The Journal of Family Practice

A 15-year-old African American boy with no previous medical problems presented with a 2-month history of hair loss and pruritic papules on the occipital scalp that had developed after a barber shaved the area. Physical examination revealed 2 dozen 1 to 2 mm keloidal papules on the posterior neck and occipital scalp with areas of focal crusting (FIGURE).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Acne keloidalis nuchae is a chronic folliculitis that is characterized by smooth, dome-shaped papules on the posterior scalp and neck that become confluent, forming firm papules and hairless, keloid-like plaques.¹ Seen almost exclusively in young, postpubescent African American males, the condition is often asymptomatic, although some patients complain that the affected area itches. The cause of acne keloidalis nuchae may be associated with an acute pseudofolliculitis secondary to close-shaved curly hair reentering the skin; this leads to a foreign body reaction to hair protein and subsequent fibrosis.²

Differential Dx includes acne vulgaris

Acne keloidalis nuchae is diagnosed based on the appearance and location of the papules and keloid-like plaques as well as the patient’s history. The differential diagnosis includes acne vulgaris, hidradenitis suppurativa, and pseudofolliculitis barbae.

Acne vulgaris is a disorder of the pilosebaceous follicles primarily seen on the face, upper part of the chest, and back. Unlike acne keloidalis, it is characterized by the presence of comedones.^1,3

Hidradenitis suppurativa is characterized by secondary inflammation of the apocrine glands, which produces inflamed nodules and abscesses, primarily in the axillae, groin, and anogenital region.¹

Pseudofolliculitis barbae looks very similar to the initial presentation of acne keloidalis nuchae, and in fact, the pathophysiologic mechanism is the same. That said, pseudofolliculitis barbae occurs on the beard area and rarely produces keloidal papules.³

Treat with steroids, antibiotics

Treatment of acne keloidalis nuchae is often difficult. Early treatment, however, decreases the potential for developing larger lesions and long-term disfigurement.¹

Acne keloidalis nuchae is often improved with a combination of topical or intralesional steroids, topical tretinoin, and systemic antibiotics. Topical steroid therapy is indicated for mild to moderate acne keloidalis nuchae. Application of tretinoin 0.01% gel once or twice daily for several months has an anti-inflammatory effect and alters keratinocyte differentiation, which may discharge ingrown hairs. Topical and systemic antibiotics minimize infection associated with pseudofolliculitis and have anti-inflammatory effects.^1,3 Intralesional steroid injections (triamcinolone acetonide 2.5-5 mg/cc) with 0.1 cc injected into each lesion every 2 to 3 weeks for 3 to 6 injections can reduce inflammation and pruritus and reduce the thickness of keloidal scars.³ (For a how-to video that illustrates intralesional injections, go to http://www.jfponline.com/multimedia/video.html.)

Surgical management is generally reserved for large lesions that do not respond to medical management. Surgical excision with healing by secondary intention has been reported to cause fewer recurrences than surgical excision with primary closure.⁴ The use of CO₂ laser ablation can be considered for advanced cases.⁵

Teach patients with acne keloidalis nuchae that they can prevent further irritation of the affected area by not wearing head gear that rubs on the involved area. Patients should also refrain from shaving the posterior scalp and neck to prevent the pseudofolliculitis that may be causing this condition.^1,3 Electric barber trimmers that leave a short stubble but do not cleanly shave the skin are OK to use.

Our patient’s papules flattened and became asymptomatic over several months of treatment with tretinoin 0.01% gel, doxycycline 100 mg daily, and a series of biweekly intralesion steroid injections. A flat-scarred patch remained.

CORRESPONDENCE
Robert T. Brodell, MD, Division of Dermatology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216; rbrodell@umc.edu

A 15-year-old African American boy with no previous medical problems presented with a 2-month history of hair loss and pruritic papules on the occipital scalp that had developed after a barber shaved the area. Physical examination revealed 2 dozen 1 to 2 mm keloidal papules on the posterior neck and occipital scalp with areas of focal crusting (FIGURE).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Acne keloidalis nuchae is a chronic folliculitis that is characterized by smooth, dome-shaped papules on the posterior scalp and neck that become confluent, forming firm papules and hairless, keloid-like plaques.¹ Seen almost exclusively in young, postpubescent African American males, the condition is often asymptomatic, although some patients complain that the affected area itches. The cause of acne keloidalis nuchae may be associated with an acute pseudofolliculitis secondary to close-shaved curly hair reentering the skin; this leads to a foreign body reaction to hair protein and subsequent fibrosis.²

Differential Dx includes acne vulgaris

Acne keloidalis nuchae is diagnosed based on the appearance and location of the papules and keloid-like plaques as well as the patient’s history. The differential diagnosis includes acne vulgaris, hidradenitis suppurativa, and pseudofolliculitis barbae.

Acne vulgaris is a disorder of the pilosebaceous follicles primarily seen on the face, upper part of the chest, and back. Unlike acne keloidalis, it is characterized by the presence of comedones.^1,3

Hidradenitis suppurativa is characterized by secondary inflammation of the apocrine glands, which produces inflamed nodules and abscesses, primarily in the axillae, groin, and anogenital region.¹

Pseudofolliculitis barbae looks very similar to the initial presentation of acne keloidalis nuchae, and in fact, the pathophysiologic mechanism is the same. That said, pseudofolliculitis barbae occurs on the beard area and rarely produces keloidal papules.³

Treat with steroids, antibiotics

Treatment of acne keloidalis nuchae is often difficult. Early treatment, however, decreases the potential for developing larger lesions and long-term disfigurement.¹

Acne keloidalis nuchae is often improved with a combination of topical or intralesional steroids, topical tretinoin, and systemic antibiotics. Topical steroid therapy is indicated for mild to moderate acne keloidalis nuchae. Application of tretinoin 0.01% gel once or twice daily for several months has an anti-inflammatory effect and alters keratinocyte differentiation, which may discharge ingrown hairs. Topical and systemic antibiotics minimize infection associated with pseudofolliculitis and have anti-inflammatory effects.^1,3 Intralesional steroid injections (triamcinolone acetonide 2.5-5 mg/cc) with 0.1 cc injected into each lesion every 2 to 3 weeks for 3 to 6 injections can reduce inflammation and pruritus and reduce the thickness of keloidal scars.³ (For a how-to video that illustrates intralesional injections, go to http://www.jfponline.com/multimedia/video.html.)

Surgical management is generally reserved for large lesions that do not respond to medical management. Surgical excision with healing by secondary intention has been reported to cause fewer recurrences than surgical excision with primary closure.⁴ The use of CO₂ laser ablation can be considered for advanced cases.⁵

Teach patients with acne keloidalis nuchae that they can prevent further irritation of the affected area by not wearing head gear that rubs on the involved area. Patients should also refrain from shaving the posterior scalp and neck to prevent the pseudofolliculitis that may be causing this condition.^1,3 Electric barber trimmers that leave a short stubble but do not cleanly shave the skin are OK to use.

Our patient’s papules flattened and became asymptomatic over several months of treatment with tretinoin 0.01% gel, doxycycline 100 mg daily, and a series of biweekly intralesion steroid injections. A flat-scarred patch remained.

CORRESPONDENCE
Robert T. Brodell, MD, Division of Dermatology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216; rbrodell@umc.edu

A 15-year-old African American boy with no previous medical problems presented with a 2-month history of hair loss and pruritic papules on the occipital scalp that had developed after a barber shaved the area. Physical examination revealed 2 dozen 1 to 2 mm keloidal papules on the posterior neck and occipital scalp with areas of focal crusting (FIGURE).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Acne keloidalis nuchae is a chronic folliculitis that is characterized by smooth, dome-shaped papules on the posterior scalp and neck that become confluent, forming firm papules and hairless, keloid-like plaques.¹ Seen almost exclusively in young, postpubescent African American males, the condition is often asymptomatic, although some patients complain that the affected area itches. The cause of acne keloidalis nuchae may be associated with an acute pseudofolliculitis secondary to close-shaved curly hair reentering the skin; this leads to a foreign body reaction to hair protein and subsequent fibrosis.²

Differential Dx includes acne vulgaris

Acne keloidalis nuchae is diagnosed based on the appearance and location of the papules and keloid-like plaques as well as the patient’s history. The differential diagnosis includes acne vulgaris, hidradenitis suppurativa, and pseudofolliculitis barbae.

Acne vulgaris is a disorder of the pilosebaceous follicles primarily seen on the face, upper part of the chest, and back. Unlike acne keloidalis, it is characterized by the presence of comedones.^1,3

Hidradenitis suppurativa is characterized by secondary inflammation of the apocrine glands, which produces inflamed nodules and abscesses, primarily in the axillae, groin, and anogenital region.¹

Pseudofolliculitis barbae looks very similar to the initial presentation of acne keloidalis nuchae, and in fact, the pathophysiologic mechanism is the same. That said, pseudofolliculitis barbae occurs on the beard area and rarely produces keloidal papules.³

Treat with steroids, antibiotics

Treatment of acne keloidalis nuchae is often difficult. Early treatment, however, decreases the potential for developing larger lesions and long-term disfigurement.¹

Acne keloidalis nuchae is often improved with a combination of topical or intralesional steroids, topical tretinoin, and systemic antibiotics. Topical steroid therapy is indicated for mild to moderate acne keloidalis nuchae. Application of tretinoin 0.01% gel once or twice daily for several months has an anti-inflammatory effect and alters keratinocyte differentiation, which may discharge ingrown hairs. Topical and systemic antibiotics minimize infection associated with pseudofolliculitis and have anti-inflammatory effects.^1,3 Intralesional steroid injections (triamcinolone acetonide 2.5-5 mg/cc) with 0.1 cc injected into each lesion every 2 to 3 weeks for 3 to 6 injections can reduce inflammation and pruritus and reduce the thickness of keloidal scars.³ (For a how-to video that illustrates intralesional injections, go to http://www.jfponline.com/multimedia/video.html.)

Surgical management is generally reserved for large lesions that do not respond to medical management. Surgical excision with healing by secondary intention has been reported to cause fewer recurrences than surgical excision with primary closure.⁴ The use of CO₂ laser ablation can be considered for advanced cases.⁵

Teach patients with acne keloidalis nuchae that they can prevent further irritation of the affected area by not wearing head gear that rubs on the involved area. Patients should also refrain from shaving the posterior scalp and neck to prevent the pseudofolliculitis that may be causing this condition.^1,3 Electric barber trimmers that leave a short stubble but do not cleanly shave the skin are OK to use.

Our patient’s papules flattened and became asymptomatic over several months of treatment with tretinoin 0.01% gel, doxycycline 100 mg daily, and a series of biweekly intralesion steroid injections. A flat-scarred patch remained.

CORRESPONDENCE
Robert T. Brodell, MD, Division of Dermatology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216; rbrodell@umc.edu

What brought this report to mind was the October launch of the “Family Medicine for America’s Health” initiative at the American Academy of Family Physicians Assembly. The initiative, led by a collaboration of 8 family medicine organizations, seeks to organize and reinvigorate family medicine to respond to today’s health care challenges.

Can we rise to the challenge and create better health, better health care, and lower cost for patients and communities? As detailed in an article in Annals of Family Medicine,² the goals of Family Medicine for America’s Health are “... to strategically align work to improve practice models, payment, technology, workforce and education, and research to support the Triple Aim.”² The Triple Aim is an effort to create better health, better health care, and lower cost for patients and communities. Family Medicine for America’s Health “... is also a humble invitation to patients and to clinical and policy partners to collaborate in making family medicine even more effective.”² Teams will develop initiatives in 6 areas—technology, practice, payment, workforce education, research, and engagement—to bring family medicine to the center stage of health care reform.


To quote the famous American philosopher Yogi Berra, “It’s déjà vu all over again.” Although we have clearly made significant progress over the past half century, family medicine has a long way to go. The landscape of health care in the United States has changed markedly, but the principles of family medicine remain the same. The implementation of these principles, however, is what is so difficult for us today.

That is why each of us needs to step up to the plate and work with our family medicine organizations to improve primary care delivery in the United States. Doing so will ensure that it is not “déjà vu all over again” 50 years from now.

What brought this report to mind was the October launch of the “Family Medicine for America’s Health” initiative at the American Academy of Family Physicians Assembly. The initiative, led by a collaboration of 8 family medicine organizations, seeks to organize and reinvigorate family medicine to respond to today’s health care challenges.

Can we rise to the challenge and create better health, better health care, and lower cost for patients and communities? As detailed in an article in Annals of Family Medicine,² the goals of Family Medicine for America’s Health are “... to strategically align work to improve practice models, payment, technology, workforce and education, and research to support the Triple Aim.”² The Triple Aim is an effort to create better health, better health care, and lower cost for patients and communities. Family Medicine for America’s Health “... is also a humble invitation to patients and to clinical and policy partners to collaborate in making family medicine even more effective.”² Teams will develop initiatives in 6 areas—technology, practice, payment, workforce education, research, and engagement—to bring family medicine to the center stage of health care reform.


To quote the famous American philosopher Yogi Berra, “It’s déjà vu all over again.” Although we have clearly made significant progress over the past half century, family medicine has a long way to go. The landscape of health care in the United States has changed markedly, but the principles of family medicine remain the same. The implementation of these principles, however, is what is so difficult for us today.

That is why each of us needs to step up to the plate and work with our family medicine organizations to improve primary care delivery in the United States. Doing so will ensure that it is not “déjà vu all over again” 50 years from now.

What brought this report to mind was the October launch of the “Family Medicine for America’s Health” initiative at the American Academy of Family Physicians Assembly. The initiative, led by a collaboration of 8 family medicine organizations, seeks to organize and reinvigorate family medicine to respond to today’s health care challenges.

Can we rise to the challenge and create better health, better health care, and lower cost for patients and communities? As detailed in an article in Annals of Family Medicine,² the goals of Family Medicine for America’s Health are “... to strategically align work to improve practice models, payment, technology, workforce and education, and research to support the Triple Aim.”² The Triple Aim is an effort to create better health, better health care, and lower cost for patients and communities. Family Medicine for America’s Health “... is also a humble invitation to patients and to clinical and policy partners to collaborate in making family medicine even more effective.”² Teams will develop initiatives in 6 areas—technology, practice, payment, workforce education, research, and engagement—to bring family medicine to the center stage of health care reform.


To quote the famous American philosopher Yogi Berra, “It’s déjà vu all over again.” Although we have clearly made significant progress over the past half century, family medicine has a long way to go. The landscape of health care in the United States has changed markedly, but the principles of family medicine remain the same. The implementation of these principles, however, is what is so difficult for us today.

That is why each of us needs to step up to the plate and work with our family medicine organizations to improve primary care delivery in the United States. Doing so will ensure that it is not “déjà vu all over again” 50 years from now.

When a public health intervention succeeds and achieves long-term suppression of the target problem, an unfortunate irony is that, with time, the intervention can seem less vital. So it is with vaccines. Many patients and physicians today have never experienced the infectious diseases that once caused millions of deaths and much disability each year, and they therefore do not appreciate the impact these diseases had when they were prevalent.

It is estimated that just 9 of the routinely recommended vaccines prevent 42,000 deaths and 20 million cases of disease in every birth cohort.¹ With many of these diseases thus held at bay, attention shifted instead to the supposed risks of vaccines. Many people mistakenly believe a vaccine’s potential for harm is more likely than the chance of acquiring the disease it prevents, and they therefore refuse vaccines for themselves and their children, with little chance in the short term of suffering an adverse outcome for their decision.

In this review—which can inform primary care physicians’ discussions with vaccine-hesitant patients—we first highlight 2 preventable diseases, measles and Haemophilus influenzae type b (Hib) infection. Recent residency graduates may never see these diseases thanks to sustained vaccination programs. However, the risk of acquiring these infections has not disappeared entirely. After considering these examples, we examine the totality of the morbidity and mortality prevented by vaccination and describe the safety of current vaccines and the systems in place to assure their continued safety.

Measles: No longer endemic to the United States, but still a risk from importation


In the pre-vaccine era, measles (rubeola) infected more than 500,000 Americans annually and killed roughly 500.² This highly communicable systemic acute viral infection was once considered universal in childhood. After vaccine licensure in 1963, widespread immunization reduced the incidence by more than 98%, and by 2000 it had eliminated endemic measles from the United States. However, the disease has now reappeared—largely due to international travel and neglect in becoming vaccinated. As of October 31, 2014, the United States had 20 outbreaks and 603 cases of measles reported in 2014—a dramatic increase over recent years.³

Clinical appearance. Acute measles infection is characterized by high fever, cough, coryza, conjunctivitis, and rash. Koplik spots are a 24^- to 72-hour pathognomonic exanthem of blue-white spots 1 to 3 mm in diameter on an erythematous base along the buccal mucosa. The resolving exanthem coincides with the eruption of a blanching, maculopapular exanthem originating at the hairline, progressing down the trunk and out to the limbs (sparing the palms and soles), coalescing, and then fading with a fine desquamation in the same order of appearance over 7 days. Additional associated symptoms include anorexia, diarrhea, and generalized lymphadenopathy.^2,4

Complications are common with measles. Acute measles infection is rarely fatal. However, serious complications occur in nearly one-third of reported cases.² During the 1989-1991 measles resurgence in the United States, more than 100 deaths occurred among the 55,000 cases reported.^5-7 In early 2011, the United States saw the highest reported number of measles cases since 1996 due to importation. Of the 118 reported cases, 105 (89%) occurred in unvaccinated people, 47 (40%) required hospitalization, and 9 individuals developed pneumonia.⁸

While acute measles is rarely fatal, serious complications occur in nearly one-third of cases. Complications of measles infection are shown in TABLE 1.^2,4 Pneumonia (viral or superimposed bacterial) accounts for 60% of measles-related deaths.² Neurologic complications, while less frequent, can be severe.

Acute encephalitis occurs in 1 in 1000 to 2000 cases and presents within a week following the exanthem with fever, headache, vomiting, meningismus, change in mental status, convulsions, and coma.² Encephalitis has a fatality rate of 15%, leaving another 25% with residual neurologic damage.² Subacute sclerosing panencephalitis (SSPE) occurs in 5 to 10 cases per million (in the United States), on average 7 years after the initial measles infection.^9,10 After an insidious onset, behavior and intellect deteriorate, followed by ataxia, myoclonic seizures, and ultimately death. In the United States, the number of reported cases of SSPE has declined with the reduction in measles cases. However, in countries with less robust measles immunization eradication programs, the risk of developing SSPE remains.^9,10

Hib: Contained but not eradicated

Hib was once the leading cause of meningitis and a major cause of other invasive bacterial diseases, but it has been greatly controlled since the advent of routine Hib vaccination in 1990.¹¹ Hib is an encapsulated, gram-negative coccobacillus. There are 6 major capsular serotypes of Haemophilus influenzae, but serotype b was linked to major invasive disease in humans 95% of the time.¹² The spectrum of diseases caused by Hib is seen in TABLE 2.^13-15 Hib is transmitted by respiratory droplets from noninfected as well as infected carriers. Asymptomatic nasal carriage in the pre-vaccine era varied from 0.5% to 5%.¹²

Hib is primarily a disease of young children, with almost all cases occurring in children younger than 5 years of age (66% in those younger than 18 months). Other risk factors for invasive disease are those that increase the spread of respiratory droplets: crowding, lower socioeconomic status, day care attendance, large household size, and school-aged siblings. American Indian and Alaskan Native populations remain at higher risk due to incomplete vaccination rates and the sociodemographic risk factors noted above. Breastfeeding is protective.¹²

Three percent to 6% of cases of invasive Hib disease are fatal; another 20% can have long-term sequelae such as hearing loss. In the early 1990s, the peak incidence of Hib disease reached 41 cases per 100,000 population.¹² The reduction in incidence of Hib disease brought about by universal vaccination has been attributed to individual immunity, decreased asymptomatic nasal carriage, and herd immunity.¹²

Despite this progress, Hib continues to evade eradication. In Minnesota in 2008, 5 children, ages 5 months to 3 years, contracted invasive Hib disease (3 with meningitis, 1 with pneumonia, 1 with epiglottitis).¹⁶ Of the 5, only one was up to date with Hib vaccination; the others had not received vaccine because of shortages or parent refusal. These children were unrelated and had not been in contact with each other.

In a daycare outbreak in the United Kingdom, 2 cases of Hib disease (meningitis and septic arthritis) were identified in fully immunized children younger than 18 months, presumably due to a lack of complete vaccine efficacy.¹⁷ A study of nasal carriage (performed just prior to rifampin prophylaxis) among other attendees and caregivers revealed 3 asymptomatic carriers.¹⁷ Although Hib is largely well-contained in developed countries due to vaccination policies, the burden of disease in developing countries is estimated to be approximately 8.1 million serious illnesses with 371,000 deaths annually.¹³

The totality of morbidity and mortality prevented by vaccines

It is estimated that using just 9 routinely recommended vaccines prevents 
42,000 deaths and 20 million cases of disease in every birth cohort. Measles and Hib are 2 examples of vaccine-preventable diseases and the reduction in morbidity and mortality achievable with vaccines. TABLE 3¹⁸ summarizes the number of pre-vaccine era cases for selected diseases. Routine vaccination against 7 common childhood diseases not only prevents many thousands of deaths, as mentioned earlier,¹ but it saves $13.5 billion in direct costs in each birth cohort and saves society $68.8 billion in costs that include disability and lost productivity of both patients and caregivers.¹

Put simply, every dollar spent on the vaccination program saves $10 in direct and indirect costs to society.¹ Sustaining these successes and averting the resurgence of contained diseases requires a commitment to high immunization rates without delays and lapses—an effort made more challenging in light of misinformation about vaccine safety and resultant parental vaccine hesitancy.

Vaccine safety is ensured
 by rigorous systems


Despite an impressive record of safety, vaccines still cause anxiety among patients and parents in family practices. A recent survey identified concerns of long-term complications, autism, and thimerosal effects to be foremost on the minds of parents, whereas short-term effects were of much less concern.¹⁹ Causation of autism related to vaccines has been dismissed; the initial linkages have been shown to be fraudulent.²⁰ With the exception of some influenza vaccine preparations, thimerosal is no longer present in routinely administered children’s vaccines and has been shown not to be associated with autism.^21,22 To address parents’ and patients’ concerns about vaccine safety, and especially those surrounding short- and long-term complications, physicians should have a general understanding of the pre- and post-licensure mechanisms in the United States.

Pre-licensure safety is under the purview of vaccine manufacturers and the Center for Biologics Evaluation and Research at the US Food and Drug Administration (http://www.fda.gov/biologicsbloodvaccines/vaccines/default.htm). For licensure, manufacturers must provide clinical data to demonstrate sufficient safety and efficacy. Accordingly, pre-licensure assessments are conducted in a “closed system” under a research protocol. The vaccine recipients are volitional research subjects selected according to inclusion and exclusion criteria. They are also compensated. However, sample sizes are rarely large enough to exclude rare serious adverse events.

Once licensure has been granted, the focus of safety then shifts to the “open system” of usual clinical practice. Vaccine recipients are unselected members of the general population and may have underlying medical conditions, and sometimes—such as with school entry mandates—are less volitional. In this sphere, the responsible parties for safety include the government, manufacturers, and health care systems.

Three ongoing systems function to assure vaccine safety: the Vaccine Adverse Event Reporting System (VAERS), the Vaccine Safety Datalink (VSD), and the Clinical Immunization Safety Assessment (CISA) Network.^23,24

VAERS serves as an early warning system for coincidental safety signals and can generate hypotheses for further investigation.^24,25 It is characterized by high sensitivity but low specificity as it relies on voluntary reporting from health care personnel, parents, and others. This system was instrumental in identifying the initial cases of intussusception attributable to the rotavirus vaccine, RotaShield.²⁶

The VSD is a network of 10 large, geographically diverse and linked health maintenance organizations that cover about 3% of the US population. Within this “real time” network, vaccination (exposure) can be compared with outpatient, emergency department, hospital, and laboratory data (health outcomes), while accounting for demographic variables (confounders).^27,28 VSD studies linked the measles, mumps, rubella, and varicella vaccine to febrile seizures²⁹ and showed no relationship between cumulative vaccine antigen exposure and autism.³⁰

The CISA was established in 2001 to investigate the pathophysiologic mechanisms and biologic risks of adverse effects following immunization and to provide evidence-based vaccine safety assessments.

Based on all available evidence, routinely recommended vaccines have attained a very high level of safety. As with other preventive services, immunizations are generally provided to healthy individuals to maintain good health; thus, a low tolerance for significant adverse events exists. Well over 100 million doses of vaccines are given each year, yet the VAERS receives, on average, only 28,000 adverse event reports per year.

These reports comprise mild, moderate, and severe reactions to vaccines, but also adverse events that may not be related in any way other than chronologically to the vaccine’s administration. Despite this relatively low number of real safety concerns, it is still more likely that patients will know someone who has had a vaccine-related adverse event than someone who has had some of the diseases the vaccines prevent.³¹

Final thoughts

Current anti-vaccine sentiments appear to arise from varying perspectives.To appreciate the benefit 
of vaccine acceptance,
 we need only look to Europe, where high levels of vaccine refusal has led to a resurgence of vaccine-preventable diseases such as measles. Some are held by parents of children who have allegedly suffered a severe vaccine related adverse event; others by those opposed to government-mandated school immunization requirements; and some from those who have a dislike of vaccine manufacturers. These sentiments persist in part because of a low level of vaccine preventable diseases: When such illnesses are no longer deemed a threat, those who have concerns about vaccine safety, no matter how invalid, believe their concerns should trump all other considerations.

To appreciate the true benefit of vaccine acceptance, we need only look to Europe, where the anti-vaccine movement has led to high levels of vaccine refusal and a resurgence of vaccine-preventable diseases, such as measles, with their associated morbidity and mortality.³² In advocating for continued acceptance and widespread use of vaccines, family physicians can convey to patients and parents the magnitude of associated health benefits while confidently attesting to the effectiveness and safety of vaccines.

CORRESPONDENCE
John Epling, MD, MSEd, Department of Family Medicine, SUNY Upstate Medical University, 475 Irving Ave, Suite 200, Syracuse, NY 13210; eplingj@upstate.edu

When a public health intervention succeeds and achieves long-term suppression of the target problem, an unfortunate irony is that, with time, the intervention can seem less vital. So it is with vaccines. Many patients and physicians today have never experienced the infectious diseases that once caused millions of deaths and much disability each year, and they therefore do not appreciate the impact these diseases had when they were prevalent.

It is estimated that just 9 of the routinely recommended vaccines prevent 42,000 deaths and 20 million cases of disease in every birth cohort.¹ With many of these diseases thus held at bay, attention shifted instead to the supposed risks of vaccines. Many people mistakenly believe a vaccine’s potential for harm is more likely than the chance of acquiring the disease it prevents, and they therefore refuse vaccines for themselves and their children, with little chance in the short term of suffering an adverse outcome for their decision.

In this review—which can inform primary care physicians’ discussions with vaccine-hesitant patients—we first highlight 2 preventable diseases, measles and Haemophilus influenzae type b (Hib) infection. Recent residency graduates may never see these diseases thanks to sustained vaccination programs. However, the risk of acquiring these infections has not disappeared entirely. After considering these examples, we examine the totality of the morbidity and mortality prevented by vaccination and describe the safety of current vaccines and the systems in place to assure their continued safety.

Measles: No longer endemic to the United States, but still a risk from importation


In the pre-vaccine era, measles (rubeola) infected more than 500,000 Americans annually and killed roughly 500.² This highly communicable systemic acute viral infection was once considered universal in childhood. After vaccine licensure in 1963, widespread immunization reduced the incidence by more than 98%, and by 2000 it had eliminated endemic measles from the United States. However, the disease has now reappeared—largely due to international travel and neglect in becoming vaccinated. As of October 31, 2014, the United States had 20 outbreaks and 603 cases of measles reported in 2014—a dramatic increase over recent years.³

Clinical appearance. Acute measles infection is characterized by high fever, cough, coryza, conjunctivitis, and rash. Koplik spots are a 24^- to 72-hour pathognomonic exanthem of blue-white spots 1 to 3 mm in diameter on an erythematous base along the buccal mucosa. The resolving exanthem coincides with the eruption of a blanching, maculopapular exanthem originating at the hairline, progressing down the trunk and out to the limbs (sparing the palms and soles), coalescing, and then fading with a fine desquamation in the same order of appearance over 7 days. Additional associated symptoms include anorexia, diarrhea, and generalized lymphadenopathy.^2,4

Complications are common with measles. Acute measles infection is rarely fatal. However, serious complications occur in nearly one-third of reported cases.² During the 1989-1991 measles resurgence in the United States, more than 100 deaths occurred among the 55,000 cases reported.^5-7 In early 2011, the United States saw the highest reported number of measles cases since 1996 due to importation. Of the 118 reported cases, 105 (89%) occurred in unvaccinated people, 47 (40%) required hospitalization, and 9 individuals developed pneumonia.⁸

While acute measles is rarely fatal, serious complications occur in nearly one-third of cases. Complications of measles infection are shown in TABLE 1.^2,4 Pneumonia (viral or superimposed bacterial) accounts for 60% of measles-related deaths.² Neurologic complications, while less frequent, can be severe.

Acute encephalitis occurs in 1 in 1000 to 2000 cases and presents within a week following the exanthem with fever, headache, vomiting, meningismus, change in mental status, convulsions, and coma.² Encephalitis has a fatality rate of 15%, leaving another 25% with residual neurologic damage.² Subacute sclerosing panencephalitis (SSPE) occurs in 5 to 10 cases per million (in the United States), on average 7 years after the initial measles infection.^9,10 After an insidious onset, behavior and intellect deteriorate, followed by ataxia, myoclonic seizures, and ultimately death. In the United States, the number of reported cases of SSPE has declined with the reduction in measles cases. However, in countries with less robust measles immunization eradication programs, the risk of developing SSPE remains.^9,10

Hib: Contained but not eradicated

Hib was once the leading cause of meningitis and a major cause of other invasive bacterial diseases, but it has been greatly controlled since the advent of routine Hib vaccination in 1990.¹¹ Hib is an encapsulated, gram-negative coccobacillus. There are 6 major capsular serotypes of Haemophilus influenzae, but serotype b was linked to major invasive disease in humans 95% of the time.¹² The spectrum of diseases caused by Hib is seen in TABLE 2.^13-15 Hib is transmitted by respiratory droplets from noninfected as well as infected carriers. Asymptomatic nasal carriage in the pre-vaccine era varied from 0.5% to 5%.¹²

Hib is primarily a disease of young children, with almost all cases occurring in children younger than 5 years of age (66% in those younger than 18 months). Other risk factors for invasive disease are those that increase the spread of respiratory droplets: crowding, lower socioeconomic status, day care attendance, large household size, and school-aged siblings. American Indian and Alaskan Native populations remain at higher risk due to incomplete vaccination rates and the sociodemographic risk factors noted above. Breastfeeding is protective.¹²

Three percent to 6% of cases of invasive Hib disease are fatal; another 20% can have long-term sequelae such as hearing loss. In the early 1990s, the peak incidence of Hib disease reached 41 cases per 100,000 population.¹² The reduction in incidence of Hib disease brought about by universal vaccination has been attributed to individual immunity, decreased asymptomatic nasal carriage, and herd immunity.¹²

Despite this progress, Hib continues to evade eradication. In Minnesota in 2008, 5 children, ages 5 months to 3 years, contracted invasive Hib disease (3 with meningitis, 1 with pneumonia, 1 with epiglottitis).¹⁶ Of the 5, only one was up to date with Hib vaccination; the others had not received vaccine because of shortages or parent refusal. These children were unrelated and had not been in contact with each other.

In a daycare outbreak in the United Kingdom, 2 cases of Hib disease (meningitis and septic arthritis) were identified in fully immunized children younger than 18 months, presumably due to a lack of complete vaccine efficacy.¹⁷ A study of nasal carriage (performed just prior to rifampin prophylaxis) among other attendees and caregivers revealed 3 asymptomatic carriers.¹⁷ Although Hib is largely well-contained in developed countries due to vaccination policies, the burden of disease in developing countries is estimated to be approximately 8.1 million serious illnesses with 371,000 deaths annually.¹³

The totality of morbidity and mortality prevented by vaccines

It is estimated that using just 9 routinely recommended vaccines prevents 
42,000 deaths and 20 million cases of disease in every birth cohort. Measles and Hib are 2 examples of vaccine-preventable diseases and the reduction in morbidity and mortality achievable with vaccines. TABLE 3¹⁸ summarizes the number of pre-vaccine era cases for selected diseases. Routine vaccination against 7 common childhood diseases not only prevents many thousands of deaths, as mentioned earlier,¹ but it saves $13.5 billion in direct costs in each birth cohort and saves society $68.8 billion in costs that include disability and lost productivity of both patients and caregivers.¹

Put simply, every dollar spent on the vaccination program saves $10 in direct and indirect costs to society.¹ Sustaining these successes and averting the resurgence of contained diseases requires a commitment to high immunization rates without delays and lapses—an effort made more challenging in light of misinformation about vaccine safety and resultant parental vaccine hesitancy.

Vaccine safety is ensured
 by rigorous systems


Despite an impressive record of safety, vaccines still cause anxiety among patients and parents in family practices. A recent survey identified concerns of long-term complications, autism, and thimerosal effects to be foremost on the minds of parents, whereas short-term effects were of much less concern.¹⁹ Causation of autism related to vaccines has been dismissed; the initial linkages have been shown to be fraudulent.²⁰ With the exception of some influenza vaccine preparations, thimerosal is no longer present in routinely administered children’s vaccines and has been shown not to be associated with autism.^21,22 To address parents’ and patients’ concerns about vaccine safety, and especially those surrounding short- and long-term complications, physicians should have a general understanding of the pre- and post-licensure mechanisms in the United States.

Pre-licensure safety is under the purview of vaccine manufacturers and the Center for Biologics Evaluation and Research at the US Food and Drug Administration (http://www.fda.gov/biologicsbloodvaccines/vaccines/default.htm). For licensure, manufacturers must provide clinical data to demonstrate sufficient safety and efficacy. Accordingly, pre-licensure assessments are conducted in a “closed system” under a research protocol. The vaccine recipients are volitional research subjects selected according to inclusion and exclusion criteria. They are also compensated. However, sample sizes are rarely large enough to exclude rare serious adverse events.

Once licensure has been granted, the focus of safety then shifts to the “open system” of usual clinical practice. Vaccine recipients are unselected members of the general population and may have underlying medical conditions, and sometimes—such as with school entry mandates—are less volitional. In this sphere, the responsible parties for safety include the government, manufacturers, and health care systems.

Three ongoing systems function to assure vaccine safety: the Vaccine Adverse Event Reporting System (VAERS), the Vaccine Safety Datalink (VSD), and the Clinical Immunization Safety Assessment (CISA) Network.^23,24

VAERS serves as an early warning system for coincidental safety signals and can generate hypotheses for further investigation.^24,25 It is characterized by high sensitivity but low specificity as it relies on voluntary reporting from health care personnel, parents, and others. This system was instrumental in identifying the initial cases of intussusception attributable to the rotavirus vaccine, RotaShield.²⁶

The VSD is a network of 10 large, geographically diverse and linked health maintenance organizations that cover about 3% of the US population. Within this “real time” network, vaccination (exposure) can be compared with outpatient, emergency department, hospital, and laboratory data (health outcomes), while accounting for demographic variables (confounders).^27,28 VSD studies linked the measles, mumps, rubella, and varicella vaccine to febrile seizures²⁹ and showed no relationship between cumulative vaccine antigen exposure and autism.³⁰

The CISA was established in 2001 to investigate the pathophysiologic mechanisms and biologic risks of adverse effects following immunization and to provide evidence-based vaccine safety assessments.

Based on all available evidence, routinely recommended vaccines have attained a very high level of safety. As with other preventive services, immunizations are generally provided to healthy individuals to maintain good health; thus, a low tolerance for significant adverse events exists. Well over 100 million doses of vaccines are given each year, yet the VAERS receives, on average, only 28,000 adverse event reports per year.

These reports comprise mild, moderate, and severe reactions to vaccines, but also adverse events that may not be related in any way other than chronologically to the vaccine’s administration. Despite this relatively low number of real safety concerns, it is still more likely that patients will know someone who has had a vaccine-related adverse event than someone who has had some of the diseases the vaccines prevent.³¹

Final thoughts

Current anti-vaccine sentiments appear to arise from varying perspectives.To appreciate the benefit 
of vaccine acceptance,
 we need only look to Europe, where high levels of vaccine refusal has led to a resurgence of vaccine-preventable diseases such as measles. Some are held by parents of children who have allegedly suffered a severe vaccine related adverse event; others by those opposed to government-mandated school immunization requirements; and some from those who have a dislike of vaccine manufacturers. These sentiments persist in part because of a low level of vaccine preventable diseases: When such illnesses are no longer deemed a threat, those who have concerns about vaccine safety, no matter how invalid, believe their concerns should trump all other considerations.

To appreciate the true benefit of vaccine acceptance, we need only look to Europe, where the anti-vaccine movement has led to high levels of vaccine refusal and a resurgence of vaccine-preventable diseases, such as measles, with their associated morbidity and mortality.³² In advocating for continued acceptance and widespread use of vaccines, family physicians can convey to patients and parents the magnitude of associated health benefits while confidently attesting to the effectiveness and safety of vaccines.

CORRESPONDENCE
John Epling, MD, MSEd, Department of Family Medicine, SUNY Upstate Medical University, 475 Irving Ave, Suite 200, Syracuse, NY 13210; eplingj@upstate.edu

When a public health intervention succeeds and achieves long-term suppression of the target problem, an unfortunate irony is that, with time, the intervention can seem less vital. So it is with vaccines. Many patients and physicians today have never experienced the infectious diseases that once caused millions of deaths and much disability each year, and they therefore do not appreciate the impact these diseases had when they were prevalent.

It is estimated that just 9 of the routinely recommended vaccines prevent 42,000 deaths and 20 million cases of disease in every birth cohort.¹ With many of these diseases thus held at bay, attention shifted instead to the supposed risks of vaccines. Many people mistakenly believe a vaccine’s potential for harm is more likely than the chance of acquiring the disease it prevents, and they therefore refuse vaccines for themselves and their children, with little chance in the short term of suffering an adverse outcome for their decision.

In this review—which can inform primary care physicians’ discussions with vaccine-hesitant patients—we first highlight 2 preventable diseases, measles and Haemophilus influenzae type b (Hib) infection. Recent residency graduates may never see these diseases thanks to sustained vaccination programs. However, the risk of acquiring these infections has not disappeared entirely. After considering these examples, we examine the totality of the morbidity and mortality prevented by vaccination and describe the safety of current vaccines and the systems in place to assure their continued safety.

Measles: No longer endemic to the United States, but still a risk from importation


In the pre-vaccine era, measles (rubeola) infected more than 500,000 Americans annually and killed roughly 500.² This highly communicable systemic acute viral infection was once considered universal in childhood. After vaccine licensure in 1963, widespread immunization reduced the incidence by more than 98%, and by 2000 it had eliminated endemic measles from the United States. However, the disease has now reappeared—largely due to international travel and neglect in becoming vaccinated. As of October 31, 2014, the United States had 20 outbreaks and 603 cases of measles reported in 2014—a dramatic increase over recent years.³

Clinical appearance. Acute measles infection is characterized by high fever, cough, coryza, conjunctivitis, and rash. Koplik spots are a 24^- to 72-hour pathognomonic exanthem of blue-white spots 1 to 3 mm in diameter on an erythematous base along the buccal mucosa. The resolving exanthem coincides with the eruption of a blanching, maculopapular exanthem originating at the hairline, progressing down the trunk and out to the limbs (sparing the palms and soles), coalescing, and then fading with a fine desquamation in the same order of appearance over 7 days. Additional associated symptoms include anorexia, diarrhea, and generalized lymphadenopathy.^2,4

Complications are common with measles. Acute measles infection is rarely fatal. However, serious complications occur in nearly one-third of reported cases.² During the 1989-1991 measles resurgence in the United States, more than 100 deaths occurred among the 55,000 cases reported.^5-7 In early 2011, the United States saw the highest reported number of measles cases since 1996 due to importation. Of the 118 reported cases, 105 (89%) occurred in unvaccinated people, 47 (40%) required hospitalization, and 9 individuals developed pneumonia.⁸

While acute measles is rarely fatal, serious complications occur in nearly one-third of cases. Complications of measles infection are shown in TABLE 1.^2,4 Pneumonia (viral or superimposed bacterial) accounts for 60% of measles-related deaths.² Neurologic complications, while less frequent, can be severe.

Acute encephalitis occurs in 1 in 1000 to 2000 cases and presents within a week following the exanthem with fever, headache, vomiting, meningismus, change in mental status, convulsions, and coma.² Encephalitis has a fatality rate of 15%, leaving another 25% with residual neurologic damage.² Subacute sclerosing panencephalitis (SSPE) occurs in 5 to 10 cases per million (in the United States), on average 7 years after the initial measles infection.^9,10 After an insidious onset, behavior and intellect deteriorate, followed by ataxia, myoclonic seizures, and ultimately death. In the United States, the number of reported cases of SSPE has declined with the reduction in measles cases. However, in countries with less robust measles immunization eradication programs, the risk of developing SSPE remains.^9,10

Hib: Contained but not eradicated

Hib was once the leading cause of meningitis and a major cause of other invasive bacterial diseases, but it has been greatly controlled since the advent of routine Hib vaccination in 1990.¹¹ Hib is an encapsulated, gram-negative coccobacillus. There are 6 major capsular serotypes of Haemophilus influenzae, but serotype b was linked to major invasive disease in humans 95% of the time.¹² The spectrum of diseases caused by Hib is seen in TABLE 2.^13-15 Hib is transmitted by respiratory droplets from noninfected as well as infected carriers. Asymptomatic nasal carriage in the pre-vaccine era varied from 0.5% to 5%.¹²

Hib is primarily a disease of young children, with almost all cases occurring in children younger than 5 years of age (66% in those younger than 18 months). Other risk factors for invasive disease are those that increase the spread of respiratory droplets: crowding, lower socioeconomic status, day care attendance, large household size, and school-aged siblings. American Indian and Alaskan Native populations remain at higher risk due to incomplete vaccination rates and the sociodemographic risk factors noted above. Breastfeeding is protective.¹²

Three percent to 6% of cases of invasive Hib disease are fatal; another 20% can have long-term sequelae such as hearing loss. In the early 1990s, the peak incidence of Hib disease reached 41 cases per 100,000 population.¹² The reduction in incidence of Hib disease brought about by universal vaccination has been attributed to individual immunity, decreased asymptomatic nasal carriage, and herd immunity.¹²

Despite this progress, Hib continues to evade eradication. In Minnesota in 2008, 5 children, ages 5 months to 3 years, contracted invasive Hib disease (3 with meningitis, 1 with pneumonia, 1 with epiglottitis).¹⁶ Of the 5, only one was up to date with Hib vaccination; the others had not received vaccine because of shortages or parent refusal. These children were unrelated and had not been in contact with each other.

In a daycare outbreak in the United Kingdom, 2 cases of Hib disease (meningitis and septic arthritis) were identified in fully immunized children younger than 18 months, presumably due to a lack of complete vaccine efficacy.¹⁷ A study of nasal carriage (performed just prior to rifampin prophylaxis) among other attendees and caregivers revealed 3 asymptomatic carriers.¹⁷ Although Hib is largely well-contained in developed countries due to vaccination policies, the burden of disease in developing countries is estimated to be approximately 8.1 million serious illnesses with 371,000 deaths annually.¹³

The totality of morbidity and mortality prevented by vaccines

It is estimated that using just 9 routinely recommended vaccines prevents 
42,000 deaths and 20 million cases of disease in every birth cohort. Measles and Hib are 2 examples of vaccine-preventable diseases and the reduction in morbidity and mortality achievable with vaccines. TABLE 3¹⁸ summarizes the number of pre-vaccine era cases for selected diseases. Routine vaccination against 7 common childhood diseases not only prevents many thousands of deaths, as mentioned earlier,¹ but it saves $13.5 billion in direct costs in each birth cohort and saves society $68.8 billion in costs that include disability and lost productivity of both patients and caregivers.¹

Put simply, every dollar spent on the vaccination program saves $10 in direct and indirect costs to society.¹ Sustaining these successes and averting the resurgence of contained diseases requires a commitment to high immunization rates without delays and lapses—an effort made more challenging in light of misinformation about vaccine safety and resultant parental vaccine hesitancy.

Vaccine safety is ensured
 by rigorous systems


Despite an impressive record of safety, vaccines still cause anxiety among patients and parents in family practices. A recent survey identified concerns of long-term complications, autism, and thimerosal effects to be foremost on the minds of parents, whereas short-term effects were of much less concern.¹⁹ Causation of autism related to vaccines has been dismissed; the initial linkages have been shown to be fraudulent.²⁰ With the exception of some influenza vaccine preparations, thimerosal is no longer present in routinely administered children’s vaccines and has been shown not to be associated with autism.^21,22 To address parents’ and patients’ concerns about vaccine safety, and especially those surrounding short- and long-term complications, physicians should have a general understanding of the pre- and post-licensure mechanisms in the United States.

Pre-licensure safety is under the purview of vaccine manufacturers and the Center for Biologics Evaluation and Research at the US Food and Drug Administration (http://www.fda.gov/biologicsbloodvaccines/vaccines/default.htm). For licensure, manufacturers must provide clinical data to demonstrate sufficient safety and efficacy. Accordingly, pre-licensure assessments are conducted in a “closed system” under a research protocol. The vaccine recipients are volitional research subjects selected according to inclusion and exclusion criteria. They are also compensated. However, sample sizes are rarely large enough to exclude rare serious adverse events.

Once licensure has been granted, the focus of safety then shifts to the “open system” of usual clinical practice. Vaccine recipients are unselected members of the general population and may have underlying medical conditions, and sometimes—such as with school entry mandates—are less volitional. In this sphere, the responsible parties for safety include the government, manufacturers, and health care systems.

Three ongoing systems function to assure vaccine safety: the Vaccine Adverse Event Reporting System (VAERS), the Vaccine Safety Datalink (VSD), and the Clinical Immunization Safety Assessment (CISA) Network.^23,24

VAERS serves as an early warning system for coincidental safety signals and can generate hypotheses for further investigation.^24,25 It is characterized by high sensitivity but low specificity as it relies on voluntary reporting from health care personnel, parents, and others. This system was instrumental in identifying the initial cases of intussusception attributable to the rotavirus vaccine, RotaShield.²⁶

The VSD is a network of 10 large, geographically diverse and linked health maintenance organizations that cover about 3% of the US population. Within this “real time” network, vaccination (exposure) can be compared with outpatient, emergency department, hospital, and laboratory data (health outcomes), while accounting for demographic variables (confounders).^27,28 VSD studies linked the measles, mumps, rubella, and varicella vaccine to febrile seizures²⁹ and showed no relationship between cumulative vaccine antigen exposure and autism.³⁰

The CISA was established in 2001 to investigate the pathophysiologic mechanisms and biologic risks of adverse effects following immunization and to provide evidence-based vaccine safety assessments.

Based on all available evidence, routinely recommended vaccines have attained a very high level of safety. As with other preventive services, immunizations are generally provided to healthy individuals to maintain good health; thus, a low tolerance for significant adverse events exists. Well over 100 million doses of vaccines are given each year, yet the VAERS receives, on average, only 28,000 adverse event reports per year.

These reports comprise mild, moderate, and severe reactions to vaccines, but also adverse events that may not be related in any way other than chronologically to the vaccine’s administration. Despite this relatively low number of real safety concerns, it is still more likely that patients will know someone who has had a vaccine-related adverse event than someone who has had some of the diseases the vaccines prevent.³¹

Final thoughts

Current anti-vaccine sentiments appear to arise from varying perspectives.To appreciate the benefit 
of vaccine acceptance,
 we need only look to Europe, where high levels of vaccine refusal has led to a resurgence of vaccine-preventable diseases such as measles. Some are held by parents of children who have allegedly suffered a severe vaccine related adverse event; others by those opposed to government-mandated school immunization requirements; and some from those who have a dislike of vaccine manufacturers. These sentiments persist in part because of a low level of vaccine preventable diseases: When such illnesses are no longer deemed a threat, those who have concerns about vaccine safety, no matter how invalid, believe their concerns should trump all other considerations.

To appreciate the true benefit of vaccine acceptance, we need only look to Europe, where the anti-vaccine movement has led to high levels of vaccine refusal and a resurgence of vaccine-preventable diseases, such as measles, with their associated morbidity and mortality.³² In advocating for continued acceptance and widespread use of vaccines, family physicians can convey to patients and parents the magnitude of associated health benefits while confidently attesting to the effectiveness and safety of vaccines.

CORRESPONDENCE
John Epling, MD, MSEd, Department of Family Medicine, SUNY Upstate Medical University, 475 Irving Ave, Suite 200, Syracuse, NY 13210; eplingj@upstate.edu

From the 1960s to the ’90s, the prevalence of gout more than doubled among US residents.¹ In the years since,^1-5 gout has become increasingly prevalent worldwide. The key causes—an aging population, poor diet, widespread use of diuretics to treat cardiovascular disease, and comorbidities that promote hyperuricemia—have made the presentation of gout more complex and harder to manage, as well.^4-6

In fact, gout is frequently poorly managed. Initiation and maintenance of urate-lowering therapy (ULT)—as well as monitoring of serum urate—is not done often enough, and there is significant variation in medications used to treat gout. As a result, recommended serum urate targets commonly remain unattained.^7-9

We can do better. Enhanced understanding of risk factors for gout, augmented by recent research and the approval of 2 new pharmacologic agents (febuxostat in 2009¹⁰ and pegloticase in 2010¹¹), led to the American College of Rheumatology (ACR)’s first edition of gout guidelines, published in 2012.^12,13 The key components of gout management—patient education, lifestyle modifications, and pharmacologic therapy—are detailed in the text and tables that follow.

Understanding gout

Gout is actually a heterogeneous spectrum of diseases. It is characterized by an elevated serum urate concentration, with recurrent attacks of acute arthritis associated with monosodium urate crystals in synovial fluid leukocytes, but may also include tophi— typically painless nodular deposits of monosodium urate crystals in tissues in and around the joints—interstitial renal disease, and uric acid nephrolithiasis.¹⁴ Symptoms occur when the excess uric acid, the result of inefficient excretion rather than overproduction,^2,12,14,15 is deposited in restricted joint spaces.

Who’s at risk?

Risk factors include numerous cardiovascular and metabolic conditions, such as increased adiposity, hypertension, dyslipidemia, heart failure, insulin resistance, hyperglycemia, and renal disease.^3,6,12 Older age, genetics, poor diet, alcohol consumption, and medications associated with hyperuricemia, such as loop and thiazide diuretics and low-dose acetylsalicylic acid, are risk factors, as well.

Defined as a serum urate level ≥6.8 mg/dL—the point at which urate becomes insoluble in extracellular fluids^12,16,17—hyperuricemia is the most important modifiable risk factor for the development of gout. It can precipitate painful episodic attacks and complications such as chronic arthritis, urolithiasis, and tophi.¹²

What you’ll see

Patients often present with acute onset of pain and inflammation of a single joint, usually the first metatarsophalangeal. Other joints and soft tissues that may be involved to a lesser extent include (in order of frequency) the insteps, ankles, heels, knees, fingers, and elbows.¹⁴ Polyarticular attacks are an atypical manifestation and are sometimes confused with rheumatoid arthritis or osteoarthritis, particularly in the elderly.

Asymptomatic hyperuricemia alone does not establish a diagnosis of gout and there is no evidence to support urate-lowering therapy for isolated hyperuricemia. Clinical evaluation should include a history of symptom severity, disease burden, and comorbidities, and a thorough physical examination focused on findings such as tophi and acute and chronic synovitis.¹² Imaging studies are not recommended for the evaluation of gout because therapy is guided by symptoms.¹⁴

Asymptomatic hyperuricemia alone does not establish a diagnosis of gout, and there is no evidence to support ULT for isolated hyperuricemia. However, advice regarding lifestyle modifications and treatment of associated comorbidities may be warranted for such patients.¹⁸

How best to manage gout

Optimal gout management encompasses nonpharmacologic therapy, symptom management of acute attacks, and combination anti-inflammatory and ULT prophylaxis for patients with chronic gout.^12,13 It is important to work with patients to track and document both the number and the severity of acute attacks occurring over a 12-month period so that those who qualify for ULT can begin it without delay.¹² It is important to discuss treatment objectives and management of comorbidities, as well.

Review the medications the patient is taking, and consider eliminating prescription drugs associated with hyperuricemia if the risks outweigh the benefits.^19-21 In many cases, however, lifestyle modification—ie, eating a heart-healthy diet, exercising regularly, and losing weight—may do more to prevent gout attacks and manage complications than stopping medications that provide cardioprotection.⁶ The ACR divides food and beverages into 3 simple categories—avoid, limit, or encourage (TABLE 1.)¹²

Responding to an acute attack

Whenever possible, initiate pharmacologic therapy within 24 hours of symptom onset, because this has been associated with decreased pain and shorter duration of an acute attack.^8,13 The choice of drug should be guided by the severity of the attack, as determined by both a pain score on a visual analog scale (VAS) and the number of affected joints; patient preference, prior response, and associated comorbidities are also important considerations (TABLE 2^8,13,14). When medications are prescribed for acute attacks or chronic gout, a discussion of adverse effects, drug interactions, contraindications, cost, and the importance of adherence is needed, as well.

For mild to moderate pain (≤6 out of 10 on a VAS) involving a few small joints or one or 2 large joints, monotherapy with a nonsteroidal anti-inflammatory drug (NSAID), a corticosteroid, or colchicine is recommended. For severe pain (>6 out of 10) and/or polyarticular involvement (≥4 joints in more than one region of the body), combination therapy is recommended (eg, colchicine and either an NSAID or a corticosteroid).¹³ Prednisone, methylprednisolone, and adrenocorticotropic hormone are options for patients who are NPO. Acute gout therapy should be continued until the attack resolves, which can range from 5 to 14 days.¹³

Colchicine considerations. The dose of colchicine recommended by the ACR for an acute gout attack (1.2 mg loading dose, followed by 0.6 mg one hour later, then followed after 12 hours, as needed, by up to 0.6 mg once or twice a day) is substantially lower than the dosing schedule used historically (1.0 mg loading dose, followed by 0.5 mg every 2-3 hours). Higher doses have not proven to be more effective, however, and typically led to gastrointestinal toxicity, causing patients to stop taking the drug before acute symptoms resolved.^8,13,22

Keep in mind, too, that colchicine therapy should not be initiated more than 36 hours after symptom onset, as therapy is less effective beyond this time frame.^8,13 In addition, concurrent use with P-glycoprotein and CYP3A4 inhibitors—eg, clarithromycin and erythromycin and some antifungals, antiretrovirals, calcium-channel blockers, immunosuppressants, and statins—may increase the risk of colchicine toxicity and should be avoided.

Treating chronic gout

Management of recurrent or progressive gout is aimed at reducing and maintaining serum urate levels <6.0 mg/dL, using ULT (TABLE 3^12,23-25) combined with anti-inflammatory prophylaxis to reduce the frequency of gout flares and the size and number of tophi.^12,23 Patients who meet one or more of the following criteria qualify for ULT:

• the presence of tophi

• ≥2 acute attacks per year
• chronic kidney disease (CKD) stages 2 through 5

• a history of urolithiasis.¹²

Both ULT and anti-inflammatory therapy should be started after an acute gout attack resolves, but patients already on prophylactic therapy should continue the regimen both during and after acute attacks to avoid more frequent exacerbations.^9,12 If gout symptoms persist despite a serum urate level of <6.0 mg/dL, increase the dose of ULT to achieve a target of <5 mg/dL to reduce the frequency of flares and the size and number of tophi.^12,26

Allopurinol, a xanthine oxidase inhibitor, is typically used as first-line ULT due to efficacy and low cost.¹³ Febuxostat, also a xanthine oxidase inhibitor, is an additional first-line option, although the US Food and Drug Administration issued a warning based on postmarketing reports of hepatic failure.²⁵ In the case of a xanthine oxidase allergy or intolerance, probenecid may be used as an alternative first-line therapy. First-line agents for anti-inflammatory prophylaxis include low-dose colchicine (0.6 mg once or twice daily) and low-dose NSAIDs. Oral corticosteroids (<10 mg/d) are considered second-line therapy.¹³

Allopurinol hypersensitivity. Although allopurinol is generally well tolerated, about 2% of patients develop a mild rash and up to 5% of patients stop taking it because of an adverse effect.²⁵ More importantly, allopurinol hypersensitivity syndrome (AHS) is rare but potentially fatal; in the United States, it is estimated that one in every 1000 patients treated with allopurinol will develop AHS.^12,27

Allopurinol hypersensitivity syndrome is rare, but potentially fatal. AHS is characterized by a rash (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis), eosinophilia, leukocytosis, fever, hepatitis, and renal failure.^12,25 There is no cure; the mainstay of treatment is early diagnosis, withdrawal of allopurinol, and supportive care.²⁵ Because of the high mortality rate (20%-25%),^12,27 genetic screening for allele HLA-B*5801 prior to starting allopurinol therapy is recommended for patients in high-risk groups: Koreans with CKD (stage 3 or worse) and all Han Chinese and Thai patients, regardless of kidney function.¹² Alternative therapies should be used for patients who test positive for the allele.

Duration of therapy

Pharmacologic treatment of an acute gout attack should continue until the attack resolves, which can range from 5 to 14 days. The duration of treatment for chronic gout is far longer.

Anti-inflammatory prophylaxis should continue for whichever is greater: 3 months after the target serum urate level is achieved for patients with no evidence of tophi; or 6 months after the target serum urate level is achieved and previously detected tophi have resolved.¹³

ULT should continue indefinitely,¹² with monitoring of serum urate levels every 2 to 5 weeks until the target is achieved and every 6 months thereafter.

Not responding to therapy? Consider nonadherence, refractory gout

Studies have found that less than half of patients started on urate-lowering therapy take their medication as prescribed for the entire first year of therapy. If a patient is not responding as expected, consider whether he or she is taking the medication as prescribed. Gout therapy has one of the lowest adherence rates of any chronic disorder.^7,8,12,28-30 Studies have found that less than half of patients started on ULT take their medication as prescribed for the entire first year of therapy.^9,28

To promote adherence, schedule more frequent follow-up appointments after initiating urate-lowering therapy. Evidence suggests that nonadherence is especially likely among younger and healthier individuals, possibly because they have little experience managing chronic conditions or needing ongoing care.^28-30 Such patients may also be unsure of when and how to take their medication. To promote adherence, physicians should schedule more frequent follow-up appointments after initiating ULT to assess management of the disease and stress the importance of following the medication regimen as prescribed.^9,28

Not all patients who don’t respond to ULT are nonadherent, of course. Some have refractory gout. If uric acid levels do not reach the goal of <6 mg/dL (or <5 mg/dL) at the maximum dose of a first-line xanthine oxidase inhibitor, add a uricosuric agent such as probenecid, fenofibrate, or losartan.¹²

Pegloticase, a pegylated recombinant form of urate oxidase enzyme that converts uric acid to allantoin³¹ (a water-soluble metabolite of uric acid), is a possible therapeutic option for patients who do not achieve adequate serum urate levels and continue to have symptoms of gout.¹² Candidates for pegloticase therapy, which is administered intravenously, include adult patients with gout refractory to conventional ULT or excessive uric acid accumulation due to chemotherapy and those with contraindications to conventional ULT.

Pegloticase is associated with anaphylactic and infusion reactions, requires extensive monitoring, and costs thousands of dollars per month, however. Thus, it is important to carefully evaluate the extent of disease burden (ie, gout symptoms and effect on quality of life) and determine whether the patient has taken ULT and uricosuric drugs as prescribed before considering this option. Pegloticase requires the same anti-inflammatory prophylaxis as other forms of ULT, but there is no consensus on the duration of use.¹²

CORRESPONDENCE
Tatum Mead, PharmD, University of Missouri-Kansas City School of Pharmacy, Health Sciences Building, Room 2243, 2464 Charlotte Street, Kansas City, MO 64108-2792; meadt@umkc.edu

From the 1960s to the ’90s, the prevalence of gout more than doubled among US residents.¹ In the years since,^1-5 gout has become increasingly prevalent worldwide. The key causes—an aging population, poor diet, widespread use of diuretics to treat cardiovascular disease, and comorbidities that promote hyperuricemia—have made the presentation of gout more complex and harder to manage, as well.^4-6

In fact, gout is frequently poorly managed. Initiation and maintenance of urate-lowering therapy (ULT)—as well as monitoring of serum urate—is not done often enough, and there is significant variation in medications used to treat gout. As a result, recommended serum urate targets commonly remain unattained.^7-9

We can do better. Enhanced understanding of risk factors for gout, augmented by recent research and the approval of 2 new pharmacologic agents (febuxostat in 2009¹⁰ and pegloticase in 2010¹¹), led to the American College of Rheumatology (ACR)’s first edition of gout guidelines, published in 2012.^12,13 The key components of gout management—patient education, lifestyle modifications, and pharmacologic therapy—are detailed in the text and tables that follow.

Understanding gout

Gout is actually a heterogeneous spectrum of diseases. It is characterized by an elevated serum urate concentration, with recurrent attacks of acute arthritis associated with monosodium urate crystals in synovial fluid leukocytes, but may also include tophi— typically painless nodular deposits of monosodium urate crystals in tissues in and around the joints—interstitial renal disease, and uric acid nephrolithiasis.¹⁴ Symptoms occur when the excess uric acid, the result of inefficient excretion rather than overproduction,^2,12,14,15 is deposited in restricted joint spaces.

Who’s at risk?

Risk factors include numerous cardiovascular and metabolic conditions, such as increased adiposity, hypertension, dyslipidemia, heart failure, insulin resistance, hyperglycemia, and renal disease.^3,6,12 Older age, genetics, poor diet, alcohol consumption, and medications associated with hyperuricemia, such as loop and thiazide diuretics and low-dose acetylsalicylic acid, are risk factors, as well.

Defined as a serum urate level ≥6.8 mg/dL—the point at which urate becomes insoluble in extracellular fluids^12,16,17—hyperuricemia is the most important modifiable risk factor for the development of gout. It can precipitate painful episodic attacks and complications such as chronic arthritis, urolithiasis, and tophi.¹²

What you’ll see

Patients often present with acute onset of pain and inflammation of a single joint, usually the first metatarsophalangeal. Other joints and soft tissues that may be involved to a lesser extent include (in order of frequency) the insteps, ankles, heels, knees, fingers, and elbows.¹⁴ Polyarticular attacks are an atypical manifestation and are sometimes confused with rheumatoid arthritis or osteoarthritis, particularly in the elderly.

Asymptomatic hyperuricemia alone does not establish a diagnosis of gout and there is no evidence to support urate-lowering therapy for isolated hyperuricemia. Clinical evaluation should include a history of symptom severity, disease burden, and comorbidities, and a thorough physical examination focused on findings such as tophi and acute and chronic synovitis.¹² Imaging studies are not recommended for the evaluation of gout because therapy is guided by symptoms.¹⁴

Asymptomatic hyperuricemia alone does not establish a diagnosis of gout, and there is no evidence to support ULT for isolated hyperuricemia. However, advice regarding lifestyle modifications and treatment of associated comorbidities may be warranted for such patients.¹⁸

How best to manage gout

Optimal gout management encompasses nonpharmacologic therapy, symptom management of acute attacks, and combination anti-inflammatory and ULT prophylaxis for patients with chronic gout.^12,13 It is important to work with patients to track and document both the number and the severity of acute attacks occurring over a 12-month period so that those who qualify for ULT can begin it without delay.¹² It is important to discuss treatment objectives and management of comorbidities, as well.

Review the medications the patient is taking, and consider eliminating prescription drugs associated with hyperuricemia if the risks outweigh the benefits.^19-21 In many cases, however, lifestyle modification—ie, eating a heart-healthy diet, exercising regularly, and losing weight—may do more to prevent gout attacks and manage complications than stopping medications that provide cardioprotection.⁶ The ACR divides food and beverages into 3 simple categories—avoid, limit, or encourage (TABLE 1.)¹²

Responding to an acute attack

Whenever possible, initiate pharmacologic therapy within 24 hours of symptom onset, because this has been associated with decreased pain and shorter duration of an acute attack.^8,13 The choice of drug should be guided by the severity of the attack, as determined by both a pain score on a visual analog scale (VAS) and the number of affected joints; patient preference, prior response, and associated comorbidities are also important considerations (TABLE 2^8,13,14). When medications are prescribed for acute attacks or chronic gout, a discussion of adverse effects, drug interactions, contraindications, cost, and the importance of adherence is needed, as well.

For mild to moderate pain (≤6 out of 10 on a VAS) involving a few small joints or one or 2 large joints, monotherapy with a nonsteroidal anti-inflammatory drug (NSAID), a corticosteroid, or colchicine is recommended. For severe pain (>6 out of 10) and/or polyarticular involvement (≥4 joints in more than one region of the body), combination therapy is recommended (eg, colchicine and either an NSAID or a corticosteroid).¹³ Prednisone, methylprednisolone, and adrenocorticotropic hormone are options for patients who are NPO. Acute gout therapy should be continued until the attack resolves, which can range from 5 to 14 days.¹³

Colchicine considerations. The dose of colchicine recommended by the ACR for an acute gout attack (1.2 mg loading dose, followed by 0.6 mg one hour later, then followed after 12 hours, as needed, by up to 0.6 mg once or twice a day) is substantially lower than the dosing schedule used historically (1.0 mg loading dose, followed by 0.5 mg every 2-3 hours). Higher doses have not proven to be more effective, however, and typically led to gastrointestinal toxicity, causing patients to stop taking the drug before acute symptoms resolved.^8,13,22

Keep in mind, too, that colchicine therapy should not be initiated more than 36 hours after symptom onset, as therapy is less effective beyond this time frame.^8,13 In addition, concurrent use with P-glycoprotein and CYP3A4 inhibitors—eg, clarithromycin and erythromycin and some antifungals, antiretrovirals, calcium-channel blockers, immunosuppressants, and statins—may increase the risk of colchicine toxicity and should be avoided.

Treating chronic gout

Management of recurrent or progressive gout is aimed at reducing and maintaining serum urate levels <6.0 mg/dL, using ULT (TABLE 3^12,23-25) combined with anti-inflammatory prophylaxis to reduce the frequency of gout flares and the size and number of tophi.^12,23 Patients who meet one or more of the following criteria qualify for ULT:

• the presence of tophi

• ≥2 acute attacks per year
• chronic kidney disease (CKD) stages 2 through 5

• a history of urolithiasis.¹²

Both ULT and anti-inflammatory therapy should be started after an acute gout attack resolves, but patients already on prophylactic therapy should continue the regimen both during and after acute attacks to avoid more frequent exacerbations.^9,12 If gout symptoms persist despite a serum urate level of <6.0 mg/dL, increase the dose of ULT to achieve a target of <5 mg/dL to reduce the frequency of flares and the size and number of tophi.^12,26

Allopurinol, a xanthine oxidase inhibitor, is typically used as first-line ULT due to efficacy and low cost.¹³ Febuxostat, also a xanthine oxidase inhibitor, is an additional first-line option, although the US Food and Drug Administration issued a warning based on postmarketing reports of hepatic failure.²⁵ In the case of a xanthine oxidase allergy or intolerance, probenecid may be used as an alternative first-line therapy. First-line agents for anti-inflammatory prophylaxis include low-dose colchicine (0.6 mg once or twice daily) and low-dose NSAIDs. Oral corticosteroids (<10 mg/d) are considered second-line therapy.¹³

Allopurinol hypersensitivity. Although allopurinol is generally well tolerated, about 2% of patients develop a mild rash and up to 5% of patients stop taking it because of an adverse effect.²⁵ More importantly, allopurinol hypersensitivity syndrome (AHS) is rare but potentially fatal; in the United States, it is estimated that one in every 1000 patients treated with allopurinol will develop AHS.^12,27

Allopurinol hypersensitivity syndrome is rare, but potentially fatal. AHS is characterized by a rash (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis), eosinophilia, leukocytosis, fever, hepatitis, and renal failure.^12,25 There is no cure; the mainstay of treatment is early diagnosis, withdrawal of allopurinol, and supportive care.²⁵ Because of the high mortality rate (20%-25%),^12,27 genetic screening for allele HLA-B*5801 prior to starting allopurinol therapy is recommended for patients in high-risk groups: Koreans with CKD (stage 3 or worse) and all Han Chinese and Thai patients, regardless of kidney function.¹² Alternative therapies should be used for patients who test positive for the allele.

Duration of therapy

Pharmacologic treatment of an acute gout attack should continue until the attack resolves, which can range from 5 to 14 days. The duration of treatment for chronic gout is far longer.

Anti-inflammatory prophylaxis should continue for whichever is greater: 3 months after the target serum urate level is achieved for patients with no evidence of tophi; or 6 months after the target serum urate level is achieved and previously detected tophi have resolved.¹³

ULT should continue indefinitely,¹² with monitoring of serum urate levels every 2 to 5 weeks until the target is achieved and every 6 months thereafter.

Not responding to therapy? Consider nonadherence, refractory gout

Studies have found that less than half of patients started on urate-lowering therapy take their medication as prescribed for the entire first year of therapy. If a patient is not responding as expected, consider whether he or she is taking the medication as prescribed. Gout therapy has one of the lowest adherence rates of any chronic disorder.^7,8,12,28-30 Studies have found that less than half of patients started on ULT take their medication as prescribed for the entire first year of therapy.^9,28

To promote adherence, schedule more frequent follow-up appointments after initiating urate-lowering therapy. Evidence suggests that nonadherence is especially likely among younger and healthier individuals, possibly because they have little experience managing chronic conditions or needing ongoing care.^28-30 Such patients may also be unsure of when and how to take their medication. To promote adherence, physicians should schedule more frequent follow-up appointments after initiating ULT to assess management of the disease and stress the importance of following the medication regimen as prescribed.^9,28

Not all patients who don’t respond to ULT are nonadherent, of course. Some have refractory gout. If uric acid levels do not reach the goal of <6 mg/dL (or <5 mg/dL) at the maximum dose of a first-line xanthine oxidase inhibitor, add a uricosuric agent such as probenecid, fenofibrate, or losartan.¹²

Pegloticase, a pegylated recombinant form of urate oxidase enzyme that converts uric acid to allantoin³¹ (a water-soluble metabolite of uric acid), is a possible therapeutic option for patients who do not achieve adequate serum urate levels and continue to have symptoms of gout.¹² Candidates for pegloticase therapy, which is administered intravenously, include adult patients with gout refractory to conventional ULT or excessive uric acid accumulation due to chemotherapy and those with contraindications to conventional ULT.

Pegloticase is associated with anaphylactic and infusion reactions, requires extensive monitoring, and costs thousands of dollars per month, however. Thus, it is important to carefully evaluate the extent of disease burden (ie, gout symptoms and effect on quality of life) and determine whether the patient has taken ULT and uricosuric drugs as prescribed before considering this option. Pegloticase requires the same anti-inflammatory prophylaxis as other forms of ULT, but there is no consensus on the duration of use.¹²

CORRESPONDENCE
Tatum Mead, PharmD, University of Missouri-Kansas City School of Pharmacy, Health Sciences Building, Room 2243, 2464 Charlotte Street, Kansas City, MO 64108-2792; meadt@umkc.edu

From the 1960s to the ’90s, the prevalence of gout more than doubled among US residents.¹ In the years since,^1-5 gout has become increasingly prevalent worldwide. The key causes—an aging population, poor diet, widespread use of diuretics to treat cardiovascular disease, and comorbidities that promote hyperuricemia—have made the presentation of gout more complex and harder to manage, as well.^4-6

In fact, gout is frequently poorly managed. Initiation and maintenance of urate-lowering therapy (ULT)—as well as monitoring of serum urate—is not done often enough, and there is significant variation in medications used to treat gout. As a result, recommended serum urate targets commonly remain unattained.^7-9

We can do better. Enhanced understanding of risk factors for gout, augmented by recent research and the approval of 2 new pharmacologic agents (febuxostat in 2009¹⁰ and pegloticase in 2010¹¹), led to the American College of Rheumatology (ACR)’s first edition of gout guidelines, published in 2012.^12,13 The key components of gout management—patient education, lifestyle modifications, and pharmacologic therapy—are detailed in the text and tables that follow.

Understanding gout

Gout is actually a heterogeneous spectrum of diseases. It is characterized by an elevated serum urate concentration, with recurrent attacks of acute arthritis associated with monosodium urate crystals in synovial fluid leukocytes, but may also include tophi— typically painless nodular deposits of monosodium urate crystals in tissues in and around the joints—interstitial renal disease, and uric acid nephrolithiasis.¹⁴ Symptoms occur when the excess uric acid, the result of inefficient excretion rather than overproduction,^2,12,14,15 is deposited in restricted joint spaces.

Who’s at risk?

Risk factors include numerous cardiovascular and metabolic conditions, such as increased adiposity, hypertension, dyslipidemia, heart failure, insulin resistance, hyperglycemia, and renal disease.^3,6,12 Older age, genetics, poor diet, alcohol consumption, and medications associated with hyperuricemia, such as loop and thiazide diuretics and low-dose acetylsalicylic acid, are risk factors, as well.

Defined as a serum urate level ≥6.8 mg/dL—the point at which urate becomes insoluble in extracellular fluids^12,16,17—hyperuricemia is the most important modifiable risk factor for the development of gout. It can precipitate painful episodic attacks and complications such as chronic arthritis, urolithiasis, and tophi.¹²

What you’ll see

Patients often present with acute onset of pain and inflammation of a single joint, usually the first metatarsophalangeal. Other joints and soft tissues that may be involved to a lesser extent include (in order of frequency) the insteps, ankles, heels, knees, fingers, and elbows.¹⁴ Polyarticular attacks are an atypical manifestation and are sometimes confused with rheumatoid arthritis or osteoarthritis, particularly in the elderly.

Asymptomatic hyperuricemia alone does not establish a diagnosis of gout and there is no evidence to support urate-lowering therapy for isolated hyperuricemia. Clinical evaluation should include a history of symptom severity, disease burden, and comorbidities, and a thorough physical examination focused on findings such as tophi and acute and chronic synovitis.¹² Imaging studies are not recommended for the evaluation of gout because therapy is guided by symptoms.¹⁴

Asymptomatic hyperuricemia alone does not establish a diagnosis of gout, and there is no evidence to support ULT for isolated hyperuricemia. However, advice regarding lifestyle modifications and treatment of associated comorbidities may be warranted for such patients.¹⁸

How best to manage gout

Optimal gout management encompasses nonpharmacologic therapy, symptom management of acute attacks, and combination anti-inflammatory and ULT prophylaxis for patients with chronic gout.^12,13 It is important to work with patients to track and document both the number and the severity of acute attacks occurring over a 12-month period so that those who qualify for ULT can begin it without delay.¹² It is important to discuss treatment objectives and management of comorbidities, as well.

Review the medications the patient is taking, and consider eliminating prescription drugs associated with hyperuricemia if the risks outweigh the benefits.^19-21 In many cases, however, lifestyle modification—ie, eating a heart-healthy diet, exercising regularly, and losing weight—may do more to prevent gout attacks and manage complications than stopping medications that provide cardioprotection.⁶ The ACR divides food and beverages into 3 simple categories—avoid, limit, or encourage (TABLE 1.)¹²

Responding to an acute attack

Whenever possible, initiate pharmacologic therapy within 24 hours of symptom onset, because this has been associated with decreased pain and shorter duration of an acute attack.^8,13 The choice of drug should be guided by the severity of the attack, as determined by both a pain score on a visual analog scale (VAS) and the number of affected joints; patient preference, prior response, and associated comorbidities are also important considerations (TABLE 2^8,13,14). When medications are prescribed for acute attacks or chronic gout, a discussion of adverse effects, drug interactions, contraindications, cost, and the importance of adherence is needed, as well.

For mild to moderate pain (≤6 out of 10 on a VAS) involving a few small joints or one or 2 large joints, monotherapy with a nonsteroidal anti-inflammatory drug (NSAID), a corticosteroid, or colchicine is recommended. For severe pain (>6 out of 10) and/or polyarticular involvement (≥4 joints in more than one region of the body), combination therapy is recommended (eg, colchicine and either an NSAID or a corticosteroid).¹³ Prednisone, methylprednisolone, and adrenocorticotropic hormone are options for patients who are NPO. Acute gout therapy should be continued until the attack resolves, which can range from 5 to 14 days.¹³

Colchicine considerations. The dose of colchicine recommended by the ACR for an acute gout attack (1.2 mg loading dose, followed by 0.6 mg one hour later, then followed after 12 hours, as needed, by up to 0.6 mg once or twice a day) is substantially lower than the dosing schedule used historically (1.0 mg loading dose, followed by 0.5 mg every 2-3 hours). Higher doses have not proven to be more effective, however, and typically led to gastrointestinal toxicity, causing patients to stop taking the drug before acute symptoms resolved.^8,13,22

Keep in mind, too, that colchicine therapy should not be initiated more than 36 hours after symptom onset, as therapy is less effective beyond this time frame.^8,13 In addition, concurrent use with P-glycoprotein and CYP3A4 inhibitors—eg, clarithromycin and erythromycin and some antifungals, antiretrovirals, calcium-channel blockers, immunosuppressants, and statins—may increase the risk of colchicine toxicity and should be avoided.

Treating chronic gout

Management of recurrent or progressive gout is aimed at reducing and maintaining serum urate levels <6.0 mg/dL, using ULT (TABLE 3^12,23-25) combined with anti-inflammatory prophylaxis to reduce the frequency of gout flares and the size and number of tophi.^12,23 Patients who meet one or more of the following criteria qualify for ULT:

• the presence of tophi

• ≥2 acute attacks per year
• chronic kidney disease (CKD) stages 2 through 5

• a history of urolithiasis.¹²

Both ULT and anti-inflammatory therapy should be started after an acute gout attack resolves, but patients already on prophylactic therapy should continue the regimen both during and after acute attacks to avoid more frequent exacerbations.^9,12 If gout symptoms persist despite a serum urate level of <6.0 mg/dL, increase the dose of ULT to achieve a target of <5 mg/dL to reduce the frequency of flares and the size and number of tophi.^12,26

Allopurinol, a xanthine oxidase inhibitor, is typically used as first-line ULT due to efficacy and low cost.¹³ Febuxostat, also a xanthine oxidase inhibitor, is an additional first-line option, although the US Food and Drug Administration issued a warning based on postmarketing reports of hepatic failure.²⁵ In the case of a xanthine oxidase allergy or intolerance, probenecid may be used as an alternative first-line therapy. First-line agents for anti-inflammatory prophylaxis include low-dose colchicine (0.6 mg once or twice daily) and low-dose NSAIDs. Oral corticosteroids (<10 mg/d) are considered second-line therapy.¹³

Allopurinol hypersensitivity. Although allopurinol is generally well tolerated, about 2% of patients develop a mild rash and up to 5% of patients stop taking it because of an adverse effect.²⁵ More importantly, allopurinol hypersensitivity syndrome (AHS) is rare but potentially fatal; in the United States, it is estimated that one in every 1000 patients treated with allopurinol will develop AHS.^12,27

Allopurinol hypersensitivity syndrome is rare, but potentially fatal. AHS is characterized by a rash (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis), eosinophilia, leukocytosis, fever, hepatitis, and renal failure.^12,25 There is no cure; the mainstay of treatment is early diagnosis, withdrawal of allopurinol, and supportive care.²⁵ Because of the high mortality rate (20%-25%),^12,27 genetic screening for allele HLA-B*5801 prior to starting allopurinol therapy is recommended for patients in high-risk groups: Koreans with CKD (stage 3 or worse) and all Han Chinese and Thai patients, regardless of kidney function.¹² Alternative therapies should be used for patients who test positive for the allele.

Duration of therapy

Pharmacologic treatment of an acute gout attack should continue until the attack resolves, which can range from 5 to 14 days. The duration of treatment for chronic gout is far longer.

Anti-inflammatory prophylaxis should continue for whichever is greater: 3 months after the target serum urate level is achieved for patients with no evidence of tophi; or 6 months after the target serum urate level is achieved and previously detected tophi have resolved.¹³

ULT should continue indefinitely,¹² with monitoring of serum urate levels every 2 to 5 weeks until the target is achieved and every 6 months thereafter.

Not responding to therapy? Consider nonadherence, refractory gout

Studies have found that less than half of patients started on urate-lowering therapy take their medication as prescribed for the entire first year of therapy. If a patient is not responding as expected, consider whether he or she is taking the medication as prescribed. Gout therapy has one of the lowest adherence rates of any chronic disorder.^7,8,12,28-30 Studies have found that less than half of patients started on ULT take their medication as prescribed for the entire first year of therapy.^9,28

To promote adherence, schedule more frequent follow-up appointments after initiating urate-lowering therapy. Evidence suggests that nonadherence is especially likely among younger and healthier individuals, possibly because they have little experience managing chronic conditions or needing ongoing care.^28-30 Such patients may also be unsure of when and how to take their medication. To promote adherence, physicians should schedule more frequent follow-up appointments after initiating ULT to assess management of the disease and stress the importance of following the medication regimen as prescribed.^9,28

Not all patients who don’t respond to ULT are nonadherent, of course. Some have refractory gout. If uric acid levels do not reach the goal of <6 mg/dL (or <5 mg/dL) at the maximum dose of a first-line xanthine oxidase inhibitor, add a uricosuric agent such as probenecid, fenofibrate, or losartan.¹²

Pegloticase, a pegylated recombinant form of urate oxidase enzyme that converts uric acid to allantoin³¹ (a water-soluble metabolite of uric acid), is a possible therapeutic option for patients who do not achieve adequate serum urate levels and continue to have symptoms of gout.¹² Candidates for pegloticase therapy, which is administered intravenously, include adult patients with gout refractory to conventional ULT or excessive uric acid accumulation due to chemotherapy and those with contraindications to conventional ULT.

Pegloticase is associated with anaphylactic and infusion reactions, requires extensive monitoring, and costs thousands of dollars per month, however. Thus, it is important to carefully evaluate the extent of disease burden (ie, gout symptoms and effect on quality of life) and determine whether the patient has taken ULT and uricosuric drugs as prescribed before considering this option. Pegloticase requires the same anti-inflammatory prophylaxis as other forms of ULT, but there is no consensus on the duration of use.¹²

CORRESPONDENCE
Tatum Mead, PharmD, University of Missouri-Kansas City School of Pharmacy, Health Sciences Building, Room 2243, 2464 Charlotte Street, Kansas City, MO 64108-2792; meadt@umkc.edu

CASE › Bob A, age 48, comes to his family physician (FP) to ask for authorization for extended medical leave from his job as an electrician. He frequently misses days at work and complains of stress on the job, saying his coworkers look down on him and make cruel jokes at his expense. He reports having chronic interpersonal conflicts and no significant relationships with family members or friends. Mr. A refuses a referral to a psychiatrist because he fears he will be “locked up and forced to take medications.”

If Mr. A were your patient, how would you proceed?

Personality disorders (PDs) are patterns of inflexible and maladaptive personality traits and behaviors that cause subjective distress and significant social or occupational impairment.¹ An individual with a PD tends to have a limited repertoire of responses to the rough-and-tumble of life, with coping mechanisms that often perpetuate difficulty and distress. Examples include distrust and suspiciousness of others’ motives (paranoid PD); disregard and violation of the rights of others (antisocial PD); instability in interpersonal relationships, self-image, and affect (borderline PD); and social inhibition, feelings of inadequacy, and hypersensitivity to negative evaluation (avoidant PD).¹

FPs may view patients with PDs as “difficult patients” because of their frequent crises and the interpersonal problems they bring into the physician-patient relationship.^2,3 Help, of course, can come in the way of a referral to a psychotherapist who specializes in treating PDs. But you can also make use of some evidence-based psychotherapy techniques to improve your patients’ lives and the quality of the physician-patient relationship. This article focuses on identifying and managing PDs in family practice, using practical strategies drawn from empirically supported therapies.

PDs are more common 
than you might suspect


Personality disorders are associated with a greater incidence of serious medical illness and reduced social functioning. The overall prevalence of PD in the community ranges from 4.4% to 14.8%, with no consistent pattern of sex differences.⁴ Between 31.4% and 45.5% of psychiatric outpatients and up to 24% of primary care patients likely meet criteria for at least one PD.^5-7 PDs impede recovery from other mental disorders,⁸ increase the risk for suicide,⁹ and are associated with substance abuse, impulsivity, and violence.^10,11 Personality pathology also is associated with greater incidence of serious medical illness^12,13 and reduced social functioning.¹⁴ Not surprisingly, patients with PDs frequently use medical and social services.¹⁵

PDs tend to be underdiagnosed, perhaps partly because of concern about stigmatization, but also due to difficulties in identifying and classifying these disorders. Published in 2013, the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) originally was to include a major revision of PDs—reflecting concern about the limitations of PD categories—but ultimately the existing categories were retained (TABLE 1).¹ There is considerable overlap among PD categories; many patients meet the criteria for more than one PD, but it is unlikely that they actually suffer from several distinct PDs. Other patients—perhaps even the majority—are best diagnosed with “unspecified personality disorder” because they do not neatly fit into one of these categories.

Suspect your patient has a PD? Evaluate these 2 areas


Identifying patients who have PDs in primary care is useful for 2 reasons: to explore the option of specialty treatment for patients who may be amenable to it, and to improve management of the patient’s complaints in the primary care setting, including a smoother doctor-patient interaction. In either case, determining the specific DSM-5 diagnosis is less important than recognizing core personality impairment: an ingrained disturbance in one’s perceptions of self and others. This can be done by paying attention to how the patient adapts to life’s challenges and if he or she has problematic interpersonal tendencies, including difficulties in the doctor-patient relationship.

Unfortunately, assessing and diagnosing PDs in the primary care setting can be challenging. Limited time doesn’t allow for extensive, personality-focused interviews. Self-report screening tools are limited, because patients may underreport key interpersonal problems such as lack of empathy. Furthermore, very few patients seek help from their FP in addressing personality dysfunction; PDs typically are identified while investigating other complaints.

The most reliable and useful areas to evaluate in a patient you suspect may have a PD are identity (one’s sense of who one is and can be) and interpersonal relationships, including the capacity for empathy and intimacy.^16,17 These should be considered longitudinally and in the context of the individual’s stage of development. For example, identity is generally less stable among adolescents compared to middle-aged adults.

A cohesive sense of identity allows one to embrace life’s tasks and challenges, to develop and strive toward personal goals, and to handle setbacks and disappointments. A person with a stable identity may develop a depressive reaction to difficult life circumstances, but with some assistance can generally bounce back and re-engage in his or her personal goals. By contrast, an individual with an unstable sense of self may feel chronically insecure and empty, with limited capacity to constructively deal with life’s ups and downs. Patients with borderline PD, for example, try to manage a fragmented identity by frantically clinging to others, while narcissistic patients tend to suppress a fragile sense of self by putting forth an arrogant and entitled attitude.

Determining the specific diagnosis of a patient you suspect has a personality disorder is less important than recognizing core personality impairment. How does the patient interact with others? As is the case with identity, an individual’s capacity for interpersonal functioning is developed early in life, through interactions with primary caregivers. Mental maps of who we are and what we can expect from others are formed and reinforced in attachment relationships, such as those with our parents; traumatic attachments, including abuse or neglect by a caregiver or loved one, are strongly associated with PD.^18,19 The resulting belief structures guide subsequent interpersonal functioning, and become interactively reinforced. For example, a person whose internal map of relationships includes others abandoning him might behave in a clingy manner, which may ultimately induce others to reject him, thus creating a self-fulfilling prophecy.

Distorted interpersonal expectations can impair a person’s capacity for sustained intimate connections (a troubled relationship history is characteristic of PDs) and limit empathic functioning.²⁰ Other people’s actions may be interpreted according to the patient’s belief structures rather than with an open mind about the other person’s experience.

Focus on the physician-patient relationship


The interpersonal dysfunction of patients with PDs will often surface in the physician-patient relationship, serving as a clue to broader interpersonal dysfunction. An FP’s relatively innocuous oversight, for example, might be taken as proof of suspected incompetence in the eyes of a patient with paranoid or narcissistic tendencies. Or a patient with a recurrent complaint who repeatedly rejects the physician’s interventions probably oscillates between seeking and rejecting nurturance in other relationships, as well. A patient who tends to make sarcastic remarks regarding the doctor’s earnest efforts likely holds negative views of others and sabotages potentially positive interactions.

So what strategies are best for managing these types of scenarios?

Bringing up a potential diagnosis of PD may be a delicate matter for the FP; patients might experience this as a jarring diagnosis in the absence of a thorough psychiatric evaluation. If the FP decides to explore whether the patient is open to discussing the relationship between moods, behaviors, and personality features, he or she can begin this conversation by noting that, as with physical health, we all have our vulnerabilities, and that these vulnerabilities may be strengthened through specialist consultation and support. In this way, the patient can view a referral as an opportunity to explore herself with professional support. If a psychiatrist or psychotherapist colleague does become involved, it is important to clarify the roles of treatment providers and to communicate with one another, should difficulties arise.

Evidence supports 
2 forms of psychotherapy


Treatment for PDs has seen considerable growth over the past decade, largely due to research on therapies that target the troubling self-injurious and suicidal features of borderline PD. Considerable evidence shows that specialized psychotherapy can significantly reduce suffering and improve functioning among these patients. The 2 major evidence-based treatments for patients with borderline PD are dialectical behavior therapy (DBT) and psychodynamic therapy.

DBT is an intensive cognitive-behavioral approach that teaches patients how to regulate their emotions and develop an accepting, mindful attitude toward their mental experience.²¹ Several randomized controlled trials (RCTs) have demonstrated the effectiveness of DBT in reducing hospitalizations and self-injurious and suicidal behavior in patients with borderline PD.²²

Psychodynamic therapy, which focuses on helping patients discover how unconscious conflicts influence their present moods and behaviors, has also been validated by multiple RCTs for patients with borderline PD.^23-25 Like DBT, empirically supported psychodynamic therapy tends to be structured, long-term (>12 months), and often intensively delivered in multiple sessions per week. However, a recent study found that a less-intensive, general psychodynamic therapy, along with occasional medication management, was equivalent to intensive DBT.²⁶

Although the research has focused primarily on borderline PD, these approaches can be applied to other PDs. These therapies focus on understanding one’s emotional and behavioral patterns, developing a healthy self-concept, and improving interpersonal relationships—areas that are relevant treatment targets across all PD types.

Indeed, studies of day treatment programs that explicitly welcome patients with a range of PD types have had promising findings.²⁷ Day treatment involves an intensive array of therapies, mostly in a group format; patients work together to support and embolden one another to make positive changes. Unfortunately, FPs may be challenged to find appropriate services for patients who are amenable to psychotherapy; public mental health resources tend to lag far behind best practices in the case of PD.

Medication might improve symptoms, not personality deficits

Judicious, circumscribed use of medications to target specific symptoms may be helpful for some patients with personality disorders. Most research on pharmacotherapy for PDs has focused on borderline PD; findings have been mixed and fairly limited.²⁸ Medication cannot address underlying identity and relational deficits, and will not result in remission of PD. Nonetheless, judicious, circumscribed use of medications to target specific symptoms may be helpful for some patients. Selective serotonin reuptake inhibitors can reduce anger and impulsive aggression in patients with borderline PD.^28,29

Atypical antipsychotics may help reduce impulsive aggression or transient psychotic symptoms.^28-30 For example, olanzapine and aripiprazole can reduce anxiety, anger/aggression, paranoia, and interpersonal sensitivity in borderline PD.^31,32 Mood stabilizers such as valproate, lamotrigine, and topiramate may also help some borderline patients, although they do so by reducing impulsivity and aggression rather than improving core unstable identity and affect.^28,29

Carefully obtained informed consent is necessary because of the danger of adverse effects with many of these medications; for example, antipsychotics have been associated with metabolic syndrome and weight gain that can threaten a patient’s already fragile self-image.³³ Polypharmacy is also a potential problem: Well-intentioned physicians may be prompted to offer multiple medications in response to patients’ unremitting complaints of distress, when a psychotherapeutic approach may need to be the primary treatment. The bottom line is that medications do not resolve personality dysfunction, and are best used symptomatically as adjuncts to psychotherapy.^28,30

Steps you can take 
during the office visit


Although it is not feasible for most FPs to provide comprehensive treatment for PD, key elements from specialized therapies can be integrated into your management of these patients. Steps you can take include using validation, promoting mentalization, and managing countertransference.

Validation, which is a component of DBT, is providing the expressed acknowledgement that the patient is entitled to her feelings.A supportive acknowledgement from you
 may counter
 a patient’s expectation
 of being invalidated,
 and over time, reduce the patient’s defensive 
rigidity. This is not the same as agreeing with a position the patient has taken on an issue, but rather conveying the sense that one sees how the patient might feel the way she does. A study of women with borderline PD and substance abuse found a validation intervention by itself was significantly helpful.³⁴ Validation can contribute to a “corrective emotional experience.” For instance, your supportive acknowledgement of a patient with a history of abuse or neglect may counter the patient’s expectation of being invalidated, and over time this can reduce the patient’s defensive rigidity.

Mentalization. Psychodynamic treatment involves a similar tack; clinicians empathize with the patient’s emotional state while also demonstrating a degree of separateness from the emotion.^23-25 This promotes mentalization in the patient—the ability to contemplate one’s own and others’ subjective mental states.¹⁸ Mentalization is often impaired in PD patients, who presume to “know” what others are thinking. A patient, for instance, “just knows” that her friend secretly hates her, based on a vaguely worded text message.

Point out that while your patient is entitled to feel what he’s feeling, it may not be in his best interest
 to act on those feelings without considering the consequences. You can help patients with mentalization by taking an inquisitive “not knowing” stance and by emphasizing a collaborative and reflective approach toward a given problem—to examine the issue together, from all sides. You can point out that while a patient is entitled to feel whatever he is feeling, it may not be in his best interest to act on the feelings without adequately considering the potential consequences of the action. This helps the patient to distinguish thoughts, feelings, and impulses from behavior. It also teaches the value of anticipatory thinking, impulse control, and affect regulation.

Countertransference. Managing your emotional reactions to a patient with PD is a well-documented challenge.³⁵ Your feelings about the patient, known as countertransference, can range from considerable concern and sympathy to severe frustration, bewilderment, and frank hostility. A common reaction is the sense that one must “do something” to respond to the patient’s emotional distress or interpersonal pressure. This may trigger an impulse to give advice or offer tests or medications despite knowing that these are unlikely to be helpful. A more useful response may be to tolerate such feelings and listen empathically to the patient’s frustration. Recognizing subtle countertransference can guard against extreme reactions and maintain an appropriate clinical focus. Discussion with a trusted colleague can be helpful.

Recognizing countertransference can guard against extreme reactions and maintain an appropriate clinical focus. Psychodynamic approaches consider managing countertransference to be a therapeutic intervention, even when psychotherapy is not explicitly being carried out. Strong emotional responses may reflect something that the patient needs the physician to experience, as the patient cannot bear to experience it himself. The patient needs to see—and learn from—the physician’s handling of unbearable (for the patient) feelings. This occurs at a level of unconscious communication and may be repeated over time. Although not discussed with the patient, a physician’s capacity for self-containment and provision of undisrupted, good medical care is in itself a psychotherapeutic accomplishment.

CASE › Based on Mr. A’s history of interpersonal conflicts and perceived persecution by coworkers, the FP consults with a psychotherapist colleague, who says Mr. A’s chronic mistrust and social isolation suggest he may have a severe identity disturbance and unspecified PD with paranoid and schizoid features. Because Mr. A refuses to see a therapist, his FP decides to focus on promoting small improvements in Mr. A’s interpersonal interactions and reducing absenteeism at work.

The FP validates Mr. A’s feelings (“it can be very stressful to constantly feel like others are at odds with you”) and tries to promote mentalizing (“I want to understand more about what you think regarding your work situation and your coworkers. Let’s try to look at this from all perspectives—maybe we can come up with some new ideas.”)

Despite wanting to help his patient, the FP feels uneasy and reluctant to engage with Mr. A, who likely evokes such feelings to keep others at a distance. The FP tactfully seeks to remain Mr. A’s ally without endorsing his distorted interpretation of events. Given Mr. A’s paranoid rejection of therapy, the FP refrains from making further such recommendations. The FP’s interventions, however, may help Mr. A warm to the idea of further help over time, and the FP’s supportive stance will help to ameliorate the patient’s distress. (For 2 additional examples of how FPs can use the strategies described in this article to help patients with PDs, see TABLE 2.)

CORRESPONDENCE
David Kealy, MSW, Psychotherapy Program, Department
of Psychiatry, University of British Columbia, #420-5950 University Boulevard, Vancouver, BC Canada V6T 1Z3; david.kealy@ubc.ca

CASE › Bob A, age 48, comes to his family physician (FP) to ask for authorization for extended medical leave from his job as an electrician. He frequently misses days at work and complains of stress on the job, saying his coworkers look down on him and make cruel jokes at his expense. He reports having chronic interpersonal conflicts and no significant relationships with family members or friends. Mr. A refuses a referral to a psychiatrist because he fears he will be “locked up and forced to take medications.”

If Mr. A were your patient, how would you proceed?

Personality disorders (PDs) are patterns of inflexible and maladaptive personality traits and behaviors that cause subjective distress and significant social or occupational impairment.¹ An individual with a PD tends to have a limited repertoire of responses to the rough-and-tumble of life, with coping mechanisms that often perpetuate difficulty and distress. Examples include distrust and suspiciousness of others’ motives (paranoid PD); disregard and violation of the rights of others (antisocial PD); instability in interpersonal relationships, self-image, and affect (borderline PD); and social inhibition, feelings of inadequacy, and hypersensitivity to negative evaluation (avoidant PD).¹

FPs may view patients with PDs as “difficult patients” because of their frequent crises and the interpersonal problems they bring into the physician-patient relationship.^2,3 Help, of course, can come in the way of a referral to a psychotherapist who specializes in treating PDs. But you can also make use of some evidence-based psychotherapy techniques to improve your patients’ lives and the quality of the physician-patient relationship. This article focuses on identifying and managing PDs in family practice, using practical strategies drawn from empirically supported therapies.

PDs are more common 
than you might suspect


Personality disorders are associated with a greater incidence of serious medical illness and reduced social functioning. The overall prevalence of PD in the community ranges from 4.4% to 14.8%, with no consistent pattern of sex differences.⁴ Between 31.4% and 45.5% of psychiatric outpatients and up to 24% of primary care patients likely meet criteria for at least one PD.^5-7 PDs impede recovery from other mental disorders,⁸ increase the risk for suicide,⁹ and are associated with substance abuse, impulsivity, and violence.^10,11 Personality pathology also is associated with greater incidence of serious medical illness^12,13 and reduced social functioning.¹⁴ Not surprisingly, patients with PDs frequently use medical and social services.¹⁵

PDs tend to be underdiagnosed, perhaps partly because of concern about stigmatization, but also due to difficulties in identifying and classifying these disorders. Published in 2013, the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) originally was to include a major revision of PDs—reflecting concern about the limitations of PD categories—but ultimately the existing categories were retained (TABLE 1).¹ There is considerable overlap among PD categories; many patients meet the criteria for more than one PD, but it is unlikely that they actually suffer from several distinct PDs. Other patients—perhaps even the majority—are best diagnosed with “unspecified personality disorder” because they do not neatly fit into one of these categories.

Suspect your patient has a PD? Evaluate these 2 areas


Identifying patients who have PDs in primary care is useful for 2 reasons: to explore the option of specialty treatment for patients who may be amenable to it, and to improve management of the patient’s complaints in the primary care setting, including a smoother doctor-patient interaction. In either case, determining the specific DSM-5 diagnosis is less important than recognizing core personality impairment: an ingrained disturbance in one’s perceptions of self and others. This can be done by paying attention to how the patient adapts to life’s challenges and if he or she has problematic interpersonal tendencies, including difficulties in the doctor-patient relationship.

Unfortunately, assessing and diagnosing PDs in the primary care setting can be challenging. Limited time doesn’t allow for extensive, personality-focused interviews. Self-report screening tools are limited, because patients may underreport key interpersonal problems such as lack of empathy. Furthermore, very few patients seek help from their FP in addressing personality dysfunction; PDs typically are identified while investigating other complaints.

The most reliable and useful areas to evaluate in a patient you suspect may have a PD are identity (one’s sense of who one is and can be) and interpersonal relationships, including the capacity for empathy and intimacy.^16,17 These should be considered longitudinally and in the context of the individual’s stage of development. For example, identity is generally less stable among adolescents compared to middle-aged adults.

A cohesive sense of identity allows one to embrace life’s tasks and challenges, to develop and strive toward personal goals, and to handle setbacks and disappointments. A person with a stable identity may develop a depressive reaction to difficult life circumstances, but with some assistance can generally bounce back and re-engage in his or her personal goals. By contrast, an individual with an unstable sense of self may feel chronically insecure and empty, with limited capacity to constructively deal with life’s ups and downs. Patients with borderline PD, for example, try to manage a fragmented identity by frantically clinging to others, while narcissistic patients tend to suppress a fragile sense of self by putting forth an arrogant and entitled attitude.

Determining the specific diagnosis of a patient you suspect has a personality disorder is less important than recognizing core personality impairment. How does the patient interact with others? As is the case with identity, an individual’s capacity for interpersonal functioning is developed early in life, through interactions with primary caregivers. Mental maps of who we are and what we can expect from others are formed and reinforced in attachment relationships, such as those with our parents; traumatic attachments, including abuse or neglect by a caregiver or loved one, are strongly associated with PD.^18,19 The resulting belief structures guide subsequent interpersonal functioning, and become interactively reinforced. For example, a person whose internal map of relationships includes others abandoning him might behave in a clingy manner, which may ultimately induce others to reject him, thus creating a self-fulfilling prophecy.

Distorted interpersonal expectations can impair a person’s capacity for sustained intimate connections (a troubled relationship history is characteristic of PDs) and limit empathic functioning.²⁰ Other people’s actions may be interpreted according to the patient’s belief structures rather than with an open mind about the other person’s experience.

Focus on the physician-patient relationship


The interpersonal dysfunction of patients with PDs will often surface in the physician-patient relationship, serving as a clue to broader interpersonal dysfunction. An FP’s relatively innocuous oversight, for example, might be taken as proof of suspected incompetence in the eyes of a patient with paranoid or narcissistic tendencies. Or a patient with a recurrent complaint who repeatedly rejects the physician’s interventions probably oscillates between seeking and rejecting nurturance in other relationships, as well. A patient who tends to make sarcastic remarks regarding the doctor’s earnest efforts likely holds negative views of others and sabotages potentially positive interactions.

So what strategies are best for managing these types of scenarios?

Bringing up a potential diagnosis of PD may be a delicate matter for the FP; patients might experience this as a jarring diagnosis in the absence of a thorough psychiatric evaluation. If the FP decides to explore whether the patient is open to discussing the relationship between moods, behaviors, and personality features, he or she can begin this conversation by noting that, as with physical health, we all have our vulnerabilities, and that these vulnerabilities may be strengthened through specialist consultation and support. In this way, the patient can view a referral as an opportunity to explore herself with professional support. If a psychiatrist or psychotherapist colleague does become involved, it is important to clarify the roles of treatment providers and to communicate with one another, should difficulties arise.

Evidence supports 
2 forms of psychotherapy


Treatment for PDs has seen considerable growth over the past decade, largely due to research on therapies that target the troubling self-injurious and suicidal features of borderline PD. Considerable evidence shows that specialized psychotherapy can significantly reduce suffering and improve functioning among these patients. The 2 major evidence-based treatments for patients with borderline PD are dialectical behavior therapy (DBT) and psychodynamic therapy.

DBT is an intensive cognitive-behavioral approach that teaches patients how to regulate their emotions and develop an accepting, mindful attitude toward their mental experience.²¹ Several randomized controlled trials (RCTs) have demonstrated the effectiveness of DBT in reducing hospitalizations and self-injurious and suicidal behavior in patients with borderline PD.²²

Psychodynamic therapy, which focuses on helping patients discover how unconscious conflicts influence their present moods and behaviors, has also been validated by multiple RCTs for patients with borderline PD.^23-25 Like DBT, empirically supported psychodynamic therapy tends to be structured, long-term (>12 months), and often intensively delivered in multiple sessions per week. However, a recent study found that a less-intensive, general psychodynamic therapy, along with occasional medication management, was equivalent to intensive DBT.²⁶

Although the research has focused primarily on borderline PD, these approaches can be applied to other PDs. These therapies focus on understanding one’s emotional and behavioral patterns, developing a healthy self-concept, and improving interpersonal relationships—areas that are relevant treatment targets across all PD types.

Indeed, studies of day treatment programs that explicitly welcome patients with a range of PD types have had promising findings.²⁷ Day treatment involves an intensive array of therapies, mostly in a group format; patients work together to support and embolden one another to make positive changes. Unfortunately, FPs may be challenged to find appropriate services for patients who are amenable to psychotherapy; public mental health resources tend to lag far behind best practices in the case of PD.

Medication might improve symptoms, not personality deficits

Judicious, circumscribed use of medications to target specific symptoms may be helpful for some patients with personality disorders. Most research on pharmacotherapy for PDs has focused on borderline PD; findings have been mixed and fairly limited.²⁸ Medication cannot address underlying identity and relational deficits, and will not result in remission of PD. Nonetheless, judicious, circumscribed use of medications to target specific symptoms may be helpful for some patients. Selective serotonin reuptake inhibitors can reduce anger and impulsive aggression in patients with borderline PD.^28,29

Atypical antipsychotics may help reduce impulsive aggression or transient psychotic symptoms.^28-30 For example, olanzapine and aripiprazole can reduce anxiety, anger/aggression, paranoia, and interpersonal sensitivity in borderline PD.^31,32 Mood stabilizers such as valproate, lamotrigine, and topiramate may also help some borderline patients, although they do so by reducing impulsivity and aggression rather than improving core unstable identity and affect.^28,29

Carefully obtained informed consent is necessary because of the danger of adverse effects with many of these medications; for example, antipsychotics have been associated with metabolic syndrome and weight gain that can threaten a patient’s already fragile self-image.³³ Polypharmacy is also a potential problem: Well-intentioned physicians may be prompted to offer multiple medications in response to patients’ unremitting complaints of distress, when a psychotherapeutic approach may need to be the primary treatment. The bottom line is that medications do not resolve personality dysfunction, and are best used symptomatically as adjuncts to psychotherapy.^28,30

Steps you can take 
during the office visit


Although it is not feasible for most FPs to provide comprehensive treatment for PD, key elements from specialized therapies can be integrated into your management of these patients. Steps you can take include using validation, promoting mentalization, and managing countertransference.

Validation, which is a component of DBT, is providing the expressed acknowledgement that the patient is entitled to her feelings.A supportive acknowledgement from you
 may counter
 a patient’s expectation
 of being invalidated,
 and over time, reduce the patient’s defensive 
rigidity. This is not the same as agreeing with a position the patient has taken on an issue, but rather conveying the sense that one sees how the patient might feel the way she does. A study of women with borderline PD and substance abuse found a validation intervention by itself was significantly helpful.³⁴ Validation can contribute to a “corrective emotional experience.” For instance, your supportive acknowledgement of a patient with a history of abuse or neglect may counter the patient’s expectation of being invalidated, and over time this can reduce the patient’s defensive rigidity.

Mentalization. Psychodynamic treatment involves a similar tack; clinicians empathize with the patient’s emotional state while also demonstrating a degree of separateness from the emotion.^23-25 This promotes mentalization in the patient—the ability to contemplate one’s own and others’ subjective mental states.¹⁸ Mentalization is often impaired in PD patients, who presume to “know” what others are thinking. A patient, for instance, “just knows” that her friend secretly hates her, based on a vaguely worded text message.

Point out that while your patient is entitled to feel what he’s feeling, it may not be in his best interest
 to act on those feelings without considering the consequences. You can help patients with mentalization by taking an inquisitive “not knowing” stance and by emphasizing a collaborative and reflective approach toward a given problem—to examine the issue together, from all sides. You can point out that while a patient is entitled to feel whatever he is feeling, it may not be in his best interest to act on the feelings without adequately considering the potential consequences of the action. This helps the patient to distinguish thoughts, feelings, and impulses from behavior. It also teaches the value of anticipatory thinking, impulse control, and affect regulation.

Countertransference. Managing your emotional reactions to a patient with PD is a well-documented challenge.³⁵ Your feelings about the patient, known as countertransference, can range from considerable concern and sympathy to severe frustration, bewilderment, and frank hostility. A common reaction is the sense that one must “do something” to respond to the patient’s emotional distress or interpersonal pressure. This may trigger an impulse to give advice or offer tests or medications despite knowing that these are unlikely to be helpful. A more useful response may be to tolerate such feelings and listen empathically to the patient’s frustration. Recognizing subtle countertransference can guard against extreme reactions and maintain an appropriate clinical focus. Discussion with a trusted colleague can be helpful.

Recognizing countertransference can guard against extreme reactions and maintain an appropriate clinical focus. Psychodynamic approaches consider managing countertransference to be a therapeutic intervention, even when psychotherapy is not explicitly being carried out. Strong emotional responses may reflect something that the patient needs the physician to experience, as the patient cannot bear to experience it himself. The patient needs to see—and learn from—the physician’s handling of unbearable (for the patient) feelings. This occurs at a level of unconscious communication and may be repeated over time. Although not discussed with the patient, a physician’s capacity for self-containment and provision of undisrupted, good medical care is in itself a psychotherapeutic accomplishment.

CASE › Based on Mr. A’s history of interpersonal conflicts and perceived persecution by coworkers, the FP consults with a psychotherapist colleague, who says Mr. A’s chronic mistrust and social isolation suggest he may have a severe identity disturbance and unspecified PD with paranoid and schizoid features. Because Mr. A refuses to see a therapist, his FP decides to focus on promoting small improvements in Mr. A’s interpersonal interactions and reducing absenteeism at work.

The FP validates Mr. A’s feelings (“it can be very stressful to constantly feel like others are at odds with you”) and tries to promote mentalizing (“I want to understand more about what you think regarding your work situation and your coworkers. Let’s try to look at this from all perspectives—maybe we can come up with some new ideas.”)

Despite wanting to help his patient, the FP feels uneasy and reluctant to engage with Mr. A, who likely evokes such feelings to keep others at a distance. The FP tactfully seeks to remain Mr. A’s ally without endorsing his distorted interpretation of events. Given Mr. A’s paranoid rejection of therapy, the FP refrains from making further such recommendations. The FP’s interventions, however, may help Mr. A warm to the idea of further help over time, and the FP’s supportive stance will help to ameliorate the patient’s distress. (For 2 additional examples of how FPs can use the strategies described in this article to help patients with PDs, see TABLE 2.)

CORRESPONDENCE
David Kealy, MSW, Psychotherapy Program, Department
of Psychiatry, University of British Columbia, #420-5950 University Boulevard, Vancouver, BC Canada V6T 1Z3; david.kealy@ubc.ca