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Birth outcomes unaffected by paternal immunosuppressive therapy
VIENNA – The use of classic systemic immunosuppressive agents by men in the months shortly before conception was not associated with increased risk of low birthweight, preterm birth, or congenital anomalies in their offspring in a large Danish national registry.
“We didn’t see any real safety signals,” Dr. Alexander Egeberg reported at the annual congress of the European Academy of Dermatology and Venereology.
He and his coinvestigators at the University of Copenhagen decided to examine this issue for a simple reason: “We know quite a lot from registry studies about the safety of these drugs when used by women during pregnancy, but very little about the safety of paternal use,” Dr. Egeberg explained.
Methotrexate, azathioprine, and cyclosporine are often prescribed for patients with moderate to severe psoriasis and psoriatic arthritis as well as other chronic inflammatory disorders. Female patients are typically told to stop using these medications if they’re trying to become pregnant, or as soon as they think they might be pregnant, but nearly half of all pregnancies are unintended.
Using linked comprehensive national Danish databases, the investigators scrutinized the medical records of all children born in Denmark during 2004-2010, as well as those of their parents. They identified 2,235 children whose fathers had been on immunosuppressive therapy for a medical condition at any time prior to conception. There were 1,246 fathers who had been on azathioprine, 848 on methotrexate, and 141 on cyclosporine.
Rates of preterm birth, congenital anomalies, and low birthweight were compared in children born to fathers using immunosuppression and in 415,589 children born to fathers with no history of exposure to the medications. These comparisons entailed multivariate regression analyses adjusted for maternal age, parity, smoking status, and the child’s gender. Dr. Egeberg and his colleagues also compared rates of these reproductive complications in the subgroup of children whose fathers had been on the medications within 3 months prior to the estimated time of conception and in children whose fathers had stopped taking the drugs by that point.
None of the adverse neonatal outcomes were significantly increased in ever or recent paternal users of the medications under study, with one exception. Paternal use of cyclosporine within the last 3 months prior to conception was associated with an adjusted 3.7-fold increased likelihood of having a baby with a congenital anomaly. Dr. Egeberg, however, was quick to state that this finding was based on small numbers of exposures: 18 paternal exposures and four affected offspring.
“The cyclosporine finding should be interpreted quite cautiously,” he emphasized.
The reproductive outcomes study was supported by Danish governmental research funds. Dr. Egeberg reported having received research funding from and serving as a consultant to Pfizer and Eli Lilly.
VIENNA – The use of classic systemic immunosuppressive agents by men in the months shortly before conception was not associated with increased risk of low birthweight, preterm birth, or congenital anomalies in their offspring in a large Danish national registry.
“We didn’t see any real safety signals,” Dr. Alexander Egeberg reported at the annual congress of the European Academy of Dermatology and Venereology.
He and his coinvestigators at the University of Copenhagen decided to examine this issue for a simple reason: “We know quite a lot from registry studies about the safety of these drugs when used by women during pregnancy, but very little about the safety of paternal use,” Dr. Egeberg explained.
Methotrexate, azathioprine, and cyclosporine are often prescribed for patients with moderate to severe psoriasis and psoriatic arthritis as well as other chronic inflammatory disorders. Female patients are typically told to stop using these medications if they’re trying to become pregnant, or as soon as they think they might be pregnant, but nearly half of all pregnancies are unintended.
Using linked comprehensive national Danish databases, the investigators scrutinized the medical records of all children born in Denmark during 2004-2010, as well as those of their parents. They identified 2,235 children whose fathers had been on immunosuppressive therapy for a medical condition at any time prior to conception. There were 1,246 fathers who had been on azathioprine, 848 on methotrexate, and 141 on cyclosporine.
Rates of preterm birth, congenital anomalies, and low birthweight were compared in children born to fathers using immunosuppression and in 415,589 children born to fathers with no history of exposure to the medications. These comparisons entailed multivariate regression analyses adjusted for maternal age, parity, smoking status, and the child’s gender. Dr. Egeberg and his colleagues also compared rates of these reproductive complications in the subgroup of children whose fathers had been on the medications within 3 months prior to the estimated time of conception and in children whose fathers had stopped taking the drugs by that point.
None of the adverse neonatal outcomes were significantly increased in ever or recent paternal users of the medications under study, with one exception. Paternal use of cyclosporine within the last 3 months prior to conception was associated with an adjusted 3.7-fold increased likelihood of having a baby with a congenital anomaly. Dr. Egeberg, however, was quick to state that this finding was based on small numbers of exposures: 18 paternal exposures and four affected offspring.
“The cyclosporine finding should be interpreted quite cautiously,” he emphasized.
The reproductive outcomes study was supported by Danish governmental research funds. Dr. Egeberg reported having received research funding from and serving as a consultant to Pfizer and Eli Lilly.
VIENNA – The use of classic systemic immunosuppressive agents by men in the months shortly before conception was not associated with increased risk of low birthweight, preterm birth, or congenital anomalies in their offspring in a large Danish national registry.
“We didn’t see any real safety signals,” Dr. Alexander Egeberg reported at the annual congress of the European Academy of Dermatology and Venereology.
He and his coinvestigators at the University of Copenhagen decided to examine this issue for a simple reason: “We know quite a lot from registry studies about the safety of these drugs when used by women during pregnancy, but very little about the safety of paternal use,” Dr. Egeberg explained.
Methotrexate, azathioprine, and cyclosporine are often prescribed for patients with moderate to severe psoriasis and psoriatic arthritis as well as other chronic inflammatory disorders. Female patients are typically told to stop using these medications if they’re trying to become pregnant, or as soon as they think they might be pregnant, but nearly half of all pregnancies are unintended.
Using linked comprehensive national Danish databases, the investigators scrutinized the medical records of all children born in Denmark during 2004-2010, as well as those of their parents. They identified 2,235 children whose fathers had been on immunosuppressive therapy for a medical condition at any time prior to conception. There were 1,246 fathers who had been on azathioprine, 848 on methotrexate, and 141 on cyclosporine.
Rates of preterm birth, congenital anomalies, and low birthweight were compared in children born to fathers using immunosuppression and in 415,589 children born to fathers with no history of exposure to the medications. These comparisons entailed multivariate regression analyses adjusted for maternal age, parity, smoking status, and the child’s gender. Dr. Egeberg and his colleagues also compared rates of these reproductive complications in the subgroup of children whose fathers had been on the medications within 3 months prior to the estimated time of conception and in children whose fathers had stopped taking the drugs by that point.
None of the adverse neonatal outcomes were significantly increased in ever or recent paternal users of the medications under study, with one exception. Paternal use of cyclosporine within the last 3 months prior to conception was associated with an adjusted 3.7-fold increased likelihood of having a baby with a congenital anomaly. Dr. Egeberg, however, was quick to state that this finding was based on small numbers of exposures: 18 paternal exposures and four affected offspring.
“The cyclosporine finding should be interpreted quite cautiously,” he emphasized.
The reproductive outcomes study was supported by Danish governmental research funds. Dr. Egeberg reported having received research funding from and serving as a consultant to Pfizer and Eli Lilly.
AT THE EADV CONGRESS
Key clinical point:
Major finding: Adjusted rates of congenital anomalies, preterm birth, and low birthweight are not increased in children with paternal use of azathioprine, methotrexate, or cyclosporine prior to conception.
Data source: This retrospective study utilized linked Danish national registries to compare rates of low birthweight, congenital anomalies, and preterm birth in all Danish children born in 2004-2010 depending upon whether or not the father had been on methotrexate, azathioprine, or cyclosporine prior to the pregnancy.
Disclosures: The study was supported by Danish governmental research funds. Dr. Egeberg reported having received research funding from, and serving as a consultant to, Pfizer and Eli Lilly.
Severe joint pain in adults with arthritis continues to rise
The prevalence of severe joint pain among adults with diagnosed arthritis continues to increase, researchers from the Centers for Disease Control and Prevention reported in the Oct. 7 Morbidity and Mortality Weekly Report.
In 2014, more than one-fourth of adults with arthritis had severe joint pain. That is about 14.6 million Americans with severe joint pain, a significant increase from 2002 when there were an estimated 10.5 million adults with severe joint pain, according to Kamil E. Barbour, PhD, and his associates from the National Center for Chronic Disease Prevention and Health Promotion (MMWR. 2016 Oct 7;65[39]:1052-6).
Severe joint pain was also more prevalent among patients with overall fair or poor health who were obese or had heart disease, diabetes, or serious psychological distress, the investigators reported.
The investigators defined people with arthritis as those who had “been told by a doctor or other health professional” that they have some form of arthritis, rheumatoid arthritis, gout, lupus, or fibromyalgia. Severe joint pain was defined as a response of 7 or higher on a scale of 0-10 for rating joint pain on average over the past 30 days.
Recently, the U.S. Department of Health & Human Services released its National Pain Strategy, the nation’s first broad, federal effort aimed at developing strategies to reduce the burden of pain among Americans. The initiatives major objectives are to take steps to reduce barriers to pain care, and to increase patient knowledge of treatment options and risks, Dr. Barbour and his associates wrote.
“Health care providers and public health practitioners can begin to implement the recommendations [from the National Pain Strategy] and improve pain care among adults with arthritis and [severe joint pain] by prioritizing self-management education and appropriate physical activity interventions as effective nonpharmacologic ways to reduce pain and improve health outcomes,” the researchers added.
jcraig@frontlinemedcom.com
On Twitter @jessnicolecraig
The prevalence of severe joint pain among adults with diagnosed arthritis continues to increase, researchers from the Centers for Disease Control and Prevention reported in the Oct. 7 Morbidity and Mortality Weekly Report.
In 2014, more than one-fourth of adults with arthritis had severe joint pain. That is about 14.6 million Americans with severe joint pain, a significant increase from 2002 when there were an estimated 10.5 million adults with severe joint pain, according to Kamil E. Barbour, PhD, and his associates from the National Center for Chronic Disease Prevention and Health Promotion (MMWR. 2016 Oct 7;65[39]:1052-6).
Severe joint pain was also more prevalent among patients with overall fair or poor health who were obese or had heart disease, diabetes, or serious psychological distress, the investigators reported.
The investigators defined people with arthritis as those who had “been told by a doctor or other health professional” that they have some form of arthritis, rheumatoid arthritis, gout, lupus, or fibromyalgia. Severe joint pain was defined as a response of 7 or higher on a scale of 0-10 for rating joint pain on average over the past 30 days.
Recently, the U.S. Department of Health & Human Services released its National Pain Strategy, the nation’s first broad, federal effort aimed at developing strategies to reduce the burden of pain among Americans. The initiatives major objectives are to take steps to reduce barriers to pain care, and to increase patient knowledge of treatment options and risks, Dr. Barbour and his associates wrote.
“Health care providers and public health practitioners can begin to implement the recommendations [from the National Pain Strategy] and improve pain care among adults with arthritis and [severe joint pain] by prioritizing self-management education and appropriate physical activity interventions as effective nonpharmacologic ways to reduce pain and improve health outcomes,” the researchers added.
jcraig@frontlinemedcom.com
On Twitter @jessnicolecraig
The prevalence of severe joint pain among adults with diagnosed arthritis continues to increase, researchers from the Centers for Disease Control and Prevention reported in the Oct. 7 Morbidity and Mortality Weekly Report.
In 2014, more than one-fourth of adults with arthritis had severe joint pain. That is about 14.6 million Americans with severe joint pain, a significant increase from 2002 when there were an estimated 10.5 million adults with severe joint pain, according to Kamil E. Barbour, PhD, and his associates from the National Center for Chronic Disease Prevention and Health Promotion (MMWR. 2016 Oct 7;65[39]:1052-6).
Severe joint pain was also more prevalent among patients with overall fair or poor health who were obese or had heart disease, diabetes, or serious psychological distress, the investigators reported.
The investigators defined people with arthritis as those who had “been told by a doctor or other health professional” that they have some form of arthritis, rheumatoid arthritis, gout, lupus, or fibromyalgia. Severe joint pain was defined as a response of 7 or higher on a scale of 0-10 for rating joint pain on average over the past 30 days.
Recently, the U.S. Department of Health & Human Services released its National Pain Strategy, the nation’s first broad, federal effort aimed at developing strategies to reduce the burden of pain among Americans. The initiatives major objectives are to take steps to reduce barriers to pain care, and to increase patient knowledge of treatment options and risks, Dr. Barbour and his associates wrote.
“Health care providers and public health practitioners can begin to implement the recommendations [from the National Pain Strategy] and improve pain care among adults with arthritis and [severe joint pain] by prioritizing self-management education and appropriate physical activity interventions as effective nonpharmacologic ways to reduce pain and improve health outcomes,” the researchers added.
jcraig@frontlinemedcom.com
On Twitter @jessnicolecraig
FROM MMWR
Key clinical point:
Major finding: The estimated number of U.S. adults with severe joint pain rose from 10.5 million in 2002 to 14.6 million in 2014.
Data source: Analysis of data from the National Health Interview Survey in 2002, 2003, 2006, 2009, and 2014.
Disclosures: The authors are federal government employees and have no financial disclosures.
RA prevention trials seek to stop clinical onset of disease
Investigators across the United States and Europe hope to answer questions surrounding the feasibility of preventing rheumatoid arthritis in a series of proof-of-concept clinical trials that are enrolling patients with various risk factors for the disease. At least five trials have begun – with one already completed – to prevent RA with disease-modifying antirheumatic drugs, including a U.S. trial with hydroxychloroquine and European trials involving methotrexate, rituximab, and abatacept. Another trial with atorvastatin is also underway.
All of the trials involve participants with different risk factors for RA and may thereby provide a range of answers about where the most promising areas for disease prevention lie.
Hydroxychloroquine
Perhaps the broadest in scope of all the studies investigating the prevention of RA is the StopRA (Strategy to Prevent the Onset of Clinically Apparent Rheumatoid Arthritis) trial, which is randomizing 200 subjects with an anticyclic citrullinated peptide 3 (anti-CCP3) that’s greater than twice the normal level, with or without arthralgia, to either hydroxychloroquine (HCQ) 200-400 mg/day or placebo for 1 year, followed by 2 years of follow-up. Pilot data indicated that a level of 40 U/mL or higher of anti-CCP3, which is twice the normal level for positivity, gave a 50% chance of developing RA in the next 3 years regardless of symptoms, family history, or other factors.
The trial’s focus on people with an elevated level of anti-CCP3 limits it to just seropositive individuals, specifically those who are anti-citrullinated protein antibody (ACPA)-positive who constitute about 60%-70% of RA patients with established RA.
The investigators chose to use HCQ because it is a safe and well-tolerated medication for RA, and it may have mechanisms of action that may work particularly well in the early development of RA by blocking inflammation and epitope spreading, Dr. Deane said. “While hydroxychloroquine might not be powerful enough to stop active RA, we hypothesize that it’s just the right drug to block key processes early in its development,” Dr. Deane said in an interview, noting that HCQ is also used to block disease flares in palindromic rheumatism and diminish autoantibody responses in systemic lupus erythematosus.
The StopRA trial is being performed by the Autoimmunity Centers of Excellence, a network sponsored by the National Institutes of Health and the National Institute of Allergy and Infectious Diseases. Enrollment began at 18 U.S. sites in April 2016 with screening of first-degree relatives of patients with RA, community-based screening at health fairs, and finding CCP positive individuals without inflammatory arthritis in rheumatology clinics. The investigators estimate that they will need to screen 20,000 individuals to enroll 200 into the study. Dr. Deane said that he and his coinvestigators hope to use the variables that will arise from the diverse population to later determine subgroups who may respond best to the intervention. “We were concerned that if we made everybody too similar we wouldn’t be able to analyze whether symptoms or other factors mattered or not in who responded to the intervention. It may also allow us to catch some people at an early phase of their autoimmunity and others at a later phase and to determine for future studies when is the best time to intervene in preclinical RA with HCQ.”
It’s possible that HCQ will just delay RA rather than prevent it, Dr. Deane said, perhaps indicating that they may find that HCQ needs to be used longer. In any case, by the time the trial is completed in 2020 the investigators hope to gain rich natural history data to determine how to proceed in future trials, whether they use higher doses, longer-term dosing, or try a different target. In addition, the infrastructure of study sites established in StopRA should be incredibly valuable for future prevention studies.
“I envision a future where everybody is screened for RA risk using good blood tests and then given the opportunity for prevention,” first involving high-risk groups such as family members of people with RA, and then ultimately opening up to population-based screening because 90% of RA occurs in individuals without family history of the disease, Dr. Deane said. An analogy for this might be cardiovascular disease, he said, where we screen the cholesterol level of patients before they have had a heart attack, and if it’s above a certain threshold we prescribe a statin, healthy eating, and exercise in an attempt to prevent cardiovascular events. In the same way, it might be possible to screen people for biomarker risk factors and prescribe a drug and/or a lifestyle change to prevent RA or even prevent many of the other rheumatic diseases including lupus and Sjögren’s syndrome.
Methotrexate
The Dutch TREAT EARLIER (Treat Early Arthralgia to Reverse or Limit Impending Exacerbation to Rheumatoid Arthritis) trial is unique among the RA prevention trials for its inclusion of patients with clinically suspect arthralgia and subclinical inflammation on MRI in the hand or foot without any requirement for seropositivity. The trial’s 200 participants are randomized to methotrexate or placebo for 1 year. All subjects receive an initial 120-mg intramuscular injection of methylprednisolone. The primary outcome measured at 2 years is the frequency of clinically detectable arthritis fulfilling the 2010 European League Against Rheumatism/American College of Rheumatology criteria for RA or of unclassified arthritis with a swollen joint count of more than two joints, both persisting for at least 4 weeks. The trial, which is investigator initiated without industry sponsorship, has been enrolling patients for about 1.5 years and will need about that much more time to complete it.
“We do this because we don’t want to confine ourselves to autoantibody-positive patients; we also want to include the autoantibody-negative patients at risk for RA. That’s relevant because in the past, autoantibody-positive patients had more severe disease and more severe joint destruction, but clinically relevant joint destruction doesn’t develop anymore [because of effective treatment], and the problem is more that RA is still a chronic disease. Both ACPA-positive and -negative RA are chronic diseases.”
All the patients included in the trial are considered to be at risk for RA by rheumatologists because of their arthralgia. Because of the clinically relevant population, the results of TREAT EARLIER might be generalized more easily to daily practice, she said in an interview.
Abatacept
The APIPPRA (Arthritis Prevention in the Preclinical Phase of Rheumatoid Arthritis with Abatacept) trial hopes to find out whether RA or clinical synovitis can be prevented with abatacept (Orencia) 125 mg weekly by comparing it against placebo over a 12-month period in 206 British and Dutch patients with arthralgia who are rheumatoid factor (RF) and ACPA-positive. Subjects who are RF negative, but who carry high levels of serum ACPA defined as three times the upper limit of normal may be included. There will be a 1-year follow-up after the intervention period to monitor patients for arthritis.
The ARIAA (Abatacept Reversing Subclinical Inflammation as Measured by MRI in ACPA Positive Arthralgia) trial is randomizing 98 German patients with ACPA-positive arthralgia to 6 months of abatacept 125 mg weekly for 6 months vs. placebo, followed by a 12-month follow-up period. The primary outcome of the double-blind trial is the proportion of patients with an improvement of acute inflammation characterized as improvement of synovitis or osteitis in the MRI of the dominant hand after 6 months of treatment. The proportion of patients who develop RA based on ACR/EULAR 2010 criteria at 6-month intervals is one of a multitude of secondary outcomes that will be measured. Individuals in the study must test positive for ACPA (with or without RF); have joint pain in the hand, feet, knee, shoulder, or elbow for at least 6 weeks prior to inclusion or in past history; and synovitis or osteitis present on MRI of the dominant hand at baseline.
The two abatacept trials, both of which are expected to be completed in 2018, are sponsored by abatacept’s manufacturer, Bristol-Myers Squibb.
Rituximab
Results from the randomized, placebo-controlled PRAIRI (Prevention of RA by Rituximab) trial that were reported at the annual European Congress of Rheumatology in June showed that a single, intravenous infusion of 1,000 mg of rituximab (Rituxan) given to people with arthralgia and a high risk for developing rheumatoid arthritis did not prevent RA, but the treatment did appear to delay the development of RA. During follow-up, 16 of the 40 people in the placebo group (40%) developed RA after a median of 12 months, and 14 of the 41 in the treated arm (34%) developed RA after a median of 17 months. A Kaplan-Meier survival analysis found that the development of RA in 25% of people occurred at about 12 months in the placebo arm, whereas in the intervention arm it did not occur until 24 months.
At three Dutch centers, the PRAIRI trial investigators enrolled people with arthralgia who had never been diagnosed with arthritis, had never used a disease-modifying antirheumatic drug, and had at least one of these two risk factors: a serum level of IgM rheumatoid factor of more than 12.5 IU/mL and a serum level of anticitrullinated peptide antibodies of more than 25 IU/mL. Enrolled participants also needed to have at least one of the following: a serum level of C-reactive protein greater than 3 mg/L, an erythrocyte sedimentation rate of greater than 28 mm/hr, and evidence of subclinical synovitis identified by either ultrasound or MRI.
Atorvastatin
The STAPRA (Statins to Prevent Rheumatoid Arthritis) trial is randomizing 220 people to double-blind treatment with either atorvastatin 40 mg or placebo for 3 years to determine whether the combined lipid-lowering and anti-inflammatory effects of statin therapy may be able to prevent the development of clinical arthritis in people at increased risk for RA. The participants must test positive for RF and ACPA or a high ACPA titer of three times the cut-off value. Arthralgia is not required, and participants must not have current clinically apparent synovitis. The main endpoint is the development of clinical arthritis as confirmed by a rheumatologist in the study. The trial is scheduled to be completed in 2020.
Investigators across the United States and Europe hope to answer questions surrounding the feasibility of preventing rheumatoid arthritis in a series of proof-of-concept clinical trials that are enrolling patients with various risk factors for the disease. At least five trials have begun – with one already completed – to prevent RA with disease-modifying antirheumatic drugs, including a U.S. trial with hydroxychloroquine and European trials involving methotrexate, rituximab, and abatacept. Another trial with atorvastatin is also underway.
All of the trials involve participants with different risk factors for RA and may thereby provide a range of answers about where the most promising areas for disease prevention lie.
Hydroxychloroquine
Perhaps the broadest in scope of all the studies investigating the prevention of RA is the StopRA (Strategy to Prevent the Onset of Clinically Apparent Rheumatoid Arthritis) trial, which is randomizing 200 subjects with an anticyclic citrullinated peptide 3 (anti-CCP3) that’s greater than twice the normal level, with or without arthralgia, to either hydroxychloroquine (HCQ) 200-400 mg/day or placebo for 1 year, followed by 2 years of follow-up. Pilot data indicated that a level of 40 U/mL or higher of anti-CCP3, which is twice the normal level for positivity, gave a 50% chance of developing RA in the next 3 years regardless of symptoms, family history, or other factors.
The trial’s focus on people with an elevated level of anti-CCP3 limits it to just seropositive individuals, specifically those who are anti-citrullinated protein antibody (ACPA)-positive who constitute about 60%-70% of RA patients with established RA.
The investigators chose to use HCQ because it is a safe and well-tolerated medication for RA, and it may have mechanisms of action that may work particularly well in the early development of RA by blocking inflammation and epitope spreading, Dr. Deane said. “While hydroxychloroquine might not be powerful enough to stop active RA, we hypothesize that it’s just the right drug to block key processes early in its development,” Dr. Deane said in an interview, noting that HCQ is also used to block disease flares in palindromic rheumatism and diminish autoantibody responses in systemic lupus erythematosus.
The StopRA trial is being performed by the Autoimmunity Centers of Excellence, a network sponsored by the National Institutes of Health and the National Institute of Allergy and Infectious Diseases. Enrollment began at 18 U.S. sites in April 2016 with screening of first-degree relatives of patients with RA, community-based screening at health fairs, and finding CCP positive individuals without inflammatory arthritis in rheumatology clinics. The investigators estimate that they will need to screen 20,000 individuals to enroll 200 into the study. Dr. Deane said that he and his coinvestigators hope to use the variables that will arise from the diverse population to later determine subgroups who may respond best to the intervention. “We were concerned that if we made everybody too similar we wouldn’t be able to analyze whether symptoms or other factors mattered or not in who responded to the intervention. It may also allow us to catch some people at an early phase of their autoimmunity and others at a later phase and to determine for future studies when is the best time to intervene in preclinical RA with HCQ.”
It’s possible that HCQ will just delay RA rather than prevent it, Dr. Deane said, perhaps indicating that they may find that HCQ needs to be used longer. In any case, by the time the trial is completed in 2020 the investigators hope to gain rich natural history data to determine how to proceed in future trials, whether they use higher doses, longer-term dosing, or try a different target. In addition, the infrastructure of study sites established in StopRA should be incredibly valuable for future prevention studies.
“I envision a future where everybody is screened for RA risk using good blood tests and then given the opportunity for prevention,” first involving high-risk groups such as family members of people with RA, and then ultimately opening up to population-based screening because 90% of RA occurs in individuals without family history of the disease, Dr. Deane said. An analogy for this might be cardiovascular disease, he said, where we screen the cholesterol level of patients before they have had a heart attack, and if it’s above a certain threshold we prescribe a statin, healthy eating, and exercise in an attempt to prevent cardiovascular events. In the same way, it might be possible to screen people for biomarker risk factors and prescribe a drug and/or a lifestyle change to prevent RA or even prevent many of the other rheumatic diseases including lupus and Sjögren’s syndrome.
Methotrexate
The Dutch TREAT EARLIER (Treat Early Arthralgia to Reverse or Limit Impending Exacerbation to Rheumatoid Arthritis) trial is unique among the RA prevention trials for its inclusion of patients with clinically suspect arthralgia and subclinical inflammation on MRI in the hand or foot without any requirement for seropositivity. The trial’s 200 participants are randomized to methotrexate or placebo for 1 year. All subjects receive an initial 120-mg intramuscular injection of methylprednisolone. The primary outcome measured at 2 years is the frequency of clinically detectable arthritis fulfilling the 2010 European League Against Rheumatism/American College of Rheumatology criteria for RA or of unclassified arthritis with a swollen joint count of more than two joints, both persisting for at least 4 weeks. The trial, which is investigator initiated without industry sponsorship, has been enrolling patients for about 1.5 years and will need about that much more time to complete it.
“We do this because we don’t want to confine ourselves to autoantibody-positive patients; we also want to include the autoantibody-negative patients at risk for RA. That’s relevant because in the past, autoantibody-positive patients had more severe disease and more severe joint destruction, but clinically relevant joint destruction doesn’t develop anymore [because of effective treatment], and the problem is more that RA is still a chronic disease. Both ACPA-positive and -negative RA are chronic diseases.”
All the patients included in the trial are considered to be at risk for RA by rheumatologists because of their arthralgia. Because of the clinically relevant population, the results of TREAT EARLIER might be generalized more easily to daily practice, she said in an interview.
Abatacept
The APIPPRA (Arthritis Prevention in the Preclinical Phase of Rheumatoid Arthritis with Abatacept) trial hopes to find out whether RA or clinical synovitis can be prevented with abatacept (Orencia) 125 mg weekly by comparing it against placebo over a 12-month period in 206 British and Dutch patients with arthralgia who are rheumatoid factor (RF) and ACPA-positive. Subjects who are RF negative, but who carry high levels of serum ACPA defined as three times the upper limit of normal may be included. There will be a 1-year follow-up after the intervention period to monitor patients for arthritis.
The ARIAA (Abatacept Reversing Subclinical Inflammation as Measured by MRI in ACPA Positive Arthralgia) trial is randomizing 98 German patients with ACPA-positive arthralgia to 6 months of abatacept 125 mg weekly for 6 months vs. placebo, followed by a 12-month follow-up period. The primary outcome of the double-blind trial is the proportion of patients with an improvement of acute inflammation characterized as improvement of synovitis or osteitis in the MRI of the dominant hand after 6 months of treatment. The proportion of patients who develop RA based on ACR/EULAR 2010 criteria at 6-month intervals is one of a multitude of secondary outcomes that will be measured. Individuals in the study must test positive for ACPA (with or without RF); have joint pain in the hand, feet, knee, shoulder, or elbow for at least 6 weeks prior to inclusion or in past history; and synovitis or osteitis present on MRI of the dominant hand at baseline.
The two abatacept trials, both of which are expected to be completed in 2018, are sponsored by abatacept’s manufacturer, Bristol-Myers Squibb.
Rituximab
Results from the randomized, placebo-controlled PRAIRI (Prevention of RA by Rituximab) trial that were reported at the annual European Congress of Rheumatology in June showed that a single, intravenous infusion of 1,000 mg of rituximab (Rituxan) given to people with arthralgia and a high risk for developing rheumatoid arthritis did not prevent RA, but the treatment did appear to delay the development of RA. During follow-up, 16 of the 40 people in the placebo group (40%) developed RA after a median of 12 months, and 14 of the 41 in the treated arm (34%) developed RA after a median of 17 months. A Kaplan-Meier survival analysis found that the development of RA in 25% of people occurred at about 12 months in the placebo arm, whereas in the intervention arm it did not occur until 24 months.
At three Dutch centers, the PRAIRI trial investigators enrolled people with arthralgia who had never been diagnosed with arthritis, had never used a disease-modifying antirheumatic drug, and had at least one of these two risk factors: a serum level of IgM rheumatoid factor of more than 12.5 IU/mL and a serum level of anticitrullinated peptide antibodies of more than 25 IU/mL. Enrolled participants also needed to have at least one of the following: a serum level of C-reactive protein greater than 3 mg/L, an erythrocyte sedimentation rate of greater than 28 mm/hr, and evidence of subclinical synovitis identified by either ultrasound or MRI.
Atorvastatin
The STAPRA (Statins to Prevent Rheumatoid Arthritis) trial is randomizing 220 people to double-blind treatment with either atorvastatin 40 mg or placebo for 3 years to determine whether the combined lipid-lowering and anti-inflammatory effects of statin therapy may be able to prevent the development of clinical arthritis in people at increased risk for RA. The participants must test positive for RF and ACPA or a high ACPA titer of three times the cut-off value. Arthralgia is not required, and participants must not have current clinically apparent synovitis. The main endpoint is the development of clinical arthritis as confirmed by a rheumatologist in the study. The trial is scheduled to be completed in 2020.
Investigators across the United States and Europe hope to answer questions surrounding the feasibility of preventing rheumatoid arthritis in a series of proof-of-concept clinical trials that are enrolling patients with various risk factors for the disease. At least five trials have begun – with one already completed – to prevent RA with disease-modifying antirheumatic drugs, including a U.S. trial with hydroxychloroquine and European trials involving methotrexate, rituximab, and abatacept. Another trial with atorvastatin is also underway.
All of the trials involve participants with different risk factors for RA and may thereby provide a range of answers about where the most promising areas for disease prevention lie.
Hydroxychloroquine
Perhaps the broadest in scope of all the studies investigating the prevention of RA is the StopRA (Strategy to Prevent the Onset of Clinically Apparent Rheumatoid Arthritis) trial, which is randomizing 200 subjects with an anticyclic citrullinated peptide 3 (anti-CCP3) that’s greater than twice the normal level, with or without arthralgia, to either hydroxychloroquine (HCQ) 200-400 mg/day or placebo for 1 year, followed by 2 years of follow-up. Pilot data indicated that a level of 40 U/mL or higher of anti-CCP3, which is twice the normal level for positivity, gave a 50% chance of developing RA in the next 3 years regardless of symptoms, family history, or other factors.
The trial’s focus on people with an elevated level of anti-CCP3 limits it to just seropositive individuals, specifically those who are anti-citrullinated protein antibody (ACPA)-positive who constitute about 60%-70% of RA patients with established RA.
The investigators chose to use HCQ because it is a safe and well-tolerated medication for RA, and it may have mechanisms of action that may work particularly well in the early development of RA by blocking inflammation and epitope spreading, Dr. Deane said. “While hydroxychloroquine might not be powerful enough to stop active RA, we hypothesize that it’s just the right drug to block key processes early in its development,” Dr. Deane said in an interview, noting that HCQ is also used to block disease flares in palindromic rheumatism and diminish autoantibody responses in systemic lupus erythematosus.
The StopRA trial is being performed by the Autoimmunity Centers of Excellence, a network sponsored by the National Institutes of Health and the National Institute of Allergy and Infectious Diseases. Enrollment began at 18 U.S. sites in April 2016 with screening of first-degree relatives of patients with RA, community-based screening at health fairs, and finding CCP positive individuals without inflammatory arthritis in rheumatology clinics. The investigators estimate that they will need to screen 20,000 individuals to enroll 200 into the study. Dr. Deane said that he and his coinvestigators hope to use the variables that will arise from the diverse population to later determine subgroups who may respond best to the intervention. “We were concerned that if we made everybody too similar we wouldn’t be able to analyze whether symptoms or other factors mattered or not in who responded to the intervention. It may also allow us to catch some people at an early phase of their autoimmunity and others at a later phase and to determine for future studies when is the best time to intervene in preclinical RA with HCQ.”
It’s possible that HCQ will just delay RA rather than prevent it, Dr. Deane said, perhaps indicating that they may find that HCQ needs to be used longer. In any case, by the time the trial is completed in 2020 the investigators hope to gain rich natural history data to determine how to proceed in future trials, whether they use higher doses, longer-term dosing, or try a different target. In addition, the infrastructure of study sites established in StopRA should be incredibly valuable for future prevention studies.
“I envision a future where everybody is screened for RA risk using good blood tests and then given the opportunity for prevention,” first involving high-risk groups such as family members of people with RA, and then ultimately opening up to population-based screening because 90% of RA occurs in individuals without family history of the disease, Dr. Deane said. An analogy for this might be cardiovascular disease, he said, where we screen the cholesterol level of patients before they have had a heart attack, and if it’s above a certain threshold we prescribe a statin, healthy eating, and exercise in an attempt to prevent cardiovascular events. In the same way, it might be possible to screen people for biomarker risk factors and prescribe a drug and/or a lifestyle change to prevent RA or even prevent many of the other rheumatic diseases including lupus and Sjögren’s syndrome.
Methotrexate
The Dutch TREAT EARLIER (Treat Early Arthralgia to Reverse or Limit Impending Exacerbation to Rheumatoid Arthritis) trial is unique among the RA prevention trials for its inclusion of patients with clinically suspect arthralgia and subclinical inflammation on MRI in the hand or foot without any requirement for seropositivity. The trial’s 200 participants are randomized to methotrexate or placebo for 1 year. All subjects receive an initial 120-mg intramuscular injection of methylprednisolone. The primary outcome measured at 2 years is the frequency of clinically detectable arthritis fulfilling the 2010 European League Against Rheumatism/American College of Rheumatology criteria for RA or of unclassified arthritis with a swollen joint count of more than two joints, both persisting for at least 4 weeks. The trial, which is investigator initiated without industry sponsorship, has been enrolling patients for about 1.5 years and will need about that much more time to complete it.
“We do this because we don’t want to confine ourselves to autoantibody-positive patients; we also want to include the autoantibody-negative patients at risk for RA. That’s relevant because in the past, autoantibody-positive patients had more severe disease and more severe joint destruction, but clinically relevant joint destruction doesn’t develop anymore [because of effective treatment], and the problem is more that RA is still a chronic disease. Both ACPA-positive and -negative RA are chronic diseases.”
All the patients included in the trial are considered to be at risk for RA by rheumatologists because of their arthralgia. Because of the clinically relevant population, the results of TREAT EARLIER might be generalized more easily to daily practice, she said in an interview.
Abatacept
The APIPPRA (Arthritis Prevention in the Preclinical Phase of Rheumatoid Arthritis with Abatacept) trial hopes to find out whether RA or clinical synovitis can be prevented with abatacept (Orencia) 125 mg weekly by comparing it against placebo over a 12-month period in 206 British and Dutch patients with arthralgia who are rheumatoid factor (RF) and ACPA-positive. Subjects who are RF negative, but who carry high levels of serum ACPA defined as three times the upper limit of normal may be included. There will be a 1-year follow-up after the intervention period to monitor patients for arthritis.
The ARIAA (Abatacept Reversing Subclinical Inflammation as Measured by MRI in ACPA Positive Arthralgia) trial is randomizing 98 German patients with ACPA-positive arthralgia to 6 months of abatacept 125 mg weekly for 6 months vs. placebo, followed by a 12-month follow-up period. The primary outcome of the double-blind trial is the proportion of patients with an improvement of acute inflammation characterized as improvement of synovitis or osteitis in the MRI of the dominant hand after 6 months of treatment. The proportion of patients who develop RA based on ACR/EULAR 2010 criteria at 6-month intervals is one of a multitude of secondary outcomes that will be measured. Individuals in the study must test positive for ACPA (with or without RF); have joint pain in the hand, feet, knee, shoulder, or elbow for at least 6 weeks prior to inclusion or in past history; and synovitis or osteitis present on MRI of the dominant hand at baseline.
The two abatacept trials, both of which are expected to be completed in 2018, are sponsored by abatacept’s manufacturer, Bristol-Myers Squibb.
Rituximab
Results from the randomized, placebo-controlled PRAIRI (Prevention of RA by Rituximab) trial that were reported at the annual European Congress of Rheumatology in June showed that a single, intravenous infusion of 1,000 mg of rituximab (Rituxan) given to people with arthralgia and a high risk for developing rheumatoid arthritis did not prevent RA, but the treatment did appear to delay the development of RA. During follow-up, 16 of the 40 people in the placebo group (40%) developed RA after a median of 12 months, and 14 of the 41 in the treated arm (34%) developed RA after a median of 17 months. A Kaplan-Meier survival analysis found that the development of RA in 25% of people occurred at about 12 months in the placebo arm, whereas in the intervention arm it did not occur until 24 months.
At three Dutch centers, the PRAIRI trial investigators enrolled people with arthralgia who had never been diagnosed with arthritis, had never used a disease-modifying antirheumatic drug, and had at least one of these two risk factors: a serum level of IgM rheumatoid factor of more than 12.5 IU/mL and a serum level of anticitrullinated peptide antibodies of more than 25 IU/mL. Enrolled participants also needed to have at least one of the following: a serum level of C-reactive protein greater than 3 mg/L, an erythrocyte sedimentation rate of greater than 28 mm/hr, and evidence of subclinical synovitis identified by either ultrasound or MRI.
Atorvastatin
The STAPRA (Statins to Prevent Rheumatoid Arthritis) trial is randomizing 220 people to double-blind treatment with either atorvastatin 40 mg or placebo for 3 years to determine whether the combined lipid-lowering and anti-inflammatory effects of statin therapy may be able to prevent the development of clinical arthritis in people at increased risk for RA. The participants must test positive for RF and ACPA or a high ACPA titer of three times the cut-off value. Arthralgia is not required, and participants must not have current clinically apparent synovitis. The main endpoint is the development of clinical arthritis as confirmed by a rheumatologist in the study. The trial is scheduled to be completed in 2020.
Be vigilant for restrictive lung disease in RA
LAS VEGAS – Patients with rheumatoid arthritis who have pulmonary symptoms and a restrictive pulmonary function test pattern have a high likelihood for a diagnosis of interstitial lung disease, making it necessary to put it high on the differential and to begin working collaboratively with pulmonologists, according to Jon T. Giles, MD.
Overall, 8%-15% of RA patients will develop clinically significant interstitial lung disease (ILD), although radiographic evidence of ILD can be seen in up to half of RA patients, and in one study about one in four patients had evidence of ILD on CT scanning within 2 years of RA diagnosis. The overall risk for RA patients to develop ILD has been shown to be nine times higher than for matched controls (Arthritis Rheum. 2010 Jun;62[6]:1583-91), Dr. Giles said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.
Relatively recently discovered risk factors for RA-ILD include higher levels of anti–citrullinated protein antibodies (ACPAs), and particularly antibodies against peptidylarginine deiminase (PAD), an enzyme that catalyzes arginine’s conversion to citrulline. Particularly for ever-smokers, the presence of the PAD3/4XR antibody has been highly correlated (P = .001) with having radiographic evidence of ILD. Besides currently smoking and ever smoking, other wide-ranging risk factors that have been associated with radiographic evidence of ILD include older age, being male, higher disease activity, and current use of prednisone or leflunomide, according to work that Dr. Giles conducted with his colleagues (Ann Rheum Dis. 2014 Aug;73[8]:1487-94).
An “alphabet soup” of ILD subtypes
Though there’s an “alphabet soup” of subtypes of ILD in RA, 90% of RA patients with ILD will have one of two conditions: usual interstitial pneumonitis (RA-UIP) or nonspecific interstitial pneumonitis (RA-NSIP). It’s not entirely clear whether one type of RA-ILD has a survival advantage over the other, Dr. Giles said.
Care for RA patients should include screening for ILD, said Dr. Giles. Physicians should ask about dry cough, dyspnea, and decreased exercise tolerance. Signs of ILD can include diminished oxygen saturation, a cardiac exam consistent with right heart disease, and rales. It’s not clear, he said, whether periodic chest radiographs or pulmonary function testing in asymptomatic RA patients is warranted.
Positive findings should prompt pulmonary function testing to include DLCO (diffusing capacity of lung for carbon monoxide), which may or may not be reduced in patients with clinically significant ILD. However, testing will show a restrictive pattern. A high-resolution chest CT should also be obtained.
Further evaluation should be done collaboratively with pulmonologists, and preferably with an ILD center, said Dr. Giles. A bronchoalveolar lavage and/or a lung biopsy may be considered.
Radiographic features of RA-UIP can include reticulation and honeycombing, predominantly seen in a subpleural and basilar distribution. Traction bronchiectasis may or may not be present. If a biopsy is performed, the histologic presentation of RA-UIP includes subpleural patches of dense fibrosis and honeycombing adjacent to healthy lung tissue; fibroblastic foci may be seen in the fibrotic regions.
In differentiating RA-UIP from interstitial pulmonary fibrosis (IPF), Dr. Giles said that lymphoid hyperplasia with germinal centers and peribronchial lesions are both more common in RA-UIP than in IPF. By contrast, fibroblastic foci are less common in RA-UIP than in IPF.
Sorting out the relationship between the use of disease-modifying antirheumatic drugs and ILD in RA is complicated by “complexities of attribution,” said Dr. Giles, since “RA patients with the most severe or refractory disease are more likely to both be exposed to a great number of RA therapies and higher doses and more combinations, and to have more risk factors for ILD.” Additionally, hypersensitivity pneumonitis can share some features with some subtypes of RA-ILD.
Treatment goals
Beyond maximizing smoking-cessation intervention, which should be done for all currently smoking ILD patients, treatment goals for RA-ILD are “a balancing act,” Dr. Giles said. Immunizations should be up to date for all RA-ILD patients, and any concomitant pulmonary conditions, such as asthma or chronic obstructive pulmonary disorder, should also be optimally treated. An early evaluation for lung transplant is warranted for RA-ILD as well, he said.
If patients are symptomatic, then the goal is symptom reduction, with the extent of radiographically or histologically documented involvement and the rate of decline to be factored into treatment decisions.
Immunosuppressive treatments for RA-ILD, Dr. Giles said, “are not supported by any randomized clinical trials.” However, corticosteroids are often effective for RA-NSIP; “UIP is often not steroid responsive,” he said. Other agents can include azathioprine, which can give a “double whammy” effect by addressing joint and lung disease. However, azathioprine should not be used concurrently with corticosteroids, he said.
Mycophenolate mofetil (CellCept) has known antifibrotic effects, and there have been case reports of improvement in RA-ILD. Cyclophosphamide is also occasionally used. A host of other treatments have been attempted, including the antifibrotics pirfenidone (Esbriet) and nintedanib (Ofev), although these have been studied only in interstitial pulmonary fibrosis, said Dr. Giles. “Treating symptomatic RA-ILD is always a challenge,” he said.
Dr. Giles has been a consultant to Roche/Genentech and Proximagen and has received grant funding from Pfizer.
Global Academy for Medical Education and this news organization are owned by the same parent company.
koakes@frontlinemedcom.com
On Twitter @karioakes
LAS VEGAS – Patients with rheumatoid arthritis who have pulmonary symptoms and a restrictive pulmonary function test pattern have a high likelihood for a diagnosis of interstitial lung disease, making it necessary to put it high on the differential and to begin working collaboratively with pulmonologists, according to Jon T. Giles, MD.
Overall, 8%-15% of RA patients will develop clinically significant interstitial lung disease (ILD), although radiographic evidence of ILD can be seen in up to half of RA patients, and in one study about one in four patients had evidence of ILD on CT scanning within 2 years of RA diagnosis. The overall risk for RA patients to develop ILD has been shown to be nine times higher than for matched controls (Arthritis Rheum. 2010 Jun;62[6]:1583-91), Dr. Giles said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.
Relatively recently discovered risk factors for RA-ILD include higher levels of anti–citrullinated protein antibodies (ACPAs), and particularly antibodies against peptidylarginine deiminase (PAD), an enzyme that catalyzes arginine’s conversion to citrulline. Particularly for ever-smokers, the presence of the PAD3/4XR antibody has been highly correlated (P = .001) with having radiographic evidence of ILD. Besides currently smoking and ever smoking, other wide-ranging risk factors that have been associated with radiographic evidence of ILD include older age, being male, higher disease activity, and current use of prednisone or leflunomide, according to work that Dr. Giles conducted with his colleagues (Ann Rheum Dis. 2014 Aug;73[8]:1487-94).
An “alphabet soup” of ILD subtypes
Though there’s an “alphabet soup” of subtypes of ILD in RA, 90% of RA patients with ILD will have one of two conditions: usual interstitial pneumonitis (RA-UIP) or nonspecific interstitial pneumonitis (RA-NSIP). It’s not entirely clear whether one type of RA-ILD has a survival advantage over the other, Dr. Giles said.
Care for RA patients should include screening for ILD, said Dr. Giles. Physicians should ask about dry cough, dyspnea, and decreased exercise tolerance. Signs of ILD can include diminished oxygen saturation, a cardiac exam consistent with right heart disease, and rales. It’s not clear, he said, whether periodic chest radiographs or pulmonary function testing in asymptomatic RA patients is warranted.
Positive findings should prompt pulmonary function testing to include DLCO (diffusing capacity of lung for carbon monoxide), which may or may not be reduced in patients with clinically significant ILD. However, testing will show a restrictive pattern. A high-resolution chest CT should also be obtained.
Further evaluation should be done collaboratively with pulmonologists, and preferably with an ILD center, said Dr. Giles. A bronchoalveolar lavage and/or a lung biopsy may be considered.
Radiographic features of RA-UIP can include reticulation and honeycombing, predominantly seen in a subpleural and basilar distribution. Traction bronchiectasis may or may not be present. If a biopsy is performed, the histologic presentation of RA-UIP includes subpleural patches of dense fibrosis and honeycombing adjacent to healthy lung tissue; fibroblastic foci may be seen in the fibrotic regions.
In differentiating RA-UIP from interstitial pulmonary fibrosis (IPF), Dr. Giles said that lymphoid hyperplasia with germinal centers and peribronchial lesions are both more common in RA-UIP than in IPF. By contrast, fibroblastic foci are less common in RA-UIP than in IPF.
Sorting out the relationship between the use of disease-modifying antirheumatic drugs and ILD in RA is complicated by “complexities of attribution,” said Dr. Giles, since “RA patients with the most severe or refractory disease are more likely to both be exposed to a great number of RA therapies and higher doses and more combinations, and to have more risk factors for ILD.” Additionally, hypersensitivity pneumonitis can share some features with some subtypes of RA-ILD.
Treatment goals
Beyond maximizing smoking-cessation intervention, which should be done for all currently smoking ILD patients, treatment goals for RA-ILD are “a balancing act,” Dr. Giles said. Immunizations should be up to date for all RA-ILD patients, and any concomitant pulmonary conditions, such as asthma or chronic obstructive pulmonary disorder, should also be optimally treated. An early evaluation for lung transplant is warranted for RA-ILD as well, he said.
If patients are symptomatic, then the goal is symptom reduction, with the extent of radiographically or histologically documented involvement and the rate of decline to be factored into treatment decisions.
Immunosuppressive treatments for RA-ILD, Dr. Giles said, “are not supported by any randomized clinical trials.” However, corticosteroids are often effective for RA-NSIP; “UIP is often not steroid responsive,” he said. Other agents can include azathioprine, which can give a “double whammy” effect by addressing joint and lung disease. However, azathioprine should not be used concurrently with corticosteroids, he said.
Mycophenolate mofetil (CellCept) has known antifibrotic effects, and there have been case reports of improvement in RA-ILD. Cyclophosphamide is also occasionally used. A host of other treatments have been attempted, including the antifibrotics pirfenidone (Esbriet) and nintedanib (Ofev), although these have been studied only in interstitial pulmonary fibrosis, said Dr. Giles. “Treating symptomatic RA-ILD is always a challenge,” he said.
Dr. Giles has been a consultant to Roche/Genentech and Proximagen and has received grant funding from Pfizer.
Global Academy for Medical Education and this news organization are owned by the same parent company.
koakes@frontlinemedcom.com
On Twitter @karioakes
LAS VEGAS – Patients with rheumatoid arthritis who have pulmonary symptoms and a restrictive pulmonary function test pattern have a high likelihood for a diagnosis of interstitial lung disease, making it necessary to put it high on the differential and to begin working collaboratively with pulmonologists, according to Jon T. Giles, MD.
Overall, 8%-15% of RA patients will develop clinically significant interstitial lung disease (ILD), although radiographic evidence of ILD can be seen in up to half of RA patients, and in one study about one in four patients had evidence of ILD on CT scanning within 2 years of RA diagnosis. The overall risk for RA patients to develop ILD has been shown to be nine times higher than for matched controls (Arthritis Rheum. 2010 Jun;62[6]:1583-91), Dr. Giles said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.
Relatively recently discovered risk factors for RA-ILD include higher levels of anti–citrullinated protein antibodies (ACPAs), and particularly antibodies against peptidylarginine deiminase (PAD), an enzyme that catalyzes arginine’s conversion to citrulline. Particularly for ever-smokers, the presence of the PAD3/4XR antibody has been highly correlated (P = .001) with having radiographic evidence of ILD. Besides currently smoking and ever smoking, other wide-ranging risk factors that have been associated with radiographic evidence of ILD include older age, being male, higher disease activity, and current use of prednisone or leflunomide, according to work that Dr. Giles conducted with his colleagues (Ann Rheum Dis. 2014 Aug;73[8]:1487-94).
An “alphabet soup” of ILD subtypes
Though there’s an “alphabet soup” of subtypes of ILD in RA, 90% of RA patients with ILD will have one of two conditions: usual interstitial pneumonitis (RA-UIP) or nonspecific interstitial pneumonitis (RA-NSIP). It’s not entirely clear whether one type of RA-ILD has a survival advantage over the other, Dr. Giles said.
Care for RA patients should include screening for ILD, said Dr. Giles. Physicians should ask about dry cough, dyspnea, and decreased exercise tolerance. Signs of ILD can include diminished oxygen saturation, a cardiac exam consistent with right heart disease, and rales. It’s not clear, he said, whether periodic chest radiographs or pulmonary function testing in asymptomatic RA patients is warranted.
Positive findings should prompt pulmonary function testing to include DLCO (diffusing capacity of lung for carbon monoxide), which may or may not be reduced in patients with clinically significant ILD. However, testing will show a restrictive pattern. A high-resolution chest CT should also be obtained.
Further evaluation should be done collaboratively with pulmonologists, and preferably with an ILD center, said Dr. Giles. A bronchoalveolar lavage and/or a lung biopsy may be considered.
Radiographic features of RA-UIP can include reticulation and honeycombing, predominantly seen in a subpleural and basilar distribution. Traction bronchiectasis may or may not be present. If a biopsy is performed, the histologic presentation of RA-UIP includes subpleural patches of dense fibrosis and honeycombing adjacent to healthy lung tissue; fibroblastic foci may be seen in the fibrotic regions.
In differentiating RA-UIP from interstitial pulmonary fibrosis (IPF), Dr. Giles said that lymphoid hyperplasia with germinal centers and peribronchial lesions are both more common in RA-UIP than in IPF. By contrast, fibroblastic foci are less common in RA-UIP than in IPF.
Sorting out the relationship between the use of disease-modifying antirheumatic drugs and ILD in RA is complicated by “complexities of attribution,” said Dr. Giles, since “RA patients with the most severe or refractory disease are more likely to both be exposed to a great number of RA therapies and higher doses and more combinations, and to have more risk factors for ILD.” Additionally, hypersensitivity pneumonitis can share some features with some subtypes of RA-ILD.
Treatment goals
Beyond maximizing smoking-cessation intervention, which should be done for all currently smoking ILD patients, treatment goals for RA-ILD are “a balancing act,” Dr. Giles said. Immunizations should be up to date for all RA-ILD patients, and any concomitant pulmonary conditions, such as asthma or chronic obstructive pulmonary disorder, should also be optimally treated. An early evaluation for lung transplant is warranted for RA-ILD as well, he said.
If patients are symptomatic, then the goal is symptom reduction, with the extent of radiographically or histologically documented involvement and the rate of decline to be factored into treatment decisions.
Immunosuppressive treatments for RA-ILD, Dr. Giles said, “are not supported by any randomized clinical trials.” However, corticosteroids are often effective for RA-NSIP; “UIP is often not steroid responsive,” he said. Other agents can include azathioprine, which can give a “double whammy” effect by addressing joint and lung disease. However, azathioprine should not be used concurrently with corticosteroids, he said.
Mycophenolate mofetil (CellCept) has known antifibrotic effects, and there have been case reports of improvement in RA-ILD. Cyclophosphamide is also occasionally used. A host of other treatments have been attempted, including the antifibrotics pirfenidone (Esbriet) and nintedanib (Ofev), although these have been studied only in interstitial pulmonary fibrosis, said Dr. Giles. “Treating symptomatic RA-ILD is always a challenge,” he said.
Dr. Giles has been a consultant to Roche/Genentech and Proximagen and has received grant funding from Pfizer.
Global Academy for Medical Education and this news organization are owned by the same parent company.
koakes@frontlinemedcom.com
On Twitter @karioakes
Most children with JIA get different diagnosis as adults
Two-thirds of children diagnosed with juvenile idiopathic arthritis are classified later as having a different form of arthritis as adults, with 72% of them requiring disease-modifying medication and 13% forced into retirement, according to a cross-sectional analysis of a registry database.
But among patients with inactive disease, more than one-third are off medication, and the majority have either no or very mild disabilities, reported Filipa Oliveira-Ramos, MD, of Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, and her colleagues (RMD Open 2016;2:e000304. doi: 10.1136/rmdopen-2016-000304).
The team used data from the Rheumatic Diseases Portuguese Register database to discern how rheumatic disease classifications evolve as people with JIA grow into adulthood. The analysis comprised 426 patients and examined fulfillment of adult classification criteria, function as assessed by the Health Assessment Questionnaire (HAQ), clinical disease characteristics as assessed by the Juvenile Arthritis Damage Index–articular (JADI-A) and Juvenile Arthritis Damage Index–extra-articular (JADI-E), and disease activity.
The patients were a mean of 34 years old at the time of the last visit entered into the database. The patients’ mean disease duration was 22.5 years, including 80% with at least 10 years and 24% with more than 30 years.
All had been diagnosed with JIA, at a mean age of about 10 years. Disease categories were persistent oligoarthritis (19%), extended oligoarthritis (14%), rheumatoid factor–positive polyarthritis (17%), rheumatoid factor–negative polyarthritis (18%), systemic disease (10%), enthesitis-related arthritis (19%), psoriatic arthritis (3%), and undifferentiated arthritis (1%).
A total of 72% of patients were still employed, although 13% had retired because of disease-related disability. Most (67%) still had active disease, and 72% were taking a disease-modifying antirheumatic drug.
JIA had evolved into numerous new diagnoses, the team observed. Most patients with systemic-onset JIA (92%) were classified as having adult Still’s disease – more than half (58%) with persistent systemic features and about 42% with predominately polyarticular involvement.
The majority of patients with RF-positive polyarthritis (96%) and of those with RF-negative polyarthritis as children (57%) fulfilled the adult criteria for rheumatoid arthritis.
Patients who had persistent oligoarthritis as children were, as adults, most likely be classified with spondyloarthritis (35%), although 59% remained unclassifiable.
Most of the patients with extended oligoarthritis as children were later classified as having either rheumatoid arthritis (39%) or spondyloarthritis (26%). Most patients with juvenile enthesitis-related arthritis were also reclassified as having spondyloarthritis (95%).
All of those with childhood psoriatic arthritis retained that classification as adults.
A smaller portion of patients (21%) were unclassified as adults, the investigators said. Most of these patients had RF-negative polyarticular or oligoarticular classifications as children.
In a series of multivariate analyses, the team found a number of significant associations with adult outcomes. After adjustment for International League of Associations for Rheumatology (ILAR) category, inactive adult disease was associated with shorter disease duration, less delay in diagnosis, a lower HAQ score, and less exposure to corticosteroids. A higher HAQ score was associated with a longer disease duration and exposure to biologics, while a lower HAQ was associated with the persistence of systemic disease features.
Higher JADI-A scores were associated with disability-related retirement, longer disease duration, and past or current use of biologics.
Another series of multivariate models assessed outcomes associated with inactive disease. Patients who were older at disease onset were more likely to have inactive disease as adults. A positive test for anticitrullinated protein antibodies decreased the likelihood of disease inactivity by 93%.
Finally, the investigators evaluated associations with function and clinical characteristics. Younger age at disease onset was associated with higher HAQ and JADI scores in adulthood. Patients with RF-positive polyarthritis and systemic-onset JIA were more likely to have worse JADI-A and JADI-E scores, compared with patients who had persistent oligoarthritis. Corticosteroid exposure was also predictive of worse extra-articular scores on the JADI.
“Understanding the way these juvenile diseases progress could add useful information for the ongoing discussion of a new classification capable of better unifying the language between pediatric and adult care,” the authors concluded.
None of the authors had financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
This is an important article in that it highlights one of the fundamental flaws of the juvenile idiopathic arthritis classification.
The manifestations of the rheumatic diseases often evolve over time. There may be psoriasis before arthritis, but there also may be arthritis before psoriasis. Similarly, children with an ultimate diagnosis of Crohn’s disease may first present to the rheumatologist with arthritis.
The definition of JIA requires only the onset of arthritis lasting more than 3 weeks before 16 years of age with the exclusion of other obvious cause. A careful reading of the subclassification criteria quickly reveals that many children are “unclassifiable” because of family history or other factors.
The present study makes it clear that by the time they reach adulthood, a significant number of individuals who were told they had JIA will, in fact, meet criteria for a different classification. This would be of only casual interest were it not for the fact that these children will have previously been entered into databases about the natural history of JIA with erroneous classifications.
More worrisome is that fact that some will have been included in therapeutic trials with erroneous classifications as well. The pediatric rheumatology community would do well to recognize the urgent need for a reassessment of the classification criteria and nomenclature to better reflect the diversity of causes of childhood arthritis.
Thomas Lehman, MD, is chief of pediatric rheumatology at the Hospital for Special Surgery, New York. He has no relevant disclosures.
This is an important article in that it highlights one of the fundamental flaws of the juvenile idiopathic arthritis classification.
The manifestations of the rheumatic diseases often evolve over time. There may be psoriasis before arthritis, but there also may be arthritis before psoriasis. Similarly, children with an ultimate diagnosis of Crohn’s disease may first present to the rheumatologist with arthritis.
The definition of JIA requires only the onset of arthritis lasting more than 3 weeks before 16 years of age with the exclusion of other obvious cause. A careful reading of the subclassification criteria quickly reveals that many children are “unclassifiable” because of family history or other factors.
The present study makes it clear that by the time they reach adulthood, a significant number of individuals who were told they had JIA will, in fact, meet criteria for a different classification. This would be of only casual interest were it not for the fact that these children will have previously been entered into databases about the natural history of JIA with erroneous classifications.
More worrisome is that fact that some will have been included in therapeutic trials with erroneous classifications as well. The pediatric rheumatology community would do well to recognize the urgent need for a reassessment of the classification criteria and nomenclature to better reflect the diversity of causes of childhood arthritis.
Thomas Lehman, MD, is chief of pediatric rheumatology at the Hospital for Special Surgery, New York. He has no relevant disclosures.
This is an important article in that it highlights one of the fundamental flaws of the juvenile idiopathic arthritis classification.
The manifestations of the rheumatic diseases often evolve over time. There may be psoriasis before arthritis, but there also may be arthritis before psoriasis. Similarly, children with an ultimate diagnosis of Crohn’s disease may first present to the rheumatologist with arthritis.
The definition of JIA requires only the onset of arthritis lasting more than 3 weeks before 16 years of age with the exclusion of other obvious cause. A careful reading of the subclassification criteria quickly reveals that many children are “unclassifiable” because of family history or other factors.
The present study makes it clear that by the time they reach adulthood, a significant number of individuals who were told they had JIA will, in fact, meet criteria for a different classification. This would be of only casual interest were it not for the fact that these children will have previously been entered into databases about the natural history of JIA with erroneous classifications.
More worrisome is that fact that some will have been included in therapeutic trials with erroneous classifications as well. The pediatric rheumatology community would do well to recognize the urgent need for a reassessment of the classification criteria and nomenclature to better reflect the diversity of causes of childhood arthritis.
Thomas Lehman, MD, is chief of pediatric rheumatology at the Hospital for Special Surgery, New York. He has no relevant disclosures.
Two-thirds of children diagnosed with juvenile idiopathic arthritis are classified later as having a different form of arthritis as adults, with 72% of them requiring disease-modifying medication and 13% forced into retirement, according to a cross-sectional analysis of a registry database.
But among patients with inactive disease, more than one-third are off medication, and the majority have either no or very mild disabilities, reported Filipa Oliveira-Ramos, MD, of Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, and her colleagues (RMD Open 2016;2:e000304. doi: 10.1136/rmdopen-2016-000304).
The team used data from the Rheumatic Diseases Portuguese Register database to discern how rheumatic disease classifications evolve as people with JIA grow into adulthood. The analysis comprised 426 patients and examined fulfillment of adult classification criteria, function as assessed by the Health Assessment Questionnaire (HAQ), clinical disease characteristics as assessed by the Juvenile Arthritis Damage Index–articular (JADI-A) and Juvenile Arthritis Damage Index–extra-articular (JADI-E), and disease activity.
The patients were a mean of 34 years old at the time of the last visit entered into the database. The patients’ mean disease duration was 22.5 years, including 80% with at least 10 years and 24% with more than 30 years.
All had been diagnosed with JIA, at a mean age of about 10 years. Disease categories were persistent oligoarthritis (19%), extended oligoarthritis (14%), rheumatoid factor–positive polyarthritis (17%), rheumatoid factor–negative polyarthritis (18%), systemic disease (10%), enthesitis-related arthritis (19%), psoriatic arthritis (3%), and undifferentiated arthritis (1%).
A total of 72% of patients were still employed, although 13% had retired because of disease-related disability. Most (67%) still had active disease, and 72% were taking a disease-modifying antirheumatic drug.
JIA had evolved into numerous new diagnoses, the team observed. Most patients with systemic-onset JIA (92%) were classified as having adult Still’s disease – more than half (58%) with persistent systemic features and about 42% with predominately polyarticular involvement.
The majority of patients with RF-positive polyarthritis (96%) and of those with RF-negative polyarthritis as children (57%) fulfilled the adult criteria for rheumatoid arthritis.
Patients who had persistent oligoarthritis as children were, as adults, most likely be classified with spondyloarthritis (35%), although 59% remained unclassifiable.
Most of the patients with extended oligoarthritis as children were later classified as having either rheumatoid arthritis (39%) or spondyloarthritis (26%). Most patients with juvenile enthesitis-related arthritis were also reclassified as having spondyloarthritis (95%).
All of those with childhood psoriatic arthritis retained that classification as adults.
A smaller portion of patients (21%) were unclassified as adults, the investigators said. Most of these patients had RF-negative polyarticular or oligoarticular classifications as children.
In a series of multivariate analyses, the team found a number of significant associations with adult outcomes. After adjustment for International League of Associations for Rheumatology (ILAR) category, inactive adult disease was associated with shorter disease duration, less delay in diagnosis, a lower HAQ score, and less exposure to corticosteroids. A higher HAQ score was associated with a longer disease duration and exposure to biologics, while a lower HAQ was associated with the persistence of systemic disease features.
Higher JADI-A scores were associated with disability-related retirement, longer disease duration, and past or current use of biologics.
Another series of multivariate models assessed outcomes associated with inactive disease. Patients who were older at disease onset were more likely to have inactive disease as adults. A positive test for anticitrullinated protein antibodies decreased the likelihood of disease inactivity by 93%.
Finally, the investigators evaluated associations with function and clinical characteristics. Younger age at disease onset was associated with higher HAQ and JADI scores in adulthood. Patients with RF-positive polyarthritis and systemic-onset JIA were more likely to have worse JADI-A and JADI-E scores, compared with patients who had persistent oligoarthritis. Corticosteroid exposure was also predictive of worse extra-articular scores on the JADI.
“Understanding the way these juvenile diseases progress could add useful information for the ongoing discussion of a new classification capable of better unifying the language between pediatric and adult care,” the authors concluded.
None of the authors had financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
Two-thirds of children diagnosed with juvenile idiopathic arthritis are classified later as having a different form of arthritis as adults, with 72% of them requiring disease-modifying medication and 13% forced into retirement, according to a cross-sectional analysis of a registry database.
But among patients with inactive disease, more than one-third are off medication, and the majority have either no or very mild disabilities, reported Filipa Oliveira-Ramos, MD, of Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, and her colleagues (RMD Open 2016;2:e000304. doi: 10.1136/rmdopen-2016-000304).
The team used data from the Rheumatic Diseases Portuguese Register database to discern how rheumatic disease classifications evolve as people with JIA grow into adulthood. The analysis comprised 426 patients and examined fulfillment of adult classification criteria, function as assessed by the Health Assessment Questionnaire (HAQ), clinical disease characteristics as assessed by the Juvenile Arthritis Damage Index–articular (JADI-A) and Juvenile Arthritis Damage Index–extra-articular (JADI-E), and disease activity.
The patients were a mean of 34 years old at the time of the last visit entered into the database. The patients’ mean disease duration was 22.5 years, including 80% with at least 10 years and 24% with more than 30 years.
All had been diagnosed with JIA, at a mean age of about 10 years. Disease categories were persistent oligoarthritis (19%), extended oligoarthritis (14%), rheumatoid factor–positive polyarthritis (17%), rheumatoid factor–negative polyarthritis (18%), systemic disease (10%), enthesitis-related arthritis (19%), psoriatic arthritis (3%), and undifferentiated arthritis (1%).
A total of 72% of patients were still employed, although 13% had retired because of disease-related disability. Most (67%) still had active disease, and 72% were taking a disease-modifying antirheumatic drug.
JIA had evolved into numerous new diagnoses, the team observed. Most patients with systemic-onset JIA (92%) were classified as having adult Still’s disease – more than half (58%) with persistent systemic features and about 42% with predominately polyarticular involvement.
The majority of patients with RF-positive polyarthritis (96%) and of those with RF-negative polyarthritis as children (57%) fulfilled the adult criteria for rheumatoid arthritis.
Patients who had persistent oligoarthritis as children were, as adults, most likely be classified with spondyloarthritis (35%), although 59% remained unclassifiable.
Most of the patients with extended oligoarthritis as children were later classified as having either rheumatoid arthritis (39%) or spondyloarthritis (26%). Most patients with juvenile enthesitis-related arthritis were also reclassified as having spondyloarthritis (95%).
All of those with childhood psoriatic arthritis retained that classification as adults.
A smaller portion of patients (21%) were unclassified as adults, the investigators said. Most of these patients had RF-negative polyarticular or oligoarticular classifications as children.
In a series of multivariate analyses, the team found a number of significant associations with adult outcomes. After adjustment for International League of Associations for Rheumatology (ILAR) category, inactive adult disease was associated with shorter disease duration, less delay in diagnosis, a lower HAQ score, and less exposure to corticosteroids. A higher HAQ score was associated with a longer disease duration and exposure to biologics, while a lower HAQ was associated with the persistence of systemic disease features.
Higher JADI-A scores were associated with disability-related retirement, longer disease duration, and past or current use of biologics.
Another series of multivariate models assessed outcomes associated with inactive disease. Patients who were older at disease onset were more likely to have inactive disease as adults. A positive test for anticitrullinated protein antibodies decreased the likelihood of disease inactivity by 93%.
Finally, the investigators evaluated associations with function and clinical characteristics. Younger age at disease onset was associated with higher HAQ and JADI scores in adulthood. Patients with RF-positive polyarthritis and systemic-onset JIA were more likely to have worse JADI-A and JADI-E scores, compared with patients who had persistent oligoarthritis. Corticosteroid exposure was also predictive of worse extra-articular scores on the JADI.
“Understanding the way these juvenile diseases progress could add useful information for the ongoing discussion of a new classification capable of better unifying the language between pediatric and adult care,” the authors concluded.
None of the authors had financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
Key clinical point:
Major finding: The childhood diagnosis of JIA is reclassified to another form of arthritis in two-thirds of patients in adulthood.
Data source: The Rheumatic Diseases Portuguese Register.
Disclosures: None of the authors had financial disclosures.
VIDEO: Get comfortable with screening for, treating CVD risk in RA
LAS VEGAS – When genetic risk and lifestyle risk factors collide with the baseline systemic inflammation of rheumatoid arthritis (RA), cardiovascular risk increases significantly. Helping patients to manage risk for cardiovascular disease (CVD) requires getting comfortable in making risk assessments and counseling patients about medication and lifestyle options, especially for patients who are not actively being managed by primary care physicians.
Jon Giles, MD, said that a large portion of the elevated risk for CVD in patients with RA is “driven by the fact that [RA] patients have more atherosclerosis.”
Dr. Giles, professor of medicine at Columbia University, New York, said that other CVD risk factors can boost the risk further. “If you have diabetes, smoking, high blood pressure, elevated lipids in your blood – if you have a combination of those plus inflammation, it makes that risk even higher,” Dr. Giles said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.
“There’s definitely a lot of data that suggests that, as rheumatologists, we’re not doing a very good job of screening and treating for cardiovascular disease and risk,” Dr. Giles said in an interview at the meeting. He suggests that his fellow rheumatologists become comfortable with screening and treatment guidelines for cardiovascular disease. For selected patients, coronary CT or carotid ultrasound may be valuable in guiding decision making, since very low LDL cholesterol may be correlated with an increased risk of CVD for some patients with RA.
Global Academy for Medical Education and this news organization are owned by the same parent company.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @karioakes
LAS VEGAS – When genetic risk and lifestyle risk factors collide with the baseline systemic inflammation of rheumatoid arthritis (RA), cardiovascular risk increases significantly. Helping patients to manage risk for cardiovascular disease (CVD) requires getting comfortable in making risk assessments and counseling patients about medication and lifestyle options, especially for patients who are not actively being managed by primary care physicians.
Jon Giles, MD, said that a large portion of the elevated risk for CVD in patients with RA is “driven by the fact that [RA] patients have more atherosclerosis.”
Dr. Giles, professor of medicine at Columbia University, New York, said that other CVD risk factors can boost the risk further. “If you have diabetes, smoking, high blood pressure, elevated lipids in your blood – if you have a combination of those plus inflammation, it makes that risk even higher,” Dr. Giles said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.
“There’s definitely a lot of data that suggests that, as rheumatologists, we’re not doing a very good job of screening and treating for cardiovascular disease and risk,” Dr. Giles said in an interview at the meeting. He suggests that his fellow rheumatologists become comfortable with screening and treatment guidelines for cardiovascular disease. For selected patients, coronary CT or carotid ultrasound may be valuable in guiding decision making, since very low LDL cholesterol may be correlated with an increased risk of CVD for some patients with RA.
Global Academy for Medical Education and this news organization are owned by the same parent company.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @karioakes
LAS VEGAS – When genetic risk and lifestyle risk factors collide with the baseline systemic inflammation of rheumatoid arthritis (RA), cardiovascular risk increases significantly. Helping patients to manage risk for cardiovascular disease (CVD) requires getting comfortable in making risk assessments and counseling patients about medication and lifestyle options, especially for patients who are not actively being managed by primary care physicians.
Jon Giles, MD, said that a large portion of the elevated risk for CVD in patients with RA is “driven by the fact that [RA] patients have more atherosclerosis.”
Dr. Giles, professor of medicine at Columbia University, New York, said that other CVD risk factors can boost the risk further. “If you have diabetes, smoking, high blood pressure, elevated lipids in your blood – if you have a combination of those plus inflammation, it makes that risk even higher,” Dr. Giles said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.
“There’s definitely a lot of data that suggests that, as rheumatologists, we’re not doing a very good job of screening and treating for cardiovascular disease and risk,” Dr. Giles said in an interview at the meeting. He suggests that his fellow rheumatologists become comfortable with screening and treatment guidelines for cardiovascular disease. For selected patients, coronary CT or carotid ultrasound may be valuable in guiding decision making, since very low LDL cholesterol may be correlated with an increased risk of CVD for some patients with RA.
Global Academy for Medical Education and this news organization are owned by the same parent company.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @karioakes
EXPERT ANALYSIS FROM THE ANNUAL PERSPECTIVES IN RHEUMATIC DISEASES
FDA approves biosimilar adalimumab
There are “no clinically meaningful differences” between Amgen’s biosimilar adalimumab (Amjevita) and AbbVie’s branded product Humira, the Food and Drug Administration noted it its Sept. 23 announcement of Amjevita’s approval.
Although Amjevita (adalimumab-atto) is expected to cost less than Humira, Amgen has not released price information or a launch date pending ongoing litigation with AbbVie over intellectual property rights, an Amgen spokeswoman said.
The products carry an identical black box warning of tuberculosis and other serious infections, as well as lymphoma and other malignancies “reported in children and adolescent patients treated with [tumor necrosis factor] blockers including adalimumab.” As with Humira, “the most common expected adverse reactions with Amjevita are infections and injection site reactions,” the FDA said. Both products are approved in 20 mg/0.4 mL and 40 mg/0.8 mL prefilled injections, but Humira also has a 10 mg/0.2 mL option.
Amjevita was unanimously recommended for approval by an FDA review panel in July. Although “the biosimilar pathway is still a new frontier,” it’s likely to “enhance access to treatment for patients with serious medical conditions,” Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said in the agency statement.
The approval follows the FDA’s approval of biosimilar infliximab (Inflectra) in April 2016 and biosimilar etanercept (Erelzi) in August 2016. Inflectra has not hit the U.S. market yet, but the European experience with biosimilar infliximab – generally positive – may give an indication of how Amjevita will fare in the United States. It’s perhaps a third or more less expensive than the original product (Remicade) and often used for new starts. There is uncertainty, however, about switching patients already established on Remicade, especially when it’s forced by cost issues.
Interchangeability is a concern in the United States as well. The FDA is working on the issue but has not yet released guidance, and the agency was careful to note in its statement that Amjevita was “approved as a biosimilar, not as an interchangeable product.” Biosimilar adalimumab, meanwhile, is under review in Europe, according to an Amgen statement.
The FDA approved Amjevita after reviewing structural and functional characteristics, pharmacokinetics and pharmacodynamics data, clinical immunogenicity data, and other clinical safety and effectiveness data that demonstrated similarity to Humira, including two phase III trials for plaque psoriasis and rheumatoid arthritis.
An AbbVie spokesperson said the company “anticipated Amgen’s product would be approved,” but noted the ongoing litigation.
There are “no clinically meaningful differences” between Amgen’s biosimilar adalimumab (Amjevita) and AbbVie’s branded product Humira, the Food and Drug Administration noted it its Sept. 23 announcement of Amjevita’s approval.
Although Amjevita (adalimumab-atto) is expected to cost less than Humira, Amgen has not released price information or a launch date pending ongoing litigation with AbbVie over intellectual property rights, an Amgen spokeswoman said.
The products carry an identical black box warning of tuberculosis and other serious infections, as well as lymphoma and other malignancies “reported in children and adolescent patients treated with [tumor necrosis factor] blockers including adalimumab.” As with Humira, “the most common expected adverse reactions with Amjevita are infections and injection site reactions,” the FDA said. Both products are approved in 20 mg/0.4 mL and 40 mg/0.8 mL prefilled injections, but Humira also has a 10 mg/0.2 mL option.
Amjevita was unanimously recommended for approval by an FDA review panel in July. Although “the biosimilar pathway is still a new frontier,” it’s likely to “enhance access to treatment for patients with serious medical conditions,” Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said in the agency statement.
The approval follows the FDA’s approval of biosimilar infliximab (Inflectra) in April 2016 and biosimilar etanercept (Erelzi) in August 2016. Inflectra has not hit the U.S. market yet, but the European experience with biosimilar infliximab – generally positive – may give an indication of how Amjevita will fare in the United States. It’s perhaps a third or more less expensive than the original product (Remicade) and often used for new starts. There is uncertainty, however, about switching patients already established on Remicade, especially when it’s forced by cost issues.
Interchangeability is a concern in the United States as well. The FDA is working on the issue but has not yet released guidance, and the agency was careful to note in its statement that Amjevita was “approved as a biosimilar, not as an interchangeable product.” Biosimilar adalimumab, meanwhile, is under review in Europe, according to an Amgen statement.
The FDA approved Amjevita after reviewing structural and functional characteristics, pharmacokinetics and pharmacodynamics data, clinical immunogenicity data, and other clinical safety and effectiveness data that demonstrated similarity to Humira, including two phase III trials for plaque psoriasis and rheumatoid arthritis.
An AbbVie spokesperson said the company “anticipated Amgen’s product would be approved,” but noted the ongoing litigation.
There are “no clinically meaningful differences” between Amgen’s biosimilar adalimumab (Amjevita) and AbbVie’s branded product Humira, the Food and Drug Administration noted it its Sept. 23 announcement of Amjevita’s approval.
Although Amjevita (adalimumab-atto) is expected to cost less than Humira, Amgen has not released price information or a launch date pending ongoing litigation with AbbVie over intellectual property rights, an Amgen spokeswoman said.
The products carry an identical black box warning of tuberculosis and other serious infections, as well as lymphoma and other malignancies “reported in children and adolescent patients treated with [tumor necrosis factor] blockers including adalimumab.” As with Humira, “the most common expected adverse reactions with Amjevita are infections and injection site reactions,” the FDA said. Both products are approved in 20 mg/0.4 mL and 40 mg/0.8 mL prefilled injections, but Humira also has a 10 mg/0.2 mL option.
Amjevita was unanimously recommended for approval by an FDA review panel in July. Although “the biosimilar pathway is still a new frontier,” it’s likely to “enhance access to treatment for patients with serious medical conditions,” Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said in the agency statement.
The approval follows the FDA’s approval of biosimilar infliximab (Inflectra) in April 2016 and biosimilar etanercept (Erelzi) in August 2016. Inflectra has not hit the U.S. market yet, but the European experience with biosimilar infliximab – generally positive – may give an indication of how Amjevita will fare in the United States. It’s perhaps a third or more less expensive than the original product (Remicade) and often used for new starts. There is uncertainty, however, about switching patients already established on Remicade, especially when it’s forced by cost issues.
Interchangeability is a concern in the United States as well. The FDA is working on the issue but has not yet released guidance, and the agency was careful to note in its statement that Amjevita was “approved as a biosimilar, not as an interchangeable product.” Biosimilar adalimumab, meanwhile, is under review in Europe, according to an Amgen statement.
The FDA approved Amjevita after reviewing structural and functional characteristics, pharmacokinetics and pharmacodynamics data, clinical immunogenicity data, and other clinical safety and effectiveness data that demonstrated similarity to Humira, including two phase III trials for plaque psoriasis and rheumatoid arthritis.
An AbbVie spokesperson said the company “anticipated Amgen’s product would be approved,” but noted the ongoing litigation.
VIDEO: Consider immunogenicity when choosing biologics
LAS VEGAS – Although biologics have transformed treatment of many rheumatologic disorders, their structure and mechanism of action can come with immunogenic baggage. “They’re proteins; consequently, one can expect immunogenicity,” said Daniel Furst, MD, speaking at the annual Perspectives in Rheumatic Diseases held by the Global Academy for Medical Education.
Immunogenicity can increase clearance of drugs; it can also interfere with the function of the drug. Although physicians may be tempted to think that developing an antidrug antibody to a specific drug is the principal cause for lack of efficacy in an individual patient, “in fact, it’s not that simple,” said Dr. Furst. “There are comorbidities, other drugs, which can affect the immunogenicity itself; there’s even the specific epitope that’s being affected by the drug antibody, which may or may not result in neutralization and an effect.”
In the broad class of tumor necrosis factor inhibitors (TNFIs), about 30% of patients taking adalimumab or infliximab will develop autoantibodies. This is higher than the 10% rate of autoantibody development for other TNFIs.
For non-TNFIs, including abatacept, tocilizumab, and rituximab, “the incidence of immunogenicity is significantly lower,” on the order of 1%-5%, said Dr. Furst, who has appointments at the University of California, Los Angeles, the University of Washington, Seattle, and the University of Florence, Italy.
Still, “there’s reasonable evidence that antidrug antibodies to TNFIs decrease efficacy and increase toxicity, particularly skin reactions,” he said.
Global Academy for Medical Education and this organization are owned by the same parent company.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @karioakes
LAS VEGAS – Although biologics have transformed treatment of many rheumatologic disorders, their structure and mechanism of action can come with immunogenic baggage. “They’re proteins; consequently, one can expect immunogenicity,” said Daniel Furst, MD, speaking at the annual Perspectives in Rheumatic Diseases held by the Global Academy for Medical Education.
Immunogenicity can increase clearance of drugs; it can also interfere with the function of the drug. Although physicians may be tempted to think that developing an antidrug antibody to a specific drug is the principal cause for lack of efficacy in an individual patient, “in fact, it’s not that simple,” said Dr. Furst. “There are comorbidities, other drugs, which can affect the immunogenicity itself; there’s even the specific epitope that’s being affected by the drug antibody, which may or may not result in neutralization and an effect.”
In the broad class of tumor necrosis factor inhibitors (TNFIs), about 30% of patients taking adalimumab or infliximab will develop autoantibodies. This is higher than the 10% rate of autoantibody development for other TNFIs.
For non-TNFIs, including abatacept, tocilizumab, and rituximab, “the incidence of immunogenicity is significantly lower,” on the order of 1%-5%, said Dr. Furst, who has appointments at the University of California, Los Angeles, the University of Washington, Seattle, and the University of Florence, Italy.
Still, “there’s reasonable evidence that antidrug antibodies to TNFIs decrease efficacy and increase toxicity, particularly skin reactions,” he said.
Global Academy for Medical Education and this organization are owned by the same parent company.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @karioakes
LAS VEGAS – Although biologics have transformed treatment of many rheumatologic disorders, their structure and mechanism of action can come with immunogenic baggage. “They’re proteins; consequently, one can expect immunogenicity,” said Daniel Furst, MD, speaking at the annual Perspectives in Rheumatic Diseases held by the Global Academy for Medical Education.
Immunogenicity can increase clearance of drugs; it can also interfere with the function of the drug. Although physicians may be tempted to think that developing an antidrug antibody to a specific drug is the principal cause for lack of efficacy in an individual patient, “in fact, it’s not that simple,” said Dr. Furst. “There are comorbidities, other drugs, which can affect the immunogenicity itself; there’s even the specific epitope that’s being affected by the drug antibody, which may or may not result in neutralization and an effect.”
In the broad class of tumor necrosis factor inhibitors (TNFIs), about 30% of patients taking adalimumab or infliximab will develop autoantibodies. This is higher than the 10% rate of autoantibody development for other TNFIs.
For non-TNFIs, including abatacept, tocilizumab, and rituximab, “the incidence of immunogenicity is significantly lower,” on the order of 1%-5%, said Dr. Furst, who has appointments at the University of California, Los Angeles, the University of Washington, Seattle, and the University of Florence, Italy.
Still, “there’s reasonable evidence that antidrug antibodies to TNFIs decrease efficacy and increase toxicity, particularly skin reactions,” he said.
Global Academy for Medical Education and this organization are owned by the same parent company.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @karioakes
EXPERT ANALYSIS FROM PERSPECTIVES IN RHEUMATIC DISEASES
VIDEO: Consider chikungunya for unexplained seronegative arthritis
LAS VEGAS – When rheumatologists consider a differential diagnosis that includes seronegative rheumatoid arthritis, they should also consider chikungunya, according to Len Calabrese, DO.
The patient who presents with weeks to months of unexplained arthralgia and perhaps arthritis and a negative autoimmune panel deserves consideration of chikungunya or another arbovirus, said Dr. Calabrese, speaking at the annual Perspectives in Rheumatic Diseases held by the Global Academy for Medical Education.
Among the mosquito-borne arboviruses now in play in the Western Hemisphere, chikungunya is particularly likely to cause long-lasting and sometimes debilitating joint pain weeks and even months after initial infection.
An alphavirus, chikungunya virus makes most affected individuals quite ill, and serum IgG and IgM titers persist long after infection. Testing is straightforward, as long as the virus is a candidate diagnosis, Dr. Calabrese said.
In addition to obtaining an accurate travel history, said Dr. Calabrese, physicians should consider the possibility of autochthonous transmission, which occurs when an infected individual who returns from an endemic area is bitten by mosquitoes once home. Flares of autochthonous transmission can result in pockets of locally heavy transmission far from the zones where chikungunya usually resides.
Dr. Calabrese is chair of clinical immunology and chair of osteopathic research and education at the Cleveland Clinic, and he reported no relevant financial disclosures.
Global Academy for Medical Education and this news organization are owned by the same parent company.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @karioakes
LAS VEGAS – When rheumatologists consider a differential diagnosis that includes seronegative rheumatoid arthritis, they should also consider chikungunya, according to Len Calabrese, DO.
The patient who presents with weeks to months of unexplained arthralgia and perhaps arthritis and a negative autoimmune panel deserves consideration of chikungunya or another arbovirus, said Dr. Calabrese, speaking at the annual Perspectives in Rheumatic Diseases held by the Global Academy for Medical Education.
Among the mosquito-borne arboviruses now in play in the Western Hemisphere, chikungunya is particularly likely to cause long-lasting and sometimes debilitating joint pain weeks and even months after initial infection.
An alphavirus, chikungunya virus makes most affected individuals quite ill, and serum IgG and IgM titers persist long after infection. Testing is straightforward, as long as the virus is a candidate diagnosis, Dr. Calabrese said.
In addition to obtaining an accurate travel history, said Dr. Calabrese, physicians should consider the possibility of autochthonous transmission, which occurs when an infected individual who returns from an endemic area is bitten by mosquitoes once home. Flares of autochthonous transmission can result in pockets of locally heavy transmission far from the zones where chikungunya usually resides.
Dr. Calabrese is chair of clinical immunology and chair of osteopathic research and education at the Cleveland Clinic, and he reported no relevant financial disclosures.
Global Academy for Medical Education and this news organization are owned by the same parent company.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @karioakes
LAS VEGAS – When rheumatologists consider a differential diagnosis that includes seronegative rheumatoid arthritis, they should also consider chikungunya, according to Len Calabrese, DO.
The patient who presents with weeks to months of unexplained arthralgia and perhaps arthritis and a negative autoimmune panel deserves consideration of chikungunya or another arbovirus, said Dr. Calabrese, speaking at the annual Perspectives in Rheumatic Diseases held by the Global Academy for Medical Education.
Among the mosquito-borne arboviruses now in play in the Western Hemisphere, chikungunya is particularly likely to cause long-lasting and sometimes debilitating joint pain weeks and even months after initial infection.
An alphavirus, chikungunya virus makes most affected individuals quite ill, and serum IgG and IgM titers persist long after infection. Testing is straightforward, as long as the virus is a candidate diagnosis, Dr. Calabrese said.
In addition to obtaining an accurate travel history, said Dr. Calabrese, physicians should consider the possibility of autochthonous transmission, which occurs when an infected individual who returns from an endemic area is bitten by mosquitoes once home. Flares of autochthonous transmission can result in pockets of locally heavy transmission far from the zones where chikungunya usually resides.
Dr. Calabrese is chair of clinical immunology and chair of osteopathic research and education at the Cleveland Clinic, and he reported no relevant financial disclosures.
Global Academy for Medical Education and this news organization are owned by the same parent company.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @karioakes
EXPERT ANALYSIS FROM ANNUAL PERSPECTIVES IN RHEUMATIC DISEASES
Try non-TNF biologics for RA if anti-TNF fails
Rheumatoid arthritis patients who were unsuccessfully treated with anti–tumor necrosis factor drugs fared significantly better when treated with a non-TNF biologic than with a second anti-TNF drug in a 52-week, randomized, clinical trial of 300 adults.
Overall, 69% of patients who received a non-TNF biologic achieved clinical response, defined as a good or moderate EULAR response at 24 weeks, compared with 52% of patients who received a second anti-TNF drug, wrote Jacques-Eric Gottenberg, MD, PhD, of Strasbourg (France) University Hospital and his colleagues.
Patients were randomized to a non-TNF biologic or a second anti-TNF drug, with the choice of biologic left to the clinician. Patients were assessed at 12, 24, and 52 weeks.
“In addition to the superiority of the non-TNF treatment for the primary outcome at week 24, the non-TNF treatment was associated with a better EULAR response than a second anti-TNF drug at weeks 12 and 52,” the researchers noted. Significantly more patients in the non-TNF group reported low disease activity at 6 months and 12 months, compared with the second anti-TNF group, they added.
A total of 18 patients in the non-TNF group and 13 patients in the second anti-TNF group experienced serious adverse events; the most common were serious infections (in 33% and 77% of the non-TNF and anti-TNF groups, respectively) and cardiovascular events (33% vs. 8%, respectively).
The study was supported by the French Ministry of Health and promoted by Strasbourg University Hospital. Dr. Gottenberg disclosed financial support from AbbVie, Pfizer, and Roche, and personal fees from Bristol-Myers Squibb, Merck Sharp & Dohme, UCB, GlaxoSmithKline, and Novartis.
The findings were published online Sept. 20 (JAMA 2016;316[11]:1172-80).
Rheumatoid arthritis patients who were unsuccessfully treated with anti–tumor necrosis factor drugs fared significantly better when treated with a non-TNF biologic than with a second anti-TNF drug in a 52-week, randomized, clinical trial of 300 adults.
Overall, 69% of patients who received a non-TNF biologic achieved clinical response, defined as a good or moderate EULAR response at 24 weeks, compared with 52% of patients who received a second anti-TNF drug, wrote Jacques-Eric Gottenberg, MD, PhD, of Strasbourg (France) University Hospital and his colleagues.
Patients were randomized to a non-TNF biologic or a second anti-TNF drug, with the choice of biologic left to the clinician. Patients were assessed at 12, 24, and 52 weeks.
“In addition to the superiority of the non-TNF treatment for the primary outcome at week 24, the non-TNF treatment was associated with a better EULAR response than a second anti-TNF drug at weeks 12 and 52,” the researchers noted. Significantly more patients in the non-TNF group reported low disease activity at 6 months and 12 months, compared with the second anti-TNF group, they added.
A total of 18 patients in the non-TNF group and 13 patients in the second anti-TNF group experienced serious adverse events; the most common were serious infections (in 33% and 77% of the non-TNF and anti-TNF groups, respectively) and cardiovascular events (33% vs. 8%, respectively).
The study was supported by the French Ministry of Health and promoted by Strasbourg University Hospital. Dr. Gottenberg disclosed financial support from AbbVie, Pfizer, and Roche, and personal fees from Bristol-Myers Squibb, Merck Sharp & Dohme, UCB, GlaxoSmithKline, and Novartis.
The findings were published online Sept. 20 (JAMA 2016;316[11]:1172-80).
Rheumatoid arthritis patients who were unsuccessfully treated with anti–tumor necrosis factor drugs fared significantly better when treated with a non-TNF biologic than with a second anti-TNF drug in a 52-week, randomized, clinical trial of 300 adults.
Overall, 69% of patients who received a non-TNF biologic achieved clinical response, defined as a good or moderate EULAR response at 24 weeks, compared with 52% of patients who received a second anti-TNF drug, wrote Jacques-Eric Gottenberg, MD, PhD, of Strasbourg (France) University Hospital and his colleagues.
Patients were randomized to a non-TNF biologic or a second anti-TNF drug, with the choice of biologic left to the clinician. Patients were assessed at 12, 24, and 52 weeks.
“In addition to the superiority of the non-TNF treatment for the primary outcome at week 24, the non-TNF treatment was associated with a better EULAR response than a second anti-TNF drug at weeks 12 and 52,” the researchers noted. Significantly more patients in the non-TNF group reported low disease activity at 6 months and 12 months, compared with the second anti-TNF group, they added.
A total of 18 patients in the non-TNF group and 13 patients in the second anti-TNF group experienced serious adverse events; the most common were serious infections (in 33% and 77% of the non-TNF and anti-TNF groups, respectively) and cardiovascular events (33% vs. 8%, respectively).
The study was supported by the French Ministry of Health and promoted by Strasbourg University Hospital. Dr. Gottenberg disclosed financial support from AbbVie, Pfizer, and Roche, and personal fees from Bristol-Myers Squibb, Merck Sharp & Dohme, UCB, GlaxoSmithKline, and Novartis.
The findings were published online Sept. 20 (JAMA 2016;316[11]:1172-80).
FROM JAMA
