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FDA Approves REMS for Long-Acting Opioids
A risk evaluation and mitigation strategy for extended-release and long-acting opioid medications has received Food and Drug Administration approval.
The move has been anticipated as an important element in an attempt to stem the swelling tide of abuse, misuse, and overdose of these prescription drugs while assuring continued access to the highly potent analgesics for patients with moderate to severe persistent pain, Dr. Margaret A. Hamburg said in a media briefing.
The new safety measures, which pertain to approximately 30 currently available medications, will require the manufacturers of the drugs to make FDA-approved education materials available to prescribers no later than March 1, 2013, via development grants to continuing education providers who will develop and deliver the training, said Dr. Hamburg, commissioner of the FDA. In addition, the risk evaluation and mitigation strategy (REMS) will include the distribution of a patient counseling leaflet to prescribers regarding the safe and effective use of the drugs; an updated, single-page medication guide for consumers, an implementation plan, and periodic assessments to evaluate the impact of the program on the safe use of these products, which the FDA will review and use to tweak the program as needed, she said.
"It is important to note that we are focusing on extended-release and long-acting opioid medications ... because these have very specific safety problems that have to be addressed very carefully," according to Dr. John Jenkins, director of the Office of New Drugs within the FDA’s Center for Drug Evaluation and Research. These drugs, including hydromorphone, oxycodone, morphine, oxymorphone, methadone, transdermal fentanyl, and transdermal buprenorphine, "can cause problems even when prescribed appropriately."
The prescriber education component of the REMS will include information regarding the risks and benefits of opioid therapy for individual patients, choosing patients appropriately, patient management and monitoring, and patient counseling, Dr. Jenkins explained. It will also include guidance on the potential for misuse, abuse, and addition, as well as recognizing evidence for these outcomes. The updated medication guide and patient counseling document will include information on how to safely use, store, and dispose of these analgesics, specific instructions for recognizing the signs of potential overdose and advice for preventing accidental exposure to family and household visitors, he said.
With respect to the assessment and auditing component of the program, the FDA has established goals, which the manufacturers are expected to achieve, for the percentage of prescribers who complete the training and for assessing prescribers’ understanding of the risk information. Participation in the educational programs is not mandatory for prescribers, Dr. Hamburg stated. The assessments are also required to evaluate whether the [REMS] adversely affect patient access to these drugs, she said. "Patients in pain must have continued assess to medications they need," she added.
The new REMS program is one component of a multiagency, national strategy unveiled by the White House in 2011 to address prescription drug abuse, "which is this country’s fastest-growing drug problem," said Dr. Hamburg, noting that opioid overdoses in particular were the cause of approximately 15,000 deaths among Americans in 2008 and nearly 16,000 in 2009. Called Epidemic: Responding to America's Prescription Drug Abuse Crisis, the national plan suggests expansion of state-based prescription drug-monitoring programs; seeks creation of recommendations for convenient and environmentally responsible ways to dispose of unused medications; and calls for legislative action to reduce "doctor shopping" and "pill mills."
In the absence of the legislative changes needed to fulfill the comprehensive White House plan, the REMS "is an important and timely step by FDA to supplement prescriber training and consumer information," R. Gil Kerlikowske, director of the White House Office of National Drug Control Policy, said during the telebriefing.
A risk evaluation and mitigation strategy for extended-release and long-acting opioid medications has received Food and Drug Administration approval.
The move has been anticipated as an important element in an attempt to stem the swelling tide of abuse, misuse, and overdose of these prescription drugs while assuring continued access to the highly potent analgesics for patients with moderate to severe persistent pain, Dr. Margaret A. Hamburg said in a media briefing.
The new safety measures, which pertain to approximately 30 currently available medications, will require the manufacturers of the drugs to make FDA-approved education materials available to prescribers no later than March 1, 2013, via development grants to continuing education providers who will develop and deliver the training, said Dr. Hamburg, commissioner of the FDA. In addition, the risk evaluation and mitigation strategy (REMS) will include the distribution of a patient counseling leaflet to prescribers regarding the safe and effective use of the drugs; an updated, single-page medication guide for consumers, an implementation plan, and periodic assessments to evaluate the impact of the program on the safe use of these products, which the FDA will review and use to tweak the program as needed, she said.
"It is important to note that we are focusing on extended-release and long-acting opioid medications ... because these have very specific safety problems that have to be addressed very carefully," according to Dr. John Jenkins, director of the Office of New Drugs within the FDA’s Center for Drug Evaluation and Research. These drugs, including hydromorphone, oxycodone, morphine, oxymorphone, methadone, transdermal fentanyl, and transdermal buprenorphine, "can cause problems even when prescribed appropriately."
The prescriber education component of the REMS will include information regarding the risks and benefits of opioid therapy for individual patients, choosing patients appropriately, patient management and monitoring, and patient counseling, Dr. Jenkins explained. It will also include guidance on the potential for misuse, abuse, and addition, as well as recognizing evidence for these outcomes. The updated medication guide and patient counseling document will include information on how to safely use, store, and dispose of these analgesics, specific instructions for recognizing the signs of potential overdose and advice for preventing accidental exposure to family and household visitors, he said.
With respect to the assessment and auditing component of the program, the FDA has established goals, which the manufacturers are expected to achieve, for the percentage of prescribers who complete the training and for assessing prescribers’ understanding of the risk information. Participation in the educational programs is not mandatory for prescribers, Dr. Hamburg stated. The assessments are also required to evaluate whether the [REMS] adversely affect patient access to these drugs, she said. "Patients in pain must have continued assess to medications they need," she added.
The new REMS program is one component of a multiagency, national strategy unveiled by the White House in 2011 to address prescription drug abuse, "which is this country’s fastest-growing drug problem," said Dr. Hamburg, noting that opioid overdoses in particular were the cause of approximately 15,000 deaths among Americans in 2008 and nearly 16,000 in 2009. Called Epidemic: Responding to America's Prescription Drug Abuse Crisis, the national plan suggests expansion of state-based prescription drug-monitoring programs; seeks creation of recommendations for convenient and environmentally responsible ways to dispose of unused medications; and calls for legislative action to reduce "doctor shopping" and "pill mills."
In the absence of the legislative changes needed to fulfill the comprehensive White House plan, the REMS "is an important and timely step by FDA to supplement prescriber training and consumer information," R. Gil Kerlikowske, director of the White House Office of National Drug Control Policy, said during the telebriefing.
A risk evaluation and mitigation strategy for extended-release and long-acting opioid medications has received Food and Drug Administration approval.
The move has been anticipated as an important element in an attempt to stem the swelling tide of abuse, misuse, and overdose of these prescription drugs while assuring continued access to the highly potent analgesics for patients with moderate to severe persistent pain, Dr. Margaret A. Hamburg said in a media briefing.
The new safety measures, which pertain to approximately 30 currently available medications, will require the manufacturers of the drugs to make FDA-approved education materials available to prescribers no later than March 1, 2013, via development grants to continuing education providers who will develop and deliver the training, said Dr. Hamburg, commissioner of the FDA. In addition, the risk evaluation and mitigation strategy (REMS) will include the distribution of a patient counseling leaflet to prescribers regarding the safe and effective use of the drugs; an updated, single-page medication guide for consumers, an implementation plan, and periodic assessments to evaluate the impact of the program on the safe use of these products, which the FDA will review and use to tweak the program as needed, she said.
"It is important to note that we are focusing on extended-release and long-acting opioid medications ... because these have very specific safety problems that have to be addressed very carefully," according to Dr. John Jenkins, director of the Office of New Drugs within the FDA’s Center for Drug Evaluation and Research. These drugs, including hydromorphone, oxycodone, morphine, oxymorphone, methadone, transdermal fentanyl, and transdermal buprenorphine, "can cause problems even when prescribed appropriately."
The prescriber education component of the REMS will include information regarding the risks and benefits of opioid therapy for individual patients, choosing patients appropriately, patient management and monitoring, and patient counseling, Dr. Jenkins explained. It will also include guidance on the potential for misuse, abuse, and addition, as well as recognizing evidence for these outcomes. The updated medication guide and patient counseling document will include information on how to safely use, store, and dispose of these analgesics, specific instructions for recognizing the signs of potential overdose and advice for preventing accidental exposure to family and household visitors, he said.
With respect to the assessment and auditing component of the program, the FDA has established goals, which the manufacturers are expected to achieve, for the percentage of prescribers who complete the training and for assessing prescribers’ understanding of the risk information. Participation in the educational programs is not mandatory for prescribers, Dr. Hamburg stated. The assessments are also required to evaluate whether the [REMS] adversely affect patient access to these drugs, she said. "Patients in pain must have continued assess to medications they need," she added.
The new REMS program is one component of a multiagency, national strategy unveiled by the White House in 2011 to address prescription drug abuse, "which is this country’s fastest-growing drug problem," said Dr. Hamburg, noting that opioid overdoses in particular were the cause of approximately 15,000 deaths among Americans in 2008 and nearly 16,000 in 2009. Called Epidemic: Responding to America's Prescription Drug Abuse Crisis, the national plan suggests expansion of state-based prescription drug-monitoring programs; seeks creation of recommendations for convenient and environmentally responsible ways to dispose of unused medications; and calls for legislative action to reduce "doctor shopping" and "pill mills."
In the absence of the legislative changes needed to fulfill the comprehensive White House plan, the REMS "is an important and timely step by FDA to supplement prescriber training and consumer information," R. Gil Kerlikowske, director of the White House Office of National Drug Control Policy, said during the telebriefing.
Early Data Find No Adalimumab Teratogenicity
BALTIMORE – Exposure to adalimumab was not associated with any specific pattern of minor or major birth defects in women with rheumatoid arthritis taking the biologic drug during pregnancy, according to preliminary data from an ongoing prospective cohort study.
Between November 2004 and January 2012, 312 pregnant women in the United States and Canada – 69 women with RA exposed to adalimumab, 80 women with RA who had not taken adalimumab, and 163 healthy controls – were enrolled before 20 weeks’ gestation. Their mean age was 32-33 years, and about two-thirds were white.
Major birth defects among the live births were identified in 5% of the babies born to women exposed to adalimumab, compared with about 4% among disease-matched controls who did not take adalimumab, and about 7% among healthy controls, Christina Chambers, Ph.D., of the University of California, San Diego, reported at the annual meeting of the Teratology Society.
The rate of minor structural abnormalities was similar in the three groups, at about 22%-24%, and there was no pattern of major or minor structural defects noted among the adalimumab-exposed group. (The three major malformations in the adalimumab-exposed group were one ventricular septal defect, one unilateral cryptorchidism, and one case of microcephaly.)
There were no stillbirths. The rate of spontaneous abortions was not significantly different between the three groups, nor were the rates of preterm delivery or birth weights, said Dr. Chambers, director of the California Teratogen Information Service and Clinical Research Program.
Through 1-year of follow-up, there were no malignancies among the infants and the rates of serious infections in the three groups were similar (about 3% in the two RA groups and 2% in the healthy comparison group).
The teratogenic effects of adalimumab, a tumor necrosis factor blocker, are being evaluated in the pregnancy registry, which is part of the Organization of Teratology Information Specialists (OTIS) Autoimmune Diseases in Pregnancy Project.
Adalimumab, marketed as Humira by Abbott Laboratories, was first approved in the United States in 2002 as a treatment for people with moderately to severely active RA, and has since been approved for other autoimmune diseases, including psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, and psoriasis.
The registry study is comparing outcomes in women with RA who are treated with adalimumab during pregnancy, in women with RA not treated with adalimumab during pregnancy, and in women who do not have an autoimmune disease and have not been exposed to adalimumab or any known teratogenic drug during pregnancy. The study includes medical record reviews, examination of infants for major and minor structural abnormalities, and follow-up for 1 year post partum. It is expected to continue through 2017; the pregnant women are recruited from OTIS member services and from rheumatologists, and other clinicians who care for these patients.
Although little to no placental transfer of adalimumab is expected during early pregnancy, limited information on the safety of adalimumab during pregnancy has been published, Dr. Chambers said.
Abbott Laboratories is among the sponsors of the OTIS Autoimmune Diseases in Pregnancy Project, which is also evaluating safety of medications in women with ankylosing spondylitis, psoriasis and psoriatic arthritis, and Crohn’s disease. Dr. Chambers and her coauthors have received or receive grant funding for research on medications for autoimmune diseases from Abbott and other manufacturers: Amgen, Bristol Myers Squibb, Roche Genentech, Sanofi, Teva, Par, Sandoz, and Apotex.
Information for women and clinicians interested in enrolling in the OTIS Autoimmune Diseases in Pregnancy Project is available at www.otispregnancy.org/autoimmune-studies-s13049.
BALTIMORE – Exposure to adalimumab was not associated with any specific pattern of minor or major birth defects in women with rheumatoid arthritis taking the biologic drug during pregnancy, according to preliminary data from an ongoing prospective cohort study.
Between November 2004 and January 2012, 312 pregnant women in the United States and Canada – 69 women with RA exposed to adalimumab, 80 women with RA who had not taken adalimumab, and 163 healthy controls – were enrolled before 20 weeks’ gestation. Their mean age was 32-33 years, and about two-thirds were white.
Major birth defects among the live births were identified in 5% of the babies born to women exposed to adalimumab, compared with about 4% among disease-matched controls who did not take adalimumab, and about 7% among healthy controls, Christina Chambers, Ph.D., of the University of California, San Diego, reported at the annual meeting of the Teratology Society.
The rate of minor structural abnormalities was similar in the three groups, at about 22%-24%, and there was no pattern of major or minor structural defects noted among the adalimumab-exposed group. (The three major malformations in the adalimumab-exposed group were one ventricular septal defect, one unilateral cryptorchidism, and one case of microcephaly.)
There were no stillbirths. The rate of spontaneous abortions was not significantly different between the three groups, nor were the rates of preterm delivery or birth weights, said Dr. Chambers, director of the California Teratogen Information Service and Clinical Research Program.
Through 1-year of follow-up, there were no malignancies among the infants and the rates of serious infections in the three groups were similar (about 3% in the two RA groups and 2% in the healthy comparison group).
The teratogenic effects of adalimumab, a tumor necrosis factor blocker, are being evaluated in the pregnancy registry, which is part of the Organization of Teratology Information Specialists (OTIS) Autoimmune Diseases in Pregnancy Project.
Adalimumab, marketed as Humira by Abbott Laboratories, was first approved in the United States in 2002 as a treatment for people with moderately to severely active RA, and has since been approved for other autoimmune diseases, including psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, and psoriasis.
The registry study is comparing outcomes in women with RA who are treated with adalimumab during pregnancy, in women with RA not treated with adalimumab during pregnancy, and in women who do not have an autoimmune disease and have not been exposed to adalimumab or any known teratogenic drug during pregnancy. The study includes medical record reviews, examination of infants for major and minor structural abnormalities, and follow-up for 1 year post partum. It is expected to continue through 2017; the pregnant women are recruited from OTIS member services and from rheumatologists, and other clinicians who care for these patients.
Although little to no placental transfer of adalimumab is expected during early pregnancy, limited information on the safety of adalimumab during pregnancy has been published, Dr. Chambers said.
Abbott Laboratories is among the sponsors of the OTIS Autoimmune Diseases in Pregnancy Project, which is also evaluating safety of medications in women with ankylosing spondylitis, psoriasis and psoriatic arthritis, and Crohn’s disease. Dr. Chambers and her coauthors have received or receive grant funding for research on medications for autoimmune diseases from Abbott and other manufacturers: Amgen, Bristol Myers Squibb, Roche Genentech, Sanofi, Teva, Par, Sandoz, and Apotex.
Information for women and clinicians interested in enrolling in the OTIS Autoimmune Diseases in Pregnancy Project is available at www.otispregnancy.org/autoimmune-studies-s13049.
BALTIMORE – Exposure to adalimumab was not associated with any specific pattern of minor or major birth defects in women with rheumatoid arthritis taking the biologic drug during pregnancy, according to preliminary data from an ongoing prospective cohort study.
Between November 2004 and January 2012, 312 pregnant women in the United States and Canada – 69 women with RA exposed to adalimumab, 80 women with RA who had not taken adalimumab, and 163 healthy controls – were enrolled before 20 weeks’ gestation. Their mean age was 32-33 years, and about two-thirds were white.
Major birth defects among the live births were identified in 5% of the babies born to women exposed to adalimumab, compared with about 4% among disease-matched controls who did not take adalimumab, and about 7% among healthy controls, Christina Chambers, Ph.D., of the University of California, San Diego, reported at the annual meeting of the Teratology Society.
The rate of minor structural abnormalities was similar in the three groups, at about 22%-24%, and there was no pattern of major or minor structural defects noted among the adalimumab-exposed group. (The three major malformations in the adalimumab-exposed group were one ventricular septal defect, one unilateral cryptorchidism, and one case of microcephaly.)
There were no stillbirths. The rate of spontaneous abortions was not significantly different between the three groups, nor were the rates of preterm delivery or birth weights, said Dr. Chambers, director of the California Teratogen Information Service and Clinical Research Program.
Through 1-year of follow-up, there were no malignancies among the infants and the rates of serious infections in the three groups were similar (about 3% in the two RA groups and 2% in the healthy comparison group).
The teratogenic effects of adalimumab, a tumor necrosis factor blocker, are being evaluated in the pregnancy registry, which is part of the Organization of Teratology Information Specialists (OTIS) Autoimmune Diseases in Pregnancy Project.
Adalimumab, marketed as Humira by Abbott Laboratories, was first approved in the United States in 2002 as a treatment for people with moderately to severely active RA, and has since been approved for other autoimmune diseases, including psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, and psoriasis.
The registry study is comparing outcomes in women with RA who are treated with adalimumab during pregnancy, in women with RA not treated with adalimumab during pregnancy, and in women who do not have an autoimmune disease and have not been exposed to adalimumab or any known teratogenic drug during pregnancy. The study includes medical record reviews, examination of infants for major and minor structural abnormalities, and follow-up for 1 year post partum. It is expected to continue through 2017; the pregnant women are recruited from OTIS member services and from rheumatologists, and other clinicians who care for these patients.
Although little to no placental transfer of adalimumab is expected during early pregnancy, limited information on the safety of adalimumab during pregnancy has been published, Dr. Chambers said.
Abbott Laboratories is among the sponsors of the OTIS Autoimmune Diseases in Pregnancy Project, which is also evaluating safety of medications in women with ankylosing spondylitis, psoriasis and psoriatic arthritis, and Crohn’s disease. Dr. Chambers and her coauthors have received or receive grant funding for research on medications for autoimmune diseases from Abbott and other manufacturers: Amgen, Bristol Myers Squibb, Roche Genentech, Sanofi, Teva, Par, Sandoz, and Apotex.
Information for women and clinicians interested in enrolling in the OTIS Autoimmune Diseases in Pregnancy Project is available at www.otispregnancy.org/autoimmune-studies-s13049.
AT THE ANNUAL MEETING OF THE TERATOLOGY SOCIETY
2010 RA-Classification Criteria Outperform 1987 Criteria
BERLIN – The 2010 criteria for classifying rheumatoid arthritis accomplish what they were designed to do in patients with early disease: boost the sensitivity for identifying patients who are likely to eventually develop rheumatoid arthritis and could therefore benefit from early treatment.
A comparison of the 2010 criteria (Arthritis Rheum. 2010;62:2569-81) against the 1987 rheumatoid arthritis (RA) classification criteria (Arthritis Rheum.1987;31:315-24) in a cohort of 269 patients with early disease showed that the 2010 method increased the sensitivity for finding patients with early-stage disease who were destined eventually to develop full-blown RA over the next 6 years to 86% sensitivity, compared with 78% sensitivity for the 1987 criteria, a statistically significant difference, Dr. Julia Nicolau said at the annual meeting of the European Congress of Rheumatology.
Among the 229 patients from this group with no joint erosions detectable at baseline, the 2010 criteria worked even better, primarily because the specificity of the criteria jumped from 59% in the full cohort examined to 71% when patients with one or more joint erosions were excluded. The positive predictive value of the 2010 criteria was 80% for the entire group of 269 (compared with 81% for the 1987 criteria), but in the subgroup without erosions, the positive predictive value of the 2010 criteria was 85%, said Dr. Nicolau, a rheumatologist at Rouen (France) University Hospital.
In addition, in an analysis of the area under the receiver-operator curve the 2010 criteria applied to patients without any erosions at baseline accounted for 82% of the confirmed RA cases after 6 years, significantly more than the 79% of cases identified by the 1987 criteria.
"The mind-set we had when we set up the [2010] criteria was to try to catch everybody [who would soon develop RA], and accept that we might treat some people who we don’t know will develop erosive disease," said Dr. Alan J. Silman, medical director of the U.K. Arthritis Research Campaign and a member of the committee that wrote the 2010 RA classification criteria. "Missing a case of RA is problematic because the interventions we have are fairly effective. Among patients with early arthritis, some will progress to persistent, erosive disease, and the issue is what should we use to identify the patients who should receive intervention" at an early stage. "We may treat some patients who won’t have bad outcomes [and won’t progress to erosive joints], but we accept that we need to treat a lot of patients to prevent the bad outcomes."
The results reported by Dr. Nicolau used the Very Early Arthritis Cohort, which included 269 patients with at least two swollen joints for less than 6 months who appeared to have no other type of arthritis causing their symptoms. The 2010 criteria identified 68% as having RA, while the 1987 criteria identified 59% of these early-stage patients with RA. The researchers had 6-year follow-up data for these patients, which allowed them to compare the results of baseline assessment with each of the two criteria against the eventual, long-term clinical diagnosis of RA.
Dr. Nicolau and her associates also evaluated the 1987 and 2010 criteria using a different end point as the standard for determining which patients eventually developed RA, the number of patients with at least three erosive joints after 2 years of follow-up. Against this standard, the 2010 criteria performed virtually identically as the 1987 criteria. Both criteria identified early-stage RA with 95% sensitivity, and both accounted for 82% of early-stage patients who eventually developed RA 2 years later.
Dr. Nicolau and Dr. Silman said that they had no disclosures. Dr. Silman was a member of the committee that wrote the 2010 rheumatoid arthritis classification criteria.
BERLIN – The 2010 criteria for classifying rheumatoid arthritis accomplish what they were designed to do in patients with early disease: boost the sensitivity for identifying patients who are likely to eventually develop rheumatoid arthritis and could therefore benefit from early treatment.
A comparison of the 2010 criteria (Arthritis Rheum. 2010;62:2569-81) against the 1987 rheumatoid arthritis (RA) classification criteria (Arthritis Rheum.1987;31:315-24) in a cohort of 269 patients with early disease showed that the 2010 method increased the sensitivity for finding patients with early-stage disease who were destined eventually to develop full-blown RA over the next 6 years to 86% sensitivity, compared with 78% sensitivity for the 1987 criteria, a statistically significant difference, Dr. Julia Nicolau said at the annual meeting of the European Congress of Rheumatology.
Among the 229 patients from this group with no joint erosions detectable at baseline, the 2010 criteria worked even better, primarily because the specificity of the criteria jumped from 59% in the full cohort examined to 71% when patients with one or more joint erosions were excluded. The positive predictive value of the 2010 criteria was 80% for the entire group of 269 (compared with 81% for the 1987 criteria), but in the subgroup without erosions, the positive predictive value of the 2010 criteria was 85%, said Dr. Nicolau, a rheumatologist at Rouen (France) University Hospital.
In addition, in an analysis of the area under the receiver-operator curve the 2010 criteria applied to patients without any erosions at baseline accounted for 82% of the confirmed RA cases after 6 years, significantly more than the 79% of cases identified by the 1987 criteria.
"The mind-set we had when we set up the [2010] criteria was to try to catch everybody [who would soon develop RA], and accept that we might treat some people who we don’t know will develop erosive disease," said Dr. Alan J. Silman, medical director of the U.K. Arthritis Research Campaign and a member of the committee that wrote the 2010 RA classification criteria. "Missing a case of RA is problematic because the interventions we have are fairly effective. Among patients with early arthritis, some will progress to persistent, erosive disease, and the issue is what should we use to identify the patients who should receive intervention" at an early stage. "We may treat some patients who won’t have bad outcomes [and won’t progress to erosive joints], but we accept that we need to treat a lot of patients to prevent the bad outcomes."
The results reported by Dr. Nicolau used the Very Early Arthritis Cohort, which included 269 patients with at least two swollen joints for less than 6 months who appeared to have no other type of arthritis causing their symptoms. The 2010 criteria identified 68% as having RA, while the 1987 criteria identified 59% of these early-stage patients with RA. The researchers had 6-year follow-up data for these patients, which allowed them to compare the results of baseline assessment with each of the two criteria against the eventual, long-term clinical diagnosis of RA.
Dr. Nicolau and her associates also evaluated the 1987 and 2010 criteria using a different end point as the standard for determining which patients eventually developed RA, the number of patients with at least three erosive joints after 2 years of follow-up. Against this standard, the 2010 criteria performed virtually identically as the 1987 criteria. Both criteria identified early-stage RA with 95% sensitivity, and both accounted for 82% of early-stage patients who eventually developed RA 2 years later.
Dr. Nicolau and Dr. Silman said that they had no disclosures. Dr. Silman was a member of the committee that wrote the 2010 rheumatoid arthritis classification criteria.
BERLIN – The 2010 criteria for classifying rheumatoid arthritis accomplish what they were designed to do in patients with early disease: boost the sensitivity for identifying patients who are likely to eventually develop rheumatoid arthritis and could therefore benefit from early treatment.
A comparison of the 2010 criteria (Arthritis Rheum. 2010;62:2569-81) against the 1987 rheumatoid arthritis (RA) classification criteria (Arthritis Rheum.1987;31:315-24) in a cohort of 269 patients with early disease showed that the 2010 method increased the sensitivity for finding patients with early-stage disease who were destined eventually to develop full-blown RA over the next 6 years to 86% sensitivity, compared with 78% sensitivity for the 1987 criteria, a statistically significant difference, Dr. Julia Nicolau said at the annual meeting of the European Congress of Rheumatology.
Among the 229 patients from this group with no joint erosions detectable at baseline, the 2010 criteria worked even better, primarily because the specificity of the criteria jumped from 59% in the full cohort examined to 71% when patients with one or more joint erosions were excluded. The positive predictive value of the 2010 criteria was 80% for the entire group of 269 (compared with 81% for the 1987 criteria), but in the subgroup without erosions, the positive predictive value of the 2010 criteria was 85%, said Dr. Nicolau, a rheumatologist at Rouen (France) University Hospital.
In addition, in an analysis of the area under the receiver-operator curve the 2010 criteria applied to patients without any erosions at baseline accounted for 82% of the confirmed RA cases after 6 years, significantly more than the 79% of cases identified by the 1987 criteria.
"The mind-set we had when we set up the [2010] criteria was to try to catch everybody [who would soon develop RA], and accept that we might treat some people who we don’t know will develop erosive disease," said Dr. Alan J. Silman, medical director of the U.K. Arthritis Research Campaign and a member of the committee that wrote the 2010 RA classification criteria. "Missing a case of RA is problematic because the interventions we have are fairly effective. Among patients with early arthritis, some will progress to persistent, erosive disease, and the issue is what should we use to identify the patients who should receive intervention" at an early stage. "We may treat some patients who won’t have bad outcomes [and won’t progress to erosive joints], but we accept that we need to treat a lot of patients to prevent the bad outcomes."
The results reported by Dr. Nicolau used the Very Early Arthritis Cohort, which included 269 patients with at least two swollen joints for less than 6 months who appeared to have no other type of arthritis causing their symptoms. The 2010 criteria identified 68% as having RA, while the 1987 criteria identified 59% of these early-stage patients with RA. The researchers had 6-year follow-up data for these patients, which allowed them to compare the results of baseline assessment with each of the two criteria against the eventual, long-term clinical diagnosis of RA.
Dr. Nicolau and her associates also evaluated the 1987 and 2010 criteria using a different end point as the standard for determining which patients eventually developed RA, the number of patients with at least three erosive joints after 2 years of follow-up. Against this standard, the 2010 criteria performed virtually identically as the 1987 criteria. Both criteria identified early-stage RA with 95% sensitivity, and both accounted for 82% of early-stage patients who eventually developed RA 2 years later.
Dr. Nicolau and Dr. Silman said that they had no disclosures. Dr. Silman was a member of the committee that wrote the 2010 rheumatoid arthritis classification criteria.
AT THE ANNUAL MEETING OF THE EUROPEAN CONGRESS OF RHEUMATOLOGY
Major Finding: The 2010 rheumatoid arthritis classification criteria identified RA with 86% sensitivity, significantly better than the 78% rate using the 1987 criteria.
Data Source: Data came from 269 patients with early arthritis who were followed for at least 6 years.
Disclosures: Dr. Nicolau and Dr. Silman said that they had no disclosures. Dr. Silman was a member of the committee that wrote the 2010 rheumatoid arthritis classification criteria.
Delaying Adalimumab Tx Impairs Long-Term Response
BERLIN – Delaying treatment of long-standing rheumatoid arthritis with adalimumab by 1 year leads to greater joint space narrowing 10 years later.
"This analysis demonstrates the cost of delay," remarked Dr. Edward Keystone, professor of medicine at the University of Toronto and lead investigator on the study. "Allowing a patient to have active disease a year longer is taking a toll on never catching up on quality of life, never catching up on radiographic outcome, and never catching up with persistent active disease."
These findings come from the final analysis of results of the DEO19 trial, which compared patients on methotrexate plus either adalimumab or placebo for 1 year and followed up with all patients receiving active drug for a further 9 years.
"Earlier treatment is better. You are treating to prevent irreversible joint damage, so over time, you want a patient’s quality of life to remain the same," Dr. Keystone said at the annual European Congress of Rheumatology.
Trial DEO19 was a 1-year, randomized, double-blind, placebo-controlled study of adalimumab in patients inadequately controlled on methotrexate. Patients with moderate to severely active disease were randomly assigned to receiving either adalimumab at 40 mg every other week (209 patients), adalimumab 20 mg every week (212), or placebo (200). All patients continued on methotrexate.
After the initial 1-year blinded stage, all patents were eligible to receive open-label adalimumab 40 mg for the next 9 years. Of the initial entrants, 457 went through to the open-label phase, and 202 completed the 9-year extension. Average disease duration upon entry was 11 years.
"Even at 11 years’ duration of RA, when they all have active disease, you can improve patients’ signs and symptoms when they receive adalimumab," pointed out Dr. Keystone. "It is possible to maintain quality of life and actually prevent radiographic progression or stabilize it and show minimal progression after treatment."
The 10-year follow-up data showed that 63.5% of completers reached an American College of Rheumatology 50; 48.4% reached an ACR 70 and 17.7% an ACR 90. A disease activity score 28 of less than 3.2 was achieved by 73.6% of patients, and a Health Assessment Questionnaire less than 0.5 was achieved by 42.8%.
Mean swollen joint count (SJC) persisted in patients who were originally treated with placebo as opposed to adalimumab, with a SJC of just under 5 at 10 years in the group given either dose of adalimumab at year 1 versus approximately 7.5 in the year 1 placebo group.
Furthermore, 30.3% of patients who received adalimumab originally achieved comprehensive disease control – indicated by a DAS28 C-reactive protein of less than 3.2 – at year 10 vs. 11.3% of those on placebo.
"These results show that one in three people who started on adalimumab ended up in a comprehensive disease state, that is no disability, no radiographic progression, and clinical remission," reported Dr. Keystone.
"I treat patients with 10 years of active disease and I improve them to only a few swollen joints, but I treat them at 11 years and I still can’t get them down to the level I want."
"For me, that is a surprise," said Dr. Keystone. "I thought the placebo patients would eventually reach the same level as the others who started a year earlier, but that didn’t happen."
Dr. Keystone noted that joint space narrowing continued over time as seen by the change in Sharp score over 10 years. "This is accounted for not by erosions, but by the change in joint space narrowing," Dr. Keystone noted.
Radiographic damage was assessed using the modified total Sharp score. Patients who initially received adalimumab in year 1 had significantly lower mean change in modified total Sharp score at year 10, compared with patients who initially received placebo plus methotrexate [0.7 (ADA-40) and 2.6 (ADA-20) vs. 6.2 on placebo (P = .002 and 0.01, respectively).
Dr. Keystone highlighted this dramatic increase in joint space narrowing. "Patients treated on placebo initially ended up with more joint space narrowing over that period of time."
He also pointed out that joint space narrowing decreases quality of life, in addition to patients’ work productivity and ability to stay at work or not.
"Every drug has side effects. Everyone has a different answer to this. I’d like to see a study that helps us decide when it is optimal to start these types of drugs. But 10 years is a long time to follow these patients- it’s a good study. I would start patients earlier but I would also like to see data on which patients to start."
Dr. Keystone disclosed financial relationships with Abbott, Amgen, AstraZeneca, Biotest, Bristol-Myers Squibb, Centocor, Genentech, Genzyme, Merck, Novartis, Nycomed, Pfizer, Roche, and UCB.
BERLIN – Delaying treatment of long-standing rheumatoid arthritis with adalimumab by 1 year leads to greater joint space narrowing 10 years later.
"This analysis demonstrates the cost of delay," remarked Dr. Edward Keystone, professor of medicine at the University of Toronto and lead investigator on the study. "Allowing a patient to have active disease a year longer is taking a toll on never catching up on quality of life, never catching up on radiographic outcome, and never catching up with persistent active disease."
These findings come from the final analysis of results of the DEO19 trial, which compared patients on methotrexate plus either adalimumab or placebo for 1 year and followed up with all patients receiving active drug for a further 9 years.
"Earlier treatment is better. You are treating to prevent irreversible joint damage, so over time, you want a patient’s quality of life to remain the same," Dr. Keystone said at the annual European Congress of Rheumatology.
Trial DEO19 was a 1-year, randomized, double-blind, placebo-controlled study of adalimumab in patients inadequately controlled on methotrexate. Patients with moderate to severely active disease were randomly assigned to receiving either adalimumab at 40 mg every other week (209 patients), adalimumab 20 mg every week (212), or placebo (200). All patients continued on methotrexate.
After the initial 1-year blinded stage, all patents were eligible to receive open-label adalimumab 40 mg for the next 9 years. Of the initial entrants, 457 went through to the open-label phase, and 202 completed the 9-year extension. Average disease duration upon entry was 11 years.
"Even at 11 years’ duration of RA, when they all have active disease, you can improve patients’ signs and symptoms when they receive adalimumab," pointed out Dr. Keystone. "It is possible to maintain quality of life and actually prevent radiographic progression or stabilize it and show minimal progression after treatment."
The 10-year follow-up data showed that 63.5% of completers reached an American College of Rheumatology 50; 48.4% reached an ACR 70 and 17.7% an ACR 90. A disease activity score 28 of less than 3.2 was achieved by 73.6% of patients, and a Health Assessment Questionnaire less than 0.5 was achieved by 42.8%.
Mean swollen joint count (SJC) persisted in patients who were originally treated with placebo as opposed to adalimumab, with a SJC of just under 5 at 10 years in the group given either dose of adalimumab at year 1 versus approximately 7.5 in the year 1 placebo group.
Furthermore, 30.3% of patients who received adalimumab originally achieved comprehensive disease control – indicated by a DAS28 C-reactive protein of less than 3.2 – at year 10 vs. 11.3% of those on placebo.
"These results show that one in three people who started on adalimumab ended up in a comprehensive disease state, that is no disability, no radiographic progression, and clinical remission," reported Dr. Keystone.
"I treat patients with 10 years of active disease and I improve them to only a few swollen joints, but I treat them at 11 years and I still can’t get them down to the level I want."
"For me, that is a surprise," said Dr. Keystone. "I thought the placebo patients would eventually reach the same level as the others who started a year earlier, but that didn’t happen."
Dr. Keystone noted that joint space narrowing continued over time as seen by the change in Sharp score over 10 years. "This is accounted for not by erosions, but by the change in joint space narrowing," Dr. Keystone noted.
Radiographic damage was assessed using the modified total Sharp score. Patients who initially received adalimumab in year 1 had significantly lower mean change in modified total Sharp score at year 10, compared with patients who initially received placebo plus methotrexate [0.7 (ADA-40) and 2.6 (ADA-20) vs. 6.2 on placebo (P = .002 and 0.01, respectively).
Dr. Keystone highlighted this dramatic increase in joint space narrowing. "Patients treated on placebo initially ended up with more joint space narrowing over that period of time."
He also pointed out that joint space narrowing decreases quality of life, in addition to patients’ work productivity and ability to stay at work or not.
"Every drug has side effects. Everyone has a different answer to this. I’d like to see a study that helps us decide when it is optimal to start these types of drugs. But 10 years is a long time to follow these patients- it’s a good study. I would start patients earlier but I would also like to see data on which patients to start."
Dr. Keystone disclosed financial relationships with Abbott, Amgen, AstraZeneca, Biotest, Bristol-Myers Squibb, Centocor, Genentech, Genzyme, Merck, Novartis, Nycomed, Pfizer, Roche, and UCB.
BERLIN – Delaying treatment of long-standing rheumatoid arthritis with adalimumab by 1 year leads to greater joint space narrowing 10 years later.
"This analysis demonstrates the cost of delay," remarked Dr. Edward Keystone, professor of medicine at the University of Toronto and lead investigator on the study. "Allowing a patient to have active disease a year longer is taking a toll on never catching up on quality of life, never catching up on radiographic outcome, and never catching up with persistent active disease."
These findings come from the final analysis of results of the DEO19 trial, which compared patients on methotrexate plus either adalimumab or placebo for 1 year and followed up with all patients receiving active drug for a further 9 years.
"Earlier treatment is better. You are treating to prevent irreversible joint damage, so over time, you want a patient’s quality of life to remain the same," Dr. Keystone said at the annual European Congress of Rheumatology.
Trial DEO19 was a 1-year, randomized, double-blind, placebo-controlled study of adalimumab in patients inadequately controlled on methotrexate. Patients with moderate to severely active disease were randomly assigned to receiving either adalimumab at 40 mg every other week (209 patients), adalimumab 20 mg every week (212), or placebo (200). All patients continued on methotrexate.
After the initial 1-year blinded stage, all patents were eligible to receive open-label adalimumab 40 mg for the next 9 years. Of the initial entrants, 457 went through to the open-label phase, and 202 completed the 9-year extension. Average disease duration upon entry was 11 years.
"Even at 11 years’ duration of RA, when they all have active disease, you can improve patients’ signs and symptoms when they receive adalimumab," pointed out Dr. Keystone. "It is possible to maintain quality of life and actually prevent radiographic progression or stabilize it and show minimal progression after treatment."
The 10-year follow-up data showed that 63.5% of completers reached an American College of Rheumatology 50; 48.4% reached an ACR 70 and 17.7% an ACR 90. A disease activity score 28 of less than 3.2 was achieved by 73.6% of patients, and a Health Assessment Questionnaire less than 0.5 was achieved by 42.8%.
Mean swollen joint count (SJC) persisted in patients who were originally treated with placebo as opposed to adalimumab, with a SJC of just under 5 at 10 years in the group given either dose of adalimumab at year 1 versus approximately 7.5 in the year 1 placebo group.
Furthermore, 30.3% of patients who received adalimumab originally achieved comprehensive disease control – indicated by a DAS28 C-reactive protein of less than 3.2 – at year 10 vs. 11.3% of those on placebo.
"These results show that one in three people who started on adalimumab ended up in a comprehensive disease state, that is no disability, no radiographic progression, and clinical remission," reported Dr. Keystone.
"I treat patients with 10 years of active disease and I improve them to only a few swollen joints, but I treat them at 11 years and I still can’t get them down to the level I want."
"For me, that is a surprise," said Dr. Keystone. "I thought the placebo patients would eventually reach the same level as the others who started a year earlier, but that didn’t happen."
Dr. Keystone noted that joint space narrowing continued over time as seen by the change in Sharp score over 10 years. "This is accounted for not by erosions, but by the change in joint space narrowing," Dr. Keystone noted.
Radiographic damage was assessed using the modified total Sharp score. Patients who initially received adalimumab in year 1 had significantly lower mean change in modified total Sharp score at year 10, compared with patients who initially received placebo plus methotrexate [0.7 (ADA-40) and 2.6 (ADA-20) vs. 6.2 on placebo (P = .002 and 0.01, respectively).
Dr. Keystone highlighted this dramatic increase in joint space narrowing. "Patients treated on placebo initially ended up with more joint space narrowing over that period of time."
He also pointed out that joint space narrowing decreases quality of life, in addition to patients’ work productivity and ability to stay at work or not.
"Every drug has side effects. Everyone has a different answer to this. I’d like to see a study that helps us decide when it is optimal to start these types of drugs. But 10 years is a long time to follow these patients- it’s a good study. I would start patients earlier but I would also like to see data on which patients to start."
Dr. Keystone disclosed financial relationships with Abbott, Amgen, AstraZeneca, Biotest, Bristol-Myers Squibb, Centocor, Genentech, Genzyme, Merck, Novartis, Nycomed, Pfizer, Roche, and UCB.
AT THE ANNUAL EUROPEAN CONGRESS OF RHEUMATOLOGY
Major Finding: Radiographic damage was significantly less in patients who initially received either dose of adalimumab in year 1, with a lower mean change in modified total Sharp score at year 10, compared with patients who initially received placebo plus methotrexate [0.7 (ADA-40) and 2.6 (ADA-20) vs. 6.2 on placebo (P = .002 and 0.01, respectively).
Data Source: DEO19 was a phase III, randomized, controlled, 10-year longitudinal study investigating long-term outcomes of receiving adalimumab in year 1 or delaying active treatment by 1 year. A total of 202 patients with long-standing RA completed the extension trial.
Disclosures: Dr. Keystone disclosed financial relationships with Abbott, Amgen, AstraZeneca, Biotest, BMS, Centocor, Genentech, Genzyme, Merck, Novartis, Nycomed, Pfizer, Roche, and UCB. Dr. Friar disclosed no relevant conflicts of interest.
New Biomarkers Identify Tocilizumab Responders Super Early
BERLIN – Novel serologic biomarkers of cartilage degradation and synovial tissue destruction in rheumatoid arthritis patients permit discrimination between eventual responders and nonresponders to the interleukin-6 inhibitor tocilizumab after just 2-4 weeks of treatment.
Given that early introduction of effective therapy for rheumatoid arthritis (RA) is the key to preventing joint destruction, use of these new biomarkers for early differentiation between likely tocilizumab responders and nonresponders will provide value to patients and payers alike, Anne C. Bay-Jensen, Ph.D., predicted at the annual European Congress of Rheumatology.
She investigated early changes in a slew of serum biomarkers of cartilage, bone, synovium, and systemic inflammation in response to tocilizumab treatment as a means of discriminating treatment responders from nonresponders months before the clinical impact becomes apparent.
The biomarkers included several novel tissue-specific end products of tissue turnover, providing unique information about the state of the tissue of interest. These markers included matrix metalloproteinase-mediated degradation of type II collagen (C2M) or type III collagen (C3M); matrix metalloproteinase-mediated C-reactive protein (CRPM); citrullinated and matrix metalloproteinase-degraded vimentin (VICM); and matrix metalloproteinase-destroyed type I collagen (ICTP).
The key point is that while C-reactive protein (CRP), for example, is produced in the liver, CRPM is produced specifically in the joint and reflects joint-specific tissue inflammation, as Dr. Bay-Jensen and her coworkers have previously demonstrated (Arthritis Res. Ther. 2011;13:215 [doi: 10.1186/ar3280]).
In addition to this set of novel biomarkers, she evaluated several traditional biomarkers: CRP, along with osteocalcin and CTX-1 (C-terminal telopeptide of type I collagen ) as markers of bone formation and resorption, respectively.
The biomarkers, new and old, were evaluated in a secondary analysis of the 2-year, phase III, double-blind LITHE trial, in which 1,196 RA patients with inadequate response to methotrexate were randomized to tocilizumab (Actemra) at 8 mg/kg or 4 mg/kg or to placebo on top of background methotrexate therapy.
The substudy involved 206 patients on the higher dose of tocilizumab plus methotrexate and 211 on placebo plus methotrexate. The tocilizumab group included 91 responders and 29 nonresponders at week 16 of treatment, explained Dr. Bay-Jensen, a cartilage scientist at Nordic Bioscience in Herlev, Denmark.
Levels of CRPM dropped by 33% from baseline at week 4 and by 40% by week 52 in responders to dual therapy and by significantly lesser amounts in the nonresponders. Levels remained unchanged over time in the methotrexate-plus-placebo arm.
The same pattern followed for C2M, C3M, ICM, and ICTP.
Indeed, an 11% decrease in CRPM from baseline at week 4 of treatment with tocilizumab plus methotrexate was associated with a fourfold increased likelihood of clinical response at week 16. A 7.4% reduction in C2M at week 2 indicated a 5.8-fold increased odds of a week-16 response. And a 28% decline in C3M was associated with a 9.6-fold increased likelihood of subsequent clinical response.
In contrast, the conventional marker of systemic inflammation, high-sensitivity CRP, dropped by about 35% in both responders and nonresponders, rendering it useless as a predictive tool. Osteocalcin and CTX-1 were of no value, either.
The next step in this research project will be to see if these novel biomarkers of cartilage and synovial turnover and within-joint inflammation are able to discriminate responders from nonresponders to other biologic agents that address targets other than interleukin-6, she continued.
To put these new findings in perspective, today on average physicians have to treat 3.5 rheumatoid arthritis patients with biologic therapy in order to obtain 1 good response.
"Tomorrow, using serologic biomarker profiles, there might be 10 potential candidates, 1.5 patients selected for treatment, and 1.5 responders," Dr. Bay-Jensen said.
Data from the LITHE study were supplied by Genentech. Dr. Bay-Jensen’s biomarker analysis was supported by the Danish Research Foundation. She reported having no financial conflicts.
BERLIN – Novel serologic biomarkers of cartilage degradation and synovial tissue destruction in rheumatoid arthritis patients permit discrimination between eventual responders and nonresponders to the interleukin-6 inhibitor tocilizumab after just 2-4 weeks of treatment.
Given that early introduction of effective therapy for rheumatoid arthritis (RA) is the key to preventing joint destruction, use of these new biomarkers for early differentiation between likely tocilizumab responders and nonresponders will provide value to patients and payers alike, Anne C. Bay-Jensen, Ph.D., predicted at the annual European Congress of Rheumatology.
She investigated early changes in a slew of serum biomarkers of cartilage, bone, synovium, and systemic inflammation in response to tocilizumab treatment as a means of discriminating treatment responders from nonresponders months before the clinical impact becomes apparent.
The biomarkers included several novel tissue-specific end products of tissue turnover, providing unique information about the state of the tissue of interest. These markers included matrix metalloproteinase-mediated degradation of type II collagen (C2M) or type III collagen (C3M); matrix metalloproteinase-mediated C-reactive protein (CRPM); citrullinated and matrix metalloproteinase-degraded vimentin (VICM); and matrix metalloproteinase-destroyed type I collagen (ICTP).
The key point is that while C-reactive protein (CRP), for example, is produced in the liver, CRPM is produced specifically in the joint and reflects joint-specific tissue inflammation, as Dr. Bay-Jensen and her coworkers have previously demonstrated (Arthritis Res. Ther. 2011;13:215 [doi: 10.1186/ar3280]).
In addition to this set of novel biomarkers, she evaluated several traditional biomarkers: CRP, along with osteocalcin and CTX-1 (C-terminal telopeptide of type I collagen ) as markers of bone formation and resorption, respectively.
The biomarkers, new and old, were evaluated in a secondary analysis of the 2-year, phase III, double-blind LITHE trial, in which 1,196 RA patients with inadequate response to methotrexate were randomized to tocilizumab (Actemra) at 8 mg/kg or 4 mg/kg or to placebo on top of background methotrexate therapy.
The substudy involved 206 patients on the higher dose of tocilizumab plus methotrexate and 211 on placebo plus methotrexate. The tocilizumab group included 91 responders and 29 nonresponders at week 16 of treatment, explained Dr. Bay-Jensen, a cartilage scientist at Nordic Bioscience in Herlev, Denmark.
Levels of CRPM dropped by 33% from baseline at week 4 and by 40% by week 52 in responders to dual therapy and by significantly lesser amounts in the nonresponders. Levels remained unchanged over time in the methotrexate-plus-placebo arm.
The same pattern followed for C2M, C3M, ICM, and ICTP.
Indeed, an 11% decrease in CRPM from baseline at week 4 of treatment with tocilizumab plus methotrexate was associated with a fourfold increased likelihood of clinical response at week 16. A 7.4% reduction in C2M at week 2 indicated a 5.8-fold increased odds of a week-16 response. And a 28% decline in C3M was associated with a 9.6-fold increased likelihood of subsequent clinical response.
In contrast, the conventional marker of systemic inflammation, high-sensitivity CRP, dropped by about 35% in both responders and nonresponders, rendering it useless as a predictive tool. Osteocalcin and CTX-1 were of no value, either.
The next step in this research project will be to see if these novel biomarkers of cartilage and synovial turnover and within-joint inflammation are able to discriminate responders from nonresponders to other biologic agents that address targets other than interleukin-6, she continued.
To put these new findings in perspective, today on average physicians have to treat 3.5 rheumatoid arthritis patients with biologic therapy in order to obtain 1 good response.
"Tomorrow, using serologic biomarker profiles, there might be 10 potential candidates, 1.5 patients selected for treatment, and 1.5 responders," Dr. Bay-Jensen said.
Data from the LITHE study were supplied by Genentech. Dr. Bay-Jensen’s biomarker analysis was supported by the Danish Research Foundation. She reported having no financial conflicts.
BERLIN – Novel serologic biomarkers of cartilage degradation and synovial tissue destruction in rheumatoid arthritis patients permit discrimination between eventual responders and nonresponders to the interleukin-6 inhibitor tocilizumab after just 2-4 weeks of treatment.
Given that early introduction of effective therapy for rheumatoid arthritis (RA) is the key to preventing joint destruction, use of these new biomarkers for early differentiation between likely tocilizumab responders and nonresponders will provide value to patients and payers alike, Anne C. Bay-Jensen, Ph.D., predicted at the annual European Congress of Rheumatology.
She investigated early changes in a slew of serum biomarkers of cartilage, bone, synovium, and systemic inflammation in response to tocilizumab treatment as a means of discriminating treatment responders from nonresponders months before the clinical impact becomes apparent.
The biomarkers included several novel tissue-specific end products of tissue turnover, providing unique information about the state of the tissue of interest. These markers included matrix metalloproteinase-mediated degradation of type II collagen (C2M) or type III collagen (C3M); matrix metalloproteinase-mediated C-reactive protein (CRPM); citrullinated and matrix metalloproteinase-degraded vimentin (VICM); and matrix metalloproteinase-destroyed type I collagen (ICTP).
The key point is that while C-reactive protein (CRP), for example, is produced in the liver, CRPM is produced specifically in the joint and reflects joint-specific tissue inflammation, as Dr. Bay-Jensen and her coworkers have previously demonstrated (Arthritis Res. Ther. 2011;13:215 [doi: 10.1186/ar3280]).
In addition to this set of novel biomarkers, she evaluated several traditional biomarkers: CRP, along with osteocalcin and CTX-1 (C-terminal telopeptide of type I collagen ) as markers of bone formation and resorption, respectively.
The biomarkers, new and old, were evaluated in a secondary analysis of the 2-year, phase III, double-blind LITHE trial, in which 1,196 RA patients with inadequate response to methotrexate were randomized to tocilizumab (Actemra) at 8 mg/kg or 4 mg/kg or to placebo on top of background methotrexate therapy.
The substudy involved 206 patients on the higher dose of tocilizumab plus methotrexate and 211 on placebo plus methotrexate. The tocilizumab group included 91 responders and 29 nonresponders at week 16 of treatment, explained Dr. Bay-Jensen, a cartilage scientist at Nordic Bioscience in Herlev, Denmark.
Levels of CRPM dropped by 33% from baseline at week 4 and by 40% by week 52 in responders to dual therapy and by significantly lesser amounts in the nonresponders. Levels remained unchanged over time in the methotrexate-plus-placebo arm.
The same pattern followed for C2M, C3M, ICM, and ICTP.
Indeed, an 11% decrease in CRPM from baseline at week 4 of treatment with tocilizumab plus methotrexate was associated with a fourfold increased likelihood of clinical response at week 16. A 7.4% reduction in C2M at week 2 indicated a 5.8-fold increased odds of a week-16 response. And a 28% decline in C3M was associated with a 9.6-fold increased likelihood of subsequent clinical response.
In contrast, the conventional marker of systemic inflammation, high-sensitivity CRP, dropped by about 35% in both responders and nonresponders, rendering it useless as a predictive tool. Osteocalcin and CTX-1 were of no value, either.
The next step in this research project will be to see if these novel biomarkers of cartilage and synovial turnover and within-joint inflammation are able to discriminate responders from nonresponders to other biologic agents that address targets other than interleukin-6, she continued.
To put these new findings in perspective, today on average physicians have to treat 3.5 rheumatoid arthritis patients with biologic therapy in order to obtain 1 good response.
"Tomorrow, using serologic biomarker profiles, there might be 10 potential candidates, 1.5 patients selected for treatment, and 1.5 responders," Dr. Bay-Jensen said.
Data from the LITHE study were supplied by Genentech. Dr. Bay-Jensen’s biomarker analysis was supported by the Danish Research Foundation. She reported having no financial conflicts.
AT THE ANNUAL EUROPEAN CONGRESS OF RHEUMATOLOGY
Major Finding: Novel
serologic biomarkers of within-joint inflammation, cartilage degradation, and
synovial tissue destruction measured after just 2-4 weeks of tocilizumab
therapy for rheumatoid arthritis were able to discriminate between week-16
treatment responders and nonresponders.
Data Source: This
was a substudy of the phase III LITHE trial, in which 1,196 patients with
moderate to severe rheumatoid arthritis and an inadequate response to
methotrexate were randomized to add-on therapy with one of two doses of the interleukin-6
inhibitor tocilizumab or placebo.
Disclosures: Data
from the LITHE study were supplied by Genentech. Dr. Bay-Jensen’s biomarker
analysis was supported by the Danish Research Foundation. She reported having
no financial conflicts.
Psoriatic Arthritis Screening Tests Deemed Inadequate
RALEIGH, N.C. – Current screening instruments that are designed to identify the 20%-30% of psoriasis patients who have psoriatic arthritis leave much to be desired, Dr. Jessica A. Walsh asserted at the annual meeting of the Society for Investigative Dermatology.
She asked 189 psoriasis patients who are enrolled in the Utah Psoriasis Initiative to take three of the most popular psoriatic arthritis self-administered screening questionnaires. The tests’ sensitivities and specificities proved markedly lower than previously reported in the instruments’ validation studies.
Moreover, all three tests – the Psoriatic Arthritis Screening and Evaluation (PASE), the Psoriasis Epidemiology Screening Project (PEST), and the Toronto Psoriatic Arthritis Screen (ToPAS) – differentiated only poorly among psoriatic arthritis, other types of arthritis, and fibromyalgia.
And the tests had other weak points: "The instruments were less sensitive in patients with lower psoriatic arthritis disease activity, fewer disease features, and shorter disease duration. This is suboptimal because these instruments were designed to help capture early disease," said Dr. Walsh, a rheumatologist at the University of Utah, Salt Lake City.
She is involved in a project aimed at reducing delays in diagnosis of psoriatic arthritis, an underdiagnosed condition in psoriasis patients. According to a 2011 National Psoriasis Foundation survey, 29% of psoriatic arthritis patients don’t receive their diagnosis until 2 years or more after onset of symptoms. That’s bad news, because early diagnosis and treatment help minimize symptoms, enhance quality of life, and prevent joint damage. Studies show that nearly one-half of psoriatic arthritis patients develop radiographic evidence of erosive damage within 2 years of symptom onset. Treatment can slow that progressive erosion.
All 189 psoriasis patients in Dr. Walsh’s study had musculoskeletal complaints of sufficient magnitude that they were willing to take the three screening tests in order to receive a free rheumatologic evaluation. A total of 137 patients had psoriatic arthritis, and two-thirds of them had already been diagnosed with the disease prior to participation in her study.
The gold standard to which the screening tests were compared was Dr. Walsh’s diagnostic evaluation, which included laboratory testing and imaging as warranted. When there was a discrepancy between any of the screening tests and her diagnosis, as occurred in 138 cases, a second rheumatologist with expertise in psoriatic arthritis was called in as a tiebreaker.
The sensitivities of PACE, PEST, and ToPAS were 68%, 85%, and 75%, respectively. The specificities were worse, at 50%, 45%, and 55%. These are in sharp contrast to previous studies, in which the test sensitivities were 88%-97%, with reported specificities of 79%-95%, she noted.
The frequency of discrepancies between patient responses to specific screening questions and the rheumatologic exam findings varied among the test instruments in a way that caused Dr. Walsh to believe that combining selected questions from each test and, in some cases, modifying the wording might result in a hybrid-screening instrument with improved performance. She plans to test that hypothesis.
Dr. Abrar A. Qureshi, one of the developers of PASE, said he and his coworkers have been thinking along the same lines.
"We’re working on a shorter version of PASE that might work better. Nine of the 15 questions on PASE seem to track well with inflammatory arthritis," commented Dr. Qureshi, vice chairman of the department of dermatology at Brigham and Women’s Hospital, Boston.
The Utah Psoriasis Initiative is funded by the University of Utah department of dermatology. Dr. Walsh reported having no financial conflicts.
RALEIGH, N.C. – Current screening instruments that are designed to identify the 20%-30% of psoriasis patients who have psoriatic arthritis leave much to be desired, Dr. Jessica A. Walsh asserted at the annual meeting of the Society for Investigative Dermatology.
She asked 189 psoriasis patients who are enrolled in the Utah Psoriasis Initiative to take three of the most popular psoriatic arthritis self-administered screening questionnaires. The tests’ sensitivities and specificities proved markedly lower than previously reported in the instruments’ validation studies.
Moreover, all three tests – the Psoriatic Arthritis Screening and Evaluation (PASE), the Psoriasis Epidemiology Screening Project (PEST), and the Toronto Psoriatic Arthritis Screen (ToPAS) – differentiated only poorly among psoriatic arthritis, other types of arthritis, and fibromyalgia.
And the tests had other weak points: "The instruments were less sensitive in patients with lower psoriatic arthritis disease activity, fewer disease features, and shorter disease duration. This is suboptimal because these instruments were designed to help capture early disease," said Dr. Walsh, a rheumatologist at the University of Utah, Salt Lake City.
She is involved in a project aimed at reducing delays in diagnosis of psoriatic arthritis, an underdiagnosed condition in psoriasis patients. According to a 2011 National Psoriasis Foundation survey, 29% of psoriatic arthritis patients don’t receive their diagnosis until 2 years or more after onset of symptoms. That’s bad news, because early diagnosis and treatment help minimize symptoms, enhance quality of life, and prevent joint damage. Studies show that nearly one-half of psoriatic arthritis patients develop radiographic evidence of erosive damage within 2 years of symptom onset. Treatment can slow that progressive erosion.
All 189 psoriasis patients in Dr. Walsh’s study had musculoskeletal complaints of sufficient magnitude that they were willing to take the three screening tests in order to receive a free rheumatologic evaluation. A total of 137 patients had psoriatic arthritis, and two-thirds of them had already been diagnosed with the disease prior to participation in her study.
The gold standard to which the screening tests were compared was Dr. Walsh’s diagnostic evaluation, which included laboratory testing and imaging as warranted. When there was a discrepancy between any of the screening tests and her diagnosis, as occurred in 138 cases, a second rheumatologist with expertise in psoriatic arthritis was called in as a tiebreaker.
The sensitivities of PACE, PEST, and ToPAS were 68%, 85%, and 75%, respectively. The specificities were worse, at 50%, 45%, and 55%. These are in sharp contrast to previous studies, in which the test sensitivities were 88%-97%, with reported specificities of 79%-95%, she noted.
The frequency of discrepancies between patient responses to specific screening questions and the rheumatologic exam findings varied among the test instruments in a way that caused Dr. Walsh to believe that combining selected questions from each test and, in some cases, modifying the wording might result in a hybrid-screening instrument with improved performance. She plans to test that hypothesis.
Dr. Abrar A. Qureshi, one of the developers of PASE, said he and his coworkers have been thinking along the same lines.
"We’re working on a shorter version of PASE that might work better. Nine of the 15 questions on PASE seem to track well with inflammatory arthritis," commented Dr. Qureshi, vice chairman of the department of dermatology at Brigham and Women’s Hospital, Boston.
The Utah Psoriasis Initiative is funded by the University of Utah department of dermatology. Dr. Walsh reported having no financial conflicts.
RALEIGH, N.C. – Current screening instruments that are designed to identify the 20%-30% of psoriasis patients who have psoriatic arthritis leave much to be desired, Dr. Jessica A. Walsh asserted at the annual meeting of the Society for Investigative Dermatology.
She asked 189 psoriasis patients who are enrolled in the Utah Psoriasis Initiative to take three of the most popular psoriatic arthritis self-administered screening questionnaires. The tests’ sensitivities and specificities proved markedly lower than previously reported in the instruments’ validation studies.
Moreover, all three tests – the Psoriatic Arthritis Screening and Evaluation (PASE), the Psoriasis Epidemiology Screening Project (PEST), and the Toronto Psoriatic Arthritis Screen (ToPAS) – differentiated only poorly among psoriatic arthritis, other types of arthritis, and fibromyalgia.
And the tests had other weak points: "The instruments were less sensitive in patients with lower psoriatic arthritis disease activity, fewer disease features, and shorter disease duration. This is suboptimal because these instruments were designed to help capture early disease," said Dr. Walsh, a rheumatologist at the University of Utah, Salt Lake City.
She is involved in a project aimed at reducing delays in diagnosis of psoriatic arthritis, an underdiagnosed condition in psoriasis patients. According to a 2011 National Psoriasis Foundation survey, 29% of psoriatic arthritis patients don’t receive their diagnosis until 2 years or more after onset of symptoms. That’s bad news, because early diagnosis and treatment help minimize symptoms, enhance quality of life, and prevent joint damage. Studies show that nearly one-half of psoriatic arthritis patients develop radiographic evidence of erosive damage within 2 years of symptom onset. Treatment can slow that progressive erosion.
All 189 psoriasis patients in Dr. Walsh’s study had musculoskeletal complaints of sufficient magnitude that they were willing to take the three screening tests in order to receive a free rheumatologic evaluation. A total of 137 patients had psoriatic arthritis, and two-thirds of them had already been diagnosed with the disease prior to participation in her study.
The gold standard to which the screening tests were compared was Dr. Walsh’s diagnostic evaluation, which included laboratory testing and imaging as warranted. When there was a discrepancy between any of the screening tests and her diagnosis, as occurred in 138 cases, a second rheumatologist with expertise in psoriatic arthritis was called in as a tiebreaker.
The sensitivities of PACE, PEST, and ToPAS were 68%, 85%, and 75%, respectively. The specificities were worse, at 50%, 45%, and 55%. These are in sharp contrast to previous studies, in which the test sensitivities were 88%-97%, with reported specificities of 79%-95%, she noted.
The frequency of discrepancies between patient responses to specific screening questions and the rheumatologic exam findings varied among the test instruments in a way that caused Dr. Walsh to believe that combining selected questions from each test and, in some cases, modifying the wording might result in a hybrid-screening instrument with improved performance. She plans to test that hypothesis.
Dr. Abrar A. Qureshi, one of the developers of PASE, said he and his coworkers have been thinking along the same lines.
"We’re working on a shorter version of PASE that might work better. Nine of the 15 questions on PASE seem to track well with inflammatory arthritis," commented Dr. Qureshi, vice chairman of the department of dermatology at Brigham and Women’s Hospital, Boston.
The Utah Psoriasis Initiative is funded by the University of Utah department of dermatology. Dr. Walsh reported having no financial conflicts.
AT THE ANNUAL MEETING OF SOCIETY FOR INVESTIGATIVE DERMATOLOGY
Major Finding: Three popular screening tests for psoriatic arthritis in patients with psoriasis displayed suboptimal specificities of 45%-55% in a prospective study. Those rates are considerably lower than those in previous studies.
Data Source: This was a prospective study involving 189 psoriasis patients, all with musculoskeletal complaints.
Disclosures: The presenter reported having no financial disclosures.
FDA Panel Considers Metal-on-Metal Hip Replacements
GAITHERSBURG, MD. – Evaluation of patients for adverse effects associated with a metal-on-metal hip implant should include an expedited physical exam with an orthopedic surgeon, routine x-rays, and both standard and specialized laboratory tests, a Food and Drug Administration advisory panel recommended at the end of a 2-day meeting on June 28.
Lab testing should include the standard blood tests, as well as measures of sedimentation rate and C-reactive protein level, and more sophisticated imaging with MRI or CT, if needed, according to the advisory panel of the FDA’s Orthopaedic and Rehabilitation Devices Panel, which met for 2 days to review the safety data on these devices.
Blood or serum tests for metal ions (cobalt and chromium, which have been elevated in some patients who have received metal-on-metal devices, and have been associated with device failures) also can be helpful, panelists said, although these tests are not universally available and how to use the results in determining the course of treatment is still unclear. They made similar recommendations on how to follow up symptomatic patients who have undergone hip resurfacing with a metal-on-metal device.
There was less consensus on how to follow patients who have received one of these devices but are asymptomatic; recommendations included obtaining a baseline evaluation, with an MRI (at least in patients who are part of a postmarketing study) and tests for metal ions so changes can be monitored and compared over time. One panelist called for longitudinal studies that collect this type of information at baseline, so that predictive factors for failure could be identified.
The panel was not asked to vote on any issues, only to provide advice, so that the agency can make recommendations on the safety of these devices to health care providers and patients. The agency usually follows the recommendations of its advisory panels.
Metal-on-metal hip resurfacing systems, which became popular for use in younger active patients who had healthier bone, include the femoral head with a metal covering, a femoral stem, and an acetabular component. The metal-on metal hip devices were thought to last longer. The proportion of procedures in which devices are used has declined in reaction to increased revision rates and reports of adverse events.
In May 2011, the FDA issued a public health communication regarding adverse event reports associated with these devices and subsequently ordered manufacturers to conduct post-marketing studies addressing the safety issues of their metal-on-metal total hip replacement devices. The FDA has recalled two metal-on-metal devices, including one in August 2010 for a higher than expected revision rate.
A review of metal-on metal implants in December 2011 conducted by the American Academy of Orthopaedic Surgeons concluded that the risk of revision was higher among patients who receive these implants for total hip arthroplasty and hip resurfacing than those who undergo this surgery using a different bearing. The AAOS review also found that larger femoral head components used in hip arthroplasty are associated with higher revision rates, which was also reported by speakers during the FDA panel meeting.
Alerts about local and soft tissue reactions and recommendations on metal ion testing and imaging of patients who have received one of these devices has been issued in the United Kingdom, Australia, and Canada.
When asked if they could describe any types of patients for whom the benefits of a metal-on-metal device for resurfacing or hip replacement outweigh the risks, panelists said that the decision should be up to the individual surgeon and that there might be some cases where this type of device may be useful. But the orthopedic surgeons on the panel said they rarely or never used metal-on metal implants because of these adverse event reports and availability of other options.
"I see no indication for which I would use a metal on metal [device] over any other technology," said the panel chair, Dr. William Rohr, an orthopedic surgeon who practices in Fort Bragg, Calif. He added that he had not seen any evidence indicating that the performance of the metal-on-metal devices was better than that of other options, and he considered any increased risk over the others available unacceptable, and pointed out gender differences, with women at risk of poorer outcomes
Members of FDA panels have been cleared of potential conflicts of interest; in some cases, they are given waivers but not at this meeting.
GAITHERSBURG, MD. – Evaluation of patients for adverse effects associated with a metal-on-metal hip implant should include an expedited physical exam with an orthopedic surgeon, routine x-rays, and both standard and specialized laboratory tests, a Food and Drug Administration advisory panel recommended at the end of a 2-day meeting on June 28.
Lab testing should include the standard blood tests, as well as measures of sedimentation rate and C-reactive protein level, and more sophisticated imaging with MRI or CT, if needed, according to the advisory panel of the FDA’s Orthopaedic and Rehabilitation Devices Panel, which met for 2 days to review the safety data on these devices.
Blood or serum tests for metal ions (cobalt and chromium, which have been elevated in some patients who have received metal-on-metal devices, and have been associated with device failures) also can be helpful, panelists said, although these tests are not universally available and how to use the results in determining the course of treatment is still unclear. They made similar recommendations on how to follow up symptomatic patients who have undergone hip resurfacing with a metal-on-metal device.
There was less consensus on how to follow patients who have received one of these devices but are asymptomatic; recommendations included obtaining a baseline evaluation, with an MRI (at least in patients who are part of a postmarketing study) and tests for metal ions so changes can be monitored and compared over time. One panelist called for longitudinal studies that collect this type of information at baseline, so that predictive factors for failure could be identified.
The panel was not asked to vote on any issues, only to provide advice, so that the agency can make recommendations on the safety of these devices to health care providers and patients. The agency usually follows the recommendations of its advisory panels.
Metal-on-metal hip resurfacing systems, which became popular for use in younger active patients who had healthier bone, include the femoral head with a metal covering, a femoral stem, and an acetabular component. The metal-on metal hip devices were thought to last longer. The proportion of procedures in which devices are used has declined in reaction to increased revision rates and reports of adverse events.
In May 2011, the FDA issued a public health communication regarding adverse event reports associated with these devices and subsequently ordered manufacturers to conduct post-marketing studies addressing the safety issues of their metal-on-metal total hip replacement devices. The FDA has recalled two metal-on-metal devices, including one in August 2010 for a higher than expected revision rate.
A review of metal-on metal implants in December 2011 conducted by the American Academy of Orthopaedic Surgeons concluded that the risk of revision was higher among patients who receive these implants for total hip arthroplasty and hip resurfacing than those who undergo this surgery using a different bearing. The AAOS review also found that larger femoral head components used in hip arthroplasty are associated with higher revision rates, which was also reported by speakers during the FDA panel meeting.
Alerts about local and soft tissue reactions and recommendations on metal ion testing and imaging of patients who have received one of these devices has been issued in the United Kingdom, Australia, and Canada.
When asked if they could describe any types of patients for whom the benefits of a metal-on-metal device for resurfacing or hip replacement outweigh the risks, panelists said that the decision should be up to the individual surgeon and that there might be some cases where this type of device may be useful. But the orthopedic surgeons on the panel said they rarely or never used metal-on metal implants because of these adverse event reports and availability of other options.
"I see no indication for which I would use a metal on metal [device] over any other technology," said the panel chair, Dr. William Rohr, an orthopedic surgeon who practices in Fort Bragg, Calif. He added that he had not seen any evidence indicating that the performance of the metal-on-metal devices was better than that of other options, and he considered any increased risk over the others available unacceptable, and pointed out gender differences, with women at risk of poorer outcomes
Members of FDA panels have been cleared of potential conflicts of interest; in some cases, they are given waivers but not at this meeting.
GAITHERSBURG, MD. – Evaluation of patients for adverse effects associated with a metal-on-metal hip implant should include an expedited physical exam with an orthopedic surgeon, routine x-rays, and both standard and specialized laboratory tests, a Food and Drug Administration advisory panel recommended at the end of a 2-day meeting on June 28.
Lab testing should include the standard blood tests, as well as measures of sedimentation rate and C-reactive protein level, and more sophisticated imaging with MRI or CT, if needed, according to the advisory panel of the FDA’s Orthopaedic and Rehabilitation Devices Panel, which met for 2 days to review the safety data on these devices.
Blood or serum tests for metal ions (cobalt and chromium, which have been elevated in some patients who have received metal-on-metal devices, and have been associated with device failures) also can be helpful, panelists said, although these tests are not universally available and how to use the results in determining the course of treatment is still unclear. They made similar recommendations on how to follow up symptomatic patients who have undergone hip resurfacing with a metal-on-metal device.
There was less consensus on how to follow patients who have received one of these devices but are asymptomatic; recommendations included obtaining a baseline evaluation, with an MRI (at least in patients who are part of a postmarketing study) and tests for metal ions so changes can be monitored and compared over time. One panelist called for longitudinal studies that collect this type of information at baseline, so that predictive factors for failure could be identified.
The panel was not asked to vote on any issues, only to provide advice, so that the agency can make recommendations on the safety of these devices to health care providers and patients. The agency usually follows the recommendations of its advisory panels.
Metal-on-metal hip resurfacing systems, which became popular for use in younger active patients who had healthier bone, include the femoral head with a metal covering, a femoral stem, and an acetabular component. The metal-on metal hip devices were thought to last longer. The proportion of procedures in which devices are used has declined in reaction to increased revision rates and reports of adverse events.
In May 2011, the FDA issued a public health communication regarding adverse event reports associated with these devices and subsequently ordered manufacturers to conduct post-marketing studies addressing the safety issues of their metal-on-metal total hip replacement devices. The FDA has recalled two metal-on-metal devices, including one in August 2010 for a higher than expected revision rate.
A review of metal-on metal implants in December 2011 conducted by the American Academy of Orthopaedic Surgeons concluded that the risk of revision was higher among patients who receive these implants for total hip arthroplasty and hip resurfacing than those who undergo this surgery using a different bearing. The AAOS review also found that larger femoral head components used in hip arthroplasty are associated with higher revision rates, which was also reported by speakers during the FDA panel meeting.
Alerts about local and soft tissue reactions and recommendations on metal ion testing and imaging of patients who have received one of these devices has been issued in the United Kingdom, Australia, and Canada.
When asked if they could describe any types of patients for whom the benefits of a metal-on-metal device for resurfacing or hip replacement outweigh the risks, panelists said that the decision should be up to the individual surgeon and that there might be some cases where this type of device may be useful. But the orthopedic surgeons on the panel said they rarely or never used metal-on metal implants because of these adverse event reports and availability of other options.
"I see no indication for which I would use a metal on metal [device] over any other technology," said the panel chair, Dr. William Rohr, an orthopedic surgeon who practices in Fort Bragg, Calif. He added that he had not seen any evidence indicating that the performance of the metal-on-metal devices was better than that of other options, and he considered any increased risk over the others available unacceptable, and pointed out gender differences, with women at risk of poorer outcomes
Members of FDA panels have been cleared of potential conflicts of interest; in some cases, they are given waivers but not at this meeting.
AT A MEETING OF THE FDA’S ORTHOPEDIC SURGERY AND REHABILITATION DEVICES PANEL
VTE Risk Pumped Up in Rheumatoid Arthritis
BERLIN– Rheumatoid arthritis patients face a moderately elevated risk of venous thromboembolism that continues unabated for many years, according to findings from two large studies presented at the European Congress of Rheumatology.
Dr. Seoyoung C. Kim offered a retrospective cohort study involving 22,143 patients with rheumatoid arthritis (RA) and 88,572 age- and sex-matched controls. None of the subjects had a baseline history of malignancy or venous thromboembolism (VTE). The data came from a large U.S. commercial insurance plan.
During a mean follow-up of 2 years (starting when the RA patients received their first prescription for a disease-modifying antirheumatic drug), deep vein thrombosis or pulmonary embolism occurred in 1.2% of RA patients and 0.5% of controls. The incidence among RA patients was 6.1 cases per 1,000 person-years, a rate 2.4-fold greater than in controls. The pulmonary embolism rate was 2.7 times higher than in controls, whereas the deep vein thrombosis rate was 2.2-fold higher, according to Dr. Kim of Brigham and Women’s Hospital, Boston, where she is a rheumatologist.
After adjustment for known risk factors for VTE, including surgery, hospitalization, and cardiovascular disease, the VTE risk associated with having RA remained moderately elevated, with a 40% increase compared with controls.
The mechanism underlying this increased risk is believed to hinge upon the systemic inflammation that is a central feature of RA. This inflammation is thought to predispose to thrombus formation, up-regulation of procoagulants, down-regulation of anticoagulants, and suppression of fibrinolysis, Dr. Kim noted.
Dr. Marie Holmqvist presented a prospective population-based cohort study including 8,077 patients who were newly diagnosed with RA during 1997-2009, as well as 203,329 controls.
In all, 84 RA patients were diagnosed with a pulmonary embolism during 43,178 person-years of prospective follow-up. That translated to an incidence of 1.9 cases per 1,000 person-years, compared with 1.1 cases per 1,000 person-years among controls.
The increased risk of pulmonary embolism was evident 1 year after diagnosis of RA and remained unchanged thereafter. In the period 1-4 years after diagnosis of RA, the RA group had a 1.8-fold greater risk of pulmonary embolism than did controls drawn from the general population. During years 5-9, the risk was increased 2.0-fold, and in years 10-15 the risk of pulmonary embolism in RA patients was 1.9-fold greater than in controls, although only a small number of subjects were followed that long.
Control subjects who were hospitalized for any reason had a 5.4-fold increased risk of pulmonary embolism for the next year, compared with nonhospitalized controls. The risk of pulmonary embolism in hospitalized RA patients was elevated for the next year to the same extent as in hospitalized controls. In other words, having RA didn’t pile on additional risk beyond hospitalization itself, according to Dr. Holmqvist of the Karolinska Institute, Stockholm.
Dr. Holmqvist and Dr. Kim reported having no financial conflicts. Neither study had commercial sponsorship.
BERLIN– Rheumatoid arthritis patients face a moderately elevated risk of venous thromboembolism that continues unabated for many years, according to findings from two large studies presented at the European Congress of Rheumatology.
Dr. Seoyoung C. Kim offered a retrospective cohort study involving 22,143 patients with rheumatoid arthritis (RA) and 88,572 age- and sex-matched controls. None of the subjects had a baseline history of malignancy or venous thromboembolism (VTE). The data came from a large U.S. commercial insurance plan.
During a mean follow-up of 2 years (starting when the RA patients received their first prescription for a disease-modifying antirheumatic drug), deep vein thrombosis or pulmonary embolism occurred in 1.2% of RA patients and 0.5% of controls. The incidence among RA patients was 6.1 cases per 1,000 person-years, a rate 2.4-fold greater than in controls. The pulmonary embolism rate was 2.7 times higher than in controls, whereas the deep vein thrombosis rate was 2.2-fold higher, according to Dr. Kim of Brigham and Women’s Hospital, Boston, where she is a rheumatologist.
After adjustment for known risk factors for VTE, including surgery, hospitalization, and cardiovascular disease, the VTE risk associated with having RA remained moderately elevated, with a 40% increase compared with controls.
The mechanism underlying this increased risk is believed to hinge upon the systemic inflammation that is a central feature of RA. This inflammation is thought to predispose to thrombus formation, up-regulation of procoagulants, down-regulation of anticoagulants, and suppression of fibrinolysis, Dr. Kim noted.
Dr. Marie Holmqvist presented a prospective population-based cohort study including 8,077 patients who were newly diagnosed with RA during 1997-2009, as well as 203,329 controls.
In all, 84 RA patients were diagnosed with a pulmonary embolism during 43,178 person-years of prospective follow-up. That translated to an incidence of 1.9 cases per 1,000 person-years, compared with 1.1 cases per 1,000 person-years among controls.
The increased risk of pulmonary embolism was evident 1 year after diagnosis of RA and remained unchanged thereafter. In the period 1-4 years after diagnosis of RA, the RA group had a 1.8-fold greater risk of pulmonary embolism than did controls drawn from the general population. During years 5-9, the risk was increased 2.0-fold, and in years 10-15 the risk of pulmonary embolism in RA patients was 1.9-fold greater than in controls, although only a small number of subjects were followed that long.
Control subjects who were hospitalized for any reason had a 5.4-fold increased risk of pulmonary embolism for the next year, compared with nonhospitalized controls. The risk of pulmonary embolism in hospitalized RA patients was elevated for the next year to the same extent as in hospitalized controls. In other words, having RA didn’t pile on additional risk beyond hospitalization itself, according to Dr. Holmqvist of the Karolinska Institute, Stockholm.
Dr. Holmqvist and Dr. Kim reported having no financial conflicts. Neither study had commercial sponsorship.
BERLIN– Rheumatoid arthritis patients face a moderately elevated risk of venous thromboembolism that continues unabated for many years, according to findings from two large studies presented at the European Congress of Rheumatology.
Dr. Seoyoung C. Kim offered a retrospective cohort study involving 22,143 patients with rheumatoid arthritis (RA) and 88,572 age- and sex-matched controls. None of the subjects had a baseline history of malignancy or venous thromboembolism (VTE). The data came from a large U.S. commercial insurance plan.
During a mean follow-up of 2 years (starting when the RA patients received their first prescription for a disease-modifying antirheumatic drug), deep vein thrombosis or pulmonary embolism occurred in 1.2% of RA patients and 0.5% of controls. The incidence among RA patients was 6.1 cases per 1,000 person-years, a rate 2.4-fold greater than in controls. The pulmonary embolism rate was 2.7 times higher than in controls, whereas the deep vein thrombosis rate was 2.2-fold higher, according to Dr. Kim of Brigham and Women’s Hospital, Boston, where she is a rheumatologist.
After adjustment for known risk factors for VTE, including surgery, hospitalization, and cardiovascular disease, the VTE risk associated with having RA remained moderately elevated, with a 40% increase compared with controls.
The mechanism underlying this increased risk is believed to hinge upon the systemic inflammation that is a central feature of RA. This inflammation is thought to predispose to thrombus formation, up-regulation of procoagulants, down-regulation of anticoagulants, and suppression of fibrinolysis, Dr. Kim noted.
Dr. Marie Holmqvist presented a prospective population-based cohort study including 8,077 patients who were newly diagnosed with RA during 1997-2009, as well as 203,329 controls.
In all, 84 RA patients were diagnosed with a pulmonary embolism during 43,178 person-years of prospective follow-up. That translated to an incidence of 1.9 cases per 1,000 person-years, compared with 1.1 cases per 1,000 person-years among controls.
The increased risk of pulmonary embolism was evident 1 year after diagnosis of RA and remained unchanged thereafter. In the period 1-4 years after diagnosis of RA, the RA group had a 1.8-fold greater risk of pulmonary embolism than did controls drawn from the general population. During years 5-9, the risk was increased 2.0-fold, and in years 10-15 the risk of pulmonary embolism in RA patients was 1.9-fold greater than in controls, although only a small number of subjects were followed that long.
Control subjects who were hospitalized for any reason had a 5.4-fold increased risk of pulmonary embolism for the next year, compared with nonhospitalized controls. The risk of pulmonary embolism in hospitalized RA patients was elevated for the next year to the same extent as in hospitalized controls. In other words, having RA didn’t pile on additional risk beyond hospitalization itself, according to Dr. Holmqvist of the Karolinska Institute, Stockholm.
Dr. Holmqvist and Dr. Kim reported having no financial conflicts. Neither study had commercial sponsorship.
AT THE ANNUAL EUROPEAN CONGRESS OF RHEUMATOLOGY
Major Finding: The risk of venous thromboembolism was 40% greater in RA patients than controls in one 2-year study, whereas a second study found the risk of pulmonary embolism to be 80%-100% higher in RA patients than controls who were followed for as long as 15 years.
Data Source: The American retrospective cohort study included more than 22,000 RA patients, whereas the Swedish prospective cohort study involved 8,077.
Disclosures: Neither study had commercial sponsorship. Dr. Holmqvist and Dr. Kim reported having no financial conflicts.
Tocilizumab Beats Adalimumab in Monotherapy RA Trial
BERLIN – Tocilizumab monotherapy worked substantially better than adalimumab monotherapy in a head-to-head randomized trial of 326 rheumatoid arthritis patients, suggesting that the newer drug tocilizumab has superior efficacy compared with drugs that block tumor necrosis factor, at least when methotrexate isn’t coadministered.
After 24 weeks of treatment, tocilizumab monotherapy produced remission of rheumatoid arthritis (RA) in 40% of patients, based on their disease activity score in 28 joints (DAS28), compared with an 11% remission rate in patients on adalimumab monotherapy, a significant difference, Dr. Cem Gabay reported at the annual European Congress of Rheumatology.
This is the first direct RA comparison of representatives of these two drug classes, both of which block cytokines, said Dr. Gabay, professor of pathology and immunology at the University of Geneva. Both tocilizumab (Actemra) and adalimumab (Humira) have Food and Drug Administration labeling for the treatment of RA.
"Anti-TNF [tumor necrosis factor] drugs remain the first biologic drugs to try, based on EULAR recommendations, but we showed that if a patient is on monotherapy, tocilizumab might be the better choice," Dr. Gabay said in an interview.
"If a patient is on methotrexate and tolerates methotrexate, there is no reason to stop," and those patients should continue to get a TNF inhibitor. "But many patients don’t tolerate methotrexate, and in these patients tocilizumab may be the choice for a biologic as monotherapy." About a third of RA patients who receive a biologic drug get it as monotherapy and are not on concomitant therapy with a synthetic, disease-modifying antirheumatic drug (DMARD) such as methotrexate, usually because they don’t tolerate those drugs or because their preference is to avoid them.
"This needs to be confirmed by other studies, but according to these new data, when patients cannot tolerate a synthetic DMARD they will do better on tocilizumab than with an anti-TNF drug," Dr. Gabay said. "But for the majority of patients [who are on synthetic DMARD treatment], an anti-TNF drug remains the first line. They have been around for 10 years, and are much more studied than tocilizumab."
The finding is important for RA practice because "we don’t have many head-to-head studies of biologics," commented Dr. Xavier Mariette, professor and head of rheumatology at Bicetre Hospital in Paris. But he questioned the fairness of using adalimumab as the study’s representative anti-TNF drug, noting its documented immunogenicity, especially when used in monotherapy. "Other monotherapy would have been more appropriate," he said.
In response, Dr. Gabay highlighted the separation in average DAS28 scores that occurred after 8 weeks of treatment between the two study arms, the point when patients on tocilizumab began to have significantly lower scores than the adalimumab patients. The difference seems to occur too soon to result from an immune reaction to adalimumab, Dr. Gabay said.
The ADACTA trial enrolled 326 adults with RA at 82 centers in 15 countries including the United States. Enrollment criteria included having RA for at least 6 months and a DAS28 score of more than 5.1. All patients were naive for biologic drugs, but they could have had prior or current treatment with methotrexate or other synthetic DMARDs. All DMARDs were withdrawn at least 2 weeks before the study began. The patients had a mean age of 53 years, 80% were women, their average RA duration was more than 6 years, they had a history with average of two DMARDs, slightly more than half were on an oral steroid, and their mean DAS28 score was about 6.7.
The researchers randomized patients to receive 8 mg/kg tocilizumab intravenously every 4 weeks, or 40 mg of subcutaneous adalimumab every 2 weeks. Patients also received placebo treatments to blind everyone to the active-drug assignments.
For the study’s primary end point, average change in DAS28 score from baseline to 24 weeks on treatment, the reductions averaged 1.8 points in the adalimumab group and 3.3 points in the tocilizumab group, a significant difference. Low disease activity, defined as a DAS28 score of 3.2 or less, occurred in 20% of the adalimumab patients and in 52% of those on tocilizumab, also a significant difference. A 20% improvement by the criteria of the American College of Rheumatology (ACR20) occurred in 49% of the adalimumab patients, and their ACR50 and ACR70 rates were 28% and 18%, respectively. In the tocilizumab patients, the ACR20/50/70 rates were 65%, 47%, and 33%, respectively.
The rates of serious adverse events, infections, and serious infections were all similar in the two treatment arms. Infections occurred in 42% of the adalimumab patients and in 48% of those on tocilizumab, and serious infections occurred in 3% of both groups. Serious adverse events occurred in 10% of the adalimumab patients and in 12% of those on tocilizumab. Patients on tocilizumab had moderately higher rates of elevated liver enzymes. The tocilizumab patients had a 31% rate of enzymes elevated from above the upper limit of normal (ULN) to 2.5-fold the ULN, compared with 25% of the adalimumab patients; and liver enzyme elevations of 2.6-5.0 times the ULN occurred in 6% of the tocilizumab patients and in 2% of those on adalimumab. Tocilizumab showed "no new or unexpected adverse effects," Dr. Gabay said.
The study was sponsored by Roche, the company that markets tocilizumab. Dr. Gabay reported receiving research support from and being a consultant to Roche and several other drug companies. Dr. Mariette reported receiving research support from Roche and several other drug companies.
Current standard treatment for rheumatoid arthritis is methotrexate, and data clearly show that if we combine methotrexate and a biologic it is better for the long term. Currently, the message is to follow conventional treatment and add a biologic to methotrexate. We see a trend of better responses to biologics when patients are also on methotrexate. We do not yet have sufficient data to use biologics as monotherapy in routine practice, but we know that about 30% of RA patients take biologics as monotherapy.
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Based on what is known about adalimumab, using it as the comparator anti-TNF drug against tocilizumab was not fair. Nevertheless, it was fair based on worldwide practice. Adalimumab is a very commonly used drug; the choice reflects rheumatology practice. Although adalimumab is about the same as other anti-TNF drugs when used with methotrexate, the trend favors using etanercept (Enbrel) for anti-TNF monotherapy.
The results from the ADACTA trial are clinically relevant and cannot be ignored, but we need additional information before it changes how we routinely treat patients. For the time being, we should continue to consider anti-TNF drugs to be the standard class of biologic drugs for treating RA patients. The new findings are very encouraging for tocilizumab, but we can’t yet change practice based on them.
Maxime Dougados, M.D., is professor of rheumatology at Cochin Hospital in Paris. He said that he has received research support from and has been a consultant to Roche and to several other drug companies. He made these comments in an interview.
Current standard treatment for rheumatoid arthritis is methotrexate, and data clearly show that if we combine methotrexate and a biologic it is better for the long term. Currently, the message is to follow conventional treatment and add a biologic to methotrexate. We see a trend of better responses to biologics when patients are also on methotrexate. We do not yet have sufficient data to use biologics as monotherapy in routine practice, but we know that about 30% of RA patients take biologics as monotherapy.
|
|
|
Based on what is known about adalimumab, using it as the comparator anti-TNF drug against tocilizumab was not fair. Nevertheless, it was fair based on worldwide practice. Adalimumab is a very commonly used drug; the choice reflects rheumatology practice. Although adalimumab is about the same as other anti-TNF drugs when used with methotrexate, the trend favors using etanercept (Enbrel) for anti-TNF monotherapy.
The results from the ADACTA trial are clinically relevant and cannot be ignored, but we need additional information before it changes how we routinely treat patients. For the time being, we should continue to consider anti-TNF drugs to be the standard class of biologic drugs for treating RA patients. The new findings are very encouraging for tocilizumab, but we can’t yet change practice based on them.
Maxime Dougados, M.D., is professor of rheumatology at Cochin Hospital in Paris. He said that he has received research support from and has been a consultant to Roche and to several other drug companies. He made these comments in an interview.
Current standard treatment for rheumatoid arthritis is methotrexate, and data clearly show that if we combine methotrexate and a biologic it is better for the long term. Currently, the message is to follow conventional treatment and add a biologic to methotrexate. We see a trend of better responses to biologics when patients are also on methotrexate. We do not yet have sufficient data to use biologics as monotherapy in routine practice, but we know that about 30% of RA patients take biologics as monotherapy.
|
|
|
Based on what is known about adalimumab, using it as the comparator anti-TNF drug against tocilizumab was not fair. Nevertheless, it was fair based on worldwide practice. Adalimumab is a very commonly used drug; the choice reflects rheumatology practice. Although adalimumab is about the same as other anti-TNF drugs when used with methotrexate, the trend favors using etanercept (Enbrel) for anti-TNF monotherapy.
The results from the ADACTA trial are clinically relevant and cannot be ignored, but we need additional information before it changes how we routinely treat patients. For the time being, we should continue to consider anti-TNF drugs to be the standard class of biologic drugs for treating RA patients. The new findings are very encouraging for tocilizumab, but we can’t yet change practice based on them.
Maxime Dougados, M.D., is professor of rheumatology at Cochin Hospital in Paris. He said that he has received research support from and has been a consultant to Roche and to several other drug companies. He made these comments in an interview.
BERLIN – Tocilizumab monotherapy worked substantially better than adalimumab monotherapy in a head-to-head randomized trial of 326 rheumatoid arthritis patients, suggesting that the newer drug tocilizumab has superior efficacy compared with drugs that block tumor necrosis factor, at least when methotrexate isn’t coadministered.
After 24 weeks of treatment, tocilizumab monotherapy produced remission of rheumatoid arthritis (RA) in 40% of patients, based on their disease activity score in 28 joints (DAS28), compared with an 11% remission rate in patients on adalimumab monotherapy, a significant difference, Dr. Cem Gabay reported at the annual European Congress of Rheumatology.
This is the first direct RA comparison of representatives of these two drug classes, both of which block cytokines, said Dr. Gabay, professor of pathology and immunology at the University of Geneva. Both tocilizumab (Actemra) and adalimumab (Humira) have Food and Drug Administration labeling for the treatment of RA.
"Anti-TNF [tumor necrosis factor] drugs remain the first biologic drugs to try, based on EULAR recommendations, but we showed that if a patient is on monotherapy, tocilizumab might be the better choice," Dr. Gabay said in an interview.
"If a patient is on methotrexate and tolerates methotrexate, there is no reason to stop," and those patients should continue to get a TNF inhibitor. "But many patients don’t tolerate methotrexate, and in these patients tocilizumab may be the choice for a biologic as monotherapy." About a third of RA patients who receive a biologic drug get it as monotherapy and are not on concomitant therapy with a synthetic, disease-modifying antirheumatic drug (DMARD) such as methotrexate, usually because they don’t tolerate those drugs or because their preference is to avoid them.
"This needs to be confirmed by other studies, but according to these new data, when patients cannot tolerate a synthetic DMARD they will do better on tocilizumab than with an anti-TNF drug," Dr. Gabay said. "But for the majority of patients [who are on synthetic DMARD treatment], an anti-TNF drug remains the first line. They have been around for 10 years, and are much more studied than tocilizumab."
The finding is important for RA practice because "we don’t have many head-to-head studies of biologics," commented Dr. Xavier Mariette, professor and head of rheumatology at Bicetre Hospital in Paris. But he questioned the fairness of using adalimumab as the study’s representative anti-TNF drug, noting its documented immunogenicity, especially when used in monotherapy. "Other monotherapy would have been more appropriate," he said.
In response, Dr. Gabay highlighted the separation in average DAS28 scores that occurred after 8 weeks of treatment between the two study arms, the point when patients on tocilizumab began to have significantly lower scores than the adalimumab patients. The difference seems to occur too soon to result from an immune reaction to adalimumab, Dr. Gabay said.
The ADACTA trial enrolled 326 adults with RA at 82 centers in 15 countries including the United States. Enrollment criteria included having RA for at least 6 months and a DAS28 score of more than 5.1. All patients were naive for biologic drugs, but they could have had prior or current treatment with methotrexate or other synthetic DMARDs. All DMARDs were withdrawn at least 2 weeks before the study began. The patients had a mean age of 53 years, 80% were women, their average RA duration was more than 6 years, they had a history with average of two DMARDs, slightly more than half were on an oral steroid, and their mean DAS28 score was about 6.7.
The researchers randomized patients to receive 8 mg/kg tocilizumab intravenously every 4 weeks, or 40 mg of subcutaneous adalimumab every 2 weeks. Patients also received placebo treatments to blind everyone to the active-drug assignments.
For the study’s primary end point, average change in DAS28 score from baseline to 24 weeks on treatment, the reductions averaged 1.8 points in the adalimumab group and 3.3 points in the tocilizumab group, a significant difference. Low disease activity, defined as a DAS28 score of 3.2 or less, occurred in 20% of the adalimumab patients and in 52% of those on tocilizumab, also a significant difference. A 20% improvement by the criteria of the American College of Rheumatology (ACR20) occurred in 49% of the adalimumab patients, and their ACR50 and ACR70 rates were 28% and 18%, respectively. In the tocilizumab patients, the ACR20/50/70 rates were 65%, 47%, and 33%, respectively.
The rates of serious adverse events, infections, and serious infections were all similar in the two treatment arms. Infections occurred in 42% of the adalimumab patients and in 48% of those on tocilizumab, and serious infections occurred in 3% of both groups. Serious adverse events occurred in 10% of the adalimumab patients and in 12% of those on tocilizumab. Patients on tocilizumab had moderately higher rates of elevated liver enzymes. The tocilizumab patients had a 31% rate of enzymes elevated from above the upper limit of normal (ULN) to 2.5-fold the ULN, compared with 25% of the adalimumab patients; and liver enzyme elevations of 2.6-5.0 times the ULN occurred in 6% of the tocilizumab patients and in 2% of those on adalimumab. Tocilizumab showed "no new or unexpected adverse effects," Dr. Gabay said.
The study was sponsored by Roche, the company that markets tocilizumab. Dr. Gabay reported receiving research support from and being a consultant to Roche and several other drug companies. Dr. Mariette reported receiving research support from Roche and several other drug companies.
BERLIN – Tocilizumab monotherapy worked substantially better than adalimumab monotherapy in a head-to-head randomized trial of 326 rheumatoid arthritis patients, suggesting that the newer drug tocilizumab has superior efficacy compared with drugs that block tumor necrosis factor, at least when methotrexate isn’t coadministered.
After 24 weeks of treatment, tocilizumab monotherapy produced remission of rheumatoid arthritis (RA) in 40% of patients, based on their disease activity score in 28 joints (DAS28), compared with an 11% remission rate in patients on adalimumab monotherapy, a significant difference, Dr. Cem Gabay reported at the annual European Congress of Rheumatology.
This is the first direct RA comparison of representatives of these two drug classes, both of which block cytokines, said Dr. Gabay, professor of pathology and immunology at the University of Geneva. Both tocilizumab (Actemra) and adalimumab (Humira) have Food and Drug Administration labeling for the treatment of RA.
"Anti-TNF [tumor necrosis factor] drugs remain the first biologic drugs to try, based on EULAR recommendations, but we showed that if a patient is on monotherapy, tocilizumab might be the better choice," Dr. Gabay said in an interview.
"If a patient is on methotrexate and tolerates methotrexate, there is no reason to stop," and those patients should continue to get a TNF inhibitor. "But many patients don’t tolerate methotrexate, and in these patients tocilizumab may be the choice for a biologic as monotherapy." About a third of RA patients who receive a biologic drug get it as monotherapy and are not on concomitant therapy with a synthetic, disease-modifying antirheumatic drug (DMARD) such as methotrexate, usually because they don’t tolerate those drugs or because their preference is to avoid them.
"This needs to be confirmed by other studies, but according to these new data, when patients cannot tolerate a synthetic DMARD they will do better on tocilizumab than with an anti-TNF drug," Dr. Gabay said. "But for the majority of patients [who are on synthetic DMARD treatment], an anti-TNF drug remains the first line. They have been around for 10 years, and are much more studied than tocilizumab."
The finding is important for RA practice because "we don’t have many head-to-head studies of biologics," commented Dr. Xavier Mariette, professor and head of rheumatology at Bicetre Hospital in Paris. But he questioned the fairness of using adalimumab as the study’s representative anti-TNF drug, noting its documented immunogenicity, especially when used in monotherapy. "Other monotherapy would have been more appropriate," he said.
In response, Dr. Gabay highlighted the separation in average DAS28 scores that occurred after 8 weeks of treatment between the two study arms, the point when patients on tocilizumab began to have significantly lower scores than the adalimumab patients. The difference seems to occur too soon to result from an immune reaction to adalimumab, Dr. Gabay said.
The ADACTA trial enrolled 326 adults with RA at 82 centers in 15 countries including the United States. Enrollment criteria included having RA for at least 6 months and a DAS28 score of more than 5.1. All patients were naive for biologic drugs, but they could have had prior or current treatment with methotrexate or other synthetic DMARDs. All DMARDs were withdrawn at least 2 weeks before the study began. The patients had a mean age of 53 years, 80% were women, their average RA duration was more than 6 years, they had a history with average of two DMARDs, slightly more than half were on an oral steroid, and their mean DAS28 score was about 6.7.
The researchers randomized patients to receive 8 mg/kg tocilizumab intravenously every 4 weeks, or 40 mg of subcutaneous adalimumab every 2 weeks. Patients also received placebo treatments to blind everyone to the active-drug assignments.
For the study’s primary end point, average change in DAS28 score from baseline to 24 weeks on treatment, the reductions averaged 1.8 points in the adalimumab group and 3.3 points in the tocilizumab group, a significant difference. Low disease activity, defined as a DAS28 score of 3.2 or less, occurred in 20% of the adalimumab patients and in 52% of those on tocilizumab, also a significant difference. A 20% improvement by the criteria of the American College of Rheumatology (ACR20) occurred in 49% of the adalimumab patients, and their ACR50 and ACR70 rates were 28% and 18%, respectively. In the tocilizumab patients, the ACR20/50/70 rates were 65%, 47%, and 33%, respectively.
The rates of serious adverse events, infections, and serious infections were all similar in the two treatment arms. Infections occurred in 42% of the adalimumab patients and in 48% of those on tocilizumab, and serious infections occurred in 3% of both groups. Serious adverse events occurred in 10% of the adalimumab patients and in 12% of those on tocilizumab. Patients on tocilizumab had moderately higher rates of elevated liver enzymes. The tocilizumab patients had a 31% rate of enzymes elevated from above the upper limit of normal (ULN) to 2.5-fold the ULN, compared with 25% of the adalimumab patients; and liver enzyme elevations of 2.6-5.0 times the ULN occurred in 6% of the tocilizumab patients and in 2% of those on adalimumab. Tocilizumab showed "no new or unexpected adverse effects," Dr. Gabay said.
The study was sponsored by Roche, the company that markets tocilizumab. Dr. Gabay reported receiving research support from and being a consultant to Roche and several other drug companies. Dr. Mariette reported receiving research support from Roche and several other drug companies.
AT THE ANNUAL EUROPEAN CONGRESS OF RHEUMATOLOGY
High Interferon Response, Low B Cells Presage Rheumatoid Arthritis
BERLIN – The combination of an elevated level of interferon gene expression and a low level of circulating B cells identified patients with arthralgia who had a high rate of progression to rheumatoid arthritis in a validation study of 115 patients at one center.
After 2 years of follow-up, about 70% of patients with a high level of interferon gene expression and a low level of B cells in their peripheral blood had developed rheumatoid arthritis (RA), while in contrast about 20% of arthralgia patients with low interferon gene expression and a high B-cell level developed RA, Joyce Lubbers said at the annual European Congress of Rheumatology.
Some of Ms. Lubbers’ associates on the study had previously shown, in a different group of 109 patients with arthralgia, that high interferon gene expression was linked to an increased rate of progression to RA, and that high expression of genes involved in B-cell activation was linked to a reduced risk for progressing to RA (Arthritis Rheum. 2010;62:694-704). Hence, the new findings that Ms. Lubbers reported validated the results of the previous study.
"We’ve now shown this in two independent cohorts, and we’re looking at a third group," said Ms. Lubbers, a researcher working on inflammatory disease profiling at VU University Medical Center in Amsterdam.
In practice, these easily obtained lab markers – interferon gene expression and B cell count – can couple with a patient’s clinical profile to estimate the risk of developing RA.
The next step is to test whether an intervention in arthralgia patients at high risk for progression to RA can delay or prevent the progression, or make RA less severe once it develops. Researchers in Amsterdam are currently testing whether treatment of high-risk arthralgia patients with rituximab can have a positive effect on RA progression, she said in an interview.
The study included 115 patients with arthralgia who did not have RA, joint erosions, or a history of treatment with any disease-modifying antirheumatic drug at one center in Amsterdam. During a median 23 months of follow-up, 44 patients (38%) developed RA, after a median of 8 months.
At baseline, the researchers calculated an interferon gene score for each patient, based on their expression of seven different genes involved in responses to interferon. Patients who progressed to RA had an average interferon score at baseline that was about twice the average in the nonprogressors. At 2 years of follow-up, about 60% of the high gene expressors had progressed to RA, compared with about 30% of the low expressors, a statistically significant difference.
Adding data on the number of peripheral blood B cells, quantified by fluorescent-activated cell sorting, produced a statistically significant refinement of the progression rate.
It makes physiologic sense that interferon responses and blood levels of B cells would correlate with progression to early-stage RA, Ms. Lubbers said. A low level of B cells in blood suggests that a higher than normal number of B cells had migrated out of the blood and into tissue, such as into the synovium, Ms. Lubbers said.
Ms. Lubbers said that she had no disclosures. The VU Medical Center has a patent pending on using the markers studied for identifying preclinical RA.
BERLIN – The combination of an elevated level of interferon gene expression and a low level of circulating B cells identified patients with arthralgia who had a high rate of progression to rheumatoid arthritis in a validation study of 115 patients at one center.
After 2 years of follow-up, about 70% of patients with a high level of interferon gene expression and a low level of B cells in their peripheral blood had developed rheumatoid arthritis (RA), while in contrast about 20% of arthralgia patients with low interferon gene expression and a high B-cell level developed RA, Joyce Lubbers said at the annual European Congress of Rheumatology.
Some of Ms. Lubbers’ associates on the study had previously shown, in a different group of 109 patients with arthralgia, that high interferon gene expression was linked to an increased rate of progression to RA, and that high expression of genes involved in B-cell activation was linked to a reduced risk for progressing to RA (Arthritis Rheum. 2010;62:694-704). Hence, the new findings that Ms. Lubbers reported validated the results of the previous study.
"We’ve now shown this in two independent cohorts, and we’re looking at a third group," said Ms. Lubbers, a researcher working on inflammatory disease profiling at VU University Medical Center in Amsterdam.
In practice, these easily obtained lab markers – interferon gene expression and B cell count – can couple with a patient’s clinical profile to estimate the risk of developing RA.
The next step is to test whether an intervention in arthralgia patients at high risk for progression to RA can delay or prevent the progression, or make RA less severe once it develops. Researchers in Amsterdam are currently testing whether treatment of high-risk arthralgia patients with rituximab can have a positive effect on RA progression, she said in an interview.
The study included 115 patients with arthralgia who did not have RA, joint erosions, or a history of treatment with any disease-modifying antirheumatic drug at one center in Amsterdam. During a median 23 months of follow-up, 44 patients (38%) developed RA, after a median of 8 months.
At baseline, the researchers calculated an interferon gene score for each patient, based on their expression of seven different genes involved in responses to interferon. Patients who progressed to RA had an average interferon score at baseline that was about twice the average in the nonprogressors. At 2 years of follow-up, about 60% of the high gene expressors had progressed to RA, compared with about 30% of the low expressors, a statistically significant difference.
Adding data on the number of peripheral blood B cells, quantified by fluorescent-activated cell sorting, produced a statistically significant refinement of the progression rate.
It makes physiologic sense that interferon responses and blood levels of B cells would correlate with progression to early-stage RA, Ms. Lubbers said. A low level of B cells in blood suggests that a higher than normal number of B cells had migrated out of the blood and into tissue, such as into the synovium, Ms. Lubbers said.
Ms. Lubbers said that she had no disclosures. The VU Medical Center has a patent pending on using the markers studied for identifying preclinical RA.
BERLIN – The combination of an elevated level of interferon gene expression and a low level of circulating B cells identified patients with arthralgia who had a high rate of progression to rheumatoid arthritis in a validation study of 115 patients at one center.
After 2 years of follow-up, about 70% of patients with a high level of interferon gene expression and a low level of B cells in their peripheral blood had developed rheumatoid arthritis (RA), while in contrast about 20% of arthralgia patients with low interferon gene expression and a high B-cell level developed RA, Joyce Lubbers said at the annual European Congress of Rheumatology.
Some of Ms. Lubbers’ associates on the study had previously shown, in a different group of 109 patients with arthralgia, that high interferon gene expression was linked to an increased rate of progression to RA, and that high expression of genes involved in B-cell activation was linked to a reduced risk for progressing to RA (Arthritis Rheum. 2010;62:694-704). Hence, the new findings that Ms. Lubbers reported validated the results of the previous study.
"We’ve now shown this in two independent cohorts, and we’re looking at a third group," said Ms. Lubbers, a researcher working on inflammatory disease profiling at VU University Medical Center in Amsterdam.
In practice, these easily obtained lab markers – interferon gene expression and B cell count – can couple with a patient’s clinical profile to estimate the risk of developing RA.
The next step is to test whether an intervention in arthralgia patients at high risk for progression to RA can delay or prevent the progression, or make RA less severe once it develops. Researchers in Amsterdam are currently testing whether treatment of high-risk arthralgia patients with rituximab can have a positive effect on RA progression, she said in an interview.
The study included 115 patients with arthralgia who did not have RA, joint erosions, or a history of treatment with any disease-modifying antirheumatic drug at one center in Amsterdam. During a median 23 months of follow-up, 44 patients (38%) developed RA, after a median of 8 months.
At baseline, the researchers calculated an interferon gene score for each patient, based on their expression of seven different genes involved in responses to interferon. Patients who progressed to RA had an average interferon score at baseline that was about twice the average in the nonprogressors. At 2 years of follow-up, about 60% of the high gene expressors had progressed to RA, compared with about 30% of the low expressors, a statistically significant difference.
Adding data on the number of peripheral blood B cells, quantified by fluorescent-activated cell sorting, produced a statistically significant refinement of the progression rate.
It makes physiologic sense that interferon responses and blood levels of B cells would correlate with progression to early-stage RA, Ms. Lubbers said. A low level of B cells in blood suggests that a higher than normal number of B cells had migrated out of the blood and into tissue, such as into the synovium, Ms. Lubbers said.
Ms. Lubbers said that she had no disclosures. The VU Medical Center has a patent pending on using the markers studied for identifying preclinical RA.
AT THE ANNUAL EUROPEAN CONGRESS OF RHEUMATOLOGY