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FDA needs convincing on nonradiologic axial spondyloarthritis
NEW YORK – There appears to be progress in the effort to convince the Food and Drug Administration that nonradiologic axial spondyloarthritis is a viable disease entity that deserves to be the target of therapeutic trials, according to an account of recent deliberations.
"We are happy that the FDA [now] agrees with the axSpA [axial spondyloarthritis] concept, the burden of disease, and the need to treat such patients," reported Dr. Atul Deodhar, professor of medicine and medical director of the rheumatology clinics at Oregon Health and Science University, Portland.
However, this is a process. The FDA "remains very concerned about the specificity of the ASAS [Assessment of Spondyloarthritis International Society] classification criteria," Dr. Deodhar said at the joint meetings of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis and the Spondyloarthritis Research & Treatment Network (SPARTAN).
Treatment trials for nonradiologic axSpA (nr-axSpA) followed the development of diagnostic criteria by ASAS in 2009 (Ann. Rheum. Dis. 2009;68:777-83). On the basis of randomized controlled trials in nr-axSpA patients with adalimumab (ABILITY-1) and both nr-axSpA and axSpA patients with certolizumab pegol (AS001), both drugs were approved by the European Medicines Agency for the treatment nr-axSpA. The same evidence, reviewed by an FDA advisory committee in July 2013, produced rejections the following October.
The major problem, according to Dr. Deodhar’s account, was that the FDA found the ASAS diagnostic criteria "overly broad," creating a potential for some low-risk patients to be prescribed therapies in which a favorable benefit-to-risk ratio could not be ensured. But the decision also denied these biologics to patients who could benefit.
"Rheumatologists were put in a difficult position, inducing some to label these patients as having ankylosing spondylitis to obtain third-party approval for therapies they needed," Dr. Deodhar observed. Concerned that patients with significant disability were being denied effective therapies, leaders of both SPARTAN and ASAS are attempting to work with the FDA to define more acceptable criteria.
In a joint letter from SPARTAN and ASAS to the FDA in early 2014 requesting a meeting, the key issues outlined for discussion included the need to recognize axSpA in general and nr-axSpA specifically as pathologies associated with significant morbidity and for which there is an unmet need for therapies.
At the meeting, held in June, both of these points and several others regarding the clinical importance of nr-axSpA and axSpA were conceded by the FDA officials, according to Dr. Deodhar. He recounted that some rheumatologists on staff at the FDA continue to see patients and were empathetic about the unmet need for therapies even while expressing concern about overuse of biologics.
The solution, in the opinion of FDA regulators, as described by Dr. Deodhar, is a better set of sensitive and specific diagnostic criteria for nr-axSpA that can reliably define those patients who benefit from biologics or other therapies when compared with the current standard of care. This is a goal now being pursued by SPARTAN in collaboration with ASAS. The American College of Rheumatology (ACR) and the European League Against Rheumatism may also be invited to participate.
The acknowledgment by the FDA that nr-axSpA is a disease entity that is poorly treated with current options is an important first step in a process that Dr. Deodhar and others believe will eventually lead to approval of tumor necrosis factor inhibitors.
Asked for a comment, Dr. David Borenstein, clinical professor of rheumatology at George Washington University Medical Center, Washington, said he is confident that diagnostic criteria acceptable to professional rheumatology organizations and the FDA will eventually be created.
"There has been some dissension about the reproducibility of the current axSpA criteria and how they might be used effectively by nonspecialists," agreed Dr. Borenstein, who is a past president of the ACR. "We need to tighten the criteria to make sure we are all talking about the same problem."
Dr. Deodhar reported financial relationships with Amgen, Abbott, Genentech, and Janssen.
NEW YORK – There appears to be progress in the effort to convince the Food and Drug Administration that nonradiologic axial spondyloarthritis is a viable disease entity that deserves to be the target of therapeutic trials, according to an account of recent deliberations.
"We are happy that the FDA [now] agrees with the axSpA [axial spondyloarthritis] concept, the burden of disease, and the need to treat such patients," reported Dr. Atul Deodhar, professor of medicine and medical director of the rheumatology clinics at Oregon Health and Science University, Portland.
However, this is a process. The FDA "remains very concerned about the specificity of the ASAS [Assessment of Spondyloarthritis International Society] classification criteria," Dr. Deodhar said at the joint meetings of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis and the Spondyloarthritis Research & Treatment Network (SPARTAN).
Treatment trials for nonradiologic axSpA (nr-axSpA) followed the development of diagnostic criteria by ASAS in 2009 (Ann. Rheum. Dis. 2009;68:777-83). On the basis of randomized controlled trials in nr-axSpA patients with adalimumab (ABILITY-1) and both nr-axSpA and axSpA patients with certolizumab pegol (AS001), both drugs were approved by the European Medicines Agency for the treatment nr-axSpA. The same evidence, reviewed by an FDA advisory committee in July 2013, produced rejections the following October.
The major problem, according to Dr. Deodhar’s account, was that the FDA found the ASAS diagnostic criteria "overly broad," creating a potential for some low-risk patients to be prescribed therapies in which a favorable benefit-to-risk ratio could not be ensured. But the decision also denied these biologics to patients who could benefit.
"Rheumatologists were put in a difficult position, inducing some to label these patients as having ankylosing spondylitis to obtain third-party approval for therapies they needed," Dr. Deodhar observed. Concerned that patients with significant disability were being denied effective therapies, leaders of both SPARTAN and ASAS are attempting to work with the FDA to define more acceptable criteria.
In a joint letter from SPARTAN and ASAS to the FDA in early 2014 requesting a meeting, the key issues outlined for discussion included the need to recognize axSpA in general and nr-axSpA specifically as pathologies associated with significant morbidity and for which there is an unmet need for therapies.
At the meeting, held in June, both of these points and several others regarding the clinical importance of nr-axSpA and axSpA were conceded by the FDA officials, according to Dr. Deodhar. He recounted that some rheumatologists on staff at the FDA continue to see patients and were empathetic about the unmet need for therapies even while expressing concern about overuse of biologics.
The solution, in the opinion of FDA regulators, as described by Dr. Deodhar, is a better set of sensitive and specific diagnostic criteria for nr-axSpA that can reliably define those patients who benefit from biologics or other therapies when compared with the current standard of care. This is a goal now being pursued by SPARTAN in collaboration with ASAS. The American College of Rheumatology (ACR) and the European League Against Rheumatism may also be invited to participate.
The acknowledgment by the FDA that nr-axSpA is a disease entity that is poorly treated with current options is an important first step in a process that Dr. Deodhar and others believe will eventually lead to approval of tumor necrosis factor inhibitors.
Asked for a comment, Dr. David Borenstein, clinical professor of rheumatology at George Washington University Medical Center, Washington, said he is confident that diagnostic criteria acceptable to professional rheumatology organizations and the FDA will eventually be created.
"There has been some dissension about the reproducibility of the current axSpA criteria and how they might be used effectively by nonspecialists," agreed Dr. Borenstein, who is a past president of the ACR. "We need to tighten the criteria to make sure we are all talking about the same problem."
Dr. Deodhar reported financial relationships with Amgen, Abbott, Genentech, and Janssen.
NEW YORK – There appears to be progress in the effort to convince the Food and Drug Administration that nonradiologic axial spondyloarthritis is a viable disease entity that deserves to be the target of therapeutic trials, according to an account of recent deliberations.
"We are happy that the FDA [now] agrees with the axSpA [axial spondyloarthritis] concept, the burden of disease, and the need to treat such patients," reported Dr. Atul Deodhar, professor of medicine and medical director of the rheumatology clinics at Oregon Health and Science University, Portland.
However, this is a process. The FDA "remains very concerned about the specificity of the ASAS [Assessment of Spondyloarthritis International Society] classification criteria," Dr. Deodhar said at the joint meetings of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis and the Spondyloarthritis Research & Treatment Network (SPARTAN).
Treatment trials for nonradiologic axSpA (nr-axSpA) followed the development of diagnostic criteria by ASAS in 2009 (Ann. Rheum. Dis. 2009;68:777-83). On the basis of randomized controlled trials in nr-axSpA patients with adalimumab (ABILITY-1) and both nr-axSpA and axSpA patients with certolizumab pegol (AS001), both drugs were approved by the European Medicines Agency for the treatment nr-axSpA. The same evidence, reviewed by an FDA advisory committee in July 2013, produced rejections the following October.
The major problem, according to Dr. Deodhar’s account, was that the FDA found the ASAS diagnostic criteria "overly broad," creating a potential for some low-risk patients to be prescribed therapies in which a favorable benefit-to-risk ratio could not be ensured. But the decision also denied these biologics to patients who could benefit.
"Rheumatologists were put in a difficult position, inducing some to label these patients as having ankylosing spondylitis to obtain third-party approval for therapies they needed," Dr. Deodhar observed. Concerned that patients with significant disability were being denied effective therapies, leaders of both SPARTAN and ASAS are attempting to work with the FDA to define more acceptable criteria.
In a joint letter from SPARTAN and ASAS to the FDA in early 2014 requesting a meeting, the key issues outlined for discussion included the need to recognize axSpA in general and nr-axSpA specifically as pathologies associated with significant morbidity and for which there is an unmet need for therapies.
At the meeting, held in June, both of these points and several others regarding the clinical importance of nr-axSpA and axSpA were conceded by the FDA officials, according to Dr. Deodhar. He recounted that some rheumatologists on staff at the FDA continue to see patients and were empathetic about the unmet need for therapies even while expressing concern about overuse of biologics.
The solution, in the opinion of FDA regulators, as described by Dr. Deodhar, is a better set of sensitive and specific diagnostic criteria for nr-axSpA that can reliably define those patients who benefit from biologics or other therapies when compared with the current standard of care. This is a goal now being pursued by SPARTAN in collaboration with ASAS. The American College of Rheumatology (ACR) and the European League Against Rheumatism may also be invited to participate.
The acknowledgment by the FDA that nr-axSpA is a disease entity that is poorly treated with current options is an important first step in a process that Dr. Deodhar and others believe will eventually lead to approval of tumor necrosis factor inhibitors.
Asked for a comment, Dr. David Borenstein, clinical professor of rheumatology at George Washington University Medical Center, Washington, said he is confident that diagnostic criteria acceptable to professional rheumatology organizations and the FDA will eventually be created.
"There has been some dissension about the reproducibility of the current axSpA criteria and how they might be used effectively by nonspecialists," agreed Dr. Borenstein, who is a past president of the ACR. "We need to tighten the criteria to make sure we are all talking about the same problem."
Dr. Deodhar reported financial relationships with Amgen, Abbott, Genentech, and Janssen.
EXPERT ANALYSIS AT THE 2014 GRAPPA AND SPARTAN ANNUAL MEETINGS
Physically demanding jobs link to worse ankylosing spondylitis progression
PARIS – Patients with ankylosing spondylitis who worked at more physically-demanding jobs showed greater radiographic progression than did patients who performed more sedentary jobs in a prospective cohort study with 136 patients.
The findings immediately raised questions about "our commonly given advice to patients with spondylarthritis to strenuously exercise. Should physically demanding labor be discouraged?" asked Dr. Sofia Ramiro at the annual European Congress of Rheumatology.
Dr. Ramiro stressed that the finding needs confirmation from studies in other cohorts of patients with ankylosing spondylitis (AS), but it raises the possibility that certain stresses and loads on the spine, from work or exercise, can worsen disease severity.
"If we can confirm that mechanical stress has an impact on radiographic progression, then I think we would have to analyze further and identify the type of activity having this impact, and then recommend the activity not be done," said Dr. Ramiro, a researcher at the Amsterdam Rheumatology Center, University of Amsterdam.
"I’m not saying that we would stop recommending exercise and that patients with AS should stay quiet at home, but perhaps we will advise against certain types of exercise," Dr. Ramiro said in an interview.
Dr. Ramiro and her associates previously reported this year that disease activity contributed longitudinally to radiographic AS progression during up to 12 years of follow-up (Ann. Rheum. Dis. 2014 [doi:10.1136/annrheumdis-2014-205178]). They further evaluated patients in the same cohort, 184 AS patients enrolled in OASIS (the Outcome in AS International Study), for additional factors that might affect radiographic progression either directly or indirectly. In addition to documenting a link between disease activity and radiographic progression, the report earlier this year had identified sex and disease duration as modifiers of the impact of disease activity. This impact on radiographic progression was greater in men, and early during the course of AS.
The new analysis looked for possible effects from smoking, and for chronic activity patterns using the surrogate marker of job type. The 184 patients in OASIS were sorted by their type of regular work, which identified 65 people with physically demanding (blue collar) jobs and 71 with relatively sedentary (white collar) jobs. The other 48 patients had either missing employment data or jobs with less clear links to activity levels, such as students or homemakers.
The findings showed that neither smoking nor job type appeared to have a direct influence on radiographic progression, but that smoking and a physically demanding job each had significant indirect effects. A physically demanding job linked with a 1.19-U increase in a measure of radiographic progression (the modified Stoke AS Spine Score, or mSASSS) for every 1-U increase in a measure of disease activity (the AS disease activity score, or ASDAS) during 2 years of follow-up, Dr. Ramiro reported. In contrast, the impact of a sedentary job was a 0.20-U rise in mSASSS for each 1-U rise in ASDAS. Smoking produced a 1.95-U rise in the mSASSS for each 1-U rise in ASDAS, significantly more than the 0.35 rate among nonsmokers.
Personal income, family income, and education each showed no statistically significant link with radiographic progression.
When the investigators analyzed job activity in subgroups divided by sex, they found that the relationship between a more physically demanding job and increased radiographic progression remained statistically significant in men, but the relationship was no longer significant in women.
The researchers could not include leisure activity or sports participation in their analysis as these data were not available. In addition, analysis by leisure activity may pose problems because baseline data on leisure activity may not extrapolate long-term, and patients can also have recall bias when reporting leisure activity, Dr. Ramiro said.
Dr. Ramiro said that she had no disclosures.
On Twitter @mitchelzoler
The relationships reported in this study between both job type and smoking and more extensive radiographic progression in patients with ankylosing spondylitis are probably true. This is not the first study of patients with ankylosing spondylitis to produce results that show these relationships, and the job-related effect is consistent with animal models of AS and the impact of chronic mechanical stress on progression.
Pain and other symptoms of AS improve with activity, but the findings by Dr. Ramiro as well as by others suggest that certain types of activity can worsen progression.
How this may apply to managing patients depends on the magnitude of the effect, and what options a patient might have. Many patients do not have a real choice about the work they do. In addition, we continue to advise patients to do what we consider therapeutic exercises, ideally 20-30 minutes daily. It is possible that therapeutic exercises could counterbalance the bad effects from work-related mechanical stress.
Dr. Martin Rudwaleit is a professor of rheumatology and nephrology at the Endokrinologikum in Berlin. He said that he has been a consultant to and has received honoraria from nine drug companies. He made these comments in an interview.
The relationships reported in this study between both job type and smoking and more extensive radiographic progression in patients with ankylosing spondylitis are probably true. This is not the first study of patients with ankylosing spondylitis to produce results that show these relationships, and the job-related effect is consistent with animal models of AS and the impact of chronic mechanical stress on progression.
Pain and other symptoms of AS improve with activity, but the findings by Dr. Ramiro as well as by others suggest that certain types of activity can worsen progression.
How this may apply to managing patients depends on the magnitude of the effect, and what options a patient might have. Many patients do not have a real choice about the work they do. In addition, we continue to advise patients to do what we consider therapeutic exercises, ideally 20-30 minutes daily. It is possible that therapeutic exercises could counterbalance the bad effects from work-related mechanical stress.
Dr. Martin Rudwaleit is a professor of rheumatology and nephrology at the Endokrinologikum in Berlin. He said that he has been a consultant to and has received honoraria from nine drug companies. He made these comments in an interview.
The relationships reported in this study between both job type and smoking and more extensive radiographic progression in patients with ankylosing spondylitis are probably true. This is not the first study of patients with ankylosing spondylitis to produce results that show these relationships, and the job-related effect is consistent with animal models of AS and the impact of chronic mechanical stress on progression.
Pain and other symptoms of AS improve with activity, but the findings by Dr. Ramiro as well as by others suggest that certain types of activity can worsen progression.
How this may apply to managing patients depends on the magnitude of the effect, and what options a patient might have. Many patients do not have a real choice about the work they do. In addition, we continue to advise patients to do what we consider therapeutic exercises, ideally 20-30 minutes daily. It is possible that therapeutic exercises could counterbalance the bad effects from work-related mechanical stress.
Dr. Martin Rudwaleit is a professor of rheumatology and nephrology at the Endokrinologikum in Berlin. He said that he has been a consultant to and has received honoraria from nine drug companies. He made these comments in an interview.
PARIS – Patients with ankylosing spondylitis who worked at more physically-demanding jobs showed greater radiographic progression than did patients who performed more sedentary jobs in a prospective cohort study with 136 patients.
The findings immediately raised questions about "our commonly given advice to patients with spondylarthritis to strenuously exercise. Should physically demanding labor be discouraged?" asked Dr. Sofia Ramiro at the annual European Congress of Rheumatology.
Dr. Ramiro stressed that the finding needs confirmation from studies in other cohorts of patients with ankylosing spondylitis (AS), but it raises the possibility that certain stresses and loads on the spine, from work or exercise, can worsen disease severity.
"If we can confirm that mechanical stress has an impact on radiographic progression, then I think we would have to analyze further and identify the type of activity having this impact, and then recommend the activity not be done," said Dr. Ramiro, a researcher at the Amsterdam Rheumatology Center, University of Amsterdam.
"I’m not saying that we would stop recommending exercise and that patients with AS should stay quiet at home, but perhaps we will advise against certain types of exercise," Dr. Ramiro said in an interview.
Dr. Ramiro and her associates previously reported this year that disease activity contributed longitudinally to radiographic AS progression during up to 12 years of follow-up (Ann. Rheum. Dis. 2014 [doi:10.1136/annrheumdis-2014-205178]). They further evaluated patients in the same cohort, 184 AS patients enrolled in OASIS (the Outcome in AS International Study), for additional factors that might affect radiographic progression either directly or indirectly. In addition to documenting a link between disease activity and radiographic progression, the report earlier this year had identified sex and disease duration as modifiers of the impact of disease activity. This impact on radiographic progression was greater in men, and early during the course of AS.
The new analysis looked for possible effects from smoking, and for chronic activity patterns using the surrogate marker of job type. The 184 patients in OASIS were sorted by their type of regular work, which identified 65 people with physically demanding (blue collar) jobs and 71 with relatively sedentary (white collar) jobs. The other 48 patients had either missing employment data or jobs with less clear links to activity levels, such as students or homemakers.
The findings showed that neither smoking nor job type appeared to have a direct influence on radiographic progression, but that smoking and a physically demanding job each had significant indirect effects. A physically demanding job linked with a 1.19-U increase in a measure of radiographic progression (the modified Stoke AS Spine Score, or mSASSS) for every 1-U increase in a measure of disease activity (the AS disease activity score, or ASDAS) during 2 years of follow-up, Dr. Ramiro reported. In contrast, the impact of a sedentary job was a 0.20-U rise in mSASSS for each 1-U rise in ASDAS. Smoking produced a 1.95-U rise in the mSASSS for each 1-U rise in ASDAS, significantly more than the 0.35 rate among nonsmokers.
Personal income, family income, and education each showed no statistically significant link with radiographic progression.
When the investigators analyzed job activity in subgroups divided by sex, they found that the relationship between a more physically demanding job and increased radiographic progression remained statistically significant in men, but the relationship was no longer significant in women.
The researchers could not include leisure activity or sports participation in their analysis as these data were not available. In addition, analysis by leisure activity may pose problems because baseline data on leisure activity may not extrapolate long-term, and patients can also have recall bias when reporting leisure activity, Dr. Ramiro said.
Dr. Ramiro said that she had no disclosures.
On Twitter @mitchelzoler
PARIS – Patients with ankylosing spondylitis who worked at more physically-demanding jobs showed greater radiographic progression than did patients who performed more sedentary jobs in a prospective cohort study with 136 patients.
The findings immediately raised questions about "our commonly given advice to patients with spondylarthritis to strenuously exercise. Should physically demanding labor be discouraged?" asked Dr. Sofia Ramiro at the annual European Congress of Rheumatology.
Dr. Ramiro stressed that the finding needs confirmation from studies in other cohorts of patients with ankylosing spondylitis (AS), but it raises the possibility that certain stresses and loads on the spine, from work or exercise, can worsen disease severity.
"If we can confirm that mechanical stress has an impact on radiographic progression, then I think we would have to analyze further and identify the type of activity having this impact, and then recommend the activity not be done," said Dr. Ramiro, a researcher at the Amsterdam Rheumatology Center, University of Amsterdam.
"I’m not saying that we would stop recommending exercise and that patients with AS should stay quiet at home, but perhaps we will advise against certain types of exercise," Dr. Ramiro said in an interview.
Dr. Ramiro and her associates previously reported this year that disease activity contributed longitudinally to radiographic AS progression during up to 12 years of follow-up (Ann. Rheum. Dis. 2014 [doi:10.1136/annrheumdis-2014-205178]). They further evaluated patients in the same cohort, 184 AS patients enrolled in OASIS (the Outcome in AS International Study), for additional factors that might affect radiographic progression either directly or indirectly. In addition to documenting a link between disease activity and radiographic progression, the report earlier this year had identified sex and disease duration as modifiers of the impact of disease activity. This impact on radiographic progression was greater in men, and early during the course of AS.
The new analysis looked for possible effects from smoking, and for chronic activity patterns using the surrogate marker of job type. The 184 patients in OASIS were sorted by their type of regular work, which identified 65 people with physically demanding (blue collar) jobs and 71 with relatively sedentary (white collar) jobs. The other 48 patients had either missing employment data or jobs with less clear links to activity levels, such as students or homemakers.
The findings showed that neither smoking nor job type appeared to have a direct influence on radiographic progression, but that smoking and a physically demanding job each had significant indirect effects. A physically demanding job linked with a 1.19-U increase in a measure of radiographic progression (the modified Stoke AS Spine Score, or mSASSS) for every 1-U increase in a measure of disease activity (the AS disease activity score, or ASDAS) during 2 years of follow-up, Dr. Ramiro reported. In contrast, the impact of a sedentary job was a 0.20-U rise in mSASSS for each 1-U rise in ASDAS. Smoking produced a 1.95-U rise in the mSASSS for each 1-U rise in ASDAS, significantly more than the 0.35 rate among nonsmokers.
Personal income, family income, and education each showed no statistically significant link with radiographic progression.
When the investigators analyzed job activity in subgroups divided by sex, they found that the relationship between a more physically demanding job and increased radiographic progression remained statistically significant in men, but the relationship was no longer significant in women.
The researchers could not include leisure activity or sports participation in their analysis as these data were not available. In addition, analysis by leisure activity may pose problems because baseline data on leisure activity may not extrapolate long-term, and patients can also have recall bias when reporting leisure activity, Dr. Ramiro said.
Dr. Ramiro said that she had no disclosures.
On Twitter @mitchelzoler
AT THE EULAR CONGRESS 2014
Key clinical point: Patients with AS who have more physically demanding jobs showed greater radiographic progression than did patients with more sedentary jobs.
Major finding: Physically demanding jobs linked with an average 1.19-U increase in mSASSS for every 1-U increase in ASDAS, compared with a 0.20-U increase in more sedentary patients.
Data source: Up to 12-year follow-up of a prospectively studied cohort with 136 evaluable patients.
Disclosures: Dr. Ramiro said that she had no disclosures.
Gut inflammation linked to worsening spondyloarthritis
Spondyloarthritis patients with microscopic gut inflammation had to start anti–tumor necrosis factor treatment sooner in the course of their disease than patients without gut inflammation in a prospective, observational study of 63 Belgian patients with the axial form of spondyloarthritis, the peripheral form, or both.
The finding "is in line with the hypothesis that in SpA [spondyloarthritis] gut inflammation may drive disease," Dr. Heleen Cypers said at the annual European Congress of Rheumatology.
SpA patients with microscopic gut inflammation initiated anti–tumor necrosis factor (TNF) therapy roughly twice as quickly as those without gut inflammation at each time period examined – at 6, 12, and 18 months after their initial diagnosis. After 18 months, 56% of patients with inflammation were on treatment with an anti-TNF agent, compared with almost 29% of the followed patients without microscopic gut inflammation, said Dr. Cypers, a rheumatologist at Ghent (Belgium) University.
The link between microscopic gut inflammation and a faster need to start on biologic treatment occurred at nearly identical rates in both the subset of 11 patients with acute gut inflammation and the subset of 21 patients with chronic inflammation.
Previous research by Dr. Cypers’ group had shown that chronic inflammation in the gut was associated with more extensive bone marrow edema of the sacroiliac joints, a higher risk of progression to ankylosing spondylitis, and a higher risk of developing Crohn’s disease. No information existed on the impact of gut inflammation on therapeutic decision-making in SpA, however.
The current study followed the Ghent Inflammatory Arthritis and Spondylitis Cohort (GIANT) of 63 newly diagnosed patients who underwent an ileocolonoscopy at baseline. Patients were not taking anti-TNF agents and were followed for 18 months. The decision to start anti-TNF treatment was made by a rheumatologist who was unaware of the patient’s gut history.
SpA patients who had microscopic gut inflammation at baseline were more likely to start anti-TNF treatment sooner than were patients without gut inflammation. During follow-up, just under a third of patients (9 of 31) with normal gut histology started anti-TNFs, compared with over half (18 of 32) of the patients with gut inflammation at baseline.
In most cases, anti-TNF drugs were started because first-line therapy had failed, Dr. Cypers reported. Her analysis also showed that initiation of an anti-TNF drug during follow-up was significantly linked with a higher level of C-reactive protein at baseline.
According to Dr. Cypers, the findings support the hypothesis that bowel inflammation in SpA induces a more chronic, persevering disease.
"The findings identify gut inflammation as a marker of a poor prognosis and have relevance for therapeutic decision-making in daily clinical practice. It is conceivable that assessment of gut inflammation will be included in future models for risk stratification of SpA," she said in an interview.
The underlying mechanisms explaining the link are still under investigation, but several studies have suggested that inflammation in the gut may be a triggering factor for SpA development. Interactions in the intestinal immune system also may play an important role, she said.
Future research by the group will focus on ruling out the interdependency of all of these factors, predicting response to biologic therapy based on gut histology, and determining whether therapies aiming at treating microscopic gut inflammation can affect the evolution of the disease.
Dr. Cypers said that she and her associates had no disclosures.
Spondyloarthritis patients with microscopic gut inflammation had to start anti–tumor necrosis factor treatment sooner in the course of their disease than patients without gut inflammation in a prospective, observational study of 63 Belgian patients with the axial form of spondyloarthritis, the peripheral form, or both.
The finding "is in line with the hypothesis that in SpA [spondyloarthritis] gut inflammation may drive disease," Dr. Heleen Cypers said at the annual European Congress of Rheumatology.
SpA patients with microscopic gut inflammation initiated anti–tumor necrosis factor (TNF) therapy roughly twice as quickly as those without gut inflammation at each time period examined – at 6, 12, and 18 months after their initial diagnosis. After 18 months, 56% of patients with inflammation were on treatment with an anti-TNF agent, compared with almost 29% of the followed patients without microscopic gut inflammation, said Dr. Cypers, a rheumatologist at Ghent (Belgium) University.
The link between microscopic gut inflammation and a faster need to start on biologic treatment occurred at nearly identical rates in both the subset of 11 patients with acute gut inflammation and the subset of 21 patients with chronic inflammation.
Previous research by Dr. Cypers’ group had shown that chronic inflammation in the gut was associated with more extensive bone marrow edema of the sacroiliac joints, a higher risk of progression to ankylosing spondylitis, and a higher risk of developing Crohn’s disease. No information existed on the impact of gut inflammation on therapeutic decision-making in SpA, however.
The current study followed the Ghent Inflammatory Arthritis and Spondylitis Cohort (GIANT) of 63 newly diagnosed patients who underwent an ileocolonoscopy at baseline. Patients were not taking anti-TNF agents and were followed for 18 months. The decision to start anti-TNF treatment was made by a rheumatologist who was unaware of the patient’s gut history.
SpA patients who had microscopic gut inflammation at baseline were more likely to start anti-TNF treatment sooner than were patients without gut inflammation. During follow-up, just under a third of patients (9 of 31) with normal gut histology started anti-TNFs, compared with over half (18 of 32) of the patients with gut inflammation at baseline.
In most cases, anti-TNF drugs were started because first-line therapy had failed, Dr. Cypers reported. Her analysis also showed that initiation of an anti-TNF drug during follow-up was significantly linked with a higher level of C-reactive protein at baseline.
According to Dr. Cypers, the findings support the hypothesis that bowel inflammation in SpA induces a more chronic, persevering disease.
"The findings identify gut inflammation as a marker of a poor prognosis and have relevance for therapeutic decision-making in daily clinical practice. It is conceivable that assessment of gut inflammation will be included in future models for risk stratification of SpA," she said in an interview.
The underlying mechanisms explaining the link are still under investigation, but several studies have suggested that inflammation in the gut may be a triggering factor for SpA development. Interactions in the intestinal immune system also may play an important role, she said.
Future research by the group will focus on ruling out the interdependency of all of these factors, predicting response to biologic therapy based on gut histology, and determining whether therapies aiming at treating microscopic gut inflammation can affect the evolution of the disease.
Dr. Cypers said that she and her associates had no disclosures.
Spondyloarthritis patients with microscopic gut inflammation had to start anti–tumor necrosis factor treatment sooner in the course of their disease than patients without gut inflammation in a prospective, observational study of 63 Belgian patients with the axial form of spondyloarthritis, the peripheral form, or both.
The finding "is in line with the hypothesis that in SpA [spondyloarthritis] gut inflammation may drive disease," Dr. Heleen Cypers said at the annual European Congress of Rheumatology.
SpA patients with microscopic gut inflammation initiated anti–tumor necrosis factor (TNF) therapy roughly twice as quickly as those without gut inflammation at each time period examined – at 6, 12, and 18 months after their initial diagnosis. After 18 months, 56% of patients with inflammation were on treatment with an anti-TNF agent, compared with almost 29% of the followed patients without microscopic gut inflammation, said Dr. Cypers, a rheumatologist at Ghent (Belgium) University.
The link between microscopic gut inflammation and a faster need to start on biologic treatment occurred at nearly identical rates in both the subset of 11 patients with acute gut inflammation and the subset of 21 patients with chronic inflammation.
Previous research by Dr. Cypers’ group had shown that chronic inflammation in the gut was associated with more extensive bone marrow edema of the sacroiliac joints, a higher risk of progression to ankylosing spondylitis, and a higher risk of developing Crohn’s disease. No information existed on the impact of gut inflammation on therapeutic decision-making in SpA, however.
The current study followed the Ghent Inflammatory Arthritis and Spondylitis Cohort (GIANT) of 63 newly diagnosed patients who underwent an ileocolonoscopy at baseline. Patients were not taking anti-TNF agents and were followed for 18 months. The decision to start anti-TNF treatment was made by a rheumatologist who was unaware of the patient’s gut history.
SpA patients who had microscopic gut inflammation at baseline were more likely to start anti-TNF treatment sooner than were patients without gut inflammation. During follow-up, just under a third of patients (9 of 31) with normal gut histology started anti-TNFs, compared with over half (18 of 32) of the patients with gut inflammation at baseline.
In most cases, anti-TNF drugs were started because first-line therapy had failed, Dr. Cypers reported. Her analysis also showed that initiation of an anti-TNF drug during follow-up was significantly linked with a higher level of C-reactive protein at baseline.
According to Dr. Cypers, the findings support the hypothesis that bowel inflammation in SpA induces a more chronic, persevering disease.
"The findings identify gut inflammation as a marker of a poor prognosis and have relevance for therapeutic decision-making in daily clinical practice. It is conceivable that assessment of gut inflammation will be included in future models for risk stratification of SpA," she said in an interview.
The underlying mechanisms explaining the link are still under investigation, but several studies have suggested that inflammation in the gut may be a triggering factor for SpA development. Interactions in the intestinal immune system also may play an important role, she said.
Future research by the group will focus on ruling out the interdependency of all of these factors, predicting response to biologic therapy based on gut histology, and determining whether therapies aiming at treating microscopic gut inflammation can affect the evolution of the disease.
Dr. Cypers said that she and her associates had no disclosures.
FROM THE EULAR CONGRESS 2014
Major finding: Among patients with newly diagnosed spondyloarthritis, microscopic gut inflammation at baseline was linked to a two-fold higher rate of anti-TNF treatment initiation.
Data source: A prospective, observational study of 63 Belgian patients with newly diagnosed spondyloarthritis who were followed for 18 months.
Disclosures: Dr. Cypers said that she and her associates had no disclosures.
Inflammation correlates with new bone formation in ankylosing spondylitis
Inflammation in ankylosing spondylitis was associated with new spinal bone formation in a 12-year follow-up study of 184 patients in the Outcome in AS International Study (OASIS).
"We have demonstrated here for the first time that the effect of disease activity on radiographic damage is actually rather impressive and longitudinal: Per one ASDAS unit increase a 0.7 mSASSS (modified Stoke Ankylosing Spondylitis Spine Score) units progression in 2 years can be expected. This longitudinal relationship was pertinent over the entire 12 years of follow-up," said Dr. Sofia Ramiro of the Amsterdam Rheumatology Center, University of Amsterdam.
The effect was more pronounced in men and in the earlier phases of the disease, Dr. Ramiro and her associates wrote in an article published online May 7 in Annals of the Rheumatic Diseases (doi:10.1136/annrheumdis-2014-205178).
For the study, all patients had biennial clinical and radiographic assessments and two readers independently scored the x-rays according to the mSASSS. Disease activity measures included the Bath AS Disease Activity Index (BASDAI), AS Disease Activity Index (ASDAS)-C-reactive protein (CRP), CRP, erythrocyte sedimentation rate (ESR), patient’s global assessment, and spinal pain.
As a disease activity measure, ASDAS outperformed the models with all other disease activity measures. The finding importantly adds to the validity of ASDAS as the disease activity measure of choice, the researchers said.
Patients with an ASDAS less than 1.3 at baseline had an average progression of 0.71 mSASSS units/2-years. Those with an ASDAS of more than 3.5 at baseline had a progression of 3.1 mSASSS units/2-year progression. A similar relationship was found for BASDAI: patients with a BASDAI less than 4 at baseline had an average progression of 1.4 mSASSS units/2 years, while patients with a BASDAI of 4 or more at baseline had an average progression of 2.7 mSASSS units/2 years.
However, inflammation "by far does not fully explain radiographic damage in AS: Even without measurable disease activity there is still considerable radiographic progression," they said. Patients who have inactive disease for the entire 12 years still can expect a progression of 5 mSASSS units on average. It seems as if increased bone formation in AS is partly constitutive and partly inflammation dependent.
The effect of disease activity on radiographic progression seems to be stronger in men, who had an additional progression of about 1 mSASSS unit per 2-year interval per additional unit of ASDAS. The researchers also found a stronger effect of disease activity on radiographic progression in the early phase of AS.
The models with ASDAS as the disease activity measure fitted the data better than did models with BASDAI, CRP, or BASDAI+CRP. An increase of one ASDAS unit led to an increase of 0.72 mSASSS units/2 years. An ASDAS exceeding 3.5 compared with an ASDAS of less than 1.3 resulted in an additional 2-year progression of 2.31 mSASSS units.
Dr. Romero was supported by the Fundação para a Ciência e Tecnologia (FCT) grant SFRH/BD/68684/2010.
We now have clear evidence that inflammation and new bone formation are related in ankylosing spondylitis. The current model even allows such a relationship to be quantified, with an increase of 1 ASDAS unit leading to an increase of 0.72 mSASSS units/2 years, an estimation that might also be useful for daily clinical practice.
However, the mean disease duration in this study was rather long at 20 years and can be seen as a limitation, since it is unclear whether an ASDAS increase has a similar effect on radiographic progression at an earlier stage of the disease. Thus, structural damage already present would lead to new or further bone formation over time, independent of the presence of inflammation. Further, only 30% of the study patients were women, and the limited data indicate that there is no or less correlation between parameters of activity and radiographic progression in women.
Nevertheless, the effect of elevated disease activity on new bone formation shown here is a big advance in understanding this rather complex relationship and is also potentially important for future treatment strategies, including the ‘treat to target’ approach. However, it has to be shown in therapeutic studies that lowering disease activity effectively can indeed retard radiographic progression in AS.
Long-term treatment studies in patients with early axial ankylosing spondylitis, including those with nonradiographic axial disease before structural damage is visible on x-ray, are now possible based on the new ASAS classification criteria. In light of the current evidence, we would hypothesize that early treatment with a tumor necrosis factor (TNF) blocker might retard radiographic progression, but that in long-standing ankylosing spondylitis a combination with another drug inhibiting new bone formation might be necessary. As some evidence indicates that NSAIDs might be able to inhibit radiographic progression, a clinical trial investigating the effect of combination therapy of a TNF blocker with an NSAID would be of interest.
Dr. Joachim Sieper and Dr. Denis Poddubnyy are with the Campus Benjamin Franklin, Charité, Berlin. They reported having no relevant financial disclosures. They made their remarks in an editorial that accompanied the study (Ann. Rheum Dis. 2014 May 8 [10.1136/annrheumdis-2014-205464]).
We now have clear evidence that inflammation and new bone formation are related in ankylosing spondylitis. The current model even allows such a relationship to be quantified, with an increase of 1 ASDAS unit leading to an increase of 0.72 mSASSS units/2 years, an estimation that might also be useful for daily clinical practice.
However, the mean disease duration in this study was rather long at 20 years and can be seen as a limitation, since it is unclear whether an ASDAS increase has a similar effect on radiographic progression at an earlier stage of the disease. Thus, structural damage already present would lead to new or further bone formation over time, independent of the presence of inflammation. Further, only 30% of the study patients were women, and the limited data indicate that there is no or less correlation between parameters of activity and radiographic progression in women.
Nevertheless, the effect of elevated disease activity on new bone formation shown here is a big advance in understanding this rather complex relationship and is also potentially important for future treatment strategies, including the ‘treat to target’ approach. However, it has to be shown in therapeutic studies that lowering disease activity effectively can indeed retard radiographic progression in AS.
Long-term treatment studies in patients with early axial ankylosing spondylitis, including those with nonradiographic axial disease before structural damage is visible on x-ray, are now possible based on the new ASAS classification criteria. In light of the current evidence, we would hypothesize that early treatment with a tumor necrosis factor (TNF) blocker might retard radiographic progression, but that in long-standing ankylosing spondylitis a combination with another drug inhibiting new bone formation might be necessary. As some evidence indicates that NSAIDs might be able to inhibit radiographic progression, a clinical trial investigating the effect of combination therapy of a TNF blocker with an NSAID would be of interest.
Dr. Joachim Sieper and Dr. Denis Poddubnyy are with the Campus Benjamin Franklin, Charité, Berlin. They reported having no relevant financial disclosures. They made their remarks in an editorial that accompanied the study (Ann. Rheum Dis. 2014 May 8 [10.1136/annrheumdis-2014-205464]).
We now have clear evidence that inflammation and new bone formation are related in ankylosing spondylitis. The current model even allows such a relationship to be quantified, with an increase of 1 ASDAS unit leading to an increase of 0.72 mSASSS units/2 years, an estimation that might also be useful for daily clinical practice.
However, the mean disease duration in this study was rather long at 20 years and can be seen as a limitation, since it is unclear whether an ASDAS increase has a similar effect on radiographic progression at an earlier stage of the disease. Thus, structural damage already present would lead to new or further bone formation over time, independent of the presence of inflammation. Further, only 30% of the study patients were women, and the limited data indicate that there is no or less correlation between parameters of activity and radiographic progression in women.
Nevertheless, the effect of elevated disease activity on new bone formation shown here is a big advance in understanding this rather complex relationship and is also potentially important for future treatment strategies, including the ‘treat to target’ approach. However, it has to be shown in therapeutic studies that lowering disease activity effectively can indeed retard radiographic progression in AS.
Long-term treatment studies in patients with early axial ankylosing spondylitis, including those with nonradiographic axial disease before structural damage is visible on x-ray, are now possible based on the new ASAS classification criteria. In light of the current evidence, we would hypothesize that early treatment with a tumor necrosis factor (TNF) blocker might retard radiographic progression, but that in long-standing ankylosing spondylitis a combination with another drug inhibiting new bone formation might be necessary. As some evidence indicates that NSAIDs might be able to inhibit radiographic progression, a clinical trial investigating the effect of combination therapy of a TNF blocker with an NSAID would be of interest.
Dr. Joachim Sieper and Dr. Denis Poddubnyy are with the Campus Benjamin Franklin, Charité, Berlin. They reported having no relevant financial disclosures. They made their remarks in an editorial that accompanied the study (Ann. Rheum Dis. 2014 May 8 [10.1136/annrheumdis-2014-205464]).
Inflammation in ankylosing spondylitis was associated with new spinal bone formation in a 12-year follow-up study of 184 patients in the Outcome in AS International Study (OASIS).
"We have demonstrated here for the first time that the effect of disease activity on radiographic damage is actually rather impressive and longitudinal: Per one ASDAS unit increase a 0.7 mSASSS (modified Stoke Ankylosing Spondylitis Spine Score) units progression in 2 years can be expected. This longitudinal relationship was pertinent over the entire 12 years of follow-up," said Dr. Sofia Ramiro of the Amsterdam Rheumatology Center, University of Amsterdam.
The effect was more pronounced in men and in the earlier phases of the disease, Dr. Ramiro and her associates wrote in an article published online May 7 in Annals of the Rheumatic Diseases (doi:10.1136/annrheumdis-2014-205178).
For the study, all patients had biennial clinical and radiographic assessments and two readers independently scored the x-rays according to the mSASSS. Disease activity measures included the Bath AS Disease Activity Index (BASDAI), AS Disease Activity Index (ASDAS)-C-reactive protein (CRP), CRP, erythrocyte sedimentation rate (ESR), patient’s global assessment, and spinal pain.
As a disease activity measure, ASDAS outperformed the models with all other disease activity measures. The finding importantly adds to the validity of ASDAS as the disease activity measure of choice, the researchers said.
Patients with an ASDAS less than 1.3 at baseline had an average progression of 0.71 mSASSS units/2-years. Those with an ASDAS of more than 3.5 at baseline had a progression of 3.1 mSASSS units/2-year progression. A similar relationship was found for BASDAI: patients with a BASDAI less than 4 at baseline had an average progression of 1.4 mSASSS units/2 years, while patients with a BASDAI of 4 or more at baseline had an average progression of 2.7 mSASSS units/2 years.
However, inflammation "by far does not fully explain radiographic damage in AS: Even without measurable disease activity there is still considerable radiographic progression," they said. Patients who have inactive disease for the entire 12 years still can expect a progression of 5 mSASSS units on average. It seems as if increased bone formation in AS is partly constitutive and partly inflammation dependent.
The effect of disease activity on radiographic progression seems to be stronger in men, who had an additional progression of about 1 mSASSS unit per 2-year interval per additional unit of ASDAS. The researchers also found a stronger effect of disease activity on radiographic progression in the early phase of AS.
The models with ASDAS as the disease activity measure fitted the data better than did models with BASDAI, CRP, or BASDAI+CRP. An increase of one ASDAS unit led to an increase of 0.72 mSASSS units/2 years. An ASDAS exceeding 3.5 compared with an ASDAS of less than 1.3 resulted in an additional 2-year progression of 2.31 mSASSS units.
Dr. Romero was supported by the Fundação para a Ciência e Tecnologia (FCT) grant SFRH/BD/68684/2010.
Inflammation in ankylosing spondylitis was associated with new spinal bone formation in a 12-year follow-up study of 184 patients in the Outcome in AS International Study (OASIS).
"We have demonstrated here for the first time that the effect of disease activity on radiographic damage is actually rather impressive and longitudinal: Per one ASDAS unit increase a 0.7 mSASSS (modified Stoke Ankylosing Spondylitis Spine Score) units progression in 2 years can be expected. This longitudinal relationship was pertinent over the entire 12 years of follow-up," said Dr. Sofia Ramiro of the Amsterdam Rheumatology Center, University of Amsterdam.
The effect was more pronounced in men and in the earlier phases of the disease, Dr. Ramiro and her associates wrote in an article published online May 7 in Annals of the Rheumatic Diseases (doi:10.1136/annrheumdis-2014-205178).
For the study, all patients had biennial clinical and radiographic assessments and two readers independently scored the x-rays according to the mSASSS. Disease activity measures included the Bath AS Disease Activity Index (BASDAI), AS Disease Activity Index (ASDAS)-C-reactive protein (CRP), CRP, erythrocyte sedimentation rate (ESR), patient’s global assessment, and spinal pain.
As a disease activity measure, ASDAS outperformed the models with all other disease activity measures. The finding importantly adds to the validity of ASDAS as the disease activity measure of choice, the researchers said.
Patients with an ASDAS less than 1.3 at baseline had an average progression of 0.71 mSASSS units/2-years. Those with an ASDAS of more than 3.5 at baseline had a progression of 3.1 mSASSS units/2-year progression. A similar relationship was found for BASDAI: patients with a BASDAI less than 4 at baseline had an average progression of 1.4 mSASSS units/2 years, while patients with a BASDAI of 4 or more at baseline had an average progression of 2.7 mSASSS units/2 years.
However, inflammation "by far does not fully explain radiographic damage in AS: Even without measurable disease activity there is still considerable radiographic progression," they said. Patients who have inactive disease for the entire 12 years still can expect a progression of 5 mSASSS units on average. It seems as if increased bone formation in AS is partly constitutive and partly inflammation dependent.
The effect of disease activity on radiographic progression seems to be stronger in men, who had an additional progression of about 1 mSASSS unit per 2-year interval per additional unit of ASDAS. The researchers also found a stronger effect of disease activity on radiographic progression in the early phase of AS.
The models with ASDAS as the disease activity measure fitted the data better than did models with BASDAI, CRP, or BASDAI+CRP. An increase of one ASDAS unit led to an increase of 0.72 mSASSS units/2 years. An ASDAS exceeding 3.5 compared with an ASDAS of less than 1.3 resulted in an additional 2-year progression of 2.31 mSASSS units.
Dr. Romero was supported by the Fundação para a Ciência e Tecnologia (FCT) grant SFRH/BD/68684/2010.
From Annals of Rheumatic Diseases
Key clinical point: New bone formation in ankylosing spondylitis correlates with inflammation.
Major finding: Patients with an ASDAS less than 1.3 at baseline had an average progression of 0.71 mSASSS units/2-years. Those with an ASDAS of more than 3.5 at baseline had a progression of 3.1 mSASSS units/2-year progression.
Data source: A 12-year follow up study of 184 patients in the Outcome in AS International Study (OASIS).
Disclosures: Dr. Romero was supported by the Fundação para a Ciência e Tecnologia (FCT) grant SFRH/BD/68684/2010.
Step-down etanercept fails to control ankylosing spondylitis
LIVERPOOL, ENGLAND – Reducing the once-weekly maintenance dose of etanercept from 50 mg to 25 mg was associated with worsening control of ankylosing spondylitis in an open-label, multicenter, pilot study.
Results of the ANSWER (Ankylosing Spondylitis with Etanercept Regimens) trial showed that halving the dose of the biologic almost halved the percentage of patients maintaining disease control at 6 months, from 92% to 52% of patients.
Although this was a small study, involving just 47 patients who were randomized to continue etanercept at a weekly dose of 50 mg (n = 24) or to drop down to 25 mg (n = 23) after competing 6 months’ treatment, the results suggest that other approaches are needed to see if the long-term dose of the drug can be reduced, commented study investigator Dr. Karl Gaffney of Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, England.
"A larger study is required to identify patients suitable for step-down," Dr. Gaffney said at the British Society for Rheumatology annual conference.
"We all know that anti-TNF [tumor necrosis factor] therapy is firmly established in clinical practice for patients with ankylosing spondylitis and this treatment has transformed the quality of life for many of our patients," Dr. Gaffney observed.
"The concept of dose reduction is very appealing from an economic perspective, but also in terms of the cumulative exposure and the risk of adverse effects," he added.
"In patients with rheumatoid arthritis, it’s been shown that lower doses may maintain the clinical response," Dr. Gaffney explained, citing the PRESERVE study published last year (Lancet 2013;381:918-29). However, there are limited data about whether reducing the dose of etanercept could also be successful in ankylosing spondylitis (AS) patients. This is why the ANSWER study was performed.
Patients with active AS who were not responding to conventional therapies and had not yet been treated with a biologic drug were consecutively recruited at two hospitals in England between September 2010 and September 2012. For inclusion, patients had to have sustained spinal disease and a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of four or higher. The mean age of patients in the trial was 46.7 years, and the mean BASDAI at baseline was 6.8.
All recruited patients were treated with 50 mg etanercept, once weekly, for 6 months, and those with a "sufficient" clinical response were randomized to either continue this dose for a further 6 months or step down to 25 mg for continued maintenance treatment. A sufficient clinical response was defined as a 50% reduction in BASDAI or a fall of two or more units plus reduction in axial pain of 2 cm or more.
Three months into the maintenance period, patients who had been randomized to the step-down arm started to experience loss of disease control (60.9% vs. 91.7% of 50 mg–treated patients), with the gap widening by 6 months postrandomization and 39% fewer patients maintaining disease control (P = .003).
"There’s no doubt that the 50-mg group did better," Dr. Gaffney said. There were also statistically significant differences favoring the higher dose in a number of secondary outcome measures, which included other measurements of AS disease activity and quality of life. There were no significant differences in terms of adverse events between the two groups.
"However, 52% of the 25-mg arm did maintain their BASDAI response. So theoretically, there may be a subset of patients in whom we can offer this therapeutic option," Dr. Gaffney said. He noted that even in this small group of patients with short-term follow-up that the potential cost savings of being able to reduce the dose would be significant, at around £100,000 (about U.S. $170,000).
"We all have patients who do very well [on etanercept], and I think it would be very nice to be able to say, from 6 months, who we can attempt to step down," commented Dr. Nicola Goodson of University Hospital Aintree, Liverpool. Dr. Goodson chaired the session where the study findings were reported.
Although the ANSWER investigators did look for predictors of response, none were found to be significant. Patients continue to be monitored and the investigators may look at this again. Dr. Gaffney noted that all patients who had their 50-mg dose reinstated regained their clinical response.
He also highlighted during discussion: "A number of patients in the 50-mg group asked to be moved down to 25 mg at the end of the study because they wanted to explore the option. So I think this may well have some long-term consequences, especially in a disease area where we know that the treatment is more symptom modifying than radiographically modifying."
The study was funded by Pfizer. Dr. Gaffney has received research support and honoraria from Pfizer, Merck Sharp & Dohme, AbbVie, and UCB.
LIVERPOOL, ENGLAND – Reducing the once-weekly maintenance dose of etanercept from 50 mg to 25 mg was associated with worsening control of ankylosing spondylitis in an open-label, multicenter, pilot study.
Results of the ANSWER (Ankylosing Spondylitis with Etanercept Regimens) trial showed that halving the dose of the biologic almost halved the percentage of patients maintaining disease control at 6 months, from 92% to 52% of patients.
Although this was a small study, involving just 47 patients who were randomized to continue etanercept at a weekly dose of 50 mg (n = 24) or to drop down to 25 mg (n = 23) after competing 6 months’ treatment, the results suggest that other approaches are needed to see if the long-term dose of the drug can be reduced, commented study investigator Dr. Karl Gaffney of Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, England.
"A larger study is required to identify patients suitable for step-down," Dr. Gaffney said at the British Society for Rheumatology annual conference.
"We all know that anti-TNF [tumor necrosis factor] therapy is firmly established in clinical practice for patients with ankylosing spondylitis and this treatment has transformed the quality of life for many of our patients," Dr. Gaffney observed.
"The concept of dose reduction is very appealing from an economic perspective, but also in terms of the cumulative exposure and the risk of adverse effects," he added.
"In patients with rheumatoid arthritis, it’s been shown that lower doses may maintain the clinical response," Dr. Gaffney explained, citing the PRESERVE study published last year (Lancet 2013;381:918-29). However, there are limited data about whether reducing the dose of etanercept could also be successful in ankylosing spondylitis (AS) patients. This is why the ANSWER study was performed.
Patients with active AS who were not responding to conventional therapies and had not yet been treated with a biologic drug were consecutively recruited at two hospitals in England between September 2010 and September 2012. For inclusion, patients had to have sustained spinal disease and a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of four or higher. The mean age of patients in the trial was 46.7 years, and the mean BASDAI at baseline was 6.8.
All recruited patients were treated with 50 mg etanercept, once weekly, for 6 months, and those with a "sufficient" clinical response were randomized to either continue this dose for a further 6 months or step down to 25 mg for continued maintenance treatment. A sufficient clinical response was defined as a 50% reduction in BASDAI or a fall of two or more units plus reduction in axial pain of 2 cm or more.
Three months into the maintenance period, patients who had been randomized to the step-down arm started to experience loss of disease control (60.9% vs. 91.7% of 50 mg–treated patients), with the gap widening by 6 months postrandomization and 39% fewer patients maintaining disease control (P = .003).
"There’s no doubt that the 50-mg group did better," Dr. Gaffney said. There were also statistically significant differences favoring the higher dose in a number of secondary outcome measures, which included other measurements of AS disease activity and quality of life. There were no significant differences in terms of adverse events between the two groups.
"However, 52% of the 25-mg arm did maintain their BASDAI response. So theoretically, there may be a subset of patients in whom we can offer this therapeutic option," Dr. Gaffney said. He noted that even in this small group of patients with short-term follow-up that the potential cost savings of being able to reduce the dose would be significant, at around £100,000 (about U.S. $170,000).
"We all have patients who do very well [on etanercept], and I think it would be very nice to be able to say, from 6 months, who we can attempt to step down," commented Dr. Nicola Goodson of University Hospital Aintree, Liverpool. Dr. Goodson chaired the session where the study findings were reported.
Although the ANSWER investigators did look for predictors of response, none were found to be significant. Patients continue to be monitored and the investigators may look at this again. Dr. Gaffney noted that all patients who had their 50-mg dose reinstated regained their clinical response.
He also highlighted during discussion: "A number of patients in the 50-mg group asked to be moved down to 25 mg at the end of the study because they wanted to explore the option. So I think this may well have some long-term consequences, especially in a disease area where we know that the treatment is more symptom modifying than radiographically modifying."
The study was funded by Pfizer. Dr. Gaffney has received research support and honoraria from Pfizer, Merck Sharp & Dohme, AbbVie, and UCB.
LIVERPOOL, ENGLAND – Reducing the once-weekly maintenance dose of etanercept from 50 mg to 25 mg was associated with worsening control of ankylosing spondylitis in an open-label, multicenter, pilot study.
Results of the ANSWER (Ankylosing Spondylitis with Etanercept Regimens) trial showed that halving the dose of the biologic almost halved the percentage of patients maintaining disease control at 6 months, from 92% to 52% of patients.
Although this was a small study, involving just 47 patients who were randomized to continue etanercept at a weekly dose of 50 mg (n = 24) or to drop down to 25 mg (n = 23) after competing 6 months’ treatment, the results suggest that other approaches are needed to see if the long-term dose of the drug can be reduced, commented study investigator Dr. Karl Gaffney of Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, England.
"A larger study is required to identify patients suitable for step-down," Dr. Gaffney said at the British Society for Rheumatology annual conference.
"We all know that anti-TNF [tumor necrosis factor] therapy is firmly established in clinical practice for patients with ankylosing spondylitis and this treatment has transformed the quality of life for many of our patients," Dr. Gaffney observed.
"The concept of dose reduction is very appealing from an economic perspective, but also in terms of the cumulative exposure and the risk of adverse effects," he added.
"In patients with rheumatoid arthritis, it’s been shown that lower doses may maintain the clinical response," Dr. Gaffney explained, citing the PRESERVE study published last year (Lancet 2013;381:918-29). However, there are limited data about whether reducing the dose of etanercept could also be successful in ankylosing spondylitis (AS) patients. This is why the ANSWER study was performed.
Patients with active AS who were not responding to conventional therapies and had not yet been treated with a biologic drug were consecutively recruited at two hospitals in England between September 2010 and September 2012. For inclusion, patients had to have sustained spinal disease and a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of four or higher. The mean age of patients in the trial was 46.7 years, and the mean BASDAI at baseline was 6.8.
All recruited patients were treated with 50 mg etanercept, once weekly, for 6 months, and those with a "sufficient" clinical response were randomized to either continue this dose for a further 6 months or step down to 25 mg for continued maintenance treatment. A sufficient clinical response was defined as a 50% reduction in BASDAI or a fall of two or more units plus reduction in axial pain of 2 cm or more.
Three months into the maintenance period, patients who had been randomized to the step-down arm started to experience loss of disease control (60.9% vs. 91.7% of 50 mg–treated patients), with the gap widening by 6 months postrandomization and 39% fewer patients maintaining disease control (P = .003).
"There’s no doubt that the 50-mg group did better," Dr. Gaffney said. There were also statistically significant differences favoring the higher dose in a number of secondary outcome measures, which included other measurements of AS disease activity and quality of life. There were no significant differences in terms of adverse events between the two groups.
"However, 52% of the 25-mg arm did maintain their BASDAI response. So theoretically, there may be a subset of patients in whom we can offer this therapeutic option," Dr. Gaffney said. He noted that even in this small group of patients with short-term follow-up that the potential cost savings of being able to reduce the dose would be significant, at around £100,000 (about U.S. $170,000).
"We all have patients who do very well [on etanercept], and I think it would be very nice to be able to say, from 6 months, who we can attempt to step down," commented Dr. Nicola Goodson of University Hospital Aintree, Liverpool. Dr. Goodson chaired the session where the study findings were reported.
Although the ANSWER investigators did look for predictors of response, none were found to be significant. Patients continue to be monitored and the investigators may look at this again. Dr. Gaffney noted that all patients who had their 50-mg dose reinstated regained their clinical response.
He also highlighted during discussion: "A number of patients in the 50-mg group asked to be moved down to 25 mg at the end of the study because they wanted to explore the option. So I think this may well have some long-term consequences, especially in a disease area where we know that the treatment is more symptom modifying than radiographically modifying."
The study was funded by Pfizer. Dr. Gaffney has received research support and honoraria from Pfizer, Merck Sharp & Dohme, AbbVie, and UCB.
AT RHEUMATOLOGY 2014
Key clinical point: All the patients who did not maintain disease control after halving their dose of etanercept were able to regain clinical response.
Major finding: At 6 months, 52% vs. 92% of the 25 mg– and 50 mg–treated patients maintained a clinical response (P = .003).
Data source: An open-label, multicenter, noninferiority, randomized, pilot study of 47 patients with ankylosing spondylitis treated with weekly etanercept.
Disclosures: The study was funded by Pfizer. Dr. Gaffney has received research support and honoraria from Pfizer, Merck Sharp & Dohme, AbbVie, and UCB.
Shift in approach needed for managing inflammatory arthritis in pregnancy
SNOWMASS, COLO. – The common strategy of managing inflammatory arthritis during pregnancy by stopping all prepregnancy medications and prescribing prednisone is counterproductive, Dr. Megan E.B. Clowse said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
"This sort of safe approach is actually not the safest or best approach. We all need to shift our attitude and get comfortable with at least a couple of other medications in order to help our patients have better outcomes," asserted Dr. Clowse, director of the Duke Autoimmunity in Pregnancy (DAP) Registry at Duke University, Durham, N.C.
It’s often true that rheumatoid arthritis (RA) tends to get better in pregnancy. Nonetheless, pregnancy may not be enough to control disease activity in many women, as illustrated by a nationwide Dutch study in which half of RA patients had moderate to severe disease activity by their third trimester (Arthritis Rheum. 2008;59:1241-8).
"In my experience, the patients who were on tumor necrosis factor inhibitors prepregnancy do not do as well when they come off them. So pregnancy might be good for RA disease activity, but it’s definitely not as good as a tumor necrosis factor inhibitor," according to the rheumatologist.
Roughly one-quarter of the more than 230 prospectively studied pregnancies in the DAP Registry have been in women with RA or other inflammatory arthritides. The preterm birth rate in RA patients in DAP, as in other RA registries, is higher than in the general population. Notably, all of the DAP patients with RA who had preterm birth had moderate to severe disease activity in the first and second trimesters, compared with just a single RA patient with a term delivery.
"Allowing disease to flare may actually harm the pregnancy," Dr. Clowse commented.
Her two top recommendations for nonbiologic treatment of inflammatory arthritis during pregnancy are hydroxychloroquine and sulfasalazine. Hydroxychloroquine is effective for mild arthritis, and it’s rated by the Food and Drug Administration as Pregnancy Category C, with no reports of human toxicity. Sulfasalazine has a good safety profile in pregnancy – it is Pregnancy Category B – and has good efficacy for peripheral arthritis.
"These are two very important medications that are much better – and definitely much safer – options than prednisone. These are just great options, and I try to encourage patients to take them. It’s definitely better than letting patients flare while off methotrexate before they deliver," she continued.
"TNF [tumor necrosis factor] inhibitors are, I think, another reasonable option, particularly in the population with moderate to severe disease activity. If any of these medications help you avoid prednisone, then I think you come out ahead," Dr. Clowse said.
Reassuring data regarding the safety of anti-TNF biologics in pregnancy comes from several sources. A systematic literature review by Dr. Evelyne Vinet and her coworkers at McGill University, Montreal, found no evidence of excess risk of adverse pregnancy or fetal outcomes in women exposed to etanercept (Enbrel), infliximab (Remicade), or adalimumab (Humira) during pregnancy (Arthritis Rheum. 2009;61:587-92). A report from the Organization of Teratology Information Specialists (OTIS) Registry, presented at the 2012 annual meeting of the American College of Rheumatology, found no significant difference between RA patients exposed to adalimumab in pregnancy and RA controls in rates of live birth, miscarriage, stillbirth, congenital abnormalities, or serious infections in the first year of life.
Moreover, DAP Registry data support the notion that for some patients, anti-TNF biologics during pregnancy may be a good option. In Dr. Clowse’s series of 29 RA patients, disease activity during the first trimester neatly delineated three distinct groups. Eleven patients who had a 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) averaging 1.5 in the first trimester required neither TNF inhibitors nor prednisone during their pregnancy, and they had no abnormal outcomes. Seven patients with significant first-trimester disease activity as defined by an average DAS28-CRP score of 3.4 went back on their TNF inhibitor during pregnancy, and their disease essentially went into remission, with only one preterm birth. In contrast, 11 other patients with significant first-trimester disease activity went on prednisone because they rejected TNF inhibitor therapy; their disease activity remained substantial, and 6 of the 11 had a preterm birth and/or preeclampsia.
"All of the preeclampsia occurred in the prednisone group. They also had a lot of disease activity postpartum," Dr. Clowse observed.
Infliximab and adalimumab freely pass across the placenta; etanercept and certolizumab pegol (Cimzia) do not. Regardless, no infant exposed in utero to a TNF inhibitor should receive the rotavirus vaccine during the first 5 months of life. That’s the only live-virus vaccine given during infancy in the United States; all the other vaccines can safely be given according to schedule.
Dr. Clowse said there is essentially no published literature regarding psoriatic arthritis in pregnancy. The DAP registry experience includes seven pregnancies in women with psoriatic arthritis. There were no pregnancy losses, one preterm birth, and two cases of preeclampsia.
"What I see is dramatically increased disease activity when women with psoriatic arthritis stop their TNF inhibitor. The worst psoriasis I’ve ever seen is in pregnant patients; they are really miserable off their TNF inhibitors," she said.
There is also very little in the literature about axial spondyloarthritis in pregnancy. The DAP registry’s 10 cases constitute one of the largest series. There were no pregnancy losses, no preeclampsia, and one preterm birth. Eight of the women were delivered by C-section.
"That reflects my personal bias, which is that the position required for vaginal delivery is pretty horrible for sacroiliac joint pain and leads to significant flares postpartum. That’s particularly true if the patient has an epidural and doesn’t know how hard she’s pushing on those SI joints," according to the rheumatologist.
Dr. Clowse reported serving as a consultant to UCB, which markets certolizumab pegol.
SNOWMASS, COLO. – The common strategy of managing inflammatory arthritis during pregnancy by stopping all prepregnancy medications and prescribing prednisone is counterproductive, Dr. Megan E.B. Clowse said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
"This sort of safe approach is actually not the safest or best approach. We all need to shift our attitude and get comfortable with at least a couple of other medications in order to help our patients have better outcomes," asserted Dr. Clowse, director of the Duke Autoimmunity in Pregnancy (DAP) Registry at Duke University, Durham, N.C.
It’s often true that rheumatoid arthritis (RA) tends to get better in pregnancy. Nonetheless, pregnancy may not be enough to control disease activity in many women, as illustrated by a nationwide Dutch study in which half of RA patients had moderate to severe disease activity by their third trimester (Arthritis Rheum. 2008;59:1241-8).
"In my experience, the patients who were on tumor necrosis factor inhibitors prepregnancy do not do as well when they come off them. So pregnancy might be good for RA disease activity, but it’s definitely not as good as a tumor necrosis factor inhibitor," according to the rheumatologist.
Roughly one-quarter of the more than 230 prospectively studied pregnancies in the DAP Registry have been in women with RA or other inflammatory arthritides. The preterm birth rate in RA patients in DAP, as in other RA registries, is higher than in the general population. Notably, all of the DAP patients with RA who had preterm birth had moderate to severe disease activity in the first and second trimesters, compared with just a single RA patient with a term delivery.
"Allowing disease to flare may actually harm the pregnancy," Dr. Clowse commented.
Her two top recommendations for nonbiologic treatment of inflammatory arthritis during pregnancy are hydroxychloroquine and sulfasalazine. Hydroxychloroquine is effective for mild arthritis, and it’s rated by the Food and Drug Administration as Pregnancy Category C, with no reports of human toxicity. Sulfasalazine has a good safety profile in pregnancy – it is Pregnancy Category B – and has good efficacy for peripheral arthritis.
"These are two very important medications that are much better – and definitely much safer – options than prednisone. These are just great options, and I try to encourage patients to take them. It’s definitely better than letting patients flare while off methotrexate before they deliver," she continued.
"TNF [tumor necrosis factor] inhibitors are, I think, another reasonable option, particularly in the population with moderate to severe disease activity. If any of these medications help you avoid prednisone, then I think you come out ahead," Dr. Clowse said.
Reassuring data regarding the safety of anti-TNF biologics in pregnancy comes from several sources. A systematic literature review by Dr. Evelyne Vinet and her coworkers at McGill University, Montreal, found no evidence of excess risk of adverse pregnancy or fetal outcomes in women exposed to etanercept (Enbrel), infliximab (Remicade), or adalimumab (Humira) during pregnancy (Arthritis Rheum. 2009;61:587-92). A report from the Organization of Teratology Information Specialists (OTIS) Registry, presented at the 2012 annual meeting of the American College of Rheumatology, found no significant difference between RA patients exposed to adalimumab in pregnancy and RA controls in rates of live birth, miscarriage, stillbirth, congenital abnormalities, or serious infections in the first year of life.
Moreover, DAP Registry data support the notion that for some patients, anti-TNF biologics during pregnancy may be a good option. In Dr. Clowse’s series of 29 RA patients, disease activity during the first trimester neatly delineated three distinct groups. Eleven patients who had a 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) averaging 1.5 in the first trimester required neither TNF inhibitors nor prednisone during their pregnancy, and they had no abnormal outcomes. Seven patients with significant first-trimester disease activity as defined by an average DAS28-CRP score of 3.4 went back on their TNF inhibitor during pregnancy, and their disease essentially went into remission, with only one preterm birth. In contrast, 11 other patients with significant first-trimester disease activity went on prednisone because they rejected TNF inhibitor therapy; their disease activity remained substantial, and 6 of the 11 had a preterm birth and/or preeclampsia.
"All of the preeclampsia occurred in the prednisone group. They also had a lot of disease activity postpartum," Dr. Clowse observed.
Infliximab and adalimumab freely pass across the placenta; etanercept and certolizumab pegol (Cimzia) do not. Regardless, no infant exposed in utero to a TNF inhibitor should receive the rotavirus vaccine during the first 5 months of life. That’s the only live-virus vaccine given during infancy in the United States; all the other vaccines can safely be given according to schedule.
Dr. Clowse said there is essentially no published literature regarding psoriatic arthritis in pregnancy. The DAP registry experience includes seven pregnancies in women with psoriatic arthritis. There were no pregnancy losses, one preterm birth, and two cases of preeclampsia.
"What I see is dramatically increased disease activity when women with psoriatic arthritis stop their TNF inhibitor. The worst psoriasis I’ve ever seen is in pregnant patients; they are really miserable off their TNF inhibitors," she said.
There is also very little in the literature about axial spondyloarthritis in pregnancy. The DAP registry’s 10 cases constitute one of the largest series. There were no pregnancy losses, no preeclampsia, and one preterm birth. Eight of the women were delivered by C-section.
"That reflects my personal bias, which is that the position required for vaginal delivery is pretty horrible for sacroiliac joint pain and leads to significant flares postpartum. That’s particularly true if the patient has an epidural and doesn’t know how hard she’s pushing on those SI joints," according to the rheumatologist.
Dr. Clowse reported serving as a consultant to UCB, which markets certolizumab pegol.
SNOWMASS, COLO. – The common strategy of managing inflammatory arthritis during pregnancy by stopping all prepregnancy medications and prescribing prednisone is counterproductive, Dr. Megan E.B. Clowse said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
"This sort of safe approach is actually not the safest or best approach. We all need to shift our attitude and get comfortable with at least a couple of other medications in order to help our patients have better outcomes," asserted Dr. Clowse, director of the Duke Autoimmunity in Pregnancy (DAP) Registry at Duke University, Durham, N.C.
It’s often true that rheumatoid arthritis (RA) tends to get better in pregnancy. Nonetheless, pregnancy may not be enough to control disease activity in many women, as illustrated by a nationwide Dutch study in which half of RA patients had moderate to severe disease activity by their third trimester (Arthritis Rheum. 2008;59:1241-8).
"In my experience, the patients who were on tumor necrosis factor inhibitors prepregnancy do not do as well when they come off them. So pregnancy might be good for RA disease activity, but it’s definitely not as good as a tumor necrosis factor inhibitor," according to the rheumatologist.
Roughly one-quarter of the more than 230 prospectively studied pregnancies in the DAP Registry have been in women with RA or other inflammatory arthritides. The preterm birth rate in RA patients in DAP, as in other RA registries, is higher than in the general population. Notably, all of the DAP patients with RA who had preterm birth had moderate to severe disease activity in the first and second trimesters, compared with just a single RA patient with a term delivery.
"Allowing disease to flare may actually harm the pregnancy," Dr. Clowse commented.
Her two top recommendations for nonbiologic treatment of inflammatory arthritis during pregnancy are hydroxychloroquine and sulfasalazine. Hydroxychloroquine is effective for mild arthritis, and it’s rated by the Food and Drug Administration as Pregnancy Category C, with no reports of human toxicity. Sulfasalazine has a good safety profile in pregnancy – it is Pregnancy Category B – and has good efficacy for peripheral arthritis.
"These are two very important medications that are much better – and definitely much safer – options than prednisone. These are just great options, and I try to encourage patients to take them. It’s definitely better than letting patients flare while off methotrexate before they deliver," she continued.
"TNF [tumor necrosis factor] inhibitors are, I think, another reasonable option, particularly in the population with moderate to severe disease activity. If any of these medications help you avoid prednisone, then I think you come out ahead," Dr. Clowse said.
Reassuring data regarding the safety of anti-TNF biologics in pregnancy comes from several sources. A systematic literature review by Dr. Evelyne Vinet and her coworkers at McGill University, Montreal, found no evidence of excess risk of adverse pregnancy or fetal outcomes in women exposed to etanercept (Enbrel), infliximab (Remicade), or adalimumab (Humira) during pregnancy (Arthritis Rheum. 2009;61:587-92). A report from the Organization of Teratology Information Specialists (OTIS) Registry, presented at the 2012 annual meeting of the American College of Rheumatology, found no significant difference between RA patients exposed to adalimumab in pregnancy and RA controls in rates of live birth, miscarriage, stillbirth, congenital abnormalities, or serious infections in the first year of life.
Moreover, DAP Registry data support the notion that for some patients, anti-TNF biologics during pregnancy may be a good option. In Dr. Clowse’s series of 29 RA patients, disease activity during the first trimester neatly delineated three distinct groups. Eleven patients who had a 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) averaging 1.5 in the first trimester required neither TNF inhibitors nor prednisone during their pregnancy, and they had no abnormal outcomes. Seven patients with significant first-trimester disease activity as defined by an average DAS28-CRP score of 3.4 went back on their TNF inhibitor during pregnancy, and their disease essentially went into remission, with only one preterm birth. In contrast, 11 other patients with significant first-trimester disease activity went on prednisone because they rejected TNF inhibitor therapy; their disease activity remained substantial, and 6 of the 11 had a preterm birth and/or preeclampsia.
"All of the preeclampsia occurred in the prednisone group. They also had a lot of disease activity postpartum," Dr. Clowse observed.
Infliximab and adalimumab freely pass across the placenta; etanercept and certolizumab pegol (Cimzia) do not. Regardless, no infant exposed in utero to a TNF inhibitor should receive the rotavirus vaccine during the first 5 months of life. That’s the only live-virus vaccine given during infancy in the United States; all the other vaccines can safely be given according to schedule.
Dr. Clowse said there is essentially no published literature regarding psoriatic arthritis in pregnancy. The DAP registry experience includes seven pregnancies in women with psoriatic arthritis. There were no pregnancy losses, one preterm birth, and two cases of preeclampsia.
"What I see is dramatically increased disease activity when women with psoriatic arthritis stop their TNF inhibitor. The worst psoriasis I’ve ever seen is in pregnant patients; they are really miserable off their TNF inhibitors," she said.
There is also very little in the literature about axial spondyloarthritis in pregnancy. The DAP registry’s 10 cases constitute one of the largest series. There were no pregnancy losses, no preeclampsia, and one preterm birth. Eight of the women were delivered by C-section.
"That reflects my personal bias, which is that the position required for vaginal delivery is pretty horrible for sacroiliac joint pain and leads to significant flares postpartum. That’s particularly true if the patient has an epidural and doesn’t know how hard she’s pushing on those SI joints," according to the rheumatologist.
Dr. Clowse reported serving as a consultant to UCB, which markets certolizumab pegol.
EXPERT ANALYSIS FROM THE WINTER RHEUMATOLOGY SYMPOSIUM
Smoking has damaging impact in ankylosing spondylitis
SAN DIEGO – Smoking increases the effect of inflammation on x-ray damage in people with ankylosing spondylitis by more than fivefold, results from a Dutch study demonstrated. In addition, the effect is amplified by more than 13-fold in male smokers, compared with females who don’t smoke.
Those are the key findings from OASIS (Outcome in AS International Study), which followed ankylosing spondylitis patients for up to 12 years with biannual clinical assessments, including radiographs. Lead investigator Dr. Sofia Ramiro of the Academic Medical Center at the University of Amsterdam discussed the study during a press briefing at the annual meeting of the American College of Rheumatology.
Two reviewers independently scored the x-rays of 127 patients with ankylosing spondylitis according to the Modified Stoke Ankylosing Spondylitis Supine Score (mSASSS). Dr. Ramiro and her associates evaluated the relationship between the AS Disease Activity Score and x-ray damage over a period of 12 years by assessing the effect of inflammation at one point in time on the progression of damage 2 years later.
The mean age of the 127 patients was 41 years and 71% were male. Their mean symptom duration was 18 years, 82% were human leukocyte antigen B27 (HLA-B27) positive, and 40% were smokers.
Overall, smokers had a 5.5-fold higher effect of inflammation on x-ray damage, compared with nonsmokers, and male smokers had a 13.4-fold higher effect of inflammation on damage, compared with female nonsmokers. In addition, smokers with a short symptom duration – defined as those with fewer than 18 years of symptoms – had an 8.1-fold higher effect of inflammation on damage, compared with nonsmokers with long symptom duration.
"Smoking cessation, especially among young males, seems to be an important take-home message," Dr. Ramiro commented. "It will probably lead to less radiographic damage and to better long-term outcomes."
The press briefing’s moderator, Dr. Christie M. Bartels of the division of rheumatology at the University of Wisconsin in Madison, characterized the findings as "additional compelling evidence to say that smoking cessation would be an important process measure to look at in the rheumatology clinic, so that we can help our patients achieve their optimal outcomes."
As to the possible mechanism of action behind the relationship, Dr. Ramiro speculated that "it’s not really smoking itself that’s contributing to the worse outcomes. Smoking is increasing the impact of inflammation on radiographic damage. It’s inflammation that causes the damage."
In an interview, she acknowledged certain limitations of the study, including the fact that the sample size "is not large enough to split the data into several relevant subgroups. For instance, the number of females is rather small, as is the number of HLA-B27–negative males and females."
Dr. Ramiro said that she had no relevant financial conflicts to disclose.
SAN DIEGO – Smoking increases the effect of inflammation on x-ray damage in people with ankylosing spondylitis by more than fivefold, results from a Dutch study demonstrated. In addition, the effect is amplified by more than 13-fold in male smokers, compared with females who don’t smoke.
Those are the key findings from OASIS (Outcome in AS International Study), which followed ankylosing spondylitis patients for up to 12 years with biannual clinical assessments, including radiographs. Lead investigator Dr. Sofia Ramiro of the Academic Medical Center at the University of Amsterdam discussed the study during a press briefing at the annual meeting of the American College of Rheumatology.
Two reviewers independently scored the x-rays of 127 patients with ankylosing spondylitis according to the Modified Stoke Ankylosing Spondylitis Supine Score (mSASSS). Dr. Ramiro and her associates evaluated the relationship between the AS Disease Activity Score and x-ray damage over a period of 12 years by assessing the effect of inflammation at one point in time on the progression of damage 2 years later.
The mean age of the 127 patients was 41 years and 71% were male. Their mean symptom duration was 18 years, 82% were human leukocyte antigen B27 (HLA-B27) positive, and 40% were smokers.
Overall, smokers had a 5.5-fold higher effect of inflammation on x-ray damage, compared with nonsmokers, and male smokers had a 13.4-fold higher effect of inflammation on damage, compared with female nonsmokers. In addition, smokers with a short symptom duration – defined as those with fewer than 18 years of symptoms – had an 8.1-fold higher effect of inflammation on damage, compared with nonsmokers with long symptom duration.
"Smoking cessation, especially among young males, seems to be an important take-home message," Dr. Ramiro commented. "It will probably lead to less radiographic damage and to better long-term outcomes."
The press briefing’s moderator, Dr. Christie M. Bartels of the division of rheumatology at the University of Wisconsin in Madison, characterized the findings as "additional compelling evidence to say that smoking cessation would be an important process measure to look at in the rheumatology clinic, so that we can help our patients achieve their optimal outcomes."
As to the possible mechanism of action behind the relationship, Dr. Ramiro speculated that "it’s not really smoking itself that’s contributing to the worse outcomes. Smoking is increasing the impact of inflammation on radiographic damage. It’s inflammation that causes the damage."
In an interview, she acknowledged certain limitations of the study, including the fact that the sample size "is not large enough to split the data into several relevant subgroups. For instance, the number of females is rather small, as is the number of HLA-B27–negative males and females."
Dr. Ramiro said that she had no relevant financial conflicts to disclose.
SAN DIEGO – Smoking increases the effect of inflammation on x-ray damage in people with ankylosing spondylitis by more than fivefold, results from a Dutch study demonstrated. In addition, the effect is amplified by more than 13-fold in male smokers, compared with females who don’t smoke.
Those are the key findings from OASIS (Outcome in AS International Study), which followed ankylosing spondylitis patients for up to 12 years with biannual clinical assessments, including radiographs. Lead investigator Dr. Sofia Ramiro of the Academic Medical Center at the University of Amsterdam discussed the study during a press briefing at the annual meeting of the American College of Rheumatology.
Two reviewers independently scored the x-rays of 127 patients with ankylosing spondylitis according to the Modified Stoke Ankylosing Spondylitis Supine Score (mSASSS). Dr. Ramiro and her associates evaluated the relationship between the AS Disease Activity Score and x-ray damage over a period of 12 years by assessing the effect of inflammation at one point in time on the progression of damage 2 years later.
The mean age of the 127 patients was 41 years and 71% were male. Their mean symptom duration was 18 years, 82% were human leukocyte antigen B27 (HLA-B27) positive, and 40% were smokers.
Overall, smokers had a 5.5-fold higher effect of inflammation on x-ray damage, compared with nonsmokers, and male smokers had a 13.4-fold higher effect of inflammation on damage, compared with female nonsmokers. In addition, smokers with a short symptom duration – defined as those with fewer than 18 years of symptoms – had an 8.1-fold higher effect of inflammation on damage, compared with nonsmokers with long symptom duration.
"Smoking cessation, especially among young males, seems to be an important take-home message," Dr. Ramiro commented. "It will probably lead to less radiographic damage and to better long-term outcomes."
The press briefing’s moderator, Dr. Christie M. Bartels of the division of rheumatology at the University of Wisconsin in Madison, characterized the findings as "additional compelling evidence to say that smoking cessation would be an important process measure to look at in the rheumatology clinic, so that we can help our patients achieve their optimal outcomes."
As to the possible mechanism of action behind the relationship, Dr. Ramiro speculated that "it’s not really smoking itself that’s contributing to the worse outcomes. Smoking is increasing the impact of inflammation on radiographic damage. It’s inflammation that causes the damage."
In an interview, she acknowledged certain limitations of the study, including the fact that the sample size "is not large enough to split the data into several relevant subgroups. For instance, the number of females is rather small, as is the number of HLA-B27–negative males and females."
Dr. Ramiro said that she had no relevant financial conflicts to disclose.
AT THE ACR ANNUAL MEETING
Major finding: Smokers had a 5.5-fold higher effect of inflammation on x-ray damage, compared with nonsmokers, and male smokers had a 13.4-fold higher effect of inflammation on damage, compared with female nonsmokers.
Data source: An assessment of 127 patients enrolled in the Outcome in AS International Study (OASIS), which followed ankylosing spondylitis patients for up to 12 years with biannual clinical assessments, including radiographs.
Disclosures: Dr. Ramiro said that she had no relevant financial conflicts to disclose.
Proposed axial spondyloarthritis indication for certolizumab divides FDA panel
SILVER SPRING, MD. – A Food and Drug Administration advisory panel split its vote on whether to recommend the approval of certolizumab as a treatment for axial spondyloarthritis, based on a study of 325 patients with ankylosing spondylitis or nonradiographic axial spondyloarthritis.
At a July 23 meeting, the FDA’s Arthritis Advisory Committee voted 7-6, with one abstention, to recommend approval of the tumor necrosis factor (TNF) blocker for the manufacturer’s proposed indication: treatment of "active axial spondyloarthritis, including patients with ankylosing spondylitis."
Certolizumab, a TNF blocker, was approved in 2008 for treating Crohn’s disease and in 2009 for treating rheumatoid arthritis (RA). It is marketed as Cimzia by UCB and is administered by subcutaneous injection every 4 weeks for Crohn’s disease and every other week or every 4 weeks for RA, as maintenance therapy. Currently, four other TNF inhibitors are approved for ankylosing spondylitis (AS) but none are approved for treating nonradiographic axial spondyloarthritis (nr-axSpA).
The pivotal study compared two dosing regimens of certolizumab against placebo in patients with active axial spondyloarthritis who had an inadequate response to NSAIDs or a contraindication to NSAIDs (178 patients with AS, and 147 patients with nr-axSpA). The dosing regimens were the same as those currently approved for rheumatoid arthritis: a loading dose of 400 mg in weeks 0, 2, and 4, followed by either 200 mg every 2 weeks (Q2W) or 400 mg every 4 weeks (Q4W). Requirements for enrollment included chronic back pain for at least 3 months; onset before age 45 years; and imaging criteria that included sacroiliitis (on MRI or X-ray) with at least one spondyloarthritis feature, such as inflammation, back pain, arthritis, uveitis, or dactylitis.
At 12 weeks, 58% of patients on the Q2W regimen and 64% on the Q4W regimen had achieved an ASAS (Assessment of SpondyloArthritis international Society) 20 response, the primary endpoint, compared with 38% of those on placebo, both of which were statistically significant differences. The differences remained significant at 24 weeks. ASAS20 responses in the two subpopulations, those with AS and those with nr-axSpA, also favored those treated with certolizumab.
Treatment with certolizumab also resulted in significant improvements in function and spinal mobility, with similar responses at both dosage regimens, compared with placebo, as well as improvements in spinal and sacroiliac joint inflammation, productivity, and health-related quality of life, according to UCB.
The rates of serious adverse events were similar in the certolizumab-treated and placebo groups, the safety profile of certolizumab was consistent with the known safety profile of TNF inhibitors, and no new safety signals were identified. The rate of serious infections, a known risk, was higher among those on certolizumab.
The main issue raised by the FDA was whether the data from this study were adequate to support the indication, especially for patients with nr-axSpA, which would be a new indication for an approved treatment, according to Dr. Janet Maynard, acting clinical team leader in the FDA’s Division of Pulmonary, Allergy, and Rheumatology Products. But the FDA’s analysis of the data did not suggest that the efficacy results were driven by any subgroup, and the efficacy data for AS "appear reasonable," she said at the meeting.
The panel had no substantial safety concerns – voting 13-1 that the safety profile of certolizumab was adequate to support approval of the new indication – and agreed there was evidence of efficacy. Those voting against approval, however, thought that the indication was too broad and had concerns that included the small number of patients for a new indication (nr-axSpA), the lack of a clear definition of active disease in the indication, and the possibility that primary care physicians would prescribe the biologic drug for patients with low back pain.
Panelists supporting approval said that adequate prescribing information would result in appropriate use for patients with active disease in clinical practice.
The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting; occasionally, a panelist might be given a waiver, but not at this meeting.
Certolizumab, a TNF blocker, Crohn’s disease, rheumatoid arthritis (RA), Cimzia, UCB, subcutaneous injection, Dr. Janet Maynard, FDA’s Division of Pulmonary, Allergy, and Rheumatology Products,
SILVER SPRING, MD. – A Food and Drug Administration advisory panel split its vote on whether to recommend the approval of certolizumab as a treatment for axial spondyloarthritis, based on a study of 325 patients with ankylosing spondylitis or nonradiographic axial spondyloarthritis.
At a July 23 meeting, the FDA’s Arthritis Advisory Committee voted 7-6, with one abstention, to recommend approval of the tumor necrosis factor (TNF) blocker for the manufacturer’s proposed indication: treatment of "active axial spondyloarthritis, including patients with ankylosing spondylitis."
Certolizumab, a TNF blocker, was approved in 2008 for treating Crohn’s disease and in 2009 for treating rheumatoid arthritis (RA). It is marketed as Cimzia by UCB and is administered by subcutaneous injection every 4 weeks for Crohn’s disease and every other week or every 4 weeks for RA, as maintenance therapy. Currently, four other TNF inhibitors are approved for ankylosing spondylitis (AS) but none are approved for treating nonradiographic axial spondyloarthritis (nr-axSpA).
The pivotal study compared two dosing regimens of certolizumab against placebo in patients with active axial spondyloarthritis who had an inadequate response to NSAIDs or a contraindication to NSAIDs (178 patients with AS, and 147 patients with nr-axSpA). The dosing regimens were the same as those currently approved for rheumatoid arthritis: a loading dose of 400 mg in weeks 0, 2, and 4, followed by either 200 mg every 2 weeks (Q2W) or 400 mg every 4 weeks (Q4W). Requirements for enrollment included chronic back pain for at least 3 months; onset before age 45 years; and imaging criteria that included sacroiliitis (on MRI or X-ray) with at least one spondyloarthritis feature, such as inflammation, back pain, arthritis, uveitis, or dactylitis.
At 12 weeks, 58% of patients on the Q2W regimen and 64% on the Q4W regimen had achieved an ASAS (Assessment of SpondyloArthritis international Society) 20 response, the primary endpoint, compared with 38% of those on placebo, both of which were statistically significant differences. The differences remained significant at 24 weeks. ASAS20 responses in the two subpopulations, those with AS and those with nr-axSpA, also favored those treated with certolizumab.
Treatment with certolizumab also resulted in significant improvements in function and spinal mobility, with similar responses at both dosage regimens, compared with placebo, as well as improvements in spinal and sacroiliac joint inflammation, productivity, and health-related quality of life, according to UCB.
The rates of serious adverse events were similar in the certolizumab-treated and placebo groups, the safety profile of certolizumab was consistent with the known safety profile of TNF inhibitors, and no new safety signals were identified. The rate of serious infections, a known risk, was higher among those on certolizumab.
The main issue raised by the FDA was whether the data from this study were adequate to support the indication, especially for patients with nr-axSpA, which would be a new indication for an approved treatment, according to Dr. Janet Maynard, acting clinical team leader in the FDA’s Division of Pulmonary, Allergy, and Rheumatology Products. But the FDA’s analysis of the data did not suggest that the efficacy results were driven by any subgroup, and the efficacy data for AS "appear reasonable," she said at the meeting.
The panel had no substantial safety concerns – voting 13-1 that the safety profile of certolizumab was adequate to support approval of the new indication – and agreed there was evidence of efficacy. Those voting against approval, however, thought that the indication was too broad and had concerns that included the small number of patients for a new indication (nr-axSpA), the lack of a clear definition of active disease in the indication, and the possibility that primary care physicians would prescribe the biologic drug for patients with low back pain.
Panelists supporting approval said that adequate prescribing information would result in appropriate use for patients with active disease in clinical practice.
The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting; occasionally, a panelist might be given a waiver, but not at this meeting.
SILVER SPRING, MD. – A Food and Drug Administration advisory panel split its vote on whether to recommend the approval of certolizumab as a treatment for axial spondyloarthritis, based on a study of 325 patients with ankylosing spondylitis or nonradiographic axial spondyloarthritis.
At a July 23 meeting, the FDA’s Arthritis Advisory Committee voted 7-6, with one abstention, to recommend approval of the tumor necrosis factor (TNF) blocker for the manufacturer’s proposed indication: treatment of "active axial spondyloarthritis, including patients with ankylosing spondylitis."
Certolizumab, a TNF blocker, was approved in 2008 for treating Crohn’s disease and in 2009 for treating rheumatoid arthritis (RA). It is marketed as Cimzia by UCB and is administered by subcutaneous injection every 4 weeks for Crohn’s disease and every other week or every 4 weeks for RA, as maintenance therapy. Currently, four other TNF inhibitors are approved for ankylosing spondylitis (AS) but none are approved for treating nonradiographic axial spondyloarthritis (nr-axSpA).
The pivotal study compared two dosing regimens of certolizumab against placebo in patients with active axial spondyloarthritis who had an inadequate response to NSAIDs or a contraindication to NSAIDs (178 patients with AS, and 147 patients with nr-axSpA). The dosing regimens were the same as those currently approved for rheumatoid arthritis: a loading dose of 400 mg in weeks 0, 2, and 4, followed by either 200 mg every 2 weeks (Q2W) or 400 mg every 4 weeks (Q4W). Requirements for enrollment included chronic back pain for at least 3 months; onset before age 45 years; and imaging criteria that included sacroiliitis (on MRI or X-ray) with at least one spondyloarthritis feature, such as inflammation, back pain, arthritis, uveitis, or dactylitis.
At 12 weeks, 58% of patients on the Q2W regimen and 64% on the Q4W regimen had achieved an ASAS (Assessment of SpondyloArthritis international Society) 20 response, the primary endpoint, compared with 38% of those on placebo, both of which were statistically significant differences. The differences remained significant at 24 weeks. ASAS20 responses in the two subpopulations, those with AS and those with nr-axSpA, also favored those treated with certolizumab.
Treatment with certolizumab also resulted in significant improvements in function and spinal mobility, with similar responses at both dosage regimens, compared with placebo, as well as improvements in spinal and sacroiliac joint inflammation, productivity, and health-related quality of life, according to UCB.
The rates of serious adverse events were similar in the certolizumab-treated and placebo groups, the safety profile of certolizumab was consistent with the known safety profile of TNF inhibitors, and no new safety signals were identified. The rate of serious infections, a known risk, was higher among those on certolizumab.
The main issue raised by the FDA was whether the data from this study were adequate to support the indication, especially for patients with nr-axSpA, which would be a new indication for an approved treatment, according to Dr. Janet Maynard, acting clinical team leader in the FDA’s Division of Pulmonary, Allergy, and Rheumatology Products. But the FDA’s analysis of the data did not suggest that the efficacy results were driven by any subgroup, and the efficacy data for AS "appear reasonable," she said at the meeting.
The panel had no substantial safety concerns – voting 13-1 that the safety profile of certolizumab was adequate to support approval of the new indication – and agreed there was evidence of efficacy. Those voting against approval, however, thought that the indication was too broad and had concerns that included the small number of patients for a new indication (nr-axSpA), the lack of a clear definition of active disease in the indication, and the possibility that primary care physicians would prescribe the biologic drug for patients with low back pain.
Panelists supporting approval said that adequate prescribing information would result in appropriate use for patients with active disease in clinical practice.
The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting; occasionally, a panelist might be given a waiver, but not at this meeting.
Certolizumab, a TNF blocker, Crohn’s disease, rheumatoid arthritis (RA), Cimzia, UCB, subcutaneous injection, Dr. Janet Maynard, FDA’s Division of Pulmonary, Allergy, and Rheumatology Products,
Certolizumab, a TNF blocker, Crohn’s disease, rheumatoid arthritis (RA), Cimzia, UCB, subcutaneous injection, Dr. Janet Maynard, FDA’s Division of Pulmonary, Allergy, and Rheumatology Products,
AT THE FDA ADVISORY COMMITTEE MEETING
FDA panel votes against new AS indication for TNF-blocker
SILVER SPRING, MD. – Citing uncertainties about the efficacy data in a pivotal trial, the majority of a Food and Drug Administration advisory panel recommended against expanding the approval of adalimumab to include patients with axial spondyloarthritis who do not have radiographic evidence of ankylosing spondylitis.
At a July 23 meeting, the FDA’s Arthritis Advisory Committee voted 12-1, with 1 abstention, against recommending approval of adalimumab for the indication proposed by the manufacturer, AbbVie Inc.: reducing signs and symptoms in adults with active nonradiographic axial spondyloarthritis (nr-axSpA) with objective signs of inflammation (elevated C-reactive protein or MRI findings) and who have had an inadequate response to, or are intolerant of nonsteroidal anti-inflammatory drugs.
Adalimumab is a monoclonal antibody against tumor necrosis factor (TNF) that was initially approved by the FDA in December 2002 as a treatment for rheumatoid arthritis in adults and was subsequently approved in 2006 for reducing the signs and symptoms of active ankylosing spondylitis (AS) in adults. It is also approved for psoriatic arthritis, juvenile idiopathic arthritis, Crohn’s disease, ulcerative colitis, and plaque psoriasis. It is administered by subcutaneous injection every other week.
Axial spondyloarthritis (axial SpA) includes AS and nr-axSpA; there are no FDA-approved treatments for people with nr-axSpA.
The majority of the panel agreed that no new safety signals were seen in the pivotal study and that the safety profile of adalimumab would not be expected to be different in patients with nr-axSpA and those with RA and other approved indications. But the panel voted that the manufacturer’s data did not provide substantial evidence that the drug resulted in a "clinically meaningful beneficial effect" for these patients, the efficacy criteria needed for approval.
The study compared adalimumab to placebo in 192 patients with active nr-axSpA, who had an inadequate response to NSAIDs, could not tolerate NSAIDs, or had a contraindication to NSAIDs. Patients were able to continue treatment with DMARDs, including sulfasalazine and methotrexate. The primary endpoint used to evaluate clinical responses was the ASAS (Assessment of SpondyloArthritis International Society) 40 response, which is defined as an improvement of at least 40% and absolute improvement of at least two units from baseline in at least three of four domains with no deterioration in the remaining domain (pain, function, morning stiffness, and Patient’s Global Assessment of Disease Activity).
At 12 weeks, 36% of those on adalimumab at a dose of 40 mg every other week had achieved an ASAS40 response, compared with 15% of those on placebo, a statistically significant difference. About 20% of those on adalimumab were in clinical remission at week 12, and efficacy was maintained or improved further among those who continued adalimumab in the open-label period through 68 weeks, according to the company. Adverse events were similar to those associated with the use of adalimumab in patients with AS, psoriatic arthritis, and rheumatoid arthritis.
But based on patient x-rays read at a central facility, a substantial proportion of patients in the trial had radiographic evidence of AS, an approved indication for adalimumab, which the FDA reviewer said may have affected the efficacy results. The FDA’s analysis of ASAS40 responses identified a markedly greater beneficial effect among those who had AS and had positive findings on x-rays, compared with those who had negative x-ray results and had nr-axSpA. In addition, the estimated effect of treatment in the nr-axSpA patients was described as "modest" by the FDA.
Panelists said that there is an unmet need for treatments in patients with this group, and encouraged the company to conduct another, better-designed study.
The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting; occasionally, a panelist might be given a waiver, but not at this meeting.
In July 2012, adalimumab was approved in the European Union for nr-axSpA.
SILVER SPRING, MD. – Citing uncertainties about the efficacy data in a pivotal trial, the majority of a Food and Drug Administration advisory panel recommended against expanding the approval of adalimumab to include patients with axial spondyloarthritis who do not have radiographic evidence of ankylosing spondylitis.
At a July 23 meeting, the FDA’s Arthritis Advisory Committee voted 12-1, with 1 abstention, against recommending approval of adalimumab for the indication proposed by the manufacturer, AbbVie Inc.: reducing signs and symptoms in adults with active nonradiographic axial spondyloarthritis (nr-axSpA) with objective signs of inflammation (elevated C-reactive protein or MRI findings) and who have had an inadequate response to, or are intolerant of nonsteroidal anti-inflammatory drugs.
Adalimumab is a monoclonal antibody against tumor necrosis factor (TNF) that was initially approved by the FDA in December 2002 as a treatment for rheumatoid arthritis in adults and was subsequently approved in 2006 for reducing the signs and symptoms of active ankylosing spondylitis (AS) in adults. It is also approved for psoriatic arthritis, juvenile idiopathic arthritis, Crohn’s disease, ulcerative colitis, and plaque psoriasis. It is administered by subcutaneous injection every other week.
Axial spondyloarthritis (axial SpA) includes AS and nr-axSpA; there are no FDA-approved treatments for people with nr-axSpA.
The majority of the panel agreed that no new safety signals were seen in the pivotal study and that the safety profile of adalimumab would not be expected to be different in patients with nr-axSpA and those with RA and other approved indications. But the panel voted that the manufacturer’s data did not provide substantial evidence that the drug resulted in a "clinically meaningful beneficial effect" for these patients, the efficacy criteria needed for approval.
The study compared adalimumab to placebo in 192 patients with active nr-axSpA, who had an inadequate response to NSAIDs, could not tolerate NSAIDs, or had a contraindication to NSAIDs. Patients were able to continue treatment with DMARDs, including sulfasalazine and methotrexate. The primary endpoint used to evaluate clinical responses was the ASAS (Assessment of SpondyloArthritis International Society) 40 response, which is defined as an improvement of at least 40% and absolute improvement of at least two units from baseline in at least three of four domains with no deterioration in the remaining domain (pain, function, morning stiffness, and Patient’s Global Assessment of Disease Activity).
At 12 weeks, 36% of those on adalimumab at a dose of 40 mg every other week had achieved an ASAS40 response, compared with 15% of those on placebo, a statistically significant difference. About 20% of those on adalimumab were in clinical remission at week 12, and efficacy was maintained or improved further among those who continued adalimumab in the open-label period through 68 weeks, according to the company. Adverse events were similar to those associated with the use of adalimumab in patients with AS, psoriatic arthritis, and rheumatoid arthritis.
But based on patient x-rays read at a central facility, a substantial proportion of patients in the trial had radiographic evidence of AS, an approved indication for adalimumab, which the FDA reviewer said may have affected the efficacy results. The FDA’s analysis of ASAS40 responses identified a markedly greater beneficial effect among those who had AS and had positive findings on x-rays, compared with those who had negative x-ray results and had nr-axSpA. In addition, the estimated effect of treatment in the nr-axSpA patients was described as "modest" by the FDA.
Panelists said that there is an unmet need for treatments in patients with this group, and encouraged the company to conduct another, better-designed study.
The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting; occasionally, a panelist might be given a waiver, but not at this meeting.
In July 2012, adalimumab was approved in the European Union for nr-axSpA.
SILVER SPRING, MD. – Citing uncertainties about the efficacy data in a pivotal trial, the majority of a Food and Drug Administration advisory panel recommended against expanding the approval of adalimumab to include patients with axial spondyloarthritis who do not have radiographic evidence of ankylosing spondylitis.
At a July 23 meeting, the FDA’s Arthritis Advisory Committee voted 12-1, with 1 abstention, against recommending approval of adalimumab for the indication proposed by the manufacturer, AbbVie Inc.: reducing signs and symptoms in adults with active nonradiographic axial spondyloarthritis (nr-axSpA) with objective signs of inflammation (elevated C-reactive protein or MRI findings) and who have had an inadequate response to, or are intolerant of nonsteroidal anti-inflammatory drugs.
Adalimumab is a monoclonal antibody against tumor necrosis factor (TNF) that was initially approved by the FDA in December 2002 as a treatment for rheumatoid arthritis in adults and was subsequently approved in 2006 for reducing the signs and symptoms of active ankylosing spondylitis (AS) in adults. It is also approved for psoriatic arthritis, juvenile idiopathic arthritis, Crohn’s disease, ulcerative colitis, and plaque psoriasis. It is administered by subcutaneous injection every other week.
Axial spondyloarthritis (axial SpA) includes AS and nr-axSpA; there are no FDA-approved treatments for people with nr-axSpA.
The majority of the panel agreed that no new safety signals were seen in the pivotal study and that the safety profile of adalimumab would not be expected to be different in patients with nr-axSpA and those with RA and other approved indications. But the panel voted that the manufacturer’s data did not provide substantial evidence that the drug resulted in a "clinically meaningful beneficial effect" for these patients, the efficacy criteria needed for approval.
The study compared adalimumab to placebo in 192 patients with active nr-axSpA, who had an inadequate response to NSAIDs, could not tolerate NSAIDs, or had a contraindication to NSAIDs. Patients were able to continue treatment with DMARDs, including sulfasalazine and methotrexate. The primary endpoint used to evaluate clinical responses was the ASAS (Assessment of SpondyloArthritis International Society) 40 response, which is defined as an improvement of at least 40% and absolute improvement of at least two units from baseline in at least three of four domains with no deterioration in the remaining domain (pain, function, morning stiffness, and Patient’s Global Assessment of Disease Activity).
At 12 weeks, 36% of those on adalimumab at a dose of 40 mg every other week had achieved an ASAS40 response, compared with 15% of those on placebo, a statistically significant difference. About 20% of those on adalimumab were in clinical remission at week 12, and efficacy was maintained or improved further among those who continued adalimumab in the open-label period through 68 weeks, according to the company. Adverse events were similar to those associated with the use of adalimumab in patients with AS, psoriatic arthritis, and rheumatoid arthritis.
But based on patient x-rays read at a central facility, a substantial proportion of patients in the trial had radiographic evidence of AS, an approved indication for adalimumab, which the FDA reviewer said may have affected the efficacy results. The FDA’s analysis of ASAS40 responses identified a markedly greater beneficial effect among those who had AS and had positive findings on x-rays, compared with those who had negative x-ray results and had nr-axSpA. In addition, the estimated effect of treatment in the nr-axSpA patients was described as "modest" by the FDA.
Panelists said that there is an unmet need for treatments in patients with this group, and encouraged the company to conduct another, better-designed study.
The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting; occasionally, a panelist might be given a waiver, but not at this meeting.
In July 2012, adalimumab was approved in the European Union for nr-axSpA.
AT AN FDA ADVISORY COMMITTEE MEETING
Serum biomarker predicts radiographic progression in spondyloarthritis
MADRID – Elevated serum levels of vascular endothelial growth factor may be predictive of radiographic progression in the spine, according to data from a German study of patients with spondyloarthritis.
The cutoff point appears to be at 600 pg/mL, with the effects particularly strong in patients who also develop syndesmophytes, which are bony growths that develop within ligaments.
"In patients with syndesmophytes, VEGF [vascular endothelial growth factor], as a predictor of radiographic progression, performed better than CRP [C-reactive protein]," reported Dr. Denis Poddubnyy at the annual European Congress of Rheumatology (Ann. Rheum. Dis. 2013;72:125).
"We all know that radiographic progression varies substantially among patients with spondyloarthritis," Dr. Poddubnyy observed. "Until recently there was only one strong predictor of radiographic progression: the presence of syndesmophytes at baseline," he added.
Last year, however, Dr. Poddubnyy of Charité Universitätsmedizin Berlin, Germany, and his associates published the findings of a study involving 210 patients with early axial spondyloarthritis (axSpA) who were recruited from the German Spondyloarthritis Inception Cohort (GESPIC). This study looked at baseline predictors of spinal radiographic progression over 2 years and found that in addition to radiographic damage, elevated CRP levels and cigarette smoking were independently predictive (Arthritis Rheum. 2012;64:1388-98).
The team’s research also suggested that there could be a few serum biomarkers, including VEGF, that could be predictive, so the investigators conducted a larger study in 172 patients with definite (n = 95) or nonradiographic (n = 77) axSpA to look specifically at the possible association.
Radiographs of the spine taken at baseline and at 2 years’ follow-up were reviewed independently by two readers, who used the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) to record the extent of radiographic progression. If there was a worsening of 2 units or more in mSASSS and the formation of new or increased growth of syndesmophytes, radiographic progression had occurred.
In total, 22 patients had radiographic progression, including 18 with new formation or growth of syndesmophytes.
Baseline VEGF was measured in the serum at baseline and was significantly higher in patients who developed radiographic progression at 2 years than in those who did not (562 plus or minus 357 pg/mL vs. 402 plus or minus 309 pg/mL; P = .027).
Serum VEGF levels were also significantly higher in the patients who had developed new syndesmophytes at 2 years when compared with those who had not (579 plus or minus 386 pg/mL vs. 404 plus or minus 307 pg/mL; P = .041).
"Patients with elevated VEGF had an odds ratio of 2.9 for [radiographic] progression and 3.1 for syndesmophyte formation," Dr. Poddubnyy reported. This was a little disappointing, he noted, as CRP and the erythrocyte sedimentation rate had similar predictive power.
However, in patients at high risk of progression, namely those with syndesmophytes already present at baseline, VEGF was significantly better than CRP at predicting both radiographic progression and new syndesmophyte formation or growth.
Patients with elevated VEGF at baseline were 36.6 times more likely to have radiographic progression and 13.6 times more likely to have new syndesmophyte formation or growth at 2 years than were those with levels below 600 pg/mL. In comparison, elevated CRP levels increased the risks by only 2.4 and 2.5 times, respectively.
VEGF is an essential mediator of angiogenesis and endochondral ossification, Dr. Poddubnyy observed. It’s been shown to have "a chemoattractive effect on osteoblasts and mesenchymal progenitor cells," he added, and also stimulate osteoblast differentiation and bone turnover.
While the results are very promising, further research is of course required. The possible predictive value of VEGF in relation to spinal radiographic progression in patients treated with tumor necrosis factor–alpha inhibitors remains to be seen, for example, and future studies should perhaps look at this question.
"With VEGF we are probably able to improve our prediction of spinal progression in patients with axSpA," Dr. Poddubnyy said in an interview. This is addition to assessing "classical factors," such as syndesmophytes, CRP, and smoking status.
Dr. Poddubnyy had no disclosures.
MADRID – Elevated serum levels of vascular endothelial growth factor may be predictive of radiographic progression in the spine, according to data from a German study of patients with spondyloarthritis.
The cutoff point appears to be at 600 pg/mL, with the effects particularly strong in patients who also develop syndesmophytes, which are bony growths that develop within ligaments.
"In patients with syndesmophytes, VEGF [vascular endothelial growth factor], as a predictor of radiographic progression, performed better than CRP [C-reactive protein]," reported Dr. Denis Poddubnyy at the annual European Congress of Rheumatology (Ann. Rheum. Dis. 2013;72:125).
"We all know that radiographic progression varies substantially among patients with spondyloarthritis," Dr. Poddubnyy observed. "Until recently there was only one strong predictor of radiographic progression: the presence of syndesmophytes at baseline," he added.
Last year, however, Dr. Poddubnyy of Charité Universitätsmedizin Berlin, Germany, and his associates published the findings of a study involving 210 patients with early axial spondyloarthritis (axSpA) who were recruited from the German Spondyloarthritis Inception Cohort (GESPIC). This study looked at baseline predictors of spinal radiographic progression over 2 years and found that in addition to radiographic damage, elevated CRP levels and cigarette smoking were independently predictive (Arthritis Rheum. 2012;64:1388-98).
The team’s research also suggested that there could be a few serum biomarkers, including VEGF, that could be predictive, so the investigators conducted a larger study in 172 patients with definite (n = 95) or nonradiographic (n = 77) axSpA to look specifically at the possible association.
Radiographs of the spine taken at baseline and at 2 years’ follow-up were reviewed independently by two readers, who used the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) to record the extent of radiographic progression. If there was a worsening of 2 units or more in mSASSS and the formation of new or increased growth of syndesmophytes, radiographic progression had occurred.
In total, 22 patients had radiographic progression, including 18 with new formation or growth of syndesmophytes.
Baseline VEGF was measured in the serum at baseline and was significantly higher in patients who developed radiographic progression at 2 years than in those who did not (562 plus or minus 357 pg/mL vs. 402 plus or minus 309 pg/mL; P = .027).
Serum VEGF levels were also significantly higher in the patients who had developed new syndesmophytes at 2 years when compared with those who had not (579 plus or minus 386 pg/mL vs. 404 plus or minus 307 pg/mL; P = .041).
"Patients with elevated VEGF had an odds ratio of 2.9 for [radiographic] progression and 3.1 for syndesmophyte formation," Dr. Poddubnyy reported. This was a little disappointing, he noted, as CRP and the erythrocyte sedimentation rate had similar predictive power.
However, in patients at high risk of progression, namely those with syndesmophytes already present at baseline, VEGF was significantly better than CRP at predicting both radiographic progression and new syndesmophyte formation or growth.
Patients with elevated VEGF at baseline were 36.6 times more likely to have radiographic progression and 13.6 times more likely to have new syndesmophyte formation or growth at 2 years than were those with levels below 600 pg/mL. In comparison, elevated CRP levels increased the risks by only 2.4 and 2.5 times, respectively.
VEGF is an essential mediator of angiogenesis and endochondral ossification, Dr. Poddubnyy observed. It’s been shown to have "a chemoattractive effect on osteoblasts and mesenchymal progenitor cells," he added, and also stimulate osteoblast differentiation and bone turnover.
While the results are very promising, further research is of course required. The possible predictive value of VEGF in relation to spinal radiographic progression in patients treated with tumor necrosis factor–alpha inhibitors remains to be seen, for example, and future studies should perhaps look at this question.
"With VEGF we are probably able to improve our prediction of spinal progression in patients with axSpA," Dr. Poddubnyy said in an interview. This is addition to assessing "classical factors," such as syndesmophytes, CRP, and smoking status.
Dr. Poddubnyy had no disclosures.
MADRID – Elevated serum levels of vascular endothelial growth factor may be predictive of radiographic progression in the spine, according to data from a German study of patients with spondyloarthritis.
The cutoff point appears to be at 600 pg/mL, with the effects particularly strong in patients who also develop syndesmophytes, which are bony growths that develop within ligaments.
"In patients with syndesmophytes, VEGF [vascular endothelial growth factor], as a predictor of radiographic progression, performed better than CRP [C-reactive protein]," reported Dr. Denis Poddubnyy at the annual European Congress of Rheumatology (Ann. Rheum. Dis. 2013;72:125).
"We all know that radiographic progression varies substantially among patients with spondyloarthritis," Dr. Poddubnyy observed. "Until recently there was only one strong predictor of radiographic progression: the presence of syndesmophytes at baseline," he added.
Last year, however, Dr. Poddubnyy of Charité Universitätsmedizin Berlin, Germany, and his associates published the findings of a study involving 210 patients with early axial spondyloarthritis (axSpA) who were recruited from the German Spondyloarthritis Inception Cohort (GESPIC). This study looked at baseline predictors of spinal radiographic progression over 2 years and found that in addition to radiographic damage, elevated CRP levels and cigarette smoking were independently predictive (Arthritis Rheum. 2012;64:1388-98).
The team’s research also suggested that there could be a few serum biomarkers, including VEGF, that could be predictive, so the investigators conducted a larger study in 172 patients with definite (n = 95) or nonradiographic (n = 77) axSpA to look specifically at the possible association.
Radiographs of the spine taken at baseline and at 2 years’ follow-up were reviewed independently by two readers, who used the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) to record the extent of radiographic progression. If there was a worsening of 2 units or more in mSASSS and the formation of new or increased growth of syndesmophytes, radiographic progression had occurred.
In total, 22 patients had radiographic progression, including 18 with new formation or growth of syndesmophytes.
Baseline VEGF was measured in the serum at baseline and was significantly higher in patients who developed radiographic progression at 2 years than in those who did not (562 plus or minus 357 pg/mL vs. 402 plus or minus 309 pg/mL; P = .027).
Serum VEGF levels were also significantly higher in the patients who had developed new syndesmophytes at 2 years when compared with those who had not (579 plus or minus 386 pg/mL vs. 404 plus or minus 307 pg/mL; P = .041).
"Patients with elevated VEGF had an odds ratio of 2.9 for [radiographic] progression and 3.1 for syndesmophyte formation," Dr. Poddubnyy reported. This was a little disappointing, he noted, as CRP and the erythrocyte sedimentation rate had similar predictive power.
However, in patients at high risk of progression, namely those with syndesmophytes already present at baseline, VEGF was significantly better than CRP at predicting both radiographic progression and new syndesmophyte formation or growth.
Patients with elevated VEGF at baseline were 36.6 times more likely to have radiographic progression and 13.6 times more likely to have new syndesmophyte formation or growth at 2 years than were those with levels below 600 pg/mL. In comparison, elevated CRP levels increased the risks by only 2.4 and 2.5 times, respectively.
VEGF is an essential mediator of angiogenesis and endochondral ossification, Dr. Poddubnyy observed. It’s been shown to have "a chemoattractive effect on osteoblasts and mesenchymal progenitor cells," he added, and also stimulate osteoblast differentiation and bone turnover.
While the results are very promising, further research is of course required. The possible predictive value of VEGF in relation to spinal radiographic progression in patients treated with tumor necrosis factor–alpha inhibitors remains to be seen, for example, and future studies should perhaps look at this question.
"With VEGF we are probably able to improve our prediction of spinal progression in patients with axSpA," Dr. Poddubnyy said in an interview. This is addition to assessing "classical factors," such as syndesmophytes, CRP, and smoking status.
Dr. Poddubnyy had no disclosures.
AT THE EULAR CONGRESS 2013
Major finding: Baseline serum VEGF levels were 562 plus or minus 357 pg/mL vs. 402 plus or minus 309 pg/mL in patients with and without radiographic progression, respectively, at 2 years (P = .027).
Data source: Study of 95 patients with definite axial spondyloarthritis (axSpA) and 77 with nonradiographic axSpA recruited from the German Spondyloarthritis Inception Cohort (GESPIC).
Disclosures: Dr. Poddubnyy had no disclosures.
