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Safety of corticosteroids in pregnancy: Is it the drug or the disease?
Corticosteroids such as prednisone are relatively frequently administered in pregnancy for their immunosuppressive and anti-inflammatory effects. Treatment may be initiated on a short-term basis for acute conditions. Alternatively, treatment may be more or less ongoing for severe chronic diseases such as asthma or a variety of other autoimmune conditions when disease symptoms do not remit in pregnancy. However, the safety of corticosteroid use with respect to risk of specific birth defects, preterm delivery, and low birth weight has been the subject of debate over some time.
Concerns about the teratogenicity of corticosteroids were raised as early as the 1950s, based on animal studies suggesting an increased risk for oral clefts. The association between corticosteroids and oral clefts has also been observed in some human epidemiologic studies. However, results of these studies have been inconsistent.
Similar to the NBDPS findings, in a large Danish cohort study covering 832,636 live births from 1996 to 2008, exposure to any corticosteroids during the first trimester was not associated with an increased risk for cleft lip or cleft palate. Only those exposed to topical corticosteroids had a higher risk of cleft lip with or without cleft palate (odds ratio, 1.45; 95% CI, 1.03-2.05).3 Another, smaller Danish study covered primiparous births from 1999 to 2009 (n = 83,043). The unadjusted odds of oral clefts following exposure to any corticosteroids (inhaled or oral) in the first trimester was null (OR, 0.4; 95% CI, 0.1-2.8).4
Inconsistencies across these studies, as speculated by authors of the NBDPS analysis, may result from a lack of information on the dose of drug used by the mother, the indication for its use, or any measure of the severity of the underlying maternal disease for which the corticosteroids were prescribed. It is possible that maternal disease or disease activity in and of itself is a direct cause of oral clefts or that corticosteroids are linked to increased risk for clefts through co-occurring other exposures such as smoking, alcohol, or obesity. However, these questions have yet to be answered.
With respect to other birth outcomes, a few disease-specific studies have examined birth weight or intrauterine growth restriction following corticosteroid use. In general, study findings have been reassuring. Among Danish women with Crohn’s disease, corticosteroids were not associated with reduced birth weight after adjusting for gestational age and disease activity (adjusted risk ratio, 1.1; 95% CI, 0.2-5.7).5 In another study of pregnant women with rheumatoid arthritis, birth weight was not associated with prednisone use after adjustment for gestational age at delivery and sex of the newborn.6 In a third cohort study of pregnant women with systemic lupus erythematosus, there was no a significant elevation in odds of intrauterine growth restriction following prednisone use.7
Several disease-specific studies have also examined corticosteroid use and risk of preterm birth. From the Danish cohort of pregnant women with Crohn’s disease, the researchers reported no association between prednisolone and preterm birth after adjustment for covariates. In contrast, in a separate Danish cohort of pregnant women with irritable bowel disease, there was an increased risk of preterm delivery following systemic corticosteroid use, compared with women without disease (adjusted hazard ratio, 6.3; 95% CI, 3.1-12.7).8 However, data were not available to address underlying disease severity as a possible contributing factor. Of note, among women with irritable bowel disease who did not use medication in pregnancy, there was a 50% increase in the risk of preterm birth, compared with women without disease (aHR, 1.5; 95% CI, 1.0-2.4). This suggests that the disease itself contributed to the increased risk of preterm birth.
Currently available data regarding corticosteroid use and adverse birth outcomes are generally reassuring. Recent estimates for oral clefts suggest a low elevation in risk, if any at all. This translates to a very low absolute risk for clefts, which occur in the general population in approximately 1 in 1,000 births. The clinical benefit of adequate treatment in the first trimester for inflammatory or immune-mediated diseases may far outweigh any small and tenuous risks for oral clefts.
With respect to reduced birth weight and preterm delivery, available evidence suggests either no association or that maternal disease and disease severity are driving any increased risks noted for these outcomes. Future studies of pregnancy safety for medications used to treat maternal diseases that themselves are potentially linked to adverse outcomes must incorporate appropriate measures of disease type and disease severity in the study designs.
Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is also director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures. To comment, e-mail her at obnews@frontlinemedcom.com.
References
1. Teratology. 2000 Dec;62(6):385-92.
2. Birth Defects Res A Clin Mol Teratol. 2014 Jun;100(6):499-506.
3. CMAJ. 2011 Apr 19;183(7):796-804.
4. Am J Ther. 2014 Mar-Apr;21(2):73-80.
5. Am J Gastroenterol. 2007 Jul;102(7):1406-13.
6. Arthritis Rheum. 2009 Nov;60(11):3196-206.
7. Lupus. 2010 Dec;19(14):1665-73.
8. PLoS One. 2015 Jun 17;10(6):e0129567.
Corticosteroids such as prednisone are relatively frequently administered in pregnancy for their immunosuppressive and anti-inflammatory effects. Treatment may be initiated on a short-term basis for acute conditions. Alternatively, treatment may be more or less ongoing for severe chronic diseases such as asthma or a variety of other autoimmune conditions when disease symptoms do not remit in pregnancy. However, the safety of corticosteroid use with respect to risk of specific birth defects, preterm delivery, and low birth weight has been the subject of debate over some time.
Concerns about the teratogenicity of corticosteroids were raised as early as the 1950s, based on animal studies suggesting an increased risk for oral clefts. The association between corticosteroids and oral clefts has also been observed in some human epidemiologic studies. However, results of these studies have been inconsistent.
Similar to the NBDPS findings, in a large Danish cohort study covering 832,636 live births from 1996 to 2008, exposure to any corticosteroids during the first trimester was not associated with an increased risk for cleft lip or cleft palate. Only those exposed to topical corticosteroids had a higher risk of cleft lip with or without cleft palate (odds ratio, 1.45; 95% CI, 1.03-2.05).3 Another, smaller Danish study covered primiparous births from 1999 to 2009 (n = 83,043). The unadjusted odds of oral clefts following exposure to any corticosteroids (inhaled or oral) in the first trimester was null (OR, 0.4; 95% CI, 0.1-2.8).4
Inconsistencies across these studies, as speculated by authors of the NBDPS analysis, may result from a lack of information on the dose of drug used by the mother, the indication for its use, or any measure of the severity of the underlying maternal disease for which the corticosteroids were prescribed. It is possible that maternal disease or disease activity in and of itself is a direct cause of oral clefts or that corticosteroids are linked to increased risk for clefts through co-occurring other exposures such as smoking, alcohol, or obesity. However, these questions have yet to be answered.
With respect to other birth outcomes, a few disease-specific studies have examined birth weight or intrauterine growth restriction following corticosteroid use. In general, study findings have been reassuring. Among Danish women with Crohn’s disease, corticosteroids were not associated with reduced birth weight after adjusting for gestational age and disease activity (adjusted risk ratio, 1.1; 95% CI, 0.2-5.7).5 In another study of pregnant women with rheumatoid arthritis, birth weight was not associated with prednisone use after adjustment for gestational age at delivery and sex of the newborn.6 In a third cohort study of pregnant women with systemic lupus erythematosus, there was no a significant elevation in odds of intrauterine growth restriction following prednisone use.7
Several disease-specific studies have also examined corticosteroid use and risk of preterm birth. From the Danish cohort of pregnant women with Crohn’s disease, the researchers reported no association between prednisolone and preterm birth after adjustment for covariates. In contrast, in a separate Danish cohort of pregnant women with irritable bowel disease, there was an increased risk of preterm delivery following systemic corticosteroid use, compared with women without disease (adjusted hazard ratio, 6.3; 95% CI, 3.1-12.7).8 However, data were not available to address underlying disease severity as a possible contributing factor. Of note, among women with irritable bowel disease who did not use medication in pregnancy, there was a 50% increase in the risk of preterm birth, compared with women without disease (aHR, 1.5; 95% CI, 1.0-2.4). This suggests that the disease itself contributed to the increased risk of preterm birth.
Currently available data regarding corticosteroid use and adverse birth outcomes are generally reassuring. Recent estimates for oral clefts suggest a low elevation in risk, if any at all. This translates to a very low absolute risk for clefts, which occur in the general population in approximately 1 in 1,000 births. The clinical benefit of adequate treatment in the first trimester for inflammatory or immune-mediated diseases may far outweigh any small and tenuous risks for oral clefts.
With respect to reduced birth weight and preterm delivery, available evidence suggests either no association or that maternal disease and disease severity are driving any increased risks noted for these outcomes. Future studies of pregnancy safety for medications used to treat maternal diseases that themselves are potentially linked to adverse outcomes must incorporate appropriate measures of disease type and disease severity in the study designs.
Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is also director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures. To comment, e-mail her at obnews@frontlinemedcom.com.
References
1. Teratology. 2000 Dec;62(6):385-92.
2. Birth Defects Res A Clin Mol Teratol. 2014 Jun;100(6):499-506.
3. CMAJ. 2011 Apr 19;183(7):796-804.
4. Am J Ther. 2014 Mar-Apr;21(2):73-80.
5. Am J Gastroenterol. 2007 Jul;102(7):1406-13.
6. Arthritis Rheum. 2009 Nov;60(11):3196-206.
7. Lupus. 2010 Dec;19(14):1665-73.
8. PLoS One. 2015 Jun 17;10(6):e0129567.
Corticosteroids such as prednisone are relatively frequently administered in pregnancy for their immunosuppressive and anti-inflammatory effects. Treatment may be initiated on a short-term basis for acute conditions. Alternatively, treatment may be more or less ongoing for severe chronic diseases such as asthma or a variety of other autoimmune conditions when disease symptoms do not remit in pregnancy. However, the safety of corticosteroid use with respect to risk of specific birth defects, preterm delivery, and low birth weight has been the subject of debate over some time.
Concerns about the teratogenicity of corticosteroids were raised as early as the 1950s, based on animal studies suggesting an increased risk for oral clefts. The association between corticosteroids and oral clefts has also been observed in some human epidemiologic studies. However, results of these studies have been inconsistent.
Similar to the NBDPS findings, in a large Danish cohort study covering 832,636 live births from 1996 to 2008, exposure to any corticosteroids during the first trimester was not associated with an increased risk for cleft lip or cleft palate. Only those exposed to topical corticosteroids had a higher risk of cleft lip with or without cleft palate (odds ratio, 1.45; 95% CI, 1.03-2.05).3 Another, smaller Danish study covered primiparous births from 1999 to 2009 (n = 83,043). The unadjusted odds of oral clefts following exposure to any corticosteroids (inhaled or oral) in the first trimester was null (OR, 0.4; 95% CI, 0.1-2.8).4
Inconsistencies across these studies, as speculated by authors of the NBDPS analysis, may result from a lack of information on the dose of drug used by the mother, the indication for its use, or any measure of the severity of the underlying maternal disease for which the corticosteroids were prescribed. It is possible that maternal disease or disease activity in and of itself is a direct cause of oral clefts or that corticosteroids are linked to increased risk for clefts through co-occurring other exposures such as smoking, alcohol, or obesity. However, these questions have yet to be answered.
With respect to other birth outcomes, a few disease-specific studies have examined birth weight or intrauterine growth restriction following corticosteroid use. In general, study findings have been reassuring. Among Danish women with Crohn’s disease, corticosteroids were not associated with reduced birth weight after adjusting for gestational age and disease activity (adjusted risk ratio, 1.1; 95% CI, 0.2-5.7).5 In another study of pregnant women with rheumatoid arthritis, birth weight was not associated with prednisone use after adjustment for gestational age at delivery and sex of the newborn.6 In a third cohort study of pregnant women with systemic lupus erythematosus, there was no a significant elevation in odds of intrauterine growth restriction following prednisone use.7
Several disease-specific studies have also examined corticosteroid use and risk of preterm birth. From the Danish cohort of pregnant women with Crohn’s disease, the researchers reported no association between prednisolone and preterm birth after adjustment for covariates. In contrast, in a separate Danish cohort of pregnant women with irritable bowel disease, there was an increased risk of preterm delivery following systemic corticosteroid use, compared with women without disease (adjusted hazard ratio, 6.3; 95% CI, 3.1-12.7).8 However, data were not available to address underlying disease severity as a possible contributing factor. Of note, among women with irritable bowel disease who did not use medication in pregnancy, there was a 50% increase in the risk of preterm birth, compared with women without disease (aHR, 1.5; 95% CI, 1.0-2.4). This suggests that the disease itself contributed to the increased risk of preterm birth.
Currently available data regarding corticosteroid use and adverse birth outcomes are generally reassuring. Recent estimates for oral clefts suggest a low elevation in risk, if any at all. This translates to a very low absolute risk for clefts, which occur in the general population in approximately 1 in 1,000 births. The clinical benefit of adequate treatment in the first trimester for inflammatory or immune-mediated diseases may far outweigh any small and tenuous risks for oral clefts.
With respect to reduced birth weight and preterm delivery, available evidence suggests either no association or that maternal disease and disease severity are driving any increased risks noted for these outcomes. Future studies of pregnancy safety for medications used to treat maternal diseases that themselves are potentially linked to adverse outcomes must incorporate appropriate measures of disease type and disease severity in the study designs.
Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is also director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures. To comment, e-mail her at obnews@frontlinemedcom.com.
References
1. Teratology. 2000 Dec;62(6):385-92.
2. Birth Defects Res A Clin Mol Teratol. 2014 Jun;100(6):499-506.
3. CMAJ. 2011 Apr 19;183(7):796-804.
4. Am J Ther. 2014 Mar-Apr;21(2):73-80.
5. Am J Gastroenterol. 2007 Jul;102(7):1406-13.
6. Arthritis Rheum. 2009 Nov;60(11):3196-206.
7. Lupus. 2010 Dec;19(14):1665-73.
8. PLoS One. 2015 Jun 17;10(6):e0129567.
Underweight and rapid weight loss linked to cause-specific RA mortality
Being underweight or experiencing rapid weight loss are both independently associated with an increased risk of cause-specific mortality in individuals with rheumatoid arthritis, according to new research.
In a cohort of 1,600 U.S. veterans with rheumatoid arthritis who were followed for a median of 3.2 years, researchers found that being overweight (BMI 25-30 kg/m2) was associated with a 41% lower risk of cardiovascular mortality. Cumulative weight loss of greater than 10% and weight loss greater than 3 kg/m2 per year were both significantly associated with a twofold higher risk of cardiovascular mortality.
Similarly, more rapid weight loss of more than 3 kg/m2 per year was also associated with a greater than twofold increase in the risk of cancer mortality, while less rapid weight loss did not show a significant impact (Arthritis Care Res. 2017 Apr 20. doi: 10.1002/acr.23258).
Individuals who were underweight (BMI less than 20 kg/m2) had nearly a threefold greater risk of respiratory mortality, compared with individuals with a normal BMI. Researchers saw a dose-dependent association between respiratory mortality and percent of weight loss: 5%-10% weight loss was associated with an 86% higher risk of respiratory mortality, and greater than 10% weight loss showed a more than twofold greater risk.
This appears to be the first study to examine the impact of both BMI and weight loss on cause-specific mortality in rheumatoid arthritis, according to Bryant R. England, MD, of the VA Nebraska-Western Iowa Healthcare System of Nebraska, Omaha, and his coauthors.
“In this study of cause-specific mortality, we again demonstrate that underweight BMI and weight loss both drive mortality risk, but, importantly, this risk may differ across causes,” they wrote. “In cardiovascular and cancer mortality, we identified rapid and cumulative weight loss as the weight parameters most predictive of death, while in respiratory mortality underweight BMI was the weight parameter most predictive.”
Weight loss most likely reflects a systematic process, such as inflammation, that is a well-known risk factor for cardiovascular disease and mortality in people with rheumatoid arthritis, the authors suggested. Weight loss may also reflect comorbidities, chronic illness, disease phenotype, aging, smoking, and other factors, they said.
“Overall, these data illustrate the importance of considering the dynamic nature of body composition when assessing mortality risk in RA,” they said.
The authors noted that, while the study population was predominantly composed of older men, their findings were largely in agreement with those from studies with a higher proportion of women.
The researchers received grant support from the Department of Veterans’ Affairs and the National Institutes of Health. They reported having no conflicts of interest.
Being underweight or experiencing rapid weight loss are both independently associated with an increased risk of cause-specific mortality in individuals with rheumatoid arthritis, according to new research.
In a cohort of 1,600 U.S. veterans with rheumatoid arthritis who were followed for a median of 3.2 years, researchers found that being overweight (BMI 25-30 kg/m2) was associated with a 41% lower risk of cardiovascular mortality. Cumulative weight loss of greater than 10% and weight loss greater than 3 kg/m2 per year were both significantly associated with a twofold higher risk of cardiovascular mortality.
Similarly, more rapid weight loss of more than 3 kg/m2 per year was also associated with a greater than twofold increase in the risk of cancer mortality, while less rapid weight loss did not show a significant impact (Arthritis Care Res. 2017 Apr 20. doi: 10.1002/acr.23258).
Individuals who were underweight (BMI less than 20 kg/m2) had nearly a threefold greater risk of respiratory mortality, compared with individuals with a normal BMI. Researchers saw a dose-dependent association between respiratory mortality and percent of weight loss: 5%-10% weight loss was associated with an 86% higher risk of respiratory mortality, and greater than 10% weight loss showed a more than twofold greater risk.
This appears to be the first study to examine the impact of both BMI and weight loss on cause-specific mortality in rheumatoid arthritis, according to Bryant R. England, MD, of the VA Nebraska-Western Iowa Healthcare System of Nebraska, Omaha, and his coauthors.
“In this study of cause-specific mortality, we again demonstrate that underweight BMI and weight loss both drive mortality risk, but, importantly, this risk may differ across causes,” they wrote. “In cardiovascular and cancer mortality, we identified rapid and cumulative weight loss as the weight parameters most predictive of death, while in respiratory mortality underweight BMI was the weight parameter most predictive.”
Weight loss most likely reflects a systematic process, such as inflammation, that is a well-known risk factor for cardiovascular disease and mortality in people with rheumatoid arthritis, the authors suggested. Weight loss may also reflect comorbidities, chronic illness, disease phenotype, aging, smoking, and other factors, they said.
“Overall, these data illustrate the importance of considering the dynamic nature of body composition when assessing mortality risk in RA,” they said.
The authors noted that, while the study population was predominantly composed of older men, their findings were largely in agreement with those from studies with a higher proportion of women.
The researchers received grant support from the Department of Veterans’ Affairs and the National Institutes of Health. They reported having no conflicts of interest.
Being underweight or experiencing rapid weight loss are both independently associated with an increased risk of cause-specific mortality in individuals with rheumatoid arthritis, according to new research.
In a cohort of 1,600 U.S. veterans with rheumatoid arthritis who were followed for a median of 3.2 years, researchers found that being overweight (BMI 25-30 kg/m2) was associated with a 41% lower risk of cardiovascular mortality. Cumulative weight loss of greater than 10% and weight loss greater than 3 kg/m2 per year were both significantly associated with a twofold higher risk of cardiovascular mortality.
Similarly, more rapid weight loss of more than 3 kg/m2 per year was also associated with a greater than twofold increase in the risk of cancer mortality, while less rapid weight loss did not show a significant impact (Arthritis Care Res. 2017 Apr 20. doi: 10.1002/acr.23258).
Individuals who were underweight (BMI less than 20 kg/m2) had nearly a threefold greater risk of respiratory mortality, compared with individuals with a normal BMI. Researchers saw a dose-dependent association between respiratory mortality and percent of weight loss: 5%-10% weight loss was associated with an 86% higher risk of respiratory mortality, and greater than 10% weight loss showed a more than twofold greater risk.
This appears to be the first study to examine the impact of both BMI and weight loss on cause-specific mortality in rheumatoid arthritis, according to Bryant R. England, MD, of the VA Nebraska-Western Iowa Healthcare System of Nebraska, Omaha, and his coauthors.
“In this study of cause-specific mortality, we again demonstrate that underweight BMI and weight loss both drive mortality risk, but, importantly, this risk may differ across causes,” they wrote. “In cardiovascular and cancer mortality, we identified rapid and cumulative weight loss as the weight parameters most predictive of death, while in respiratory mortality underweight BMI was the weight parameter most predictive.”
Weight loss most likely reflects a systematic process, such as inflammation, that is a well-known risk factor for cardiovascular disease and mortality in people with rheumatoid arthritis, the authors suggested. Weight loss may also reflect comorbidities, chronic illness, disease phenotype, aging, smoking, and other factors, they said.
“Overall, these data illustrate the importance of considering the dynamic nature of body composition when assessing mortality risk in RA,” they said.
The authors noted that, while the study population was predominantly composed of older men, their findings were largely in agreement with those from studies with a higher proportion of women.
The researchers received grant support from the Department of Veterans’ Affairs and the National Institutes of Health. They reported having no conflicts of interest.
Key clinical point:
Major finding: Weight loss of greater than 10% is associated with a twofold increase in cardiovascular mortality, while weight loss of more than 3 kg/m2 per year was associated with a greater than twofold increase in the risk of cancer mortality.
Data source: A longitudinal cohort study of 1,600 U.S. veterans with rheumatoid arthritis.
Disclosures: The researchers received grant support from the Department of Veterans’ Affairs and the National Institutes of Health. They reported having no conflicts of interest.
Sarilumab showed sustained effect on RA progression at 3 years
BIRMINGHAM, ENGLAND – A “durable clinical response and stabilization of structural damage” was observed at 3 years of follow-up in the Long Term Evaluation of Sarilumab in Rheumatoid Arthritis Patients (SARIL-RA-EXTEND) study.
Désirée van der Heijde, MD, PhD, who reported the findings of the EXTEND study at the British Society for Rheumatology annual conference, noted that the benefit was seen regardless of the initial treatment that had been given at baseline.
The aim of the EXTEND trial was to examine the continuity of response to sarilumab seen in the MOBILITY trial, said Dr. van der Heijde, professor of rheumatology at Leiden (The Netherlands) University Medical Center.
Sarilumab is a fully human (IgG1) monoclonal antibody that binds to interleukin (IL)-6 receptors, both soluble and membrane-bound, and thus inhibits IL-6-mediated signaling through the soluble IL-6R alpha and membrane-bound IL-6R alpha receptors. It is undergoing regulatory approval in the United States, European Union, and Japan, but was recently approved in Canada for treatment of adult patients with moderate to severe rheumatoid arthritis (RA) who have had an inadequate response to one or more biologic or nonbiologic disease-modifying antirheumatic drugs (DMARDs) (Drugs. 2017;77:705-12).
In the MOBILITY trial, 1,197 patients who were being treated with methotrexate but who had an inadequate response were randomized to receive placebo (n = 398) or sarilumab given subcutaneously every 2 weeks at one of two doses: 150 mg (n = 400) or 200 mg (n = 399).
EXTEND allowed patients completing this trial who still had active disease to continue or start (if they had been given placebo) treatment with sarilumab at a dose of 200 mg given every 2 weeks, with dose reduction to 150 mg every 2 weeks if needed, in addition to methotrexate. A total of 901 patients participated in the extension study.
“In the MOBILITY trial, all three groups were very balanced, and if you then take the patients who entered the EXTEND trial, they are very similar to the patients who also were randomized into MOBILITY,” Dr. van der Heijde said.
This was a fairly typical RA population, she observed: About 80% were female, the mean age was 50 years, and the mean duration of RA was 9 years. About 20%-25% had prior treatment with a DMARD, more than 80% were rheumatoid factor or anti-CCP antibody positive. There were similar mean C-reactive protein (CRP) levels between the groups, and the 28-joint disease activity score (DAS28) with CRP was around 6, and Clinical Disease Activity Index (CDAI) score around 40.
Radiographs that were taken at baseline, at the end of year 2, and at the end of year 3 were reread by two independent readers and scored together in one session. Data had to be extrapolated for 29 patients who did not have a radiographs taken at year 3 but who had been seen during the third year of treatment.
The significant radiographic inhibition seen at the end of the MOBILITY trial in both the 150-mg and 200-mg active treatment groups was sustained in the EXTEND study.
“There is a small progression between year 2 and 3, and this progression is quite similar in all the three treatment arms,” Dr. van der Heijde reported, nothing that all patients were taking 200 mg of sarilumab at this point.
The mean change in the modified total Sharp score (mTSS) from year 2 to 3 was 0.35 in the patients who had originally been randomized to the placebo arm, 0.64 in patients originally randomized to 150 mg sarilumab every 2 weeks, and 0.44 in those originally taking 200 mg sarilumab every 2 weeks.
From baseline to year 3, the mean change in mTSS were a respective 3.3, 1.9, and 0.8.
“If you present the data in a different way, like the percentage of patients showing no progression, you see the differentiation between the patients who started on placebo versus those who were started on sarilumab 150 mg or 200 mg,” said Dr. van der Heijde.
At year 2, 67%, 59%, and 48% of patients treated with sarilumab 200 mg, sarilumab 150 mg, or placebo, respectively had no progression in mTSS (signified by a change from baseline of 0.5 points or more).
At year 3, corresponding rates were a respective 75%, 55%, and 49%.
DAS-28-CRP response at year 3 was similar across the initial treatment groups, Dr. van der Heijde observed. Reductions seen in the MOBILITY trial were clearly continued, she said. The percentage of patients achieving DAS-28-CRP of less than 2.6 was 22%, 34%, and 36% of placebo, sarilumab 150-mg, and sarilumab 200-mg treated patients at the end of the MOBILITY study. At the end of year 2, the corresponding numbers were 60%, 62%, and 62%, and by year 3, not much had changed in the percentage of patients achieving DAS-28-CRP of less than 2.6: 58% for placebo, 62% for sarilumab 150 mg, and 68% for sarilumab 200 mg.
Similar results were seen for patients achieving a CDAI of 2.8 or lower at years 2 and 3 in the extension study.
Treatment-emergent adverse events (TEAEs) occurred in 89.7% of patients over 3 years. One in five (20%) patients experienced serious adverse events, with 23% of patients discontinuing treatment because of TEAEs. There were 9 (0.8%) deaths during the trial.
TEAEs that occurred at rates of 5% or higher in any treatment group were neutropenia in 19.4%, increased alanine aminotransferase in 13.0%, and upper respiratory tract infections in 12.7%.
There were some changes in laboratory values, Dr. van der Heijde said, but “most of the changes were very small” and in line with the effects expected with IL-6 inhibition.
The study was sponsored by Sanofi Genzyme and Regeneron Pharmaceuticals. Dr. van der Heijde and coauthors disclosed receiving consulting fees, research grants, or both from multiple pharmaceutical companies, including the sponsors of the study. Dr. van der Heijde is director of Imaging Rheumatology.
BIRMINGHAM, ENGLAND – A “durable clinical response and stabilization of structural damage” was observed at 3 years of follow-up in the Long Term Evaluation of Sarilumab in Rheumatoid Arthritis Patients (SARIL-RA-EXTEND) study.
Désirée van der Heijde, MD, PhD, who reported the findings of the EXTEND study at the British Society for Rheumatology annual conference, noted that the benefit was seen regardless of the initial treatment that had been given at baseline.
The aim of the EXTEND trial was to examine the continuity of response to sarilumab seen in the MOBILITY trial, said Dr. van der Heijde, professor of rheumatology at Leiden (The Netherlands) University Medical Center.
Sarilumab is a fully human (IgG1) monoclonal antibody that binds to interleukin (IL)-6 receptors, both soluble and membrane-bound, and thus inhibits IL-6-mediated signaling through the soluble IL-6R alpha and membrane-bound IL-6R alpha receptors. It is undergoing regulatory approval in the United States, European Union, and Japan, but was recently approved in Canada for treatment of adult patients with moderate to severe rheumatoid arthritis (RA) who have had an inadequate response to one or more biologic or nonbiologic disease-modifying antirheumatic drugs (DMARDs) (Drugs. 2017;77:705-12).
In the MOBILITY trial, 1,197 patients who were being treated with methotrexate but who had an inadequate response were randomized to receive placebo (n = 398) or sarilumab given subcutaneously every 2 weeks at one of two doses: 150 mg (n = 400) or 200 mg (n = 399).
EXTEND allowed patients completing this trial who still had active disease to continue or start (if they had been given placebo) treatment with sarilumab at a dose of 200 mg given every 2 weeks, with dose reduction to 150 mg every 2 weeks if needed, in addition to methotrexate. A total of 901 patients participated in the extension study.
“In the MOBILITY trial, all three groups were very balanced, and if you then take the patients who entered the EXTEND trial, they are very similar to the patients who also were randomized into MOBILITY,” Dr. van der Heijde said.
This was a fairly typical RA population, she observed: About 80% were female, the mean age was 50 years, and the mean duration of RA was 9 years. About 20%-25% had prior treatment with a DMARD, more than 80% were rheumatoid factor or anti-CCP antibody positive. There were similar mean C-reactive protein (CRP) levels between the groups, and the 28-joint disease activity score (DAS28) with CRP was around 6, and Clinical Disease Activity Index (CDAI) score around 40.
Radiographs that were taken at baseline, at the end of year 2, and at the end of year 3 were reread by two independent readers and scored together in one session. Data had to be extrapolated for 29 patients who did not have a radiographs taken at year 3 but who had been seen during the third year of treatment.
The significant radiographic inhibition seen at the end of the MOBILITY trial in both the 150-mg and 200-mg active treatment groups was sustained in the EXTEND study.
“There is a small progression between year 2 and 3, and this progression is quite similar in all the three treatment arms,” Dr. van der Heijde reported, nothing that all patients were taking 200 mg of sarilumab at this point.
The mean change in the modified total Sharp score (mTSS) from year 2 to 3 was 0.35 in the patients who had originally been randomized to the placebo arm, 0.64 in patients originally randomized to 150 mg sarilumab every 2 weeks, and 0.44 in those originally taking 200 mg sarilumab every 2 weeks.
From baseline to year 3, the mean change in mTSS were a respective 3.3, 1.9, and 0.8.
“If you present the data in a different way, like the percentage of patients showing no progression, you see the differentiation between the patients who started on placebo versus those who were started on sarilumab 150 mg or 200 mg,” said Dr. van der Heijde.
At year 2, 67%, 59%, and 48% of patients treated with sarilumab 200 mg, sarilumab 150 mg, or placebo, respectively had no progression in mTSS (signified by a change from baseline of 0.5 points or more).
At year 3, corresponding rates were a respective 75%, 55%, and 49%.
DAS-28-CRP response at year 3 was similar across the initial treatment groups, Dr. van der Heijde observed. Reductions seen in the MOBILITY trial were clearly continued, she said. The percentage of patients achieving DAS-28-CRP of less than 2.6 was 22%, 34%, and 36% of placebo, sarilumab 150-mg, and sarilumab 200-mg treated patients at the end of the MOBILITY study. At the end of year 2, the corresponding numbers were 60%, 62%, and 62%, and by year 3, not much had changed in the percentage of patients achieving DAS-28-CRP of less than 2.6: 58% for placebo, 62% for sarilumab 150 mg, and 68% for sarilumab 200 mg.
Similar results were seen for patients achieving a CDAI of 2.8 or lower at years 2 and 3 in the extension study.
Treatment-emergent adverse events (TEAEs) occurred in 89.7% of patients over 3 years. One in five (20%) patients experienced serious adverse events, with 23% of patients discontinuing treatment because of TEAEs. There were 9 (0.8%) deaths during the trial.
TEAEs that occurred at rates of 5% or higher in any treatment group were neutropenia in 19.4%, increased alanine aminotransferase in 13.0%, and upper respiratory tract infections in 12.7%.
There were some changes in laboratory values, Dr. van der Heijde said, but “most of the changes were very small” and in line with the effects expected with IL-6 inhibition.
The study was sponsored by Sanofi Genzyme and Regeneron Pharmaceuticals. Dr. van der Heijde and coauthors disclosed receiving consulting fees, research grants, or both from multiple pharmaceutical companies, including the sponsors of the study. Dr. van der Heijde is director of Imaging Rheumatology.
BIRMINGHAM, ENGLAND – A “durable clinical response and stabilization of structural damage” was observed at 3 years of follow-up in the Long Term Evaluation of Sarilumab in Rheumatoid Arthritis Patients (SARIL-RA-EXTEND) study.
Désirée van der Heijde, MD, PhD, who reported the findings of the EXTEND study at the British Society for Rheumatology annual conference, noted that the benefit was seen regardless of the initial treatment that had been given at baseline.
The aim of the EXTEND trial was to examine the continuity of response to sarilumab seen in the MOBILITY trial, said Dr. van der Heijde, professor of rheumatology at Leiden (The Netherlands) University Medical Center.
Sarilumab is a fully human (IgG1) monoclonal antibody that binds to interleukin (IL)-6 receptors, both soluble and membrane-bound, and thus inhibits IL-6-mediated signaling through the soluble IL-6R alpha and membrane-bound IL-6R alpha receptors. It is undergoing regulatory approval in the United States, European Union, and Japan, but was recently approved in Canada for treatment of adult patients with moderate to severe rheumatoid arthritis (RA) who have had an inadequate response to one or more biologic or nonbiologic disease-modifying antirheumatic drugs (DMARDs) (Drugs. 2017;77:705-12).
In the MOBILITY trial, 1,197 patients who were being treated with methotrexate but who had an inadequate response were randomized to receive placebo (n = 398) or sarilumab given subcutaneously every 2 weeks at one of two doses: 150 mg (n = 400) or 200 mg (n = 399).
EXTEND allowed patients completing this trial who still had active disease to continue or start (if they had been given placebo) treatment with sarilumab at a dose of 200 mg given every 2 weeks, with dose reduction to 150 mg every 2 weeks if needed, in addition to methotrexate. A total of 901 patients participated in the extension study.
“In the MOBILITY trial, all three groups were very balanced, and if you then take the patients who entered the EXTEND trial, they are very similar to the patients who also were randomized into MOBILITY,” Dr. van der Heijde said.
This was a fairly typical RA population, she observed: About 80% were female, the mean age was 50 years, and the mean duration of RA was 9 years. About 20%-25% had prior treatment with a DMARD, more than 80% were rheumatoid factor or anti-CCP antibody positive. There were similar mean C-reactive protein (CRP) levels between the groups, and the 28-joint disease activity score (DAS28) with CRP was around 6, and Clinical Disease Activity Index (CDAI) score around 40.
Radiographs that were taken at baseline, at the end of year 2, and at the end of year 3 were reread by two independent readers and scored together in one session. Data had to be extrapolated for 29 patients who did not have a radiographs taken at year 3 but who had been seen during the third year of treatment.
The significant radiographic inhibition seen at the end of the MOBILITY trial in both the 150-mg and 200-mg active treatment groups was sustained in the EXTEND study.
“There is a small progression between year 2 and 3, and this progression is quite similar in all the three treatment arms,” Dr. van der Heijde reported, nothing that all patients were taking 200 mg of sarilumab at this point.
The mean change in the modified total Sharp score (mTSS) from year 2 to 3 was 0.35 in the patients who had originally been randomized to the placebo arm, 0.64 in patients originally randomized to 150 mg sarilumab every 2 weeks, and 0.44 in those originally taking 200 mg sarilumab every 2 weeks.
From baseline to year 3, the mean change in mTSS were a respective 3.3, 1.9, and 0.8.
“If you present the data in a different way, like the percentage of patients showing no progression, you see the differentiation between the patients who started on placebo versus those who were started on sarilumab 150 mg or 200 mg,” said Dr. van der Heijde.
At year 2, 67%, 59%, and 48% of patients treated with sarilumab 200 mg, sarilumab 150 mg, or placebo, respectively had no progression in mTSS (signified by a change from baseline of 0.5 points or more).
At year 3, corresponding rates were a respective 75%, 55%, and 49%.
DAS-28-CRP response at year 3 was similar across the initial treatment groups, Dr. van der Heijde observed. Reductions seen in the MOBILITY trial were clearly continued, she said. The percentage of patients achieving DAS-28-CRP of less than 2.6 was 22%, 34%, and 36% of placebo, sarilumab 150-mg, and sarilumab 200-mg treated patients at the end of the MOBILITY study. At the end of year 2, the corresponding numbers were 60%, 62%, and 62%, and by year 3, not much had changed in the percentage of patients achieving DAS-28-CRP of less than 2.6: 58% for placebo, 62% for sarilumab 150 mg, and 68% for sarilumab 200 mg.
Similar results were seen for patients achieving a CDAI of 2.8 or lower at years 2 and 3 in the extension study.
Treatment-emergent adverse events (TEAEs) occurred in 89.7% of patients over 3 years. One in five (20%) patients experienced serious adverse events, with 23% of patients discontinuing treatment because of TEAEs. There were 9 (0.8%) deaths during the trial.
TEAEs that occurred at rates of 5% or higher in any treatment group were neutropenia in 19.4%, increased alanine aminotransferase in 13.0%, and upper respiratory tract infections in 12.7%.
There were some changes in laboratory values, Dr. van der Heijde said, but “most of the changes were very small” and in line with the effects expected with IL-6 inhibition.
The study was sponsored by Sanofi Genzyme and Regeneron Pharmaceuticals. Dr. van der Heijde and coauthors disclosed receiving consulting fees, research grants, or both from multiple pharmaceutical companies, including the sponsors of the study. Dr. van der Heijde is director of Imaging Rheumatology.
AT RHEUMATOLOGY 2017
Key clinical point:
Major finding: The mean change in the modified total Sharp score (mTSS) from year 2 to 3 was 0.35 in the patients who had originally been randomized to the placebo arm, 0.64 in patients originally randomized to 150 mg sarilumab every 2 weeks, and 0.44 in those originally taking 200 mg sarilumab every 2 weeks.
Data source: SARIL-RA-EXTEND: a multicenter, uncontrolled extension study involving 1,197 patients who had participated in the phase III SARIL-RA-MOBILITY trial.
Disclosures: The study was sponsored by Sanofi Genzyme and Regeneron Pharmaceuticals. Dr. van der Heijde and her coauthors disclosed receiving consulting fees, research grants, or both from multiple pharmaceutical companies, including the sponsors of the study. Dr. van der Heijde is director of Imaging Rheumatology.
Renflexis approved as second infliximab biosimilar
Infliximab-abda is the second infliximab biosimilar approved by the Food and Drug Administration, the agency announced April 21.
Infliximab-abda, to be marketed as Renflexis, is approved for all indications as the reference product, including Crohn’s diseases in adults and children, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis, according to the product label.
Like Remicade, Renflexis will come with a boxed warning and a Medication Guide that describes important information about its uses and risks, which include serious infections, lymphoma and other malignancies, liver injury, blood problems, lupuslike syndrome, psoriasis, and in rare cases, nervous system disorders.
Renflexis will be marketed by Merck Sharp & Dohme and is manufactured by Samsung Bioepis.
dfulton@frontlinemedcom.com
On Twitter @denisefulton
Infliximab-abda is the second infliximab biosimilar approved by the Food and Drug Administration, the agency announced April 21.
Infliximab-abda, to be marketed as Renflexis, is approved for all indications as the reference product, including Crohn’s diseases in adults and children, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis, according to the product label.
Like Remicade, Renflexis will come with a boxed warning and a Medication Guide that describes important information about its uses and risks, which include serious infections, lymphoma and other malignancies, liver injury, blood problems, lupuslike syndrome, psoriasis, and in rare cases, nervous system disorders.
Renflexis will be marketed by Merck Sharp & Dohme and is manufactured by Samsung Bioepis.
dfulton@frontlinemedcom.com
On Twitter @denisefulton
Infliximab-abda is the second infliximab biosimilar approved by the Food and Drug Administration, the agency announced April 21.
Infliximab-abda, to be marketed as Renflexis, is approved for all indications as the reference product, including Crohn’s diseases in adults and children, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis, according to the product label.
Like Remicade, Renflexis will come with a boxed warning and a Medication Guide that describes important information about its uses and risks, which include serious infections, lymphoma and other malignancies, liver injury, blood problems, lupuslike syndrome, psoriasis, and in rare cases, nervous system disorders.
Renflexis will be marketed by Merck Sharp & Dohme and is manufactured by Samsung Bioepis.
dfulton@frontlinemedcom.com
On Twitter @denisefulton
RA treatment delays raise risk of long-term disability
Initiating disease-modifying antirheumatic drugs within 6 months of a diagnosis of rheumatoid arthritis is associated with significantly lower disability scores over the long term, new research suggests.
Better diagnosis and access to early treatment has also likely played a role in a global decline in mortality from rheumatoid arthritis over a recent 25-year period, according to an analysis of World Health Organization and United Nations data, but the decline has occurred unequally across countries.
Impact of early treatment on disability
In the first of two separate studies published online April 20 in Arthritis & Rheumatology, U.K. researchers followed 602 patients from the Norfolk Arthritis Register for 20 years, starting in 1990-1994, and collected clinical data at baseline and years 1-3, 5, 7, 10, 15, and 20.
However, patients who began treatment within 6 months of diagnosis had disability scores similar to those of patients who were never initiated on treatment (Arthritis Rheumatol. 2017 April 20. doi: 10.1002/art.40090).
“This supports the importance of the “window of opportunity” construct for treatment, showing that early treatment leads to improved outcomes even into the second decade following symptom onset,” wrote first author James M. Gwinnutt, a PhD candidate at the University of Manchester (England), and his coauthors. “Increased functional disability over time could be due to worse joint damage, and it has been shown that those who receive later treatment have higher radiological scores at follow-up than those treated early.”
There were 88 deaths in the early treatment group (55%) during the follow-up period, 99 deaths (39.8%) in the late treatment group, and 78 deaths (40.4%) in the never-treated group.
When the researchers adjusted for disease severity in a comparison of mortality across the groups, they found a trend toward a reduced risk of mortality in patients treated early, compared with those who began treatment later, although this did not reach statistical significance.
However, patients in both the early treatment and late treatment groups showed significantly elevated standardized mortality rates, compared with the general population of Norfolk, while the never-treated group showed slightly – but not significantly – elevated mortality.
Overall, around one-quarter of patients (26.6%) began treatment within 6 months of the onset of symptoms, 19.9% were started on treatment within 6-12 months, 17.4% started within 1-2 years, 19% did not start treatment until more than 2 years after symptom onset, and 43.7% of the cohort never received treatment but still attended follow-up.
Patients who began earlier treatment had worse clinical characteristics than did those who began treatment later, except for tender joint counts and autoantibody status.
Researchers saw an overall decline in median swollen joint count and tender joint count in the first year after baseline, and this remained low throughout the course of the study.
Median Health Assessment Questionnaire scores also fell after baseline but then increased steadily from year 2 to year 20, exceeding baseline levels by year 7.
“This paper has two important messages, firstly about the long-term outcome of patients with RA in the modern era treated according to best practice at the time of presentation; secondly about the benefit of early treatment which is still apparent into the second decade after symptom onset with respect to functional disability,” the authors wrote.
An uneven global decline in mortality from RA
Meanwhile, a second study showed that mortality from rheumatoid arthritis declined globally across 31 countries from 1987 to 2011, according to data from the World Health Organization mortality database and the United Nations.
The absolute number of deaths where rheumatoid arthritis was registered as the underlying cause of death declined from 0.12% of all-cause deaths in 1987 to 0.09% of all-cause deaths in 2011 (Arthritis Rheumatol. 2017 April 20. doi: 10.1002/art.40091).
The mean age-standardized mortality rate declined by 48.2%, from 7.1 per million person-years in 1987-1989 to 3.7 in 2009-2011.
However, there was considerable variation between countries; the greatest reduction was seen in Finland, which had an absolute reduction of 20.6 fewer deaths per million person-years, while Croatia had an increase of 3.7 deaths per million person-years.
Younger people with rheumatoid arthritis showed the greatest reductions in mortality, while those in older age groups had smaller reductions in mortality.
“It has been suggested that changes in the management of RA toward early and aggressive treatment with disease-modifying antirheumatic drugs and subsequent biologic therapies has led to better health status and lower mortality for most people with RA over time,” wrote first author Aliasghar A. Kiadaliri, PhD, of Lund (Sweden) University, and his coauthors.
“These findings alongside aging of the population and fall in mortality may lead to an increase in the number of people with RA. Given that it appears that people with RA are now living longer, increase in burden of RA on health care systems is expected and policy makers should be made aware about to appropriately plan for this anticipated increase.”
The first study was supported by Arthritis Research UK. The second study was supported by the Swedish Research Council, Crafoord Foundation, Greta and Johan Kocks Foundation, the Faculty of Medicine Lund University, governmental funding of clinical research within Sweden’s National Health Service. No conflicts of interest were declared for either paper.
Initiating disease-modifying antirheumatic drugs within 6 months of a diagnosis of rheumatoid arthritis is associated with significantly lower disability scores over the long term, new research suggests.
Better diagnosis and access to early treatment has also likely played a role in a global decline in mortality from rheumatoid arthritis over a recent 25-year period, according to an analysis of World Health Organization and United Nations data, but the decline has occurred unequally across countries.
Impact of early treatment on disability
In the first of two separate studies published online April 20 in Arthritis & Rheumatology, U.K. researchers followed 602 patients from the Norfolk Arthritis Register for 20 years, starting in 1990-1994, and collected clinical data at baseline and years 1-3, 5, 7, 10, 15, and 20.
However, patients who began treatment within 6 months of diagnosis had disability scores similar to those of patients who were never initiated on treatment (Arthritis Rheumatol. 2017 April 20. doi: 10.1002/art.40090).
“This supports the importance of the “window of opportunity” construct for treatment, showing that early treatment leads to improved outcomes even into the second decade following symptom onset,” wrote first author James M. Gwinnutt, a PhD candidate at the University of Manchester (England), and his coauthors. “Increased functional disability over time could be due to worse joint damage, and it has been shown that those who receive later treatment have higher radiological scores at follow-up than those treated early.”
There were 88 deaths in the early treatment group (55%) during the follow-up period, 99 deaths (39.8%) in the late treatment group, and 78 deaths (40.4%) in the never-treated group.
When the researchers adjusted for disease severity in a comparison of mortality across the groups, they found a trend toward a reduced risk of mortality in patients treated early, compared with those who began treatment later, although this did not reach statistical significance.
However, patients in both the early treatment and late treatment groups showed significantly elevated standardized mortality rates, compared with the general population of Norfolk, while the never-treated group showed slightly – but not significantly – elevated mortality.
Overall, around one-quarter of patients (26.6%) began treatment within 6 months of the onset of symptoms, 19.9% were started on treatment within 6-12 months, 17.4% started within 1-2 years, 19% did not start treatment until more than 2 years after symptom onset, and 43.7% of the cohort never received treatment but still attended follow-up.
Patients who began earlier treatment had worse clinical characteristics than did those who began treatment later, except for tender joint counts and autoantibody status.
Researchers saw an overall decline in median swollen joint count and tender joint count in the first year after baseline, and this remained low throughout the course of the study.
Median Health Assessment Questionnaire scores also fell after baseline but then increased steadily from year 2 to year 20, exceeding baseline levels by year 7.
“This paper has two important messages, firstly about the long-term outcome of patients with RA in the modern era treated according to best practice at the time of presentation; secondly about the benefit of early treatment which is still apparent into the second decade after symptom onset with respect to functional disability,” the authors wrote.
An uneven global decline in mortality from RA
Meanwhile, a second study showed that mortality from rheumatoid arthritis declined globally across 31 countries from 1987 to 2011, according to data from the World Health Organization mortality database and the United Nations.
The absolute number of deaths where rheumatoid arthritis was registered as the underlying cause of death declined from 0.12% of all-cause deaths in 1987 to 0.09% of all-cause deaths in 2011 (Arthritis Rheumatol. 2017 April 20. doi: 10.1002/art.40091).
The mean age-standardized mortality rate declined by 48.2%, from 7.1 per million person-years in 1987-1989 to 3.7 in 2009-2011.
However, there was considerable variation between countries; the greatest reduction was seen in Finland, which had an absolute reduction of 20.6 fewer deaths per million person-years, while Croatia had an increase of 3.7 deaths per million person-years.
Younger people with rheumatoid arthritis showed the greatest reductions in mortality, while those in older age groups had smaller reductions in mortality.
“It has been suggested that changes in the management of RA toward early and aggressive treatment with disease-modifying antirheumatic drugs and subsequent biologic therapies has led to better health status and lower mortality for most people with RA over time,” wrote first author Aliasghar A. Kiadaliri, PhD, of Lund (Sweden) University, and his coauthors.
“These findings alongside aging of the population and fall in mortality may lead to an increase in the number of people with RA. Given that it appears that people with RA are now living longer, increase in burden of RA on health care systems is expected and policy makers should be made aware about to appropriately plan for this anticipated increase.”
The first study was supported by Arthritis Research UK. The second study was supported by the Swedish Research Council, Crafoord Foundation, Greta and Johan Kocks Foundation, the Faculty of Medicine Lund University, governmental funding of clinical research within Sweden’s National Health Service. No conflicts of interest were declared for either paper.
Initiating disease-modifying antirheumatic drugs within 6 months of a diagnosis of rheumatoid arthritis is associated with significantly lower disability scores over the long term, new research suggests.
Better diagnosis and access to early treatment has also likely played a role in a global decline in mortality from rheumatoid arthritis over a recent 25-year period, according to an analysis of World Health Organization and United Nations data, but the decline has occurred unequally across countries.
Impact of early treatment on disability
In the first of two separate studies published online April 20 in Arthritis & Rheumatology, U.K. researchers followed 602 patients from the Norfolk Arthritis Register for 20 years, starting in 1990-1994, and collected clinical data at baseline and years 1-3, 5, 7, 10, 15, and 20.
However, patients who began treatment within 6 months of diagnosis had disability scores similar to those of patients who were never initiated on treatment (Arthritis Rheumatol. 2017 April 20. doi: 10.1002/art.40090).
“This supports the importance of the “window of opportunity” construct for treatment, showing that early treatment leads to improved outcomes even into the second decade following symptom onset,” wrote first author James M. Gwinnutt, a PhD candidate at the University of Manchester (England), and his coauthors. “Increased functional disability over time could be due to worse joint damage, and it has been shown that those who receive later treatment have higher radiological scores at follow-up than those treated early.”
There were 88 deaths in the early treatment group (55%) during the follow-up period, 99 deaths (39.8%) in the late treatment group, and 78 deaths (40.4%) in the never-treated group.
When the researchers adjusted for disease severity in a comparison of mortality across the groups, they found a trend toward a reduced risk of mortality in patients treated early, compared with those who began treatment later, although this did not reach statistical significance.
However, patients in both the early treatment and late treatment groups showed significantly elevated standardized mortality rates, compared with the general population of Norfolk, while the never-treated group showed slightly – but not significantly – elevated mortality.
Overall, around one-quarter of patients (26.6%) began treatment within 6 months of the onset of symptoms, 19.9% were started on treatment within 6-12 months, 17.4% started within 1-2 years, 19% did not start treatment until more than 2 years after symptom onset, and 43.7% of the cohort never received treatment but still attended follow-up.
Patients who began earlier treatment had worse clinical characteristics than did those who began treatment later, except for tender joint counts and autoantibody status.
Researchers saw an overall decline in median swollen joint count and tender joint count in the first year after baseline, and this remained low throughout the course of the study.
Median Health Assessment Questionnaire scores also fell after baseline but then increased steadily from year 2 to year 20, exceeding baseline levels by year 7.
“This paper has two important messages, firstly about the long-term outcome of patients with RA in the modern era treated according to best practice at the time of presentation; secondly about the benefit of early treatment which is still apparent into the second decade after symptom onset with respect to functional disability,” the authors wrote.
An uneven global decline in mortality from RA
Meanwhile, a second study showed that mortality from rheumatoid arthritis declined globally across 31 countries from 1987 to 2011, according to data from the World Health Organization mortality database and the United Nations.
The absolute number of deaths where rheumatoid arthritis was registered as the underlying cause of death declined from 0.12% of all-cause deaths in 1987 to 0.09% of all-cause deaths in 2011 (Arthritis Rheumatol. 2017 April 20. doi: 10.1002/art.40091).
The mean age-standardized mortality rate declined by 48.2%, from 7.1 per million person-years in 1987-1989 to 3.7 in 2009-2011.
However, there was considerable variation between countries; the greatest reduction was seen in Finland, which had an absolute reduction of 20.6 fewer deaths per million person-years, while Croatia had an increase of 3.7 deaths per million person-years.
Younger people with rheumatoid arthritis showed the greatest reductions in mortality, while those in older age groups had smaller reductions in mortality.
“It has been suggested that changes in the management of RA toward early and aggressive treatment with disease-modifying antirheumatic drugs and subsequent biologic therapies has led to better health status and lower mortality for most people with RA over time,” wrote first author Aliasghar A. Kiadaliri, PhD, of Lund (Sweden) University, and his coauthors.
“These findings alongside aging of the population and fall in mortality may lead to an increase in the number of people with RA. Given that it appears that people with RA are now living longer, increase in burden of RA on health care systems is expected and policy makers should be made aware about to appropriately plan for this anticipated increase.”
The first study was supported by Arthritis Research UK. The second study was supported by the Swedish Research Council, Crafoord Foundation, Greta and Johan Kocks Foundation, the Faculty of Medicine Lund University, governmental funding of clinical research within Sweden’s National Health Service. No conflicts of interest were declared for either paper.
FROM ARTHRITIS & RHEUMATOLOGY
Key clinical point:
Major finding: Patients who began treatment with disease-modifying antirheumatic drugs or steroids within 6 months of the onset of symptoms have significantly reduced disability scores up to 20 years later. Also, across 31 countries, the mean age-standardized mortality rate due to RA declined by 48.2%, from 7.1 per million person-years in 1987-1989 to 3.7 in 2009-2011.
Data source: Inception cohort study of 602 patients with rheumatoid arthritis, and a study of World Health Organization and United Nations data from 31 countries.
Disclosures: The first study was supported by Arthritis Research UK. The second study was supported by the Swedish Research Council, Crafoord Foundation, Greta and Johan Kocks Foundation, the Faculty of Medicine Lund University, governmental funding of clinical research within Sweden’s National Health Service. No conflicts of interest were declared for either paper.
Short course of prednisolone may help distinguish between RA and hand OA
A short course of prednisolone may help rheumatologists differentiate between patients with rheumatoid arthritis and osteoarthritis, a proof of concept study shows.
However, the investigators caution that a positive response to the 3-day steroid course does not confirm a diagnosis of rheumatoid arthritis (RA).
For many years, rheumatologists have been using short courses of prednisolone in unclear clinical situations to differentiate between inflammatory and non-inflammatory arthritis, according to the investigators led by Uta Kiltz, MD, from Rheumazentrum Ruhrgebiet, Herne, Germany.
The pilot part of the TryCort study involved 15 patients with confirmed osteoarthritis and 15 with rheumatoid arthritis who were given 1 g of paracetamol (acetaminophen) a day for 5 days, and on days 3-5, they were given a 20-mg dose of prednisolone (Arthritis Res Ther. 2017;19:73. doi: 10.1186/s13075-017-1279-z).
Results showed that the patients with RA had greater improvements in their pain scores (0-10 on a numerical rating scale), compared with OA patients. The mean percentage improvement in pain scores at day 5 was 52.3% in the RA group and 22.0% in the OA group.
The research team considered that a 40% improvement in pain scores was the best choice between sensitivity and specificity regarding a diagnosis of RA.
At this 40% improvement cut-off, the “pred-test” was positive in 11 patients with RA and in four patients with OA (P = .012), with a sensitivity and specificity for a diagnosis of RA of 73.3% for both measures.
In order to validate the test, the researchers enrolled 95 patients with pain in their fingers and hands but without a clear diagnosis. These patients completed the 5-day intervention, and then at week 12 a rheumatologist diagnosed 47 as having RA and 48 were thought to not have RA.
The patients with diagnosed RA had a higher reduction in pain scores during the treatment with prednisolone, compared with patients without RA.
The median percentage of improvement at day 5 was higher in patients with RA than in those without RA (50% [interquartile range, 30%-60%] vs. 20% [IQR, 10%-30%]; P = .001). Overall, 40 of the 95 patients had an improvement of more than 40% in pain levels on day 5, fulfilling the criteria of a positive pred-test.
However, the authors noted that 31 patients with RA had a positive pred-test (77.5%), compared with nine (22.5%) patients without RA (P greater than .001).
The sensitivity of the pred-test for a diagnosis of RA was 0.6 (95% confidence interval, 0.5-0.8) and the specificity was 0.8 (95% CI, 0.7-0.9). The positive and negative predictive values were 0.77 and 0.70, respectively.
The authors concluded that the pred-test “performed well” but not “perfectly well.”
“We are aware that the pred-test without confirmation of other surrogate markers is not helpful in clinical decision-making processes,” they said. “We, therefore, recommend use of the test in light of other confirming factors, such as history, physical examination, imaging, and laboratory results.”
The test could be used to triage patients from primary care to rheumatologist care, they suggested.
The study was financially supported by Rheumazentrum Ruhrgebiet. The authors declared no conflicts of interest.
A short course of prednisolone may help rheumatologists differentiate between patients with rheumatoid arthritis and osteoarthritis, a proof of concept study shows.
However, the investigators caution that a positive response to the 3-day steroid course does not confirm a diagnosis of rheumatoid arthritis (RA).
For many years, rheumatologists have been using short courses of prednisolone in unclear clinical situations to differentiate between inflammatory and non-inflammatory arthritis, according to the investigators led by Uta Kiltz, MD, from Rheumazentrum Ruhrgebiet, Herne, Germany.
The pilot part of the TryCort study involved 15 patients with confirmed osteoarthritis and 15 with rheumatoid arthritis who were given 1 g of paracetamol (acetaminophen) a day for 5 days, and on days 3-5, they were given a 20-mg dose of prednisolone (Arthritis Res Ther. 2017;19:73. doi: 10.1186/s13075-017-1279-z).
Results showed that the patients with RA had greater improvements in their pain scores (0-10 on a numerical rating scale), compared with OA patients. The mean percentage improvement in pain scores at day 5 was 52.3% in the RA group and 22.0% in the OA group.
The research team considered that a 40% improvement in pain scores was the best choice between sensitivity and specificity regarding a diagnosis of RA.
At this 40% improvement cut-off, the “pred-test” was positive in 11 patients with RA and in four patients with OA (P = .012), with a sensitivity and specificity for a diagnosis of RA of 73.3% for both measures.
In order to validate the test, the researchers enrolled 95 patients with pain in their fingers and hands but without a clear diagnosis. These patients completed the 5-day intervention, and then at week 12 a rheumatologist diagnosed 47 as having RA and 48 were thought to not have RA.
The patients with diagnosed RA had a higher reduction in pain scores during the treatment with prednisolone, compared with patients without RA.
The median percentage of improvement at day 5 was higher in patients with RA than in those without RA (50% [interquartile range, 30%-60%] vs. 20% [IQR, 10%-30%]; P = .001). Overall, 40 of the 95 patients had an improvement of more than 40% in pain levels on day 5, fulfilling the criteria of a positive pred-test.
However, the authors noted that 31 patients with RA had a positive pred-test (77.5%), compared with nine (22.5%) patients without RA (P greater than .001).
The sensitivity of the pred-test for a diagnosis of RA was 0.6 (95% confidence interval, 0.5-0.8) and the specificity was 0.8 (95% CI, 0.7-0.9). The positive and negative predictive values were 0.77 and 0.70, respectively.
The authors concluded that the pred-test “performed well” but not “perfectly well.”
“We are aware that the pred-test without confirmation of other surrogate markers is not helpful in clinical decision-making processes,” they said. “We, therefore, recommend use of the test in light of other confirming factors, such as history, physical examination, imaging, and laboratory results.”
The test could be used to triage patients from primary care to rheumatologist care, they suggested.
The study was financially supported by Rheumazentrum Ruhrgebiet. The authors declared no conflicts of interest.
A short course of prednisolone may help rheumatologists differentiate between patients with rheumatoid arthritis and osteoarthritis, a proof of concept study shows.
However, the investigators caution that a positive response to the 3-day steroid course does not confirm a diagnosis of rheumatoid arthritis (RA).
For many years, rheumatologists have been using short courses of prednisolone in unclear clinical situations to differentiate between inflammatory and non-inflammatory arthritis, according to the investigators led by Uta Kiltz, MD, from Rheumazentrum Ruhrgebiet, Herne, Germany.
The pilot part of the TryCort study involved 15 patients with confirmed osteoarthritis and 15 with rheumatoid arthritis who were given 1 g of paracetamol (acetaminophen) a day for 5 days, and on days 3-5, they were given a 20-mg dose of prednisolone (Arthritis Res Ther. 2017;19:73. doi: 10.1186/s13075-017-1279-z).
Results showed that the patients with RA had greater improvements in their pain scores (0-10 on a numerical rating scale), compared with OA patients. The mean percentage improvement in pain scores at day 5 was 52.3% in the RA group and 22.0% in the OA group.
The research team considered that a 40% improvement in pain scores was the best choice between sensitivity and specificity regarding a diagnosis of RA.
At this 40% improvement cut-off, the “pred-test” was positive in 11 patients with RA and in four patients with OA (P = .012), with a sensitivity and specificity for a diagnosis of RA of 73.3% for both measures.
In order to validate the test, the researchers enrolled 95 patients with pain in their fingers and hands but without a clear diagnosis. These patients completed the 5-day intervention, and then at week 12 a rheumatologist diagnosed 47 as having RA and 48 were thought to not have RA.
The patients with diagnosed RA had a higher reduction in pain scores during the treatment with prednisolone, compared with patients without RA.
The median percentage of improvement at day 5 was higher in patients with RA than in those without RA (50% [interquartile range, 30%-60%] vs. 20% [IQR, 10%-30%]; P = .001). Overall, 40 of the 95 patients had an improvement of more than 40% in pain levels on day 5, fulfilling the criteria of a positive pred-test.
However, the authors noted that 31 patients with RA had a positive pred-test (77.5%), compared with nine (22.5%) patients without RA (P greater than .001).
The sensitivity of the pred-test for a diagnosis of RA was 0.6 (95% confidence interval, 0.5-0.8) and the specificity was 0.8 (95% CI, 0.7-0.9). The positive and negative predictive values were 0.77 and 0.70, respectively.
The authors concluded that the pred-test “performed well” but not “perfectly well.”
“We are aware that the pred-test without confirmation of other surrogate markers is not helpful in clinical decision-making processes,” they said. “We, therefore, recommend use of the test in light of other confirming factors, such as history, physical examination, imaging, and laboratory results.”
The test could be used to triage patients from primary care to rheumatologist care, they suggested.
The study was financially supported by Rheumazentrum Ruhrgebiet. The authors declared no conflicts of interest.
FROM ARTHRITIS RESEARCH & THERAPY
Key clinical point:
Major finding: The sensitivity of the pred-test for a diagnosis of RA was 0.6 (95% CI, 0.5-0.8) and the specificity was 0.8 (95% CI, 0.7-0.9).
Data source: A pilot study of 20 mg of prednisolone for 3 days in 30 patients with established RA or OA followed by a validation study of the test in 95 patients with pain in their fingers and hands but without a clear diagnosis.
Disclosures: The study was financially supported by Rheumazentrum Ruhrgebiet. The authors declared no conflicts of interest.
Triple therapy found as ‘durable’ as biologic after methotrexate failure
People with active rheumatoid arthritis who have a suboptimal response to methotrexate and then switch to triple therapy with methotrexate, sulfasalazine, and hydroxychloroquine do just as well and stay on treatment just as long as do those who switch to methotrexate and etanercept, a follow-up study to the RACAT trial shows.
Although evidence shows that patients do well on combination disease-modifying antirheumatic drugs (DMARDs) following methotrexate failure, many rheumatologists still prefer to add a tumor necrosis factor inhibitor such as etanercept, wrote first author Shana M. Peper, MD, of the University of Nebraska, Omaha, and her colleagues (Arthritis Care Res. 2017 Apr 7. doi: 10.1002/acr.23255).
The observational, follow-up study involved 289 patients with active rheumatoid arthritis with a suboptimal response to methotrexate who had participated in the 48-week, multicenter, double-blind, Rheumatoid Arthritis Comparison of Active Therapies (RACAT) trial and then consented to an additional 72 weeks of open-label extended follow-up during which patients and their physicians were free to change or continue treatment. At the end of the double-blind portion, 145 were receiving triple therapy with the conventional DMARDs and 144 were receiving combination therapy with methotrexate and etanercept.
In the RACAT trial, the primary outcome was the 48-week change in 28-joint Disease Activity Score (DAS28). At 24 weeks, patients in both groups who had an inadequate response to their assigned therapy (defined by a change in DAS28 of less than 1.2) were switched to the other treatment arm in a blinded fashion.
After 1 year, 78% of patients on triple therapy remained on it, compared with 63% of patients who began the extended follow-up on the methotrexate-etanercept combination and remained on it.
More patients switched from methotrexate-etanercept to triple therapy than the other way around (P = .005), but when the researchers removed patients who switched at the start of the extended follow-up from the analysis, continuation rates were nearly identical. The results also did not change when the researchers performed analyses using only the patients who did not switch therapy at week 24 during the blinded trial and again with patients assigned to their original randomized groups.
Average DAS28 scores were similar for each group (3.8 ± 1.4 for triple therapy vs. 3.5 ± 1.3 for methotrexate-etanercept) and remained similar at follow-up. There were also no differences between swollen or tender joint counts, patient global health assessments, or erythrocyte sedimentation rates between the groups.
“Triple therapy remained at least as durable and effective as its biologic counterpart,” the authors concluded.
“Our findings suggest that the majority of patients with active disease despite methotrexate respond to triple therapy and will continue to do so with excellent tolerability,” they wrote.
The findings also supported the approach of reserving more costly biologics for patients who continue to have disease progression despite combination conventional DMARD therapy, they added.
The authors reported no relevant funding for the follow-up analysis. One author reported having consulted for Pfizer and received research support from Bristol-Myers Squibb and AstraZeneca. Another author reported having consulted for Medac, Antares, Lilly, Coherus, and GlaxoSmithKline.
People with active rheumatoid arthritis who have a suboptimal response to methotrexate and then switch to triple therapy with methotrexate, sulfasalazine, and hydroxychloroquine do just as well and stay on treatment just as long as do those who switch to methotrexate and etanercept, a follow-up study to the RACAT trial shows.
Although evidence shows that patients do well on combination disease-modifying antirheumatic drugs (DMARDs) following methotrexate failure, many rheumatologists still prefer to add a tumor necrosis factor inhibitor such as etanercept, wrote first author Shana M. Peper, MD, of the University of Nebraska, Omaha, and her colleagues (Arthritis Care Res. 2017 Apr 7. doi: 10.1002/acr.23255).
The observational, follow-up study involved 289 patients with active rheumatoid arthritis with a suboptimal response to methotrexate who had participated in the 48-week, multicenter, double-blind, Rheumatoid Arthritis Comparison of Active Therapies (RACAT) trial and then consented to an additional 72 weeks of open-label extended follow-up during which patients and their physicians were free to change or continue treatment. At the end of the double-blind portion, 145 were receiving triple therapy with the conventional DMARDs and 144 were receiving combination therapy with methotrexate and etanercept.
In the RACAT trial, the primary outcome was the 48-week change in 28-joint Disease Activity Score (DAS28). At 24 weeks, patients in both groups who had an inadequate response to their assigned therapy (defined by a change in DAS28 of less than 1.2) were switched to the other treatment arm in a blinded fashion.
After 1 year, 78% of patients on triple therapy remained on it, compared with 63% of patients who began the extended follow-up on the methotrexate-etanercept combination and remained on it.
More patients switched from methotrexate-etanercept to triple therapy than the other way around (P = .005), but when the researchers removed patients who switched at the start of the extended follow-up from the analysis, continuation rates were nearly identical. The results also did not change when the researchers performed analyses using only the patients who did not switch therapy at week 24 during the blinded trial and again with patients assigned to their original randomized groups.
Average DAS28 scores were similar for each group (3.8 ± 1.4 for triple therapy vs. 3.5 ± 1.3 for methotrexate-etanercept) and remained similar at follow-up. There were also no differences between swollen or tender joint counts, patient global health assessments, or erythrocyte sedimentation rates between the groups.
“Triple therapy remained at least as durable and effective as its biologic counterpart,” the authors concluded.
“Our findings suggest that the majority of patients with active disease despite methotrexate respond to triple therapy and will continue to do so with excellent tolerability,” they wrote.
The findings also supported the approach of reserving more costly biologics for patients who continue to have disease progression despite combination conventional DMARD therapy, they added.
The authors reported no relevant funding for the follow-up analysis. One author reported having consulted for Pfizer and received research support from Bristol-Myers Squibb and AstraZeneca. Another author reported having consulted for Medac, Antares, Lilly, Coherus, and GlaxoSmithKline.
People with active rheumatoid arthritis who have a suboptimal response to methotrexate and then switch to triple therapy with methotrexate, sulfasalazine, and hydroxychloroquine do just as well and stay on treatment just as long as do those who switch to methotrexate and etanercept, a follow-up study to the RACAT trial shows.
Although evidence shows that patients do well on combination disease-modifying antirheumatic drugs (DMARDs) following methotrexate failure, many rheumatologists still prefer to add a tumor necrosis factor inhibitor such as etanercept, wrote first author Shana M. Peper, MD, of the University of Nebraska, Omaha, and her colleagues (Arthritis Care Res. 2017 Apr 7. doi: 10.1002/acr.23255).
The observational, follow-up study involved 289 patients with active rheumatoid arthritis with a suboptimal response to methotrexate who had participated in the 48-week, multicenter, double-blind, Rheumatoid Arthritis Comparison of Active Therapies (RACAT) trial and then consented to an additional 72 weeks of open-label extended follow-up during which patients and their physicians were free to change or continue treatment. At the end of the double-blind portion, 145 were receiving triple therapy with the conventional DMARDs and 144 were receiving combination therapy with methotrexate and etanercept.
In the RACAT trial, the primary outcome was the 48-week change in 28-joint Disease Activity Score (DAS28). At 24 weeks, patients in both groups who had an inadequate response to their assigned therapy (defined by a change in DAS28 of less than 1.2) were switched to the other treatment arm in a blinded fashion.
After 1 year, 78% of patients on triple therapy remained on it, compared with 63% of patients who began the extended follow-up on the methotrexate-etanercept combination and remained on it.
More patients switched from methotrexate-etanercept to triple therapy than the other way around (P = .005), but when the researchers removed patients who switched at the start of the extended follow-up from the analysis, continuation rates were nearly identical. The results also did not change when the researchers performed analyses using only the patients who did not switch therapy at week 24 during the blinded trial and again with patients assigned to their original randomized groups.
Average DAS28 scores were similar for each group (3.8 ± 1.4 for triple therapy vs. 3.5 ± 1.3 for methotrexate-etanercept) and remained similar at follow-up. There were also no differences between swollen or tender joint counts, patient global health assessments, or erythrocyte sedimentation rates between the groups.
“Triple therapy remained at least as durable and effective as its biologic counterpart,” the authors concluded.
“Our findings suggest that the majority of patients with active disease despite methotrexate respond to triple therapy and will continue to do so with excellent tolerability,” they wrote.
The findings also supported the approach of reserving more costly biologics for patients who continue to have disease progression despite combination conventional DMARD therapy, they added.
The authors reported no relevant funding for the follow-up analysis. One author reported having consulted for Pfizer and received research support from Bristol-Myers Squibb and AstraZeneca. Another author reported having consulted for Medac, Antares, Lilly, Coherus, and GlaxoSmithKline.
Key clinical point:
Major finding: At 1 year, people with active RA with a suboptimal response to methotrexate were just as likely to remain on triple DMARD therapy as they were on etanercept plus methotrexate.
Data source: An observational follow-up study of 289 patients with RA who had participated in the 48-week, multicenter, double-blind, RACAT trial.
Disclosures: The authors reported no relevant funding for the follow-up analysis. One author reported having consulted for Pfizer and received research support from Bristol-Myers Squibb and AstraZeneca. Another author reported having consulted for Medac, Antares, Lilly, Coherus, and GlaxoSmithKline.
FDA sends baricitinib application back for revision
, according to a statement from manufacturer Eli Lilly.
The FDA complete response letter cited the need for additional data to determine the most appropriate doses for the once-daily oral medication and to suss out safety concerns across treatment arms.
In the recently published RA-BEAM trial, a manufacturer-sponsored, international, randomized, double-blind, phase III clinical trial involving 1,305 adults with moderate to severe active RA, 70% of patients taking baricitinib plus background therapy with methotrexate met the primary efficacy end point – the proportion of patients at week 12 who showed an ACR 20 response – compared with 40% for placebo (N Engl J Med. 2017;376:652-62).
dfulton@frontlinemedcom.com
On Twitter @denisefulton
, according to a statement from manufacturer Eli Lilly.
The FDA complete response letter cited the need for additional data to determine the most appropriate doses for the once-daily oral medication and to suss out safety concerns across treatment arms.
In the recently published RA-BEAM trial, a manufacturer-sponsored, international, randomized, double-blind, phase III clinical trial involving 1,305 adults with moderate to severe active RA, 70% of patients taking baricitinib plus background therapy with methotrexate met the primary efficacy end point – the proportion of patients at week 12 who showed an ACR 20 response – compared with 40% for placebo (N Engl J Med. 2017;376:652-62).
dfulton@frontlinemedcom.com
On Twitter @denisefulton
, according to a statement from manufacturer Eli Lilly.
The FDA complete response letter cited the need for additional data to determine the most appropriate doses for the once-daily oral medication and to suss out safety concerns across treatment arms.
In the recently published RA-BEAM trial, a manufacturer-sponsored, international, randomized, double-blind, phase III clinical trial involving 1,305 adults with moderate to severe active RA, 70% of patients taking baricitinib plus background therapy with methotrexate met the primary efficacy end point – the proportion of patients at week 12 who showed an ACR 20 response – compared with 40% for placebo (N Engl J Med. 2017;376:652-62).
dfulton@frontlinemedcom.com
On Twitter @denisefulton
CCP status doesn’t influence tocilizumab’s effectiveness in RA
Among adults with rheumatoid arthritis, serologic status regarding anti–cyclic citrullinated peptide (CCP) antibodies doesn’t appear to influence the effectiveness of tocilizumab therapy, according to a report published in Seminars in Arthritis and Rheumatism.
Compared with patients who have anti-CCP antibodies, those who don’t show differences in immune activation that may affect their response to various therapies. In particular, some experts have hypothesized that monoclonal antibodies such as tocilizumab that target the interleukin-6 receptor would be more effective in patients who are seronegative for anti-CCP antibodies than in those who are seropositive. Being able to predict patient response based on easily available biomarkers like CCP status would greatly assist treatment selection, said Laura C. Cappelli, MD, of the division of rheumatology at Johns Hopkins University, Baltimore, and her associates.
All but one of these eight measures of disease activity (the mHAQ) improved significantly with tocilizumab, regardless of patient anti-CCP status. In addition, the magnitude of change did not differ by anti-CCP status. These results persisted across several sensitivity analyses, Dr. Cappelli and her associates said (Semin Arthritis Rheum. 2017 Apr 1. doi: 10.1016/j.semarthrit.2017.03.024).
The findings indicate that CCP seronegativity does not improve the response to tocilizumab in this population derived from real-world patients at diverse clinical sites, the investigators noted.
This study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Cappelli and her associates reported having no relevant financial disclosures.
Among adults with rheumatoid arthritis, serologic status regarding anti–cyclic citrullinated peptide (CCP) antibodies doesn’t appear to influence the effectiveness of tocilizumab therapy, according to a report published in Seminars in Arthritis and Rheumatism.
Compared with patients who have anti-CCP antibodies, those who don’t show differences in immune activation that may affect their response to various therapies. In particular, some experts have hypothesized that monoclonal antibodies such as tocilizumab that target the interleukin-6 receptor would be more effective in patients who are seronegative for anti-CCP antibodies than in those who are seropositive. Being able to predict patient response based on easily available biomarkers like CCP status would greatly assist treatment selection, said Laura C. Cappelli, MD, of the division of rheumatology at Johns Hopkins University, Baltimore, and her associates.
All but one of these eight measures of disease activity (the mHAQ) improved significantly with tocilizumab, regardless of patient anti-CCP status. In addition, the magnitude of change did not differ by anti-CCP status. These results persisted across several sensitivity analyses, Dr. Cappelli and her associates said (Semin Arthritis Rheum. 2017 Apr 1. doi: 10.1016/j.semarthrit.2017.03.024).
The findings indicate that CCP seronegativity does not improve the response to tocilizumab in this population derived from real-world patients at diverse clinical sites, the investigators noted.
This study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Cappelli and her associates reported having no relevant financial disclosures.
Among adults with rheumatoid arthritis, serologic status regarding anti–cyclic citrullinated peptide (CCP) antibodies doesn’t appear to influence the effectiveness of tocilizumab therapy, according to a report published in Seminars in Arthritis and Rheumatism.
Compared with patients who have anti-CCP antibodies, those who don’t show differences in immune activation that may affect their response to various therapies. In particular, some experts have hypothesized that monoclonal antibodies such as tocilizumab that target the interleukin-6 receptor would be more effective in patients who are seronegative for anti-CCP antibodies than in those who are seropositive. Being able to predict patient response based on easily available biomarkers like CCP status would greatly assist treatment selection, said Laura C. Cappelli, MD, of the division of rheumatology at Johns Hopkins University, Baltimore, and her associates.
All but one of these eight measures of disease activity (the mHAQ) improved significantly with tocilizumab, regardless of patient anti-CCP status. In addition, the magnitude of change did not differ by anti-CCP status. These results persisted across several sensitivity analyses, Dr. Cappelli and her associates said (Semin Arthritis Rheum. 2017 Apr 1. doi: 10.1016/j.semarthrit.2017.03.024).
The findings indicate that CCP seronegativity does not improve the response to tocilizumab in this population derived from real-world patients at diverse clinical sites, the investigators noted.
This study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Cappelli and her associates reported having no relevant financial disclosures.
FROM SEMINARS IN ARTHRITIS AND RHEUMATISM
Key clinical point: In adults with RA, serologic status regarding anti–cyclic citrullinated peptide antibodies doesn’t appear to influence the effectiveness of tocilizumab therapy.
Major finding: Seven of eight measures of disease activity improved significantly with tocilizumab, regardless of the patients’ CCP status.
Data source: A secondary analysis of data from a patient registry regarding 316 adults who initiated tocilizumab in a 6-year period.
Disclosures: This study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Cappelli and her associates reported having no relevant financial disclosures.
Obesity in women with RA greatly influences CRP levels
Obesity is associated with elevated C-reactive protein levels among women with rheumatoid arthritis, but this elevation reflects higher fat mass rather than RA disease activity, according to a report published online April 10 in Arthritis Care & Research.
The study findings suggest that C-reactive protein (CRP) results should be interpreted with caution among obese women with RA, noted Michael D. George, MD, of the division of rheumatology at the University of Pennsylvania, Philadelphia, and his associates.
To examine possible associations between body mass index and inflammatory markers in RA, the investigators performed a secondary analysis of data from 451 adult RA patients in three cross-sectional cohorts and 1,652 RA patients in the longitudinal Veterans Affairs Rheumatoid Arthritis Registry cohort. The investigators compared these findings with those of about 21,000 control subjects from the general population who were assessed in the 2007-2010 and 1971-1974 National Health and Nutrition Examination Survey programs.
Among women with RA, obesity was associated with elevated CRP independently of other measures of disease activity, including swollen joint count, tender joint count, and global scores of inflammation. A “strikingly similar association” was seen in the control population. This indicates that the high CRP values in obese women with RA “are not reflective of greater RA activity but rather are an expected phenomenon related to adiposity,” Dr. George and his associates said (Arthritis Care Res. 2017 Apr 10. doi: 10.1002/acr.23229).
In contrast, obesity in men with RA did not correlate with elevated CRP levels. In fact, underweight men with RA tended to have significantly higher CRP than that of normal-weight and obese men. “It was beyond the scope of this study to fully evaluate the complex relationship between RA disease activity, disease severity, weight loss, frailty, comorbidities, advancing age, and other factors that might contribute to higher levels of systemic inflammation in low-BMI men,” the investigators noted.
The National Institutes of Health, the Rheumatology Research Foundation, the U.S. Department of Veterans Affairs, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the National Institute of General Medical Sciences supported the work. Dr. George reported having no relevant disclosures; his associates reported ties to Pfizer, Novartis, and Amgen.
Obesity is associated with elevated C-reactive protein levels among women with rheumatoid arthritis, but this elevation reflects higher fat mass rather than RA disease activity, according to a report published online April 10 in Arthritis Care & Research.
The study findings suggest that C-reactive protein (CRP) results should be interpreted with caution among obese women with RA, noted Michael D. George, MD, of the division of rheumatology at the University of Pennsylvania, Philadelphia, and his associates.
To examine possible associations between body mass index and inflammatory markers in RA, the investigators performed a secondary analysis of data from 451 adult RA patients in three cross-sectional cohorts and 1,652 RA patients in the longitudinal Veterans Affairs Rheumatoid Arthritis Registry cohort. The investigators compared these findings with those of about 21,000 control subjects from the general population who were assessed in the 2007-2010 and 1971-1974 National Health and Nutrition Examination Survey programs.
Among women with RA, obesity was associated with elevated CRP independently of other measures of disease activity, including swollen joint count, tender joint count, and global scores of inflammation. A “strikingly similar association” was seen in the control population. This indicates that the high CRP values in obese women with RA “are not reflective of greater RA activity but rather are an expected phenomenon related to adiposity,” Dr. George and his associates said (Arthritis Care Res. 2017 Apr 10. doi: 10.1002/acr.23229).
In contrast, obesity in men with RA did not correlate with elevated CRP levels. In fact, underweight men with RA tended to have significantly higher CRP than that of normal-weight and obese men. “It was beyond the scope of this study to fully evaluate the complex relationship between RA disease activity, disease severity, weight loss, frailty, comorbidities, advancing age, and other factors that might contribute to higher levels of systemic inflammation in low-BMI men,” the investigators noted.
The National Institutes of Health, the Rheumatology Research Foundation, the U.S. Department of Veterans Affairs, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the National Institute of General Medical Sciences supported the work. Dr. George reported having no relevant disclosures; his associates reported ties to Pfizer, Novartis, and Amgen.
Obesity is associated with elevated C-reactive protein levels among women with rheumatoid arthritis, but this elevation reflects higher fat mass rather than RA disease activity, according to a report published online April 10 in Arthritis Care & Research.
The study findings suggest that C-reactive protein (CRP) results should be interpreted with caution among obese women with RA, noted Michael D. George, MD, of the division of rheumatology at the University of Pennsylvania, Philadelphia, and his associates.
To examine possible associations between body mass index and inflammatory markers in RA, the investigators performed a secondary analysis of data from 451 adult RA patients in three cross-sectional cohorts and 1,652 RA patients in the longitudinal Veterans Affairs Rheumatoid Arthritis Registry cohort. The investigators compared these findings with those of about 21,000 control subjects from the general population who were assessed in the 2007-2010 and 1971-1974 National Health and Nutrition Examination Survey programs.
Among women with RA, obesity was associated with elevated CRP independently of other measures of disease activity, including swollen joint count, tender joint count, and global scores of inflammation. A “strikingly similar association” was seen in the control population. This indicates that the high CRP values in obese women with RA “are not reflective of greater RA activity but rather are an expected phenomenon related to adiposity,” Dr. George and his associates said (Arthritis Care Res. 2017 Apr 10. doi: 10.1002/acr.23229).
In contrast, obesity in men with RA did not correlate with elevated CRP levels. In fact, underweight men with RA tended to have significantly higher CRP than that of normal-weight and obese men. “It was beyond the scope of this study to fully evaluate the complex relationship between RA disease activity, disease severity, weight loss, frailty, comorbidities, advancing age, and other factors that might contribute to higher levels of systemic inflammation in low-BMI men,” the investigators noted.
The National Institutes of Health, the Rheumatology Research Foundation, the U.S. Department of Veterans Affairs, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the National Institute of General Medical Sciences supported the work. Dr. George reported having no relevant disclosures; his associates reported ties to Pfizer, Novartis, and Amgen.
FROM ARTHRITIS CARE & RESEARCH
Key clinical point:
Major finding: Among women with RA, obesity was associated with elevated CRP independently of other measures of disease activity, including swollen joint count, tender joint count, and global scores of inflammation.
Data source: A secondary analysis of data from cross-sectional and longitudinal cohort studies involving 2,103 adults with RA.
Disclosures: The National Institutes of Health, the Rheumatology Research Foundation, the U.S. Department of Veterans Affairs, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the National Institute of General Medical Sciences supported the work. Dr. George reported having no relevant disclosures; his associates reported ties to Pfizer, Novartis, and Amgen.