The overall outpatient pharmacy costs for veterans have remained constant despite the reduction in outpatient pharmacy prescription numbers. This may be due to increases in DMT cost to the VHA and the use of more expensive oral agents over the previously used platform injection DMTs.

Generic Conversion

GA is available in 20 mg daily and 40 mg3 times weekly subcutaneous injection dosing. The first evidence of clinical efficacy for a generic formulation for GA was evaluated by the GATE trial.⁷ This trial was a multicenter, randomized, double-blind, active- and placebo-controlled phase 3 trial. Eligible participants were randomized to receive daily SC injection for 9 months of 20 mg generic GA (n = 5,353), 20 mg brand GA (n = 5,357), or placebo (n = 584). The primary endpoint was the mean number of gadolinium (Gd1) lesions visible on MRIs during months 7, 8, and 9, which were significantly reduced in the combined GA-treated group and in each GA group individually when compared with the placebo group, confirming the study sensitivity (ie, GA was effective under the conditions of the study). Tolerability (including injection site reactions) and safety (incidence, spectrum, and severity of adverse events [AEs]) were similar in the generic and brand GA groups. These results demonstrated that generic and brand GA had equivalent efficacy, tolerability, and safety over a 9-month period.⁷

Results of a 15-month extension of the study were presented in 2015 and showed similar efficacy, safety, and tolerability in participants treated with generic GA for 2 years and patients switched from brand to generic GA.⁸ Multiple shifts for GA occurred, most notably the conversion from branded Copaxone (Teva Pharmaceutical Industries) to generic Glatopa (Sandoz). Subsequently, Sandoz released a generic 40 mg 3 times weekly formulation. Additionally, Mylan entered the generic GA market. With 3 competing manufacturers, internal data from the VHA indicated that it was able to negotiate a single source contract for this medication that provided a savings of $32,088,904.69 between September 2016 and May 2019.

The impact of generic conversions is just being realized. Soon, patents will begin to expire for oral DMTs, leading to an expected growth of generic alternatives. Already the FDA has approved 4 generic alternatives for teriflunomide, 3 for fingolimod (with 13 tentative approvals), and 15 generic alternatives for dimethyl fumarate (DMF). Implementation of therapeutic interchanges will be pursued by VHA as clinically supported by evidence.

Criteria for Use

PBM supports utilizing criteria to help guide providers on DMT options and promote safe, effective, and value-based selection of a DMT. The PBM creates monographs and criteria for use (CFU) for new medications. The monograph contains a literature evaluation of all studies available to date that concern both safety and efficacy of the new medication. Therapeutic alternatives also are presented and assessed for key elements that may determine the most safe and effective use. Additional safety areas for the new medications such as look-alike, sound-alike potential, special populations use (ie, those who are pregnant, the elderly, and those with liver or renal dysfunction), and drug-drug interactions are presented. Lastly, and possibly most importantly in an ever-growing growing world of DMTs, the monograph describes a reasonable place in therapy for the new DMT.

CFU are additional guidance for some DMTs. The development of CFU are based on several questions that arise during the monograph development for a DMT. These include, but are not limited to:

• Are there safety concerns that require the drug to receive a review to ensure safe prescribing (eg, agents with REMS programs, or safety concerns in specific populations)?
• Does the drug require a specialty provider type with knowledge and experience in those disease states to ensure appropriate and safe prescribing (eg restricted to infectious diseases)?
• Do VHA or non-VHA guidelines suggest alternative therapy be used prior to the agent?
• Is a review deemed necessary to ensure the preferred agent is used first (eg, second-line therapy)?

The CFU defines parameters of drug use consistent with high quality and evidence-based patient care. CFUs also serve as a basis for monitoring local, regional, and national patterns of pharmacologic care and help guide health care providers (HCPs) on appropriate use of medication.

CFUs are designed to ensure the HCP is safely starting a medication that has evidence for efficacy for their patient. For example, alemtuzumab is a high-risk, high-efficacy DMT. The alemtuzumab CFU acknowledges this by having exclusion criteria that prevent a veteran at high risk (ie, on another immunosuppressant) from being exposed to severe AEs (ie, severe leukopenia) that are associated with the medication. On the other hand, the inclusion criteria recognize the benefits of alemtuzumab and allows those with highly active MS who have failed other DMTs to receive the medication.

The drug monograph and CFU process is an important part of VHA efforts to optimize patient care. After a draft version is developed, HCPs can provide feedback on the exclusion/inclusion criteria and describe how they anticipate using the medication in their practice. This insight can be beneficial for MS treatment as diverse HCPs may have distinct viewpoints on how DMTs should be started. Pharmacists and physicians on a national level then discuss and decide together what to include in the final drafts of the drug monograph and CFU. Final documents are disseminated to all sites, which encourages consistent practices across the VHA.⁹ These documents are reviewed on a regular basis and updated as needed based on available literature evidence.

It is well accepted that early use of DMT correlates with lower accumulated long-term disability.¹⁰ However, discontinuation of DMT should be treated with equal importance. This benefits the patient by reducing their risk of AEs from DMTs and provides cost savings. Age and disease stability are factors to consider for DMT discontinuation. In a study with patients aged > 45 years and another with patients aged > 60 years, discontinuing DMT rarely had a negative impact and improved quality of life.^11,12 A retrospective meta-analysis of age-dependent efficacy of current DMTs predicted that DMT loses efficacy at age 53 years. In addition, higher efficacy DMT only outperforms lower efficacy DMT in patients aged < 40.5 years.¹³ Stability of disease and lack of relapses for ≥ 2 years also may be a positive predictor to safely discontinue DMT.^14,15 The growing literature to support safe discontinuation of DMT makes this a more convincing strategy to avoid unnecessary costs associated with current DMTs. With an average age of 59 years for veterans with MS, this may be one of the largest areas of cost avoidance to consider.

Off-Label Use

Other potential ways to reduce DMT costs is to consider off-label treatments. The OLYMPUS trial studied off-label use of rituximab, an anti-CD20 antibody like ocrelizumab. It did not meet statistical significance for its primary endpoint; however, in a subgroup analysis, off-label use was found to be more effective in a population aged < 51 years.¹⁶ Other case reports and smaller scale studies also describe rituximab’s efficacy in MS.^17,18 In 2018, the FDA approved the first rituximab biosimilar.¹⁹ Further competition from biosimilars likely will make rituximab an even more cost-effective choice when compared with ocrelizumab.

Alternate Dosing Regimens

Extended interval dosing of natalizumab has been studied, extending the standard infusion interval from every 4 weeks to 5- to 8-week intervals. One recent article compared these interval extensions and found that all extended intervals of up to 56 days did not increase new or enhancing lesions on MRI when compared with standard interval dosing.²⁰ Another larger randomized trial is underway to evaluate efficacy and safety of extended interval dosing of natalizumab (NCT03689972). Utilization of this dosing may reduce natalizumab annual costs by up to 50%.

Safety Monitoring

DMF is an oral DMT on the VHA formulary with CFU. Since leukopenia is a known AE, baseline and quarterly monitoring of the complete blood count (CBC) is recommended for patients taking DMF. Additionally, DMF should be held if white blood cell count (WBC) falls below 2,000/mm³.²¹ There have been recent reports of death secondary to progressive multifocal leukoencephalopathy (PML) among European patients taking DMF.^22-24 This has raised concerns about adherence to recommended CBC monitoring in veterans taking DMF. The association of DMF and leukopenia has been evident since early clinical trials.²⁵ Leukopenia in immunocompromised patients increases the risk of PML.

In the long-term extension study ENDORSE, 6% to 7% of patients continuing DMF had WBC counts of 3.0×10⁹/L compared with 7% to 10% in the new to DMF group.²⁶ In addition 6% to 8% of patients continuing DMF had lymphocyte counts of 0.5×10⁹/L, compared with 5% to 9% in the new to DMF group. The cases of PML occurred in patients who had low lymphocyte counts over an extended period with no adjustment to DMF therapy, such as holding the drug until WBC counts returned to normal levels or stopping the drug. Discussion and review within VHA resulted in the recommendation for quarterly WBC monitoring criteria.

PBM and VA Center for Medication Safety (MedSafe) conducted a medication usage evaluation (MUE) on adherence to the WBC monitoring set forth in the CFU. Data collection began in fourth quarter of fiscal year (FY) 2015 with the most recent reporting period of fourth quarter of FY 2017. The Medication Utilization Evaluation Tool tracks patients with no reported WBC in 90 days and WBC < 2,000/mm³. Over the reporting period, 20% to 23% of patients have not received appropriate quarterly monitoring. Additionally, there have been 4 cases where the WBC decreased below the threshold limit. To ensure safe and effective use of DMF, it is important to adhere to the monitoring requirements set forth in the CFU.

Impact of REMS and Special Distribution

As DMTs increase in efficacy, there are often more risks associated with them. Some of these high-risk medications, including natalizumab and alemtuzumab, have REMS programs and/or have special distribution procedures. Although REMS are imperative for patient safety, the complexity of these programs can be difficult to navigate, which can create a barrier to access. The PBM helps to assist all sites with navigating and adhering to required actions to dispense and administer these medications through a national Special Handling Drugs Microsoft SharePoint site, which provides access to REMS forms and procurement information when drugs are dispensed from specialty pharmacies. Easing this process nationwide empowers more sites to be confident they can dispense specialty medications appropriately.

Clinical Pharmacists

The VHA is unique in its utilization of pharmacists in outpatient clinic settings. Utilization of an interdisciplinary team for medication management has been highly used in VHA for areas like primary care; however, pharmacist involvement in specialty areas is on the rise and MS is no exception. Pharmacists stationed in clinics, such as neurology or spinal cord injury, can impact care for veterans with MS. Interdisciplinary teams that include a pharmacist have been shown to increase patient adherence to DMTs.²⁷ However, pharmacists often assist with medication education and monitoring, which adds an additional layer of safety to DMT treatment. At the VHA, pharmacists also can obtain a scope of practice that allows them to prescribe medications and increase access to care for veterans with MS.

Education

The VHA demonstrates how education on a disease state like MS can be distributed on a large, national scale through drug monographs, CFU, and Microsoft SharePoint sites. In addition, VHA has created the MS Centers of Excellence (MSCoE) that serve as a hub of specialized health care providers in all aspects of MS care.

A core function of the MSCoE is to provide education to both HCPs and patients. The MSCoE and its regional hubs support sites that may not have an HCP who specializes in MS by providing advice on DMT selection, how to obtain specialty medications, and monitoring that needs to be completed to ensure veterans’ safety. The MSCoE also has partnered with the National MS Society to hold a lecture series on topics in MS. This free series is available online to all HCPs who interact with patients who have MS and is a way that VA is extending its best practices and expertise beyond its own health care system. There also is a quarterly newsletter for veterans with MS that highlights new information on DMTs that can affect their care.

Conclusion

It is an exciting and challenging period in MS treatment. New DMTs are being approved and entering clinical trials at a rapid pace. These new DMT agents may offer increased efficacy, improvements in AE profiles, and the possibility of increased medication adherence—but often at a higher cost. The utilization of CFU and formulary management provides the ability to ensure the safe and appropriate use of medications by veterans, with a secondary outcome of controlling pharmacy expenditures.

The VHA had expenditures of $142,135,938 for DMT use in FY 2018. As the VHA sees the new contract prices for DMT in January 2020, we are reminded that costs will continue to rise with some pharmaceutical manufacturers implementing prices 8% to 11% higher than 2019 prices, when the consumer price index defines an increase of 1.0% for 2020 and 1.4% in 2021.²⁸ It is imperative that the VHA formulary be managed judiciously and the necessary measures be in place for VHA practitioners to enable effective, safe and value-based care to the veteran population.

Multiple Sclerosis (MS) is a chronic demyelinating disease of the central nervous system that affects nearly 1 million people in the US.¹ In addition to the accumulation of functional limitations, patients with MS commonly experience mental health and physical symptoms such as depression, anxiety, stress, fatigue, and pain. Day-to-day life with MS requires adaptation to challenges and active maintenance of health and well-being over time. Behavioral intervention and treatment, whether in the form of psychotherapy, health behavior coaching, or the promotion of active self-management, is an integral component of interprofessional care and key aspect of living well with MS.

Behavioral Comorbidities

Depression

Depression is a common concern among individuals with MS. Population-based studies suggest that individuals with MS have a roughly 1 in 4 chance of developing major depressive disorder over their lifetime.² However, at any given time, between 40% and 60% of individuals with MS report clinically meaningful levels of depressive symptoms.³ Although the relationship between MS disease characteristics and depression is unclear, some evidence suggests that depressive symptoms are more common at certain points in illness, such as early in the disease process as individuals grapple with the onset of new symptoms, late in the disease process as they accumulate greater disability, and during active clinical relapses.^3-5

Depression often is comorbid with, and adds to the symptom burden of, other common conditions in MS such as fatigue and cognitive dysfunction.^6-8 Thus, it is not surprising that it associated with poorer overall quality of life (QOL).⁹ Depression also is a risk factor for suicidal ideation and suicide for patients with MS.^10,11

Fortunately, several behavioral interventions show promise in treating depression in patients with MS. Both individual and group formats of cognitive behavioral therapy (CBT), a treatment focused on challenging maladaptive patterns of thought and behavior, have been shown to improve depressive symptoms for people with MS.^12,13 Several brief and efficient group-based programs grounded in CBT and focused on the development of specific skills, including problem solving, goal setting, relationship management, and managing emotions, have been shown to reduce depressive symptoms.^13,14 CBT for depression in MS has been shown to be effective when delivered via telephone.^15,16

Anxiety

Anxiety is common among individuals with MS. Existing data suggest more than one-third of individuals with MS will qualify for a diagnosis of anxiety disorder during their lifetime.¹⁷ The characteristics of anxiety disorders are broad and heterogenous, including generalized anxiety disorder, panic disorder, obsessive compulsive disorders, and health-specific phobias such as needle/injection anxiety. Some estimates suggest a point prevalence of 34% for the presence of clinically meaningful symptoms.¹⁸ Similar to depression, anxiety symptoms can be more common during periods of stress, threat, and transition including early in the disease course while adapting to new diagnosis, late in the disease course with increasing disability, and during clinical relapses.^19-21

The efficacy of behavioral interventions for anxiety in MS is less well established than it is for depression, but some preliminary evidence suggests that individual CBT may be effective for reducing general symptoms of anxiety as well as health-related anxiety.^22,23 Brief, targeted CBT also has been shown to improve injection anxiety, removing a barrier to self-care including the administration of MS disease modifying therapies (DMTs).²⁴

Stress

Stress is commonly conceptualized as a person’s perception that efforts to manage internal and external demands exceed available coping resources.²⁵ Such demands involve both psychological and physiological processes and come in many forms for people with MS and can include daily hassles, major life events, traumatic stress, and perceptions of global nonspecific stress. The relationship between stress and MS remains complex and poorly understood. Nonetheless, individuals with MS frequently report that stress exacerbates their symptoms.²⁶

Some evidence also suggests stress may exacerbate the MS disease process, resulting in more frequent relapses and increased lesion activity visible on MRI.^27,28 In addition to mindfulness (described below), stress inoculation training (CBT and relaxation training), and stress-focused group-based self-management have been shown to be beneficial.^29,30 In an intriguing and rigorous trial, a 24-week stress management therapy based on CBT was associated with the development of fewer new MS lesions visible on MRI.³¹

Adaptation to Illness

MS presents challenges that vary between patients and over time. Individuals may confront new physical and cognitive limitations that inhibit the completion of daily tasks, reduce independence, and limit participation in valued and meaningful activities. In addition, the unpredictability of the disease contributes to perceptions of uncertainty and uncontrollability, which in turn result in higher illness impact and poorer psychological outcomes.³² Building cognitive and behavioral skills to address these challenges can promote adaptation to illness and reduce overall distress associated with chronic illness.³³ Psychosocial intervention also can address the uncertainty commonly experienced by individuals with MS.³⁴

Self-Management

As with any chronic illness, living well with MS requires ongoing commitment and active engagement with health and personal care over time. The process of building knowledge and skills to manage the day-to-day physical, emotional, and social aspects of living with illness often is referred to as self-management.³⁵ For individuals with MS, this may take the form of participation in programs that address adaptation and psychological distress like those described above, but it also may include improving health behavior (eg, physical activity, DMT adherence, modification of maladaptive habits like smoking or hazardous alcohol use) and symptom management (eg, fatigue, pain). Self-management programs typically include education, the practice of identifying, problem solving, and following through with specific and realistic health and wellness goals, as well as the bolstering of self-efficacy.

Physical Activity

Once discouraged for patients with MS, physical activity is now considered a cornerstone of health and wellness. Physical activity and interventions that target various forms of exercise have been shown to improve strength and endurance, reduce functional decline, enhance QOL, and likely reduce mortality.^35-39 A variety of brief behavioral interventions have been shown to improve physical activity in MS. Structured group-based exercise classes focusing on various activities such as aerobic training (eg, cycling) or resistance training (eg, lower extremity strengthening) have demonstrated improvements in various measures of fitness and mood states such as depression and QOL. Brief home-based telephone counseling interventions based in social cognitive theory (eg, goal setting, navigating obstacles) and motivational interviewing strategies (eg, open-ended questions, affirmation, reflective listening, summarizing) also have been shown to be effective not only at increasing physical activity and improving depression and fatigue.^40,41

Adherence to Treatment

One primary focus of adherence to treatment is medication management. For individuals with MS, DMTs represent a primary means of reducing disease burden and delaying functional decline. Many DMTs require consistent self-administration over time. Some evidence suggests that poorer adherence is associated with a greater risk of relapse and more rapid disease progression.^42,43 Brief telephone counseling, again based on social cognitive theory, and principles of motivational interviewing combined with home telehealth monitoring by a care coordinator has been shown to improve adherence to DMTs.⁴⁴

Mindfulness

In recent years, mindfulness training has emerged as a popular and common behavioral intervention among individuals with MS. Programs like Mindfulness-Based Stress Reduction (MBSR) provide training in meditation techniques designed to promote mindfulness, which is defined as paying attention to present moment experience, including sensations, thoughts, and emotions, without judgment or attachment.⁴⁵ Cultivating mindfulness helps people with MS cope with and adapt to symptoms and stressors.⁴⁶ Mindfulness interventions typically are delivered in a group format. For example, MBSR consists of 8 in-person group sessions with daily meditation practice homework. Mindfulness interventions also have been delivered effectively with smartphone apps.⁴⁷ Mindfulness programs have been shown to improve depression, anxiety, fatigue, stress, and QOL for patients with MS.^48-50

Fatigue

More than 90% of individuals with MS report fatigue, and many identify it as their most disabling symptom.⁵¹ Often defined as “a subjective lack of physical and/or mental energy that is perceived by the individual or caregiver to interfere with usual and desired activities,” fatigue has been shown to be associated with longer disease duration, greater physical disability, progressive subtype, and depressive symptoms, although the relative and possibly overlapping impact of these issues is only partially understood.^52,53 Fatigue is associated with poorer overall mental health and negatively impacts work and social roles.⁵⁴

Several behavioral interventions have been developed to address fatigue in MS. Using both individual and group based formats and across several modalities (eg, in-person, telephone, online modules, or a combination), behavioral fatigue interventions most commonly combine traditional general CBT skills (eg, addressing maladaptive thoughts and behaviors) with a variety of fatigue-specific skill building exercises that may include fatigue education, energy conservation strategies, improving sleep, enlisting social support, and self-management goal setting strategies.^35,55-57

Pain

Chronic pain is common and disabling in people with MS.^58,59 Nearly 50% report experiencing moderate to severe chronic pain.^59,60 Individuals with MS reporting pain often are older, more disabled (higher Expanded Disability Status Scale score), and have longer disease duration that those who are not experiencing chronic pain.⁶¹ Patients report various types of pain in the following order of frequency: dysesthetic pain (18.1%), back pain (16.4%), painful tonic spasms (11.0%), Lhermitte sign (9.0%), visceral pain (2.9%), and trigeminal neuralgia (2.0%).⁶¹ Chronic pain has a negative impact on QOL in the areas of sleep, work, maintaining relationships, recreational activities, and overall life enjoyment.⁵⁹ Additionally, research has shown that greater pain intensity and pain-related interference with activities of daily living are both associated with greater depression severity.^62,63

The literature supports the use of behavioral interventions for pain in people with MS.⁶¹ Behavioral interventions include in-person exercise interventions (eg, water aerobics, cycling, rowing ergometer, treadmill walking, and resistance training), self-hypnosis, and telephone-based self-management programs based on CBT.^35,64,65 As described above, CBT-based self-management programs combine learning CBT skills (eg, modifying maladaptive thoughts) with pain-specific skill building such as pain education, pacing activities, and improving sleep. Of note, MS education including, but not limited to, pain was as effective as a CBT-based self-management program in reducing pain intensity and interference.³⁵ In addition, there is evidence to support acceptance- and mindfulness-based interventions for chronic pain, and online mindfulness-based cognitive therapy for MS related pain is currently being tested in a randomized controlled trial.^35,66

Conclusion

People with MS face significant challenges in coping with and adapting to a chronic and unpredictable disease. However, there is considerable evidence that behavioral interventions can improve many of the most common and disabling symptoms in MS including depression, anxiety, stress, fatigue, and pain as well as health behavior and self-care. Research also suggests that improvements in one of these problems (eg, physical inactivity) can influence improvement in other symptoms (eg, depression and fatigue). Unlike other treatment options, behavioral interventions can be delivered in various formats (eg, in-person and electronic health), are time-limited, and cause few (if any) undesirable systemic adverse effects. Behavioral interventions are therefore, an essential part of interprofessional care and rehabilitation for patients with MS.

Multiple Sclerosis (MS) is a chronic demyelinating disease of the central nervous system that affects nearly 1 million people in the US.¹ In addition to the accumulation of functional limitations, patients with MS commonly experience mental health and physical symptoms such as depression, anxiety, stress, fatigue, and pain. Day-to-day life with MS requires adaptation to challenges and active maintenance of health and well-being over time. Behavioral intervention and treatment, whether in the form of psychotherapy, health behavior coaching, or the promotion of active self-management, is an integral component of interprofessional care and key aspect of living well with MS.

Behavioral Comorbidities

Depression

Depression is a common concern among individuals with MS. Population-based studies suggest that individuals with MS have a roughly 1 in 4 chance of developing major depressive disorder over their lifetime.² However, at any given time, between 40% and 60% of individuals with MS report clinically meaningful levels of depressive symptoms.³ Although the relationship between MS disease characteristics and depression is unclear, some evidence suggests that depressive symptoms are more common at certain points in illness, such as early in the disease process as individuals grapple with the onset of new symptoms, late in the disease process as they accumulate greater disability, and during active clinical relapses.^3-5

Depression often is comorbid with, and adds to the symptom burden of, other common conditions in MS such as fatigue and cognitive dysfunction.^6-8 Thus, it is not surprising that it associated with poorer overall quality of life (QOL).⁹ Depression also is a risk factor for suicidal ideation and suicide for patients with MS.^10,11

Fortunately, several behavioral interventions show promise in treating depression in patients with MS. Both individual and group formats of cognitive behavioral therapy (CBT), a treatment focused on challenging maladaptive patterns of thought and behavior, have been shown to improve depressive symptoms for people with MS.^12,13 Several brief and efficient group-based programs grounded in CBT and focused on the development of specific skills, including problem solving, goal setting, relationship management, and managing emotions, have been shown to reduce depressive symptoms.^13,14 CBT for depression in MS has been shown to be effective when delivered via telephone.^15,16

Anxiety

Anxiety is common among individuals with MS. Existing data suggest more than one-third of individuals with MS will qualify for a diagnosis of anxiety disorder during their lifetime.¹⁷ The characteristics of anxiety disorders are broad and heterogenous, including generalized anxiety disorder, panic disorder, obsessive compulsive disorders, and health-specific phobias such as needle/injection anxiety. Some estimates suggest a point prevalence of 34% for the presence of clinically meaningful symptoms.¹⁸ Similar to depression, anxiety symptoms can be more common during periods of stress, threat, and transition including early in the disease course while adapting to new diagnosis, late in the disease course with increasing disability, and during clinical relapses.^19-21

The efficacy of behavioral interventions for anxiety in MS is less well established than it is for depression, but some preliminary evidence suggests that individual CBT may be effective for reducing general symptoms of anxiety as well as health-related anxiety.^22,23 Brief, targeted CBT also has been shown to improve injection anxiety, removing a barrier to self-care including the administration of MS disease modifying therapies (DMTs).²⁴

Stress

Stress is commonly conceptualized as a person’s perception that efforts to manage internal and external demands exceed available coping resources.²⁵ Such demands involve both psychological and physiological processes and come in many forms for people with MS and can include daily hassles, major life events, traumatic stress, and perceptions of global nonspecific stress. The relationship between stress and MS remains complex and poorly understood. Nonetheless, individuals with MS frequently report that stress exacerbates their symptoms.²⁶

Some evidence also suggests stress may exacerbate the MS disease process, resulting in more frequent relapses and increased lesion activity visible on MRI.^27,28 In addition to mindfulness (described below), stress inoculation training (CBT and relaxation training), and stress-focused group-based self-management have been shown to be beneficial.^29,30 In an intriguing and rigorous trial, a 24-week stress management therapy based on CBT was associated with the development of fewer new MS lesions visible on MRI.³¹

Adaptation to Illness

MS presents challenges that vary between patients and over time. Individuals may confront new physical and cognitive limitations that inhibit the completion of daily tasks, reduce independence, and limit participation in valued and meaningful activities. In addition, the unpredictability of the disease contributes to perceptions of uncertainty and uncontrollability, which in turn result in higher illness impact and poorer psychological outcomes.³² Building cognitive and behavioral skills to address these challenges can promote adaptation to illness and reduce overall distress associated with chronic illness.³³ Psychosocial intervention also can address the uncertainty commonly experienced by individuals with MS.³⁴

Self-Management

As with any chronic illness, living well with MS requires ongoing commitment and active engagement with health and personal care over time. The process of building knowledge and skills to manage the day-to-day physical, emotional, and social aspects of living with illness often is referred to as self-management.³⁵ For individuals with MS, this may take the form of participation in programs that address adaptation and psychological distress like those described above, but it also may include improving health behavior (eg, physical activity, DMT adherence, modification of maladaptive habits like smoking or hazardous alcohol use) and symptom management (eg, fatigue, pain). Self-management programs typically include education, the practice of identifying, problem solving, and following through with specific and realistic health and wellness goals, as well as the bolstering of self-efficacy.

Physical Activity

Once discouraged for patients with MS, physical activity is now considered a cornerstone of health and wellness. Physical activity and interventions that target various forms of exercise have been shown to improve strength and endurance, reduce functional decline, enhance QOL, and likely reduce mortality.^35-39 A variety of brief behavioral interventions have been shown to improve physical activity in MS. Structured group-based exercise classes focusing on various activities such as aerobic training (eg, cycling) or resistance training (eg, lower extremity strengthening) have demonstrated improvements in various measures of fitness and mood states such as depression and QOL. Brief home-based telephone counseling interventions based in social cognitive theory (eg, goal setting, navigating obstacles) and motivational interviewing strategies (eg, open-ended questions, affirmation, reflective listening, summarizing) also have been shown to be effective not only at increasing physical activity and improving depression and fatigue.^40,41

Adherence to Treatment

One primary focus of adherence to treatment is medication management. For individuals with MS, DMTs represent a primary means of reducing disease burden and delaying functional decline. Many DMTs require consistent self-administration over time. Some evidence suggests that poorer adherence is associated with a greater risk of relapse and more rapid disease progression.^42,43 Brief telephone counseling, again based on social cognitive theory, and principles of motivational interviewing combined with home telehealth monitoring by a care coordinator has been shown to improve adherence to DMTs.⁴⁴

Mindfulness

In recent years, mindfulness training has emerged as a popular and common behavioral intervention among individuals with MS. Programs like Mindfulness-Based Stress Reduction (MBSR) provide training in meditation techniques designed to promote mindfulness, which is defined as paying attention to present moment experience, including sensations, thoughts, and emotions, without judgment or attachment.⁴⁵ Cultivating mindfulness helps people with MS cope with and adapt to symptoms and stressors.⁴⁶ Mindfulness interventions typically are delivered in a group format. For example, MBSR consists of 8 in-person group sessions with daily meditation practice homework. Mindfulness interventions also have been delivered effectively with smartphone apps.⁴⁷ Mindfulness programs have been shown to improve depression, anxiety, fatigue, stress, and QOL for patients with MS.^48-50

Fatigue

More than 90% of individuals with MS report fatigue, and many identify it as their most disabling symptom.⁵¹ Often defined as “a subjective lack of physical and/or mental energy that is perceived by the individual or caregiver to interfere with usual and desired activities,” fatigue has been shown to be associated with longer disease duration, greater physical disability, progressive subtype, and depressive symptoms, although the relative and possibly overlapping impact of these issues is only partially understood.^52,53 Fatigue is associated with poorer overall mental health and negatively impacts work and social roles.⁵⁴

Several behavioral interventions have been developed to address fatigue in MS. Using both individual and group based formats and across several modalities (eg, in-person, telephone, online modules, or a combination), behavioral fatigue interventions most commonly combine traditional general CBT skills (eg, addressing maladaptive thoughts and behaviors) with a variety of fatigue-specific skill building exercises that may include fatigue education, energy conservation strategies, improving sleep, enlisting social support, and self-management goal setting strategies.^35,55-57

Pain

Chronic pain is common and disabling in people with MS.^58,59 Nearly 50% report experiencing moderate to severe chronic pain.^59,60 Individuals with MS reporting pain often are older, more disabled (higher Expanded Disability Status Scale score), and have longer disease duration that those who are not experiencing chronic pain.⁶¹ Patients report various types of pain in the following order of frequency: dysesthetic pain (18.1%), back pain (16.4%), painful tonic spasms (11.0%), Lhermitte sign (9.0%), visceral pain (2.9%), and trigeminal neuralgia (2.0%).⁶¹ Chronic pain has a negative impact on QOL in the areas of sleep, work, maintaining relationships, recreational activities, and overall life enjoyment.⁵⁹ Additionally, research has shown that greater pain intensity and pain-related interference with activities of daily living are both associated with greater depression severity.^62,63

The literature supports the use of behavioral interventions for pain in people with MS.⁶¹ Behavioral interventions include in-person exercise interventions (eg, water aerobics, cycling, rowing ergometer, treadmill walking, and resistance training), self-hypnosis, and telephone-based self-management programs based on CBT.^35,64,65 As described above, CBT-based self-management programs combine learning CBT skills (eg, modifying maladaptive thoughts) with pain-specific skill building such as pain education, pacing activities, and improving sleep. Of note, MS education including, but not limited to, pain was as effective as a CBT-based self-management program in reducing pain intensity and interference.³⁵ In addition, there is evidence to support acceptance- and mindfulness-based interventions for chronic pain, and online mindfulness-based cognitive therapy for MS related pain is currently being tested in a randomized controlled trial.^35,66

Conclusion

People with MS face significant challenges in coping with and adapting to a chronic and unpredictable disease. However, there is considerable evidence that behavioral interventions can improve many of the most common and disabling symptoms in MS including depression, anxiety, stress, fatigue, and pain as well as health behavior and self-care. Research also suggests that improvements in one of these problems (eg, physical inactivity) can influence improvement in other symptoms (eg, depression and fatigue). Unlike other treatment options, behavioral interventions can be delivered in various formats (eg, in-person and electronic health), are time-limited, and cause few (if any) undesirable systemic adverse effects. Behavioral interventions are therefore, an essential part of interprofessional care and rehabilitation for patients with MS.

Multiple Sclerosis (MS) is a chronic demyelinating disease of the central nervous system that affects nearly 1 million people in the US.¹ In addition to the accumulation of functional limitations, patients with MS commonly experience mental health and physical symptoms such as depression, anxiety, stress, fatigue, and pain. Day-to-day life with MS requires adaptation to challenges and active maintenance of health and well-being over time. Behavioral intervention and treatment, whether in the form of psychotherapy, health behavior coaching, or the promotion of active self-management, is an integral component of interprofessional care and key aspect of living well with MS.

Behavioral Comorbidities

Depression

Depression is a common concern among individuals with MS. Population-based studies suggest that individuals with MS have a roughly 1 in 4 chance of developing major depressive disorder over their lifetime.² However, at any given time, between 40% and 60% of individuals with MS report clinically meaningful levels of depressive symptoms.³ Although the relationship between MS disease characteristics and depression is unclear, some evidence suggests that depressive symptoms are more common at certain points in illness, such as early in the disease process as individuals grapple with the onset of new symptoms, late in the disease process as they accumulate greater disability, and during active clinical relapses.^3-5

Depression often is comorbid with, and adds to the symptom burden of, other common conditions in MS such as fatigue and cognitive dysfunction.^6-8 Thus, it is not surprising that it associated with poorer overall quality of life (QOL).⁹ Depression also is a risk factor for suicidal ideation and suicide for patients with MS.^10,11

Fortunately, several behavioral interventions show promise in treating depression in patients with MS. Both individual and group formats of cognitive behavioral therapy (CBT), a treatment focused on challenging maladaptive patterns of thought and behavior, have been shown to improve depressive symptoms for people with MS.^12,13 Several brief and efficient group-based programs grounded in CBT and focused on the development of specific skills, including problem solving, goal setting, relationship management, and managing emotions, have been shown to reduce depressive symptoms.^13,14 CBT for depression in MS has been shown to be effective when delivered via telephone.^15,16

Anxiety

Anxiety is common among individuals with MS. Existing data suggest more than one-third of individuals with MS will qualify for a diagnosis of anxiety disorder during their lifetime.¹⁷ The characteristics of anxiety disorders are broad and heterogenous, including generalized anxiety disorder, panic disorder, obsessive compulsive disorders, and health-specific phobias such as needle/injection anxiety. Some estimates suggest a point prevalence of 34% for the presence of clinically meaningful symptoms.¹⁸ Similar to depression, anxiety symptoms can be more common during periods of stress, threat, and transition including early in the disease course while adapting to new diagnosis, late in the disease course with increasing disability, and during clinical relapses.^19-21

The efficacy of behavioral interventions for anxiety in MS is less well established than it is for depression, but some preliminary evidence suggests that individual CBT may be effective for reducing general symptoms of anxiety as well as health-related anxiety.^22,23 Brief, targeted CBT also has been shown to improve injection anxiety, removing a barrier to self-care including the administration of MS disease modifying therapies (DMTs).²⁴

Stress

Stress is commonly conceptualized as a person’s perception that efforts to manage internal and external demands exceed available coping resources.²⁵ Such demands involve both psychological and physiological processes and come in many forms for people with MS and can include daily hassles, major life events, traumatic stress, and perceptions of global nonspecific stress. The relationship between stress and MS remains complex and poorly understood. Nonetheless, individuals with MS frequently report that stress exacerbates their symptoms.²⁶

Some evidence also suggests stress may exacerbate the MS disease process, resulting in more frequent relapses and increased lesion activity visible on MRI.^27,28 In addition to mindfulness (described below), stress inoculation training (CBT and relaxation training), and stress-focused group-based self-management have been shown to be beneficial.^29,30 In an intriguing and rigorous trial, a 24-week stress management therapy based on CBT was associated with the development of fewer new MS lesions visible on MRI.³¹

Adaptation to Illness

MS presents challenges that vary between patients and over time. Individuals may confront new physical and cognitive limitations that inhibit the completion of daily tasks, reduce independence, and limit participation in valued and meaningful activities. In addition, the unpredictability of the disease contributes to perceptions of uncertainty and uncontrollability, which in turn result in higher illness impact and poorer psychological outcomes.³² Building cognitive and behavioral skills to address these challenges can promote adaptation to illness and reduce overall distress associated with chronic illness.³³ Psychosocial intervention also can address the uncertainty commonly experienced by individuals with MS.³⁴

Self-Management

As with any chronic illness, living well with MS requires ongoing commitment and active engagement with health and personal care over time. The process of building knowledge and skills to manage the day-to-day physical, emotional, and social aspects of living with illness often is referred to as self-management.³⁵ For individuals with MS, this may take the form of participation in programs that address adaptation and psychological distress like those described above, but it also may include improving health behavior (eg, physical activity, DMT adherence, modification of maladaptive habits like smoking or hazardous alcohol use) and symptom management (eg, fatigue, pain). Self-management programs typically include education, the practice of identifying, problem solving, and following through with specific and realistic health and wellness goals, as well as the bolstering of self-efficacy.

Physical Activity

Once discouraged for patients with MS, physical activity is now considered a cornerstone of health and wellness. Physical activity and interventions that target various forms of exercise have been shown to improve strength and endurance, reduce functional decline, enhance QOL, and likely reduce mortality.^35-39 A variety of brief behavioral interventions have been shown to improve physical activity in MS. Structured group-based exercise classes focusing on various activities such as aerobic training (eg, cycling) or resistance training (eg, lower extremity strengthening) have demonstrated improvements in various measures of fitness and mood states such as depression and QOL. Brief home-based telephone counseling interventions based in social cognitive theory (eg, goal setting, navigating obstacles) and motivational interviewing strategies (eg, open-ended questions, affirmation, reflective listening, summarizing) also have been shown to be effective not only at increasing physical activity and improving depression and fatigue.^40,41

Adherence to Treatment

One primary focus of adherence to treatment is medication management. For individuals with MS, DMTs represent a primary means of reducing disease burden and delaying functional decline. Many DMTs require consistent self-administration over time. Some evidence suggests that poorer adherence is associated with a greater risk of relapse and more rapid disease progression.^42,43 Brief telephone counseling, again based on social cognitive theory, and principles of motivational interviewing combined with home telehealth monitoring by a care coordinator has been shown to improve adherence to DMTs.⁴⁴

Mindfulness

In recent years, mindfulness training has emerged as a popular and common behavioral intervention among individuals with MS. Programs like Mindfulness-Based Stress Reduction (MBSR) provide training in meditation techniques designed to promote mindfulness, which is defined as paying attention to present moment experience, including sensations, thoughts, and emotions, without judgment or attachment.⁴⁵ Cultivating mindfulness helps people with MS cope with and adapt to symptoms and stressors.⁴⁶ Mindfulness interventions typically are delivered in a group format. For example, MBSR consists of 8 in-person group sessions with daily meditation practice homework. Mindfulness interventions also have been delivered effectively with smartphone apps.⁴⁷ Mindfulness programs have been shown to improve depression, anxiety, fatigue, stress, and QOL for patients with MS.^48-50

Fatigue

More than 90% of individuals with MS report fatigue, and many identify it as their most disabling symptom.⁵¹ Often defined as “a subjective lack of physical and/or mental energy that is perceived by the individual or caregiver to interfere with usual and desired activities,” fatigue has been shown to be associated with longer disease duration, greater physical disability, progressive subtype, and depressive symptoms, although the relative and possibly overlapping impact of these issues is only partially understood.^52,53 Fatigue is associated with poorer overall mental health and negatively impacts work and social roles.⁵⁴

Several behavioral interventions have been developed to address fatigue in MS. Using both individual and group based formats and across several modalities (eg, in-person, telephone, online modules, or a combination), behavioral fatigue interventions most commonly combine traditional general CBT skills (eg, addressing maladaptive thoughts and behaviors) with a variety of fatigue-specific skill building exercises that may include fatigue education, energy conservation strategies, improving sleep, enlisting social support, and self-management goal setting strategies.^35,55-57

Pain

Chronic pain is common and disabling in people with MS.^58,59 Nearly 50% report experiencing moderate to severe chronic pain.^59,60 Individuals with MS reporting pain often are older, more disabled (higher Expanded Disability Status Scale score), and have longer disease duration that those who are not experiencing chronic pain.⁶¹ Patients report various types of pain in the following order of frequency: dysesthetic pain (18.1%), back pain (16.4%), painful tonic spasms (11.0%), Lhermitte sign (9.0%), visceral pain (2.9%), and trigeminal neuralgia (2.0%).⁶¹ Chronic pain has a negative impact on QOL in the areas of sleep, work, maintaining relationships, recreational activities, and overall life enjoyment.⁵⁹ Additionally, research has shown that greater pain intensity and pain-related interference with activities of daily living are both associated with greater depression severity.^62,63

The literature supports the use of behavioral interventions for pain in people with MS.⁶¹ Behavioral interventions include in-person exercise interventions (eg, water aerobics, cycling, rowing ergometer, treadmill walking, and resistance training), self-hypnosis, and telephone-based self-management programs based on CBT.^35,64,65 As described above, CBT-based self-management programs combine learning CBT skills (eg, modifying maladaptive thoughts) with pain-specific skill building such as pain education, pacing activities, and improving sleep. Of note, MS education including, but not limited to, pain was as effective as a CBT-based self-management program in reducing pain intensity and interference.³⁵ In addition, there is evidence to support acceptance- and mindfulness-based interventions for chronic pain, and online mindfulness-based cognitive therapy for MS related pain is currently being tested in a randomized controlled trial.^35,66

Conclusion

People with MS face significant challenges in coping with and adapting to a chronic and unpredictable disease. However, there is considerable evidence that behavioral interventions can improve many of the most common and disabling symptoms in MS including depression, anxiety, stress, fatigue, and pain as well as health behavior and self-care. Research also suggests that improvements in one of these problems (eg, physical inactivity) can influence improvement in other symptoms (eg, depression and fatigue). Unlike other treatment options, behavioral interventions can be delivered in various formats (eg, in-person and electronic health), are time-limited, and cause few (if any) undesirable systemic adverse effects. Behavioral interventions are therefore, an essential part of interprofessional care and rehabilitation for patients with MS.

A number of large registries exist for multiple sclerosis (MS) in North America and Europe. The Scandinavian countries have some of the longest running and integrated MS registries to date. The Danish MS Registry was initiated in 1948 and has been consistently maintained to track MS epidemiologic trends.² Similar databases exist in Swedenand Norway that were created in the later 20th century.^3,4 The Rochester Epidemiology Project, launched by Len Kurland at the Mayo Clinic, has tracked the morbidity of MS and many other conditions in Olmsted county Minnesota for > 60 years.⁵

The Canadian provinces of British Columbia, Ontario, and Manitoba also have long standing MS registries.^6-8 Other North American MS registries have gathered state-wide cases, such as the New York State MS Consortium.⁹ Some registries have gathered a population-based sample throughout the US, such as the Sonya Slifka MS Study.¹⁰ The North American Research Consortium on MS (NARCOMS) registry is a patient-driven registry within the US that has enrolled > 30,000 cases.¹¹ The MSBase is the largest online registry to date utilizing data from several countries.¹² The MS Bioscreen, based at the University of California San Francisco, is a recent effort to create a longitudinal clinical dataset.¹³ This electronic registry integrates clinical disease morbidity scales, neuroimaging, genetics and laboratory data for individual patients with the goal of providing predictive tools.

The US military provides a unique population to study MS and has the oldest and largest nation-wide MS cohort in existence starting with World War I service members and continuing through the recent Gulf War Era.¹⁴ With the advent of EHRs in the US Department of Veterans Affairs (VA) Veterans Health Administration (VHA) in the mid-1990s and large clinical databases, the possibility of an integrated registry for chronic conditions was created. In this report, we describe the creation of the VA MS Surveillance Registry (MSSR) and the initial roll out to several VA medical centers within the MS Center of Excellence (MSCoE). The MSSR is a unique platform with potential for improving MS patient care and clinical research.

Methods

The MSSR was designed by MSCoE health care providers in conjunction with IT specialists from the VA Northwest Innovation Center. Between 2012 and 2013, the team developed and tested a core template for data entry and refined an efficient data dashboard display to optimize clinical decisions. IT programmers created data entry templates that were tested by 4 to 5 clinicians who provided feedback in biweekly meetings. Technical problems were addressed and enhancements added and the trial process was repeated.

After creation of the prototype MS Assessment Tool (MSAT) data entry template that fed into the prototype MSSR, our team received a grant in 2013 for national development and sustainment. The MSSR was established on the VA Converged Registries Solution (CRS) platform, which is a hardware and software architecture designed to host individual clinical registries and eliminate duplicative development effort while maximizing the ability to create new patient registries. The common platform includes a relational database, Health Level 7 messaging, software classes, security modules, extraction services, and other components. The CR obtains data from the VA Corporate Data Warehouse (CDW), directly from the Veterans Health Information Systems and Technology Architecture (VISTA) and via direct user input using MSAT.

From 2016 to 2019, data from patients with MS followed in several VA MS regional programs were inputted into MSSR. A roll-out process to start patient data entry at VA medical centers began in 2017 that included an orientation, technical support, and quality assurance review. Twelve sites from Veteran Integrated Service Network (VISN) 5 (mid-Atlantic) and VISN 20 (Pacific Northwest) were included in the initial roll-out.

Results

After a live or remote telehealth or telephone visit, a clinician can access MSAT from the Computerized Patient Record System (CPRS) or directly from the MSSR online portal (Figure 1). The tool uses radio buttons and pull-down menus and takes about 5 to 15 minutes to complete with a list of required variables. Data is auto-saved for efficiency, and the key variables that are collected in MSAT are noted in Table 1. The MSAT subsequently creates a text integration utility progress note with health factors that is processed through an integration engine and eventually transmitted to VISTA and becomes part of the EHR and available to all health care providers involved in that patient’s care. Additionally, data from VA outpatient and inpatient utilization files, pharmacy, prosthetics, laboratory, and radiology databases are included in the CDW and are included in MSSR. With data from 1998 to the present, the MSAT and CDW databases can provide longitudinal data analysis.

Between 18,000 and 20,000 patients with MS are evaluated in the VHA annually, and 56,000 unique patients have been assessed since 1998. From 2016 to 2019, 1,743 patients with MS or related disorders were enrolled in MSSR (Table 2 and Figure 2). The mean (SD) age of patients was 56.0 (12.9) years and the male:female ratio was 2.7. Racial minorities make up 40% of the cohort. Among those with definite and possible MS, the mean disease duration was 22.7 years and the mean (SD) European Database for MS disability score was 4.7 (2.4) (Table 3). Three-quarters of the MSSR cohort have used ≥ 1 MS disease modifying therapy and 65% were classified as relapsing-remitting MS. An electronic dashboard was developed for health care providers to easily access demographic and clinical data for individuals and groups of patients (Figure 3). Standard and ad hoc reports can be generated from the MSSR. Larger longitudinal analyses can be performed with MSAT and clinical data from CDW. Data on comorbid conditions, pharmacy, radiology and prosthetics utilization, outpatient clinic and inpatient admission can be accessed for each patient or a group of patients.

In 2015, MSCoE published a larger national survey of the VA MS population.¹⁵ This study revealed that the majority of clinical features and demographics of the MSSR were not significantly different from other major US MS registries including the North American Research Committee on MS, the New York State MS Consortium, and the Sonya Slifka Study.^16-18

Discussion

The MSSR is novel in that it combines a traditional MS registry with individual clinical and utilization data within the largest integrated health system in the US. This new registry leverages the existing databases related to cost of care, utilization, and pharmacy services to provide surveillance tools for longitudinal follow-up of the MS population within the VHA. Because the structure of the MSAT and MSSR were developed in a partnership between IT developers and clinicians, there has been mutual buy-in for those who use it and maintain it. This registry can be a test bed for standardized patient outcomes including the recently released MS Quality measures from the American Academy of Neurology.¹⁹

To achieve greater numbers across populations, there has been efforts in Europe to combine registries into a common European Register for MS. A recent survey found that although many European registries were heterogeneous, it would be possible to have a minimum common data set for limited epidemiologic studies.²⁰ Still many registries do not have environmental or genetic data to evaluate etiologic questions.²¹ Additionally, most registries are not set up to evaluate cost or quality of care within a health care system.

Recommendations for maximizing the impact of existing MS registries were recently released by a panel of MS clinicians and researchers.²² The first recommendation was to create a broad network of registries that would communicate and collaborate. This group of MS registries would have strategic oversight and direction that would greatly streamline and leverage existing and future efforts. Second, registries should standardize data collection and management thereby enhancing the ability to share data and perform meta-analyses with aggregated data. Third, the collection of physician- and patient-reported outcomes should be encouraged to provide a more complete picture of MS. Finally, registries should prioritize research questions and utilize new technologies for data collection. These recommendations would help to coordinate existing registries and accelerate knowledge discovery.

The MSSR will contribute to the growing registry network of data. The MSSR can address questions about clinical outcomes, cost, quality with a growing data repository and linked biobank. Based on the CR platform, the MSSR allows for integration with other VA clinical registries, including registries for traumatic brain injuries, oncology, HIV, hepatitis C virus, and eye injuries. Identifying case outcomes related to other registries is optimized with the CR common structure.

Conclusion

The MSSR has been a useful tool for clinicians managing individual patients and their regional referral populations with real-time access to clinical and utilization data. It will also be a useful research tool in tracking epidemiological trends for the military population. The MSSR has enhanced clinical management of MS and serves as a national source for clinical outcomes.

A number of large registries exist for multiple sclerosis (MS) in North America and Europe. The Scandinavian countries have some of the longest running and integrated MS registries to date. The Danish MS Registry was initiated in 1948 and has been consistently maintained to track MS epidemiologic trends.² Similar databases exist in Swedenand Norway that were created in the later 20th century.^3,4 The Rochester Epidemiology Project, launched by Len Kurland at the Mayo Clinic, has tracked the morbidity of MS and many other conditions in Olmsted county Minnesota for > 60 years.⁵

The Canadian provinces of British Columbia, Ontario, and Manitoba also have long standing MS registries.^6-8 Other North American MS registries have gathered state-wide cases, such as the New York State MS Consortium.⁹ Some registries have gathered a population-based sample throughout the US, such as the Sonya Slifka MS Study.¹⁰ The North American Research Consortium on MS (NARCOMS) registry is a patient-driven registry within the US that has enrolled > 30,000 cases.¹¹ The MSBase is the largest online registry to date utilizing data from several countries.¹² The MS Bioscreen, based at the University of California San Francisco, is a recent effort to create a longitudinal clinical dataset.¹³ This electronic registry integrates clinical disease morbidity scales, neuroimaging, genetics and laboratory data for individual patients with the goal of providing predictive tools.

The US military provides a unique population to study MS and has the oldest and largest nation-wide MS cohort in existence starting with World War I service members and continuing through the recent Gulf War Era.¹⁴ With the advent of EHRs in the US Department of Veterans Affairs (VA) Veterans Health Administration (VHA) in the mid-1990s and large clinical databases, the possibility of an integrated registry for chronic conditions was created. In this report, we describe the creation of the VA MS Surveillance Registry (MSSR) and the initial roll out to several VA medical centers within the MS Center of Excellence (MSCoE). The MSSR is a unique platform with potential for improving MS patient care and clinical research.

Methods

The MSSR was designed by MSCoE health care providers in conjunction with IT specialists from the VA Northwest Innovation Center. Between 2012 and 2013, the team developed and tested a core template for data entry and refined an efficient data dashboard display to optimize clinical decisions. IT programmers created data entry templates that were tested by 4 to 5 clinicians who provided feedback in biweekly meetings. Technical problems were addressed and enhancements added and the trial process was repeated.

After creation of the prototype MS Assessment Tool (MSAT) data entry template that fed into the prototype MSSR, our team received a grant in 2013 for national development and sustainment. The MSSR was established on the VA Converged Registries Solution (CRS) platform, which is a hardware and software architecture designed to host individual clinical registries and eliminate duplicative development effort while maximizing the ability to create new patient registries. The common platform includes a relational database, Health Level 7 messaging, software classes, security modules, extraction services, and other components. The CR obtains data from the VA Corporate Data Warehouse (CDW), directly from the Veterans Health Information Systems and Technology Architecture (VISTA) and via direct user input using MSAT.

From 2016 to 2019, data from patients with MS followed in several VA MS regional programs were inputted into MSSR. A roll-out process to start patient data entry at VA medical centers began in 2017 that included an orientation, technical support, and quality assurance review. Twelve sites from Veteran Integrated Service Network (VISN) 5 (mid-Atlantic) and VISN 20 (Pacific Northwest) were included in the initial roll-out.

Results

After a live or remote telehealth or telephone visit, a clinician can access MSAT from the Computerized Patient Record System (CPRS) or directly from the MSSR online portal (Figure 1). The tool uses radio buttons and pull-down menus and takes about 5 to 15 minutes to complete with a list of required variables. Data is auto-saved for efficiency, and the key variables that are collected in MSAT are noted in Table 1. The MSAT subsequently creates a text integration utility progress note with health factors that is processed through an integration engine and eventually transmitted to VISTA and becomes part of the EHR and available to all health care providers involved in that patient’s care. Additionally, data from VA outpatient and inpatient utilization files, pharmacy, prosthetics, laboratory, and radiology databases are included in the CDW and are included in MSSR. With data from 1998 to the present, the MSAT and CDW databases can provide longitudinal data analysis.

Between 18,000 and 20,000 patients with MS are evaluated in the VHA annually, and 56,000 unique patients have been assessed since 1998. From 2016 to 2019, 1,743 patients with MS or related disorders were enrolled in MSSR (Table 2 and Figure 2). The mean (SD) age of patients was 56.0 (12.9) years and the male:female ratio was 2.7. Racial minorities make up 40% of the cohort. Among those with definite and possible MS, the mean disease duration was 22.7 years and the mean (SD) European Database for MS disability score was 4.7 (2.4) (Table 3). Three-quarters of the MSSR cohort have used ≥ 1 MS disease modifying therapy and 65% were classified as relapsing-remitting MS. An electronic dashboard was developed for health care providers to easily access demographic and clinical data for individuals and groups of patients (Figure 3). Standard and ad hoc reports can be generated from the MSSR. Larger longitudinal analyses can be performed with MSAT and clinical data from CDW. Data on comorbid conditions, pharmacy, radiology and prosthetics utilization, outpatient clinic and inpatient admission can be accessed for each patient or a group of patients.

In 2015, MSCoE published a larger national survey of the VA MS population.¹⁵ This study revealed that the majority of clinical features and demographics of the MSSR were not significantly different from other major US MS registries including the North American Research Committee on MS, the New York State MS Consortium, and the Sonya Slifka Study.^16-18

Discussion

The MSSR is novel in that it combines a traditional MS registry with individual clinical and utilization data within the largest integrated health system in the US. This new registry leverages the existing databases related to cost of care, utilization, and pharmacy services to provide surveillance tools for longitudinal follow-up of the MS population within the VHA. Because the structure of the MSAT and MSSR were developed in a partnership between IT developers and clinicians, there has been mutual buy-in for those who use it and maintain it. This registry can be a test bed for standardized patient outcomes including the recently released MS Quality measures from the American Academy of Neurology.¹⁹

To achieve greater numbers across populations, there has been efforts in Europe to combine registries into a common European Register for MS. A recent survey found that although many European registries were heterogeneous, it would be possible to have a minimum common data set for limited epidemiologic studies.²⁰ Still many registries do not have environmental or genetic data to evaluate etiologic questions.²¹ Additionally, most registries are not set up to evaluate cost or quality of care within a health care system.

Recommendations for maximizing the impact of existing MS registries were recently released by a panel of MS clinicians and researchers.²² The first recommendation was to create a broad network of registries that would communicate and collaborate. This group of MS registries would have strategic oversight and direction that would greatly streamline and leverage existing and future efforts. Second, registries should standardize data collection and management thereby enhancing the ability to share data and perform meta-analyses with aggregated data. Third, the collection of physician- and patient-reported outcomes should be encouraged to provide a more complete picture of MS. Finally, registries should prioritize research questions and utilize new technologies for data collection. These recommendations would help to coordinate existing registries and accelerate knowledge discovery.

The MSSR will contribute to the growing registry network of data. The MSSR can address questions about clinical outcomes, cost, quality with a growing data repository and linked biobank. Based on the CR platform, the MSSR allows for integration with other VA clinical registries, including registries for traumatic brain injuries, oncology, HIV, hepatitis C virus, and eye injuries. Identifying case outcomes related to other registries is optimized with the CR common structure.

Conclusion

The MSSR has been a useful tool for clinicians managing individual patients and their regional referral populations with real-time access to clinical and utilization data. It will also be a useful research tool in tracking epidemiological trends for the military population. The MSSR has enhanced clinical management of MS and serves as a national source for clinical outcomes.

A number of large registries exist for multiple sclerosis (MS) in North America and Europe. The Scandinavian countries have some of the longest running and integrated MS registries to date. The Danish MS Registry was initiated in 1948 and has been consistently maintained to track MS epidemiologic trends.² Similar databases exist in Swedenand Norway that were created in the later 20th century.^3,4 The Rochester Epidemiology Project, launched by Len Kurland at the Mayo Clinic, has tracked the morbidity of MS and many other conditions in Olmsted county Minnesota for > 60 years.⁵

The Canadian provinces of British Columbia, Ontario, and Manitoba also have long standing MS registries.^6-8 Other North American MS registries have gathered state-wide cases, such as the New York State MS Consortium.⁹ Some registries have gathered a population-based sample throughout the US, such as the Sonya Slifka MS Study.¹⁰ The North American Research Consortium on MS (NARCOMS) registry is a patient-driven registry within the US that has enrolled > 30,000 cases.¹¹ The MSBase is the largest online registry to date utilizing data from several countries.¹² The MS Bioscreen, based at the University of California San Francisco, is a recent effort to create a longitudinal clinical dataset.¹³ This electronic registry integrates clinical disease morbidity scales, neuroimaging, genetics and laboratory data for individual patients with the goal of providing predictive tools.

The US military provides a unique population to study MS and has the oldest and largest nation-wide MS cohort in existence starting with World War I service members and continuing through the recent Gulf War Era.¹⁴ With the advent of EHRs in the US Department of Veterans Affairs (VA) Veterans Health Administration (VHA) in the mid-1990s and large clinical databases, the possibility of an integrated registry for chronic conditions was created. In this report, we describe the creation of the VA MS Surveillance Registry (MSSR) and the initial roll out to several VA medical centers within the MS Center of Excellence (MSCoE). The MSSR is a unique platform with potential for improving MS patient care and clinical research.

Methods

The MSSR was designed by MSCoE health care providers in conjunction with IT specialists from the VA Northwest Innovation Center. Between 2012 and 2013, the team developed and tested a core template for data entry and refined an efficient data dashboard display to optimize clinical decisions. IT programmers created data entry templates that were tested by 4 to 5 clinicians who provided feedback in biweekly meetings. Technical problems were addressed and enhancements added and the trial process was repeated.

After creation of the prototype MS Assessment Tool (MSAT) data entry template that fed into the prototype MSSR, our team received a grant in 2013 for national development and sustainment. The MSSR was established on the VA Converged Registries Solution (CRS) platform, which is a hardware and software architecture designed to host individual clinical registries and eliminate duplicative development effort while maximizing the ability to create new patient registries. The common platform includes a relational database, Health Level 7 messaging, software classes, security modules, extraction services, and other components. The CR obtains data from the VA Corporate Data Warehouse (CDW), directly from the Veterans Health Information Systems and Technology Architecture (VISTA) and via direct user input using MSAT.

From 2016 to 2019, data from patients with MS followed in several VA MS regional programs were inputted into MSSR. A roll-out process to start patient data entry at VA medical centers began in 2017 that included an orientation, technical support, and quality assurance review. Twelve sites from Veteran Integrated Service Network (VISN) 5 (mid-Atlantic) and VISN 20 (Pacific Northwest) were included in the initial roll-out.

Results

After a live or remote telehealth or telephone visit, a clinician can access MSAT from the Computerized Patient Record System (CPRS) or directly from the MSSR online portal (Figure 1). The tool uses radio buttons and pull-down menus and takes about 5 to 15 minutes to complete with a list of required variables. Data is auto-saved for efficiency, and the key variables that are collected in MSAT are noted in Table 1. The MSAT subsequently creates a text integration utility progress note with health factors that is processed through an integration engine and eventually transmitted to VISTA and becomes part of the EHR and available to all health care providers involved in that patient’s care. Additionally, data from VA outpatient and inpatient utilization files, pharmacy, prosthetics, laboratory, and radiology databases are included in the CDW and are included in MSSR. With data from 1998 to the present, the MSAT and CDW databases can provide longitudinal data analysis.

Between 18,000 and 20,000 patients with MS are evaluated in the VHA annually, and 56,000 unique patients have been assessed since 1998. From 2016 to 2019, 1,743 patients with MS or related disorders were enrolled in MSSR (Table 2 and Figure 2). The mean (SD) age of patients was 56.0 (12.9) years and the male:female ratio was 2.7. Racial minorities make up 40% of the cohort. Among those with definite and possible MS, the mean disease duration was 22.7 years and the mean (SD) European Database for MS disability score was 4.7 (2.4) (Table 3). Three-quarters of the MSSR cohort have used ≥ 1 MS disease modifying therapy and 65% were classified as relapsing-remitting MS. An electronic dashboard was developed for health care providers to easily access demographic and clinical data for individuals and groups of patients (Figure 3). Standard and ad hoc reports can be generated from the MSSR. Larger longitudinal analyses can be performed with MSAT and clinical data from CDW. Data on comorbid conditions, pharmacy, radiology and prosthetics utilization, outpatient clinic and inpatient admission can be accessed for each patient or a group of patients.

In 2015, MSCoE published a larger national survey of the VA MS population.¹⁵ This study revealed that the majority of clinical features and demographics of the MSSR were not significantly different from other major US MS registries including the North American Research Committee on MS, the New York State MS Consortium, and the Sonya Slifka Study.^16-18

Discussion

The MSSR is novel in that it combines a traditional MS registry with individual clinical and utilization data within the largest integrated health system in the US. This new registry leverages the existing databases related to cost of care, utilization, and pharmacy services to provide surveillance tools for longitudinal follow-up of the MS population within the VHA. Because the structure of the MSAT and MSSR were developed in a partnership between IT developers and clinicians, there has been mutual buy-in for those who use it and maintain it. This registry can be a test bed for standardized patient outcomes including the recently released MS Quality measures from the American Academy of Neurology.¹⁹

To achieve greater numbers across populations, there has been efforts in Europe to combine registries into a common European Register for MS. A recent survey found that although many European registries were heterogeneous, it would be possible to have a minimum common data set for limited epidemiologic studies.²⁰ Still many registries do not have environmental or genetic data to evaluate etiologic questions.²¹ Additionally, most registries are not set up to evaluate cost or quality of care within a health care system.

Recommendations for maximizing the impact of existing MS registries were recently released by a panel of MS clinicians and researchers.²² The first recommendation was to create a broad network of registries that would communicate and collaborate. This group of MS registries would have strategic oversight and direction that would greatly streamline and leverage existing and future efforts. Second, registries should standardize data collection and management thereby enhancing the ability to share data and perform meta-analyses with aggregated data. Third, the collection of physician- and patient-reported outcomes should be encouraged to provide a more complete picture of MS. Finally, registries should prioritize research questions and utilize new technologies for data collection. These recommendations would help to coordinate existing registries and accelerate knowledge discovery.

The MSSR will contribute to the growing registry network of data. The MSSR can address questions about clinical outcomes, cost, quality with a growing data repository and linked biobank. Based on the CR platform, the MSSR allows for integration with other VA clinical registries, including registries for traumatic brain injuries, oncology, HIV, hepatitis C virus, and eye injuries. Identifying case outcomes related to other registries is optimized with the CR common structure.

Conclusion

The MSSR has been a useful tool for clinicians managing individual patients and their regional referral populations with real-time access to clinical and utilization data. It will also be a useful research tool in tracking epidemiological trends for the military population. The MSSR has enhanced clinical management of MS and serves as a national source for clinical outcomes.

Breast cancer is the second most common malignancy in women (after primary skin cancer) and is the second leading cause of cancer-related death in this population. In 2020, the American Cancer Society reported an estimated 276,480 new breast cancer diagnoses and 42,170 breast cancer–related deaths.¹ Despite the fact that routine screening with mammography and sonography is standard, the incidence of advanced breast cancer at the time of diagnosis has remained stable over time, suggesting that life-threatening breast cancers are not being caught at an earlier stage. The number of breast cancers with distant metastases at the time of diagnosis also has not decreased.² Therefore, although screening tests are valuable, they are imperfect and not without limitations.

Cutaneous metastasis is defined as the spread of malignant cells from an internal neoplasm to the skin, which can occur either by contiguous invasion or by distant metastasis through hematogenous or lymphatic routes.³ The diagnosis of cutaneous metastasis requires a high index of suspicion on the part of the clinician.⁴ Of the various internal malignancies in women, breast cancer most frequently results in metastasis to the skin,⁵ with up to 24% of patients with metastatic breast cancer developing cutaneous lesions.⁶

In recent years, there have been multiple reports of skin lesions prompting the diagnosis of a previously unknown breast cancer. In a study by Lookingbill et al,⁶ 6.3% of patients with breast cancer presented with cutaneous involvement at the time of diagnosis, with 3.5% having skin symptoms as the presenting sign. Although there have been studies analyzing cutaneous metastasis from various internal malignancies, none thus far have focused on cutaneous metastasis as a presenting sign of breast cancer. This systematic review aimed to highlight the diverse clinical presentations of cutaneous metastatic breast cancer and their clinical implications.

Methods

Study Selection
This study utilized the PRISMA guidelines for systematic reviews.⁷ A review of the literature was conducted using the following databases: MEDLINE/PubMed, EMBASE, Cochrane library, CINAHL, and EBSCO.

Search Strategy and Analysis
We completed our search of each of the databases on December 16, 2017, using the phrases cutaneous metastasis and breast cancer to find relevant case reports and retrospective studies. Three authors (C.J., S.R., and M.A.) manually reviewed the resulting abstracts. If an abstract did not include enough information to determine inclusion, the full-text version was reviewed by 2 of the authors (C.J. and S.R.). Two of the authors (C.J. and M.A.) also assessed each source for relevancy and included the articles deemed eligible (Figure 1).

For a retrospective review to be included, it must have specified the number of breast cancer cases and the number of cutaneous metastases presenting initially or simultaneously to the breast cancer diagnosis. Bansal et al⁸ defined a simultaneous diagnosis as a skin lesion presenting with other concerns associated with the primary malignancy.

Results

The initial search of MEDLINE/PubMed, EMBASE, Cochrane library, CINAHL, and EBSCO yielded a total of 722 articles. Seven other articles found separately while undergoing our initial research were added to this total. Abstracts were manually screened, with 657 articles discarded after failing to meet the predetermined inclusion criteria. After removal of 25 duplicate articles, the full text of the remaining 47 articles were reviewed, leading to the elimination of an additional 11 articles that did not meet the necessary criteria. This resulted in 36 articles (Figure 1), including 27 individual case reports (Table 1) and 9 retrospective reviews (Table 2). Approximately 13.7% of patients in the 9 retrospective reviews presented with a skin lesion before or simultaneous to the diagnosis of breast cancer (Figure 2).

Forty-one percent (17/41) of the patients with cutaneous metastasis as a presenting feature of their breast cancer fell outside the age range for breast cancer screening recommended by the US Preventive Services Task Force,⁴² with 24% of the patients younger than 50 years and 17% older than 74 years (Figure 3).

Comment

Our systematic review demonstrated that cutaneous lesions may be the first clinical manifestation of an undetected primary malignancy.⁴⁰ These lesions often occur on the chest but may involve the face, abdomen, or extremities. Although asymptomatic erythematous nodules and plaques are the most common clinical presentations, lesions may be tender or pruritic or may even resemble benign skin conditions, including dermatitis, cellulitis, urticaria, and papulovesicular eruptions, causing them to go unrecognized.

Nevertheless, cutaneous metastasis of a visceral malignancy generally is observed late in the disease course, often following the diagnosis of a primary malignancy.¹⁴ Breast cancer is the most common internal malignancy to feature cutaneous spread, with the largest case series revealing a 23.9% rate of cutaneous metastases in females with breast carcinoma.⁶ Because of its proximity, the chest wall is the most common location for cutaneous lesions of metastatic breast cancer.

Malignant cells from a primary breast tumor may spread to the skin via lymphatic, hematogenous, or contiguous tissue dissemination, as well as iatrogenically through direct implantation during surgical procedures.³ The mechanism of neoplasm spread may likewise influence the clinical appearance of the resulting lesions. The localized lymphedema with a peau d’orange appearance of inflammatory metastatic breast carcinoma or the erythematous plaques of carcinoma erysipeloides are caused by embolized tumor cells obstructing dermal lymphatic vessels.^3,11 On the other hand, the indurated erythematous plaques of carcinoma en cuirasse are caused by diffuse cutaneous and subcutaneous infiltration of tumor cells that also may be associated with marked reduction in breast volume.³

A primary breast cancer is classically diagnosed with a combination of clinical breast examination, radiologic imaging (ultrasound, mammogram, breast magnetic resonance imaging, or computed tomography), and fine-needle aspiration or lesional biopsy with histopathology.⁹ Given that in 20% of metastasized breast cancers the primary tumor may not be identified, a negative breast examination and imaging do not rule out breast cancer, especially if cutaneous biopsy reveals a primary malignancy.⁴³ Histopathology and immunohistochemistry can thereby confirm the presence of metastatic cutaneous lesions and help characterize the breast cancer type involved, with adenocarcinomas being most commonly implicated.²⁸ Although both ductal and lobular adenocarcinomas stain positive for cytokeratin 7, estrogen receptor, progesterone receptor, gross cystic disease fluid protein 15, carcinoembryonic antigen, and mammaglobin, only the former shows positivity for e-cadherin markers.³ Conversely, inflammatory carcinoma stains positive for CD31 and podoplanin, telangiectatic carcinoma stains positive for CD31, and mammary Paget disease stains positive for cytokeratin 7 and mucin 1, cell surface associated.³ Apart from cutaneous biopsy, fine-needle aspiration cytology can likewise provide a simple and rapid method of diagnosis with high sensitivity and specificity.¹⁴

Conclusion

Although cutaneous metastasis as the presenting sign of a breast malignancy is rare, a high index of suspicion should be exercised when encountering rapid-onset, out-of-place nodules or plaques in female patients, particularly nodules or plaques presenting on the chest.

Breast cancer is the second most common malignancy in women (after primary skin cancer) and is the second leading cause of cancer-related death in this population. In 2020, the American Cancer Society reported an estimated 276,480 new breast cancer diagnoses and 42,170 breast cancer–related deaths.¹ Despite the fact that routine screening with mammography and sonography is standard, the incidence of advanced breast cancer at the time of diagnosis has remained stable over time, suggesting that life-threatening breast cancers are not being caught at an earlier stage. The number of breast cancers with distant metastases at the time of diagnosis also has not decreased.² Therefore, although screening tests are valuable, they are imperfect and not without limitations.

Cutaneous metastasis is defined as the spread of malignant cells from an internal neoplasm to the skin, which can occur either by contiguous invasion or by distant metastasis through hematogenous or lymphatic routes.³ The diagnosis of cutaneous metastasis requires a high index of suspicion on the part of the clinician.⁴ Of the various internal malignancies in women, breast cancer most frequently results in metastasis to the skin,⁵ with up to 24% of patients with metastatic breast cancer developing cutaneous lesions.⁶

In recent years, there have been multiple reports of skin lesions prompting the diagnosis of a previously unknown breast cancer. In a study by Lookingbill et al,⁶ 6.3% of patients with breast cancer presented with cutaneous involvement at the time of diagnosis, with 3.5% having skin symptoms as the presenting sign. Although there have been studies analyzing cutaneous metastasis from various internal malignancies, none thus far have focused on cutaneous metastasis as a presenting sign of breast cancer. This systematic review aimed to highlight the diverse clinical presentations of cutaneous metastatic breast cancer and their clinical implications.

Methods

Study Selection
This study utilized the PRISMA guidelines for systematic reviews.⁷ A review of the literature was conducted using the following databases: MEDLINE/PubMed, EMBASE, Cochrane library, CINAHL, and EBSCO.

Search Strategy and Analysis
We completed our search of each of the databases on December 16, 2017, using the phrases cutaneous metastasis and breast cancer to find relevant case reports and retrospective studies. Three authors (C.J., S.R., and M.A.) manually reviewed the resulting abstracts. If an abstract did not include enough information to determine inclusion, the full-text version was reviewed by 2 of the authors (C.J. and S.R.). Two of the authors (C.J. and M.A.) also assessed each source for relevancy and included the articles deemed eligible (Figure 1).

For a retrospective review to be included, it must have specified the number of breast cancer cases and the number of cutaneous metastases presenting initially or simultaneously to the breast cancer diagnosis. Bansal et al⁸ defined a simultaneous diagnosis as a skin lesion presenting with other concerns associated with the primary malignancy.

Results

The initial search of MEDLINE/PubMed, EMBASE, Cochrane library, CINAHL, and EBSCO yielded a total of 722 articles. Seven other articles found separately while undergoing our initial research were added to this total. Abstracts were manually screened, with 657 articles discarded after failing to meet the predetermined inclusion criteria. After removal of 25 duplicate articles, the full text of the remaining 47 articles were reviewed, leading to the elimination of an additional 11 articles that did not meet the necessary criteria. This resulted in 36 articles (Figure 1), including 27 individual case reports (Table 1) and 9 retrospective reviews (Table 2). Approximately 13.7% of patients in the 9 retrospective reviews presented with a skin lesion before or simultaneous to the diagnosis of breast cancer (Figure 2).

Forty-one percent (17/41) of the patients with cutaneous metastasis as a presenting feature of their breast cancer fell outside the age range for breast cancer screening recommended by the US Preventive Services Task Force,⁴² with 24% of the patients younger than 50 years and 17% older than 74 years (Figure 3).

Comment

Our systematic review demonstrated that cutaneous lesions may be the first clinical manifestation of an undetected primary malignancy.⁴⁰ These lesions often occur on the chest but may involve the face, abdomen, or extremities. Although asymptomatic erythematous nodules and plaques are the most common clinical presentations, lesions may be tender or pruritic or may even resemble benign skin conditions, including dermatitis, cellulitis, urticaria, and papulovesicular eruptions, causing them to go unrecognized.

Nevertheless, cutaneous metastasis of a visceral malignancy generally is observed late in the disease course, often following the diagnosis of a primary malignancy.¹⁴ Breast cancer is the most common internal malignancy to feature cutaneous spread, with the largest case series revealing a 23.9% rate of cutaneous metastases in females with breast carcinoma.⁶ Because of its proximity, the chest wall is the most common location for cutaneous lesions of metastatic breast cancer.

Malignant cells from a primary breast tumor may spread to the skin via lymphatic, hematogenous, or contiguous tissue dissemination, as well as iatrogenically through direct implantation during surgical procedures.³ The mechanism of neoplasm spread may likewise influence the clinical appearance of the resulting lesions. The localized lymphedema with a peau d’orange appearance of inflammatory metastatic breast carcinoma or the erythematous plaques of carcinoma erysipeloides are caused by embolized tumor cells obstructing dermal lymphatic vessels.^3,11 On the other hand, the indurated erythematous plaques of carcinoma en cuirasse are caused by diffuse cutaneous and subcutaneous infiltration of tumor cells that also may be associated with marked reduction in breast volume.³

A primary breast cancer is classically diagnosed with a combination of clinical breast examination, radiologic imaging (ultrasound, mammogram, breast magnetic resonance imaging, or computed tomography), and fine-needle aspiration or lesional biopsy with histopathology.⁹ Given that in 20% of metastasized breast cancers the primary tumor may not be identified, a negative breast examination and imaging do not rule out breast cancer, especially if cutaneous biopsy reveals a primary malignancy.⁴³ Histopathology and immunohistochemistry can thereby confirm the presence of metastatic cutaneous lesions and help characterize the breast cancer type involved, with adenocarcinomas being most commonly implicated.²⁸ Although both ductal and lobular adenocarcinomas stain positive for cytokeratin 7, estrogen receptor, progesterone receptor, gross cystic disease fluid protein 15, carcinoembryonic antigen, and mammaglobin, only the former shows positivity for e-cadherin markers.³ Conversely, inflammatory carcinoma stains positive for CD31 and podoplanin, telangiectatic carcinoma stains positive for CD31, and mammary Paget disease stains positive for cytokeratin 7 and mucin 1, cell surface associated.³ Apart from cutaneous biopsy, fine-needle aspiration cytology can likewise provide a simple and rapid method of diagnosis with high sensitivity and specificity.¹⁴

Conclusion

Although cutaneous metastasis as the presenting sign of a breast malignancy is rare, a high index of suspicion should be exercised when encountering rapid-onset, out-of-place nodules or plaques in female patients, particularly nodules or plaques presenting on the chest.

Breast cancer is the second most common malignancy in women (after primary skin cancer) and is the second leading cause of cancer-related death in this population. In 2020, the American Cancer Society reported an estimated 276,480 new breast cancer diagnoses and 42,170 breast cancer–related deaths.¹ Despite the fact that routine screening with mammography and sonography is standard, the incidence of advanced breast cancer at the time of diagnosis has remained stable over time, suggesting that life-threatening breast cancers are not being caught at an earlier stage. The number of breast cancers with distant metastases at the time of diagnosis also has not decreased.² Therefore, although screening tests are valuable, they are imperfect and not without limitations.

Cutaneous metastasis is defined as the spread of malignant cells from an internal neoplasm to the skin, which can occur either by contiguous invasion or by distant metastasis through hematogenous or lymphatic routes.³ The diagnosis of cutaneous metastasis requires a high index of suspicion on the part of the clinician.⁴ Of the various internal malignancies in women, breast cancer most frequently results in metastasis to the skin,⁵ with up to 24% of patients with metastatic breast cancer developing cutaneous lesions.⁶

In recent years, there have been multiple reports of skin lesions prompting the diagnosis of a previously unknown breast cancer. In a study by Lookingbill et al,⁶ 6.3% of patients with breast cancer presented with cutaneous involvement at the time of diagnosis, with 3.5% having skin symptoms as the presenting sign. Although there have been studies analyzing cutaneous metastasis from various internal malignancies, none thus far have focused on cutaneous metastasis as a presenting sign of breast cancer. This systematic review aimed to highlight the diverse clinical presentations of cutaneous metastatic breast cancer and their clinical implications.

Methods

Study Selection
This study utilized the PRISMA guidelines for systematic reviews.⁷ A review of the literature was conducted using the following databases: MEDLINE/PubMed, EMBASE, Cochrane library, CINAHL, and EBSCO.

Search Strategy and Analysis
We completed our search of each of the databases on December 16, 2017, using the phrases cutaneous metastasis and breast cancer to find relevant case reports and retrospective studies. Three authors (C.J., S.R., and M.A.) manually reviewed the resulting abstracts. If an abstract did not include enough information to determine inclusion, the full-text version was reviewed by 2 of the authors (C.J. and S.R.). Two of the authors (C.J. and M.A.) also assessed each source for relevancy and included the articles deemed eligible (Figure 1).

For a retrospective review to be included, it must have specified the number of breast cancer cases and the number of cutaneous metastases presenting initially or simultaneously to the breast cancer diagnosis. Bansal et al⁸ defined a simultaneous diagnosis as a skin lesion presenting with other concerns associated with the primary malignancy.

Results

The initial search of MEDLINE/PubMed, EMBASE, Cochrane library, CINAHL, and EBSCO yielded a total of 722 articles. Seven other articles found separately while undergoing our initial research were added to this total. Abstracts were manually screened, with 657 articles discarded after failing to meet the predetermined inclusion criteria. After removal of 25 duplicate articles, the full text of the remaining 47 articles were reviewed, leading to the elimination of an additional 11 articles that did not meet the necessary criteria. This resulted in 36 articles (Figure 1), including 27 individual case reports (Table 1) and 9 retrospective reviews (Table 2). Approximately 13.7% of patients in the 9 retrospective reviews presented with a skin lesion before or simultaneous to the diagnosis of breast cancer (Figure 2).

Forty-one percent (17/41) of the patients with cutaneous metastasis as a presenting feature of their breast cancer fell outside the age range for breast cancer screening recommended by the US Preventive Services Task Force,⁴² with 24% of the patients younger than 50 years and 17% older than 74 years (Figure 3).

Comment

Our systematic review demonstrated that cutaneous lesions may be the first clinical manifestation of an undetected primary malignancy.⁴⁰ These lesions often occur on the chest but may involve the face, abdomen, or extremities. Although asymptomatic erythematous nodules and plaques are the most common clinical presentations, lesions may be tender or pruritic or may even resemble benign skin conditions, including dermatitis, cellulitis, urticaria, and papulovesicular eruptions, causing them to go unrecognized.

Nevertheless, cutaneous metastasis of a visceral malignancy generally is observed late in the disease course, often following the diagnosis of a primary malignancy.¹⁴ Breast cancer is the most common internal malignancy to feature cutaneous spread, with the largest case series revealing a 23.9% rate of cutaneous metastases in females with breast carcinoma.⁶ Because of its proximity, the chest wall is the most common location for cutaneous lesions of metastatic breast cancer.

Malignant cells from a primary breast tumor may spread to the skin via lymphatic, hematogenous, or contiguous tissue dissemination, as well as iatrogenically through direct implantation during surgical procedures.³ The mechanism of neoplasm spread may likewise influence the clinical appearance of the resulting lesions. The localized lymphedema with a peau d’orange appearance of inflammatory metastatic breast carcinoma or the erythematous plaques of carcinoma erysipeloides are caused by embolized tumor cells obstructing dermal lymphatic vessels.^3,11 On the other hand, the indurated erythematous plaques of carcinoma en cuirasse are caused by diffuse cutaneous and subcutaneous infiltration of tumor cells that also may be associated with marked reduction in breast volume.³

A primary breast cancer is classically diagnosed with a combination of clinical breast examination, radiologic imaging (ultrasound, mammogram, breast magnetic resonance imaging, or computed tomography), and fine-needle aspiration or lesional biopsy with histopathology.⁹ Given that in 20% of metastasized breast cancers the primary tumor may not be identified, a negative breast examination and imaging do not rule out breast cancer, especially if cutaneous biopsy reveals a primary malignancy.⁴³ Histopathology and immunohistochemistry can thereby confirm the presence of metastatic cutaneous lesions and help characterize the breast cancer type involved, with adenocarcinomas being most commonly implicated.²⁸ Although both ductal and lobular adenocarcinomas stain positive for cytokeratin 7, estrogen receptor, progesterone receptor, gross cystic disease fluid protein 15, carcinoembryonic antigen, and mammaglobin, only the former shows positivity for e-cadherin markers.³ Conversely, inflammatory carcinoma stains positive for CD31 and podoplanin, telangiectatic carcinoma stains positive for CD31, and mammary Paget disease stains positive for cytokeratin 7 and mucin 1, cell surface associated.³ Apart from cutaneous biopsy, fine-needle aspiration cytology can likewise provide a simple and rapid method of diagnosis with high sensitivity and specificity.¹⁴

Conclusion

Although cutaneous metastasis as the presenting sign of a breast malignancy is rare, a high index of suspicion should be exercised when encountering rapid-onset, out-of-place nodules or plaques in female patients, particularly nodules or plaques presenting on the chest.

Gynecologic malignancies continue to be a major cause of cancer-related mortality in women. In 2020, a number of developments changed practice in gynecologic oncology. In this Update, we highlight 3 important articles. The first showed that human papillomavirus (HPV) vaccination reduced the rate of cervical cancer. The next evaluated a novel targeted therapeutic approach using the combination of pembrolizumab and lenvatinib in women with recurrent endometrial carcinoma that progressed after prior systemic therapy. Finally, the third article showed that talcum powder was not associated with an increased risk of ovarian cancer. We provide here a brief overview of the major findings of these studies and how these results are influencing practice.

Evidence establishes that HPV vaccination cuts risk of invasive cervical cancer

Lei J, Ploner A, Elfström KM, et al. HPV vaccination and the risk of invasive cervical cancer. N Engl J Med. 2020;383:1340-1348.

HPV infection is associated with 99% of cervical cancers, and approximately 65% to 75% of cases involve HPV 16 or 18.^1,2 The quadrivalent HPV (6, 11, 16, 18) vaccine was approved by the US Food and Drug Administration in 2006 for the prevention of cervical intraepithelial lesions and genital warts associated with HPV.^3-5 Previous studies of the HPV vaccine showed it to be effective in preventing HPV infection, genital warts, and high-grade precancerous cervical lesions, such as cervical intraepithelial neoplasia grade 2 (CIN2) and grade 3 (CIN3).^6-8 While the vaccine offers a number of advantages, the long-term goal of the vaccine—to reduce the incidence of invasive cervical cancer—was not shown until recently.

Large study followed HPV vaccinated and unvaccinated women

Lei and colleagues conducted a registry based cohort study from 2006 through 2017 of women aged 10 to 30 years who were living in Sweden.⁹ They followed the women from their 10th birthday until they were diagnosed with cervical cancer, died, emigrated from Sweden, were lost to follow-up, or turned 31 years of age. In the study, the unique personal identity numbers assigned to all Swedish residents were linked to a number of large national administrative databases. Beginning in 2007 in Sweden, the quadrivalent vaccine was subsidized for use in girls aged 13 to 17, and a subsequent catch-up period that started in 2012 incorporated women who had not been vaccinated.

Continue to: Cervical cancer rates were lowest in women vaccinated before age 17...

Cervical cancer rates were lowest in women vaccinated before age 17

A total of 1,672,983 women were included in the study; 527,871 received at least one dose of the HPV vaccine. During the study period, cervical cancer was diagnosed in 19 women who had received the quadrivalent HPV vaccine and in 538 women who had not received the vaccine. Women who initiated vaccination before age 17 had the lowest rates of cervical cancer (4 cases per 100,000 persons), followed by women vaccinated after age 17 (54 cases per 100,000 persons) and then those who were not vaccinated (94 cases per 100,000 persons).

After adjusting for confounders, the incidence rate ratio (RR) of cervical cancer was significantly lower among vaccinated women compared with unvaccinated women (RR, 0.37; 95% confidence interval [CI], 0.21– 0.57) (FIGURE 1).⁹ In addition, women who were vaccinated before age 17 demonstrated the greatest benefit. For those vaccinated before age 17 versus those who were unvaccinated, the RR was 0.12 (95% CI, 0.00–0.34). For women vaccinated between age 17 and 30 versus unvaccinated women, the RR was 0.47 (95% CI, 0.27–0.75).

Promising option for patients with advanced endometrial cancer: Lenvatinib plus pembrolizumab

Makker V, Taylor MH, Aghajanian C, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer. J Clin Oncol. 2020;38:2981-2992.

Advanced stage endometrial cancer is associated with a 17% 5-year survival rate.¹⁰ Paclitaxel with carboplatin is the standard first-line treatment for advanced, recurrent, and metastatic endometrial cancer; for women who do not respond to this regimen, effective treatment options are limited.^11,12

The immunotherapy approach

Immunotherapy is a more recently developed treatment, an approach in which the immune system is activated to target cancer cells. Pembrolizumab is a commonly used agent for many solid tumors.¹³ This drug binds to the programmed cell death receptor 1 (PD-1) or PD-ligand 1 (PD-L1), a component of the immune checkpoint, which then allows the immune system to target and destroy cancer cells.¹⁴

Prembrolizumab is FDA approved for use in the treatment of microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) solid tumors that have progressed after prior therapy and for which there are no satisfactory alternative treatment options.¹⁵ Endometrial cancers frequently display microsatellite instability and mismatch repair defects.¹⁶

Lenvatinib is an oral multikinase inhibitor that targets vascular endothelial growth factor receptors 1, 2, and 3; fibroblast growth factor receptors 1, 2, 3, and 4; and platelet derived growth factor receptor alpha, RET, and KIT.^17-19 In a phase 2 study of lenvatinib monotherapy for advanced previously treated endometrial cancer, the response rate was 14.3%.²⁰

While some preclinical studies have examined the combination of immune checkpoint inhibitors with lenvatinib,^21-23 a recent study is the first to evaluate this combination in patients with advanced tumors.²⁴

Continue to: Prembrolizumab-lenvatinib combination therapy...

Prembrolizumab-lenvatinib combination therapy

Makker and colleagues conducted an ongoing multinational, open-label, phase 1B/2 study of lenvatinib 20 mg daily orally plus pembrolizumab 200 mg intravenously once every 3 weeks in patients with select solid tumors.²⁴ Women with previously treated endometrial carcinoma (N = 125) were included. Of the study participants, 49% were PD-L1 positive and 10% were MSI-H/dMMR. The primary end point was objective response rate (ORR) at 24 weeks, which was 38.0% (95% CI, 28.8%–47.8%).

The median duration of response was 21.2 months (95% CI, 7.6 months to not estimable). The ORR was similar in patients with PD-L1 expressing tumors (35.8%; 95% CI, 23.1%–50.2%), who are more likely to respond to immunotherapy, compared with those without PD-L1 expression (39.5%; 95% CI, 25.0%–55.6%). For patients with MSI-H/dMMR, there was a higher ORR (63.6%; 95% CI, 30.8%–89.1%, versus 36.2%; 95% CI, 26.5%–46.7%).

Median progression-free survival was 7.4 months (95% CI, 5.3–8.7 months) and median overall survival was 16.7 months (15 months to not estimable). Moderate to severe treatment-related adverse events occurred in 83 patients (66.9%), and 22 patients (17.7%) discontinued 1 or both study drugs because of adverse effects. Two deaths were judged to be treatment related.

What is the risk of ovarian cancer in women who use powder in the genital area?

O’Brien KM, Tworoger SS, Harris HR, et al. Association of powder use in the genital area with risk of ovarian cancer. JAMA. 2020;323:49-59.

Women apply talcum powder to their genital area to keep skin dry and to prevent rashes. Powder can be applied by direct application, sanitary napkins, diaphragms, or tampons. Most powder products contain the mineral talc. Because it often is found in nature with asbestos, a known carcinogen, talc’s carcinogenic effects have been investigated.^26,27

Talc also might ascend through the genital tract and irritate the epithelial lining of the fallopian tubes or ovaries, possibly triggering an inflammatory response that may promote carcinogenesis.^28,29 Case-control studies have reported a possible association between genital powder use and ovarian cancer.^30,31 Since these studies, talc-related lawsuits and media coverage have increased.^32,33

Large prospective cohorts provide data for analysis

In a pooled analysis of 4 large US-based observational cohorts between 1976 and 2017, O’Brien and colleagues noted that 38% of the 252,745 women included in the study self-reported the use of powder in the genital area.³⁴ With a median of 11.2 years of follow-up, 2,168 women developed ovarian cancer (58 cases/100,000 person-years). Among women who reported using genital powder, the incidence of ovarian cancer was 61 cases/100,000 person-years, while for women who reported never using genital powder, the incidence was 55 cases/100,000 person-years. This corresponded to an estimated hazard ratio (HR) of 1.08 (95% CI, 0.99–1.17).

Frequent powder use, long-term use, and never use. Similar findings were seen for those with frequent use versus never use (HR, 1.09; 95% CI, 0.97–1.23) and long-term use versus never use (HR, 1.01; 95% CI, 0.82– 1.25). When restricting the group to women with a patent reproductive tract at baseline, the HR was 1.13 (95% CI, 1.01–1.26), but the P value for interaction comparing women with versus women without a patent reproductive tract was 0.15 (FIGURE 2).³⁴

Bottom line. In contrast to a prior meta-analysis, in this study there was no statistically significant association between the self-reported use of powder in the genital area and the incidence of ovarian cancer. ●

Gynecologic malignancies continue to be a major cause of cancer-related mortality in women. In 2020, a number of developments changed practice in gynecologic oncology. In this Update, we highlight 3 important articles. The first showed that human papillomavirus (HPV) vaccination reduced the rate of cervical cancer. The next evaluated a novel targeted therapeutic approach using the combination of pembrolizumab and lenvatinib in women with recurrent endometrial carcinoma that progressed after prior systemic therapy. Finally, the third article showed that talcum powder was not associated with an increased risk of ovarian cancer. We provide here a brief overview of the major findings of these studies and how these results are influencing practice.

Evidence establishes that HPV vaccination cuts risk of invasive cervical cancer

Lei J, Ploner A, Elfström KM, et al. HPV vaccination and the risk of invasive cervical cancer. N Engl J Med. 2020;383:1340-1348.

HPV infection is associated with 99% of cervical cancers, and approximately 65% to 75% of cases involve HPV 16 or 18.^1,2 The quadrivalent HPV (6, 11, 16, 18) vaccine was approved by the US Food and Drug Administration in 2006 for the prevention of cervical intraepithelial lesions and genital warts associated with HPV.^3-5 Previous studies of the HPV vaccine showed it to be effective in preventing HPV infection, genital warts, and high-grade precancerous cervical lesions, such as cervical intraepithelial neoplasia grade 2 (CIN2) and grade 3 (CIN3).^6-8 While the vaccine offers a number of advantages, the long-term goal of the vaccine—to reduce the incidence of invasive cervical cancer—was not shown until recently.

Large study followed HPV vaccinated and unvaccinated women

Lei and colleagues conducted a registry based cohort study from 2006 through 2017 of women aged 10 to 30 years who were living in Sweden.⁹ They followed the women from their 10th birthday until they were diagnosed with cervical cancer, died, emigrated from Sweden, were lost to follow-up, or turned 31 years of age. In the study, the unique personal identity numbers assigned to all Swedish residents were linked to a number of large national administrative databases. Beginning in 2007 in Sweden, the quadrivalent vaccine was subsidized for use in girls aged 13 to 17, and a subsequent catch-up period that started in 2012 incorporated women who had not been vaccinated.

Continue to: Cervical cancer rates were lowest in women vaccinated before age 17...

Cervical cancer rates were lowest in women vaccinated before age 17

A total of 1,672,983 women were included in the study; 527,871 received at least one dose of the HPV vaccine. During the study period, cervical cancer was diagnosed in 19 women who had received the quadrivalent HPV vaccine and in 538 women who had not received the vaccine. Women who initiated vaccination before age 17 had the lowest rates of cervical cancer (4 cases per 100,000 persons), followed by women vaccinated after age 17 (54 cases per 100,000 persons) and then those who were not vaccinated (94 cases per 100,000 persons).

After adjusting for confounders, the incidence rate ratio (RR) of cervical cancer was significantly lower among vaccinated women compared with unvaccinated women (RR, 0.37; 95% confidence interval [CI], 0.21– 0.57) (FIGURE 1).⁹ In addition, women who were vaccinated before age 17 demonstrated the greatest benefit. For those vaccinated before age 17 versus those who were unvaccinated, the RR was 0.12 (95% CI, 0.00–0.34). For women vaccinated between age 17 and 30 versus unvaccinated women, the RR was 0.47 (95% CI, 0.27–0.75).

Promising option for patients with advanced endometrial cancer: Lenvatinib plus pembrolizumab

Makker V, Taylor MH, Aghajanian C, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer. J Clin Oncol. 2020;38:2981-2992.

Advanced stage endometrial cancer is associated with a 17% 5-year survival rate.¹⁰ Paclitaxel with carboplatin is the standard first-line treatment for advanced, recurrent, and metastatic endometrial cancer; for women who do not respond to this regimen, effective treatment options are limited.^11,12

The immunotherapy approach

Immunotherapy is a more recently developed treatment, an approach in which the immune system is activated to target cancer cells. Pembrolizumab is a commonly used agent for many solid tumors.¹³ This drug binds to the programmed cell death receptor 1 (PD-1) or PD-ligand 1 (PD-L1), a component of the immune checkpoint, which then allows the immune system to target and destroy cancer cells.¹⁴

Prembrolizumab is FDA approved for use in the treatment of microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) solid tumors that have progressed after prior therapy and for which there are no satisfactory alternative treatment options.¹⁵ Endometrial cancers frequently display microsatellite instability and mismatch repair defects.¹⁶

Lenvatinib is an oral multikinase inhibitor that targets vascular endothelial growth factor receptors 1, 2, and 3; fibroblast growth factor receptors 1, 2, 3, and 4; and platelet derived growth factor receptor alpha, RET, and KIT.^17-19 In a phase 2 study of lenvatinib monotherapy for advanced previously treated endometrial cancer, the response rate was 14.3%.²⁰

While some preclinical studies have examined the combination of immune checkpoint inhibitors with lenvatinib,^21-23 a recent study is the first to evaluate this combination in patients with advanced tumors.²⁴

Continue to: Prembrolizumab-lenvatinib combination therapy...

Prembrolizumab-lenvatinib combination therapy

Makker and colleagues conducted an ongoing multinational, open-label, phase 1B/2 study of lenvatinib 20 mg daily orally plus pembrolizumab 200 mg intravenously once every 3 weeks in patients with select solid tumors.²⁴ Women with previously treated endometrial carcinoma (N = 125) were included. Of the study participants, 49% were PD-L1 positive and 10% were MSI-H/dMMR. The primary end point was objective response rate (ORR) at 24 weeks, which was 38.0% (95% CI, 28.8%–47.8%).

The median duration of response was 21.2 months (95% CI, 7.6 months to not estimable). The ORR was similar in patients with PD-L1 expressing tumors (35.8%; 95% CI, 23.1%–50.2%), who are more likely to respond to immunotherapy, compared with those without PD-L1 expression (39.5%; 95% CI, 25.0%–55.6%). For patients with MSI-H/dMMR, there was a higher ORR (63.6%; 95% CI, 30.8%–89.1%, versus 36.2%; 95% CI, 26.5%–46.7%).

Median progression-free survival was 7.4 months (95% CI, 5.3–8.7 months) and median overall survival was 16.7 months (15 months to not estimable). Moderate to severe treatment-related adverse events occurred in 83 patients (66.9%), and 22 patients (17.7%) discontinued 1 or both study drugs because of adverse effects. Two deaths were judged to be treatment related.

What is the risk of ovarian cancer in women who use powder in the genital area?

O’Brien KM, Tworoger SS, Harris HR, et al. Association of powder use in the genital area with risk of ovarian cancer. JAMA. 2020;323:49-59.

Women apply talcum powder to their genital area to keep skin dry and to prevent rashes. Powder can be applied by direct application, sanitary napkins, diaphragms, or tampons. Most powder products contain the mineral talc. Because it often is found in nature with asbestos, a known carcinogen, talc’s carcinogenic effects have been investigated.^26,27

Talc also might ascend through the genital tract and irritate the epithelial lining of the fallopian tubes or ovaries, possibly triggering an inflammatory response that may promote carcinogenesis.^28,29 Case-control studies have reported a possible association between genital powder use and ovarian cancer.^30,31 Since these studies, talc-related lawsuits and media coverage have increased.^32,33

Large prospective cohorts provide data for analysis

In a pooled analysis of 4 large US-based observational cohorts between 1976 and 2017, O’Brien and colleagues noted that 38% of the 252,745 women included in the study self-reported the use of powder in the genital area.³⁴ With a median of 11.2 years of follow-up, 2,168 women developed ovarian cancer (58 cases/100,000 person-years). Among women who reported using genital powder, the incidence of ovarian cancer was 61 cases/100,000 person-years, while for women who reported never using genital powder, the incidence was 55 cases/100,000 person-years. This corresponded to an estimated hazard ratio (HR) of 1.08 (95% CI, 0.99–1.17).

Frequent powder use, long-term use, and never use. Similar findings were seen for those with frequent use versus never use (HR, 1.09; 95% CI, 0.97–1.23) and long-term use versus never use (HR, 1.01; 95% CI, 0.82– 1.25). When restricting the group to women with a patent reproductive tract at baseline, the HR was 1.13 (95% CI, 1.01–1.26), but the P value for interaction comparing women with versus women without a patent reproductive tract was 0.15 (FIGURE 2).³⁴

Bottom line. In contrast to a prior meta-analysis, in this study there was no statistically significant association between the self-reported use of powder in the genital area and the incidence of ovarian cancer. ●

Gynecologic malignancies continue to be a major cause of cancer-related mortality in women. In 2020, a number of developments changed practice in gynecologic oncology. In this Update, we highlight 3 important articles. The first showed that human papillomavirus (HPV) vaccination reduced the rate of cervical cancer. The next evaluated a novel targeted therapeutic approach using the combination of pembrolizumab and lenvatinib in women with recurrent endometrial carcinoma that progressed after prior systemic therapy. Finally, the third article showed that talcum powder was not associated with an increased risk of ovarian cancer. We provide here a brief overview of the major findings of these studies and how these results are influencing practice.

Evidence establishes that HPV vaccination cuts risk of invasive cervical cancer

Lei J, Ploner A, Elfström KM, et al. HPV vaccination and the risk of invasive cervical cancer. N Engl J Med. 2020;383:1340-1348.

HPV infection is associated with 99% of cervical cancers, and approximately 65% to 75% of cases involve HPV 16 or 18.^1,2 The quadrivalent HPV (6, 11, 16, 18) vaccine was approved by the US Food and Drug Administration in 2006 for the prevention of cervical intraepithelial lesions and genital warts associated with HPV.^3-5 Previous studies of the HPV vaccine showed it to be effective in preventing HPV infection, genital warts, and high-grade precancerous cervical lesions, such as cervical intraepithelial neoplasia grade 2 (CIN2) and grade 3 (CIN3).^6-8 While the vaccine offers a number of advantages, the long-term goal of the vaccine—to reduce the incidence of invasive cervical cancer—was not shown until recently.

Large study followed HPV vaccinated and unvaccinated women

Lei and colleagues conducted a registry based cohort study from 2006 through 2017 of women aged 10 to 30 years who were living in Sweden.⁹ They followed the women from their 10th birthday until they were diagnosed with cervical cancer, died, emigrated from Sweden, were lost to follow-up, or turned 31 years of age. In the study, the unique personal identity numbers assigned to all Swedish residents were linked to a number of large national administrative databases. Beginning in 2007 in Sweden, the quadrivalent vaccine was subsidized for use in girls aged 13 to 17, and a subsequent catch-up period that started in 2012 incorporated women who had not been vaccinated.

Continue to: Cervical cancer rates were lowest in women vaccinated before age 17...

Cervical cancer rates were lowest in women vaccinated before age 17

A total of 1,672,983 women were included in the study; 527,871 received at least one dose of the HPV vaccine. During the study period, cervical cancer was diagnosed in 19 women who had received the quadrivalent HPV vaccine and in 538 women who had not received the vaccine. Women who initiated vaccination before age 17 had the lowest rates of cervical cancer (4 cases per 100,000 persons), followed by women vaccinated after age 17 (54 cases per 100,000 persons) and then those who were not vaccinated (94 cases per 100,000 persons).

After adjusting for confounders, the incidence rate ratio (RR) of cervical cancer was significantly lower among vaccinated women compared with unvaccinated women (RR, 0.37; 95% confidence interval [CI], 0.21– 0.57) (FIGURE 1).⁹ In addition, women who were vaccinated before age 17 demonstrated the greatest benefit. For those vaccinated before age 17 versus those who were unvaccinated, the RR was 0.12 (95% CI, 0.00–0.34). For women vaccinated between age 17 and 30 versus unvaccinated women, the RR was 0.47 (95% CI, 0.27–0.75).

Promising option for patients with advanced endometrial cancer: Lenvatinib plus pembrolizumab

Makker V, Taylor MH, Aghajanian C, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer. J Clin Oncol. 2020;38:2981-2992.

Advanced stage endometrial cancer is associated with a 17% 5-year survival rate.¹⁰ Paclitaxel with carboplatin is the standard first-line treatment for advanced, recurrent, and metastatic endometrial cancer; for women who do not respond to this regimen, effective treatment options are limited.^11,12

The immunotherapy approach

Immunotherapy is a more recently developed treatment, an approach in which the immune system is activated to target cancer cells. Pembrolizumab is a commonly used agent for many solid tumors.¹³ This drug binds to the programmed cell death receptor 1 (PD-1) or PD-ligand 1 (PD-L1), a component of the immune checkpoint, which then allows the immune system to target and destroy cancer cells.¹⁴

Prembrolizumab is FDA approved for use in the treatment of microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) solid tumors that have progressed after prior therapy and for which there are no satisfactory alternative treatment options.¹⁵ Endometrial cancers frequently display microsatellite instability and mismatch repair defects.¹⁶

Lenvatinib is an oral multikinase inhibitor that targets vascular endothelial growth factor receptors 1, 2, and 3; fibroblast growth factor receptors 1, 2, 3, and 4; and platelet derived growth factor receptor alpha, RET, and KIT.^17-19 In a phase 2 study of lenvatinib monotherapy for advanced previously treated endometrial cancer, the response rate was 14.3%.²⁰

While some preclinical studies have examined the combination of immune checkpoint inhibitors with lenvatinib,^21-23 a recent study is the first to evaluate this combination in patients with advanced tumors.²⁴

Continue to: Prembrolizumab-lenvatinib combination therapy...

Prembrolizumab-lenvatinib combination therapy

Makker and colleagues conducted an ongoing multinational, open-label, phase 1B/2 study of lenvatinib 20 mg daily orally plus pembrolizumab 200 mg intravenously once every 3 weeks in patients with select solid tumors.²⁴ Women with previously treated endometrial carcinoma (N = 125) were included. Of the study participants, 49% were PD-L1 positive and 10% were MSI-H/dMMR. The primary end point was objective response rate (ORR) at 24 weeks, which was 38.0% (95% CI, 28.8%–47.8%).

The median duration of response was 21.2 months (95% CI, 7.6 months to not estimable). The ORR was similar in patients with PD-L1 expressing tumors (35.8%; 95% CI, 23.1%–50.2%), who are more likely to respond to immunotherapy, compared with those without PD-L1 expression (39.5%; 95% CI, 25.0%–55.6%). For patients with MSI-H/dMMR, there was a higher ORR (63.6%; 95% CI, 30.8%–89.1%, versus 36.2%; 95% CI, 26.5%–46.7%).

Median progression-free survival was 7.4 months (95% CI, 5.3–8.7 months) and median overall survival was 16.7 months (15 months to not estimable). Moderate to severe treatment-related adverse events occurred in 83 patients (66.9%), and 22 patients (17.7%) discontinued 1 or both study drugs because of adverse effects. Two deaths were judged to be treatment related.

What is the risk of ovarian cancer in women who use powder in the genital area?

O’Brien KM, Tworoger SS, Harris HR, et al. Association of powder use in the genital area with risk of ovarian cancer. JAMA. 2020;323:49-59.

Women apply talcum powder to their genital area to keep skin dry and to prevent rashes. Powder can be applied by direct application, sanitary napkins, diaphragms, or tampons. Most powder products contain the mineral talc. Because it often is found in nature with asbestos, a known carcinogen, talc’s carcinogenic effects have been investigated.^26,27

Talc also might ascend through the genital tract and irritate the epithelial lining of the fallopian tubes or ovaries, possibly triggering an inflammatory response that may promote carcinogenesis.^28,29 Case-control studies have reported a possible association between genital powder use and ovarian cancer.^30,31 Since these studies, talc-related lawsuits and media coverage have increased.^32,33

Large prospective cohorts provide data for analysis

In a pooled analysis of 4 large US-based observational cohorts between 1976 and 2017, O’Brien and colleagues noted that 38% of the 252,745 women included in the study self-reported the use of powder in the genital area.³⁴ With a median of 11.2 years of follow-up, 2,168 women developed ovarian cancer (58 cases/100,000 person-years). Among women who reported using genital powder, the incidence of ovarian cancer was 61 cases/100,000 person-years, while for women who reported never using genital powder, the incidence was 55 cases/100,000 person-years. This corresponded to an estimated hazard ratio (HR) of 1.08 (95% CI, 0.99–1.17).

Frequent powder use, long-term use, and never use. Similar findings were seen for those with frequent use versus never use (HR, 1.09; 95% CI, 0.97–1.23) and long-term use versus never use (HR, 1.01; 95% CI, 0.82– 1.25). When restricting the group to women with a patent reproductive tract at baseline, the HR was 1.13 (95% CI, 1.01–1.26), but the P value for interaction comparing women with versus women without a patent reproductive tract was 0.15 (FIGURE 2).³⁴

Bottom line. In contrast to a prior meta-analysis, in this study there was no statistically significant association between the self-reported use of powder in the genital area and the incidence of ovarian cancer. ●