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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.
Expert panel sets broad SpA treat-to-target goals
MADRID – A panel of clinicians with expertise in the management of patients with spondyloarthritis took another step toward better defining this disease category and the goals of its treatment by producing the first "treat-to-target" recommendations for spondyloarthritis.
The new recommendations will "guide physicians, patients, and other stakeholders on how to optimize reduction of signs and symptoms and, ideally, outcomes, and will drive" the current research agenda, Dr. Josef S. Smolen said while presenting the panel’s recommendations at the annual European Congress of Rheumatology.
"Treat to target proposes a stepwise approach to achieving optimal outcomes based on available evidence and expert opinion. Treat to target has been successfully applied to management of diabetes, hypertension, hyperlipidemia, and rheumatoid arthritis," and the new task force set out to address whether it could be used when treating patients with spondyloarthritis (SpA), a question that required the expert task force to review the evidence for setting specific treatment goals for patients with SpA, said Dr. Smolen, professor of medicine at the Medical University of Vienna.
The task force eventually decided that the treat-to-target concept was applicable to SpA, but that the data available so far prevented the task force from setting specific treatment goals. While the recommendations underscore the importance of treating SpA patients with a goal of remission or inactive disease, and failing that, at least low disease activity, they fall short of giving clinicians guidance on how to best measure and define remission or low disease activity or how to achieve these goals.
For example, for axial SpA – the subtype that received the most specific recommendations – the panel advised clinicians to guide treatment decisions by using a "validated composite measure of disease activity" such as the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) plus acute phase reactants, or the Ankylosing Spondylitis Disease Activity Score (ASDAS) with or without functional measures such as the Bath Ankylosing Spondylitis Functional Index (BASFI). But the recommendations say nothing about what scores by these measures would define remission or low disease activity. The recommendations also talk about using other factors to further gauge axial SpA disease activity such as MRI analysis of inflammation and radiographic progression, but again Dr. Smolen provided no specific targets when using these measures.
For other, less well studied types of SpA, the new recommendations were even more nebulous. For psoriatic arthritis, the panel indicated that "validated measures of musculoskeletal disease activity" should be "performed and documented regularly" as should other factors such as spinal and extraarticular manifestations, imaging findings, and comorbidities, but the recommendations gave no specifics on what any of these measures might be or what level might equal remission or low disease. The same held true for peripheral SpA.
Other factors touched on by the new recommendations include the need for individualized and shared decision making between physicians and patients, the need for coordination of care among rheumatologists and other medical specialists who treat SpA patients (dermatologists, gastroenterologists, and ophthalmologists), and the need to take into account extraarticular manifestations of SpA diseases, comorbidities, and treatment risks along with the goal of low disease activity.
"I think it was important to document that there is a paucity of trials that have looked at strategies to treat" SpA. "For rheumatoid arthritis we have strategies, but not in spondyloarthritis, and I think it is important to say that," said Dr. Jürgen Braun, medical director of Rheumazentrum Ruhrgebiet in Herne, Germany.
SpA also lags behind rheumatoid arthritis by not having any treatments proven to slow radiographic progression. "Although we say that it is presumably important to treat inflammation [in patients with SpA], we are not sure," said Dr. Braun, who served as a member of the treat-to-target task force.
Even though the task force’s report highlights the absence of evidence for most facets of SpA management, "in the absence of evidence you need eminence, and that’s what was produced." Dr. Braun predicted that rheumatologists and other clinicians who care for patients with SpA would welcome these new recommendations despite their shortcomings. "What we say is what clinicians feel: If a patient’s CRP is elevated we must do something about it, but the evidence supporting this is limited. Presumably, it is important to treat inflammation, but we are not yet sure," he said in an interview.
"We don’t have trial results yet where you set up a quantifiable endpoint as your target, but that is coming," said Dr. Philip J. Mease, director of the rheumatology clinical research division at Swedish Medical Center in Seattle and a member of the task force. For example, the results from the Tight Control of Psoriatic Arthritis (TICOPA) trial "will tell us whether more aggressive treatment to a quantifiable target is appropriate and makes a difference. We anticipate that it will, but evidence is currently lacking." The primary endpoint of the TICOPA trial is change in the ACR20 response, but the trial includes several other clinical measures as secondary endpoints, including the Assessment in Ankylosing Spondylitis (ASAS), the BASDAI, and the psoriasis area severity index (PASI).
"The rheumatoid model is prompting us to develop quantifiable measures like the ASDAS and the new Psoriatic Arthritis Disease Activity Score (PASDAS) that we’ll start to see used. I just spoke with a colleague about the need to also develop a similar measure for peripheral SpA," Dr. Mease said in an interview.
The task force that developed the treat-to-target recommendations included 16 physicians and patients on its steering committee and 16 on an advisory committee. The majority came from various European locations, but about a quarter of the task force members were from the United States. To arrive at its recommendations, the task force used a comprehensive literature review that identified 22 published reports that addressed treatment targets for SpA (Ann. Rheum. Dis. 2013 June 10 [doi:10.1136/annrheumdis-2013-203860]). The treat-to-target recommendations were published online a few days before Dr. Smolen’s presentation at the meeting (Ann. Rheum. Dis. 2013 June 8 [doi:10.1136/annrheumdis-2013-203419]).
Dr. Smolen, Dr. Braun, and Dr. Mease said that they had no disclosures relevant to the topic.
On Twitter @mitchelzoler
MADRID – A panel of clinicians with expertise in the management of patients with spondyloarthritis took another step toward better defining this disease category and the goals of its treatment by producing the first "treat-to-target" recommendations for spondyloarthritis.
The new recommendations will "guide physicians, patients, and other stakeholders on how to optimize reduction of signs and symptoms and, ideally, outcomes, and will drive" the current research agenda, Dr. Josef S. Smolen said while presenting the panel’s recommendations at the annual European Congress of Rheumatology.
"Treat to target proposes a stepwise approach to achieving optimal outcomes based on available evidence and expert opinion. Treat to target has been successfully applied to management of diabetes, hypertension, hyperlipidemia, and rheumatoid arthritis," and the new task force set out to address whether it could be used when treating patients with spondyloarthritis (SpA), a question that required the expert task force to review the evidence for setting specific treatment goals for patients with SpA, said Dr. Smolen, professor of medicine at the Medical University of Vienna.
The task force eventually decided that the treat-to-target concept was applicable to SpA, but that the data available so far prevented the task force from setting specific treatment goals. While the recommendations underscore the importance of treating SpA patients with a goal of remission or inactive disease, and failing that, at least low disease activity, they fall short of giving clinicians guidance on how to best measure and define remission or low disease activity or how to achieve these goals.
For example, for axial SpA – the subtype that received the most specific recommendations – the panel advised clinicians to guide treatment decisions by using a "validated composite measure of disease activity" such as the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) plus acute phase reactants, or the Ankylosing Spondylitis Disease Activity Score (ASDAS) with or without functional measures such as the Bath Ankylosing Spondylitis Functional Index (BASFI). But the recommendations say nothing about what scores by these measures would define remission or low disease activity. The recommendations also talk about using other factors to further gauge axial SpA disease activity such as MRI analysis of inflammation and radiographic progression, but again Dr. Smolen provided no specific targets when using these measures.
For other, less well studied types of SpA, the new recommendations were even more nebulous. For psoriatic arthritis, the panel indicated that "validated measures of musculoskeletal disease activity" should be "performed and documented regularly" as should other factors such as spinal and extraarticular manifestations, imaging findings, and comorbidities, but the recommendations gave no specifics on what any of these measures might be or what level might equal remission or low disease. The same held true for peripheral SpA.
Other factors touched on by the new recommendations include the need for individualized and shared decision making between physicians and patients, the need for coordination of care among rheumatologists and other medical specialists who treat SpA patients (dermatologists, gastroenterologists, and ophthalmologists), and the need to take into account extraarticular manifestations of SpA diseases, comorbidities, and treatment risks along with the goal of low disease activity.
"I think it was important to document that there is a paucity of trials that have looked at strategies to treat" SpA. "For rheumatoid arthritis we have strategies, but not in spondyloarthritis, and I think it is important to say that," said Dr. Jürgen Braun, medical director of Rheumazentrum Ruhrgebiet in Herne, Germany.
SpA also lags behind rheumatoid arthritis by not having any treatments proven to slow radiographic progression. "Although we say that it is presumably important to treat inflammation [in patients with SpA], we are not sure," said Dr. Braun, who served as a member of the treat-to-target task force.
Even though the task force’s report highlights the absence of evidence for most facets of SpA management, "in the absence of evidence you need eminence, and that’s what was produced." Dr. Braun predicted that rheumatologists and other clinicians who care for patients with SpA would welcome these new recommendations despite their shortcomings. "What we say is what clinicians feel: If a patient’s CRP is elevated we must do something about it, but the evidence supporting this is limited. Presumably, it is important to treat inflammation, but we are not yet sure," he said in an interview.
"We don’t have trial results yet where you set up a quantifiable endpoint as your target, but that is coming," said Dr. Philip J. Mease, director of the rheumatology clinical research division at Swedish Medical Center in Seattle and a member of the task force. For example, the results from the Tight Control of Psoriatic Arthritis (TICOPA) trial "will tell us whether more aggressive treatment to a quantifiable target is appropriate and makes a difference. We anticipate that it will, but evidence is currently lacking." The primary endpoint of the TICOPA trial is change in the ACR20 response, but the trial includes several other clinical measures as secondary endpoints, including the Assessment in Ankylosing Spondylitis (ASAS), the BASDAI, and the psoriasis area severity index (PASI).
"The rheumatoid model is prompting us to develop quantifiable measures like the ASDAS and the new Psoriatic Arthritis Disease Activity Score (PASDAS) that we’ll start to see used. I just spoke with a colleague about the need to also develop a similar measure for peripheral SpA," Dr. Mease said in an interview.
The task force that developed the treat-to-target recommendations included 16 physicians and patients on its steering committee and 16 on an advisory committee. The majority came from various European locations, but about a quarter of the task force members were from the United States. To arrive at its recommendations, the task force used a comprehensive literature review that identified 22 published reports that addressed treatment targets for SpA (Ann. Rheum. Dis. 2013 June 10 [doi:10.1136/annrheumdis-2013-203860]). The treat-to-target recommendations were published online a few days before Dr. Smolen’s presentation at the meeting (Ann. Rheum. Dis. 2013 June 8 [doi:10.1136/annrheumdis-2013-203419]).
Dr. Smolen, Dr. Braun, and Dr. Mease said that they had no disclosures relevant to the topic.
On Twitter @mitchelzoler
MADRID – A panel of clinicians with expertise in the management of patients with spondyloarthritis took another step toward better defining this disease category and the goals of its treatment by producing the first "treat-to-target" recommendations for spondyloarthritis.
The new recommendations will "guide physicians, patients, and other stakeholders on how to optimize reduction of signs and symptoms and, ideally, outcomes, and will drive" the current research agenda, Dr. Josef S. Smolen said while presenting the panel’s recommendations at the annual European Congress of Rheumatology.
"Treat to target proposes a stepwise approach to achieving optimal outcomes based on available evidence and expert opinion. Treat to target has been successfully applied to management of diabetes, hypertension, hyperlipidemia, and rheumatoid arthritis," and the new task force set out to address whether it could be used when treating patients with spondyloarthritis (SpA), a question that required the expert task force to review the evidence for setting specific treatment goals for patients with SpA, said Dr. Smolen, professor of medicine at the Medical University of Vienna.
The task force eventually decided that the treat-to-target concept was applicable to SpA, but that the data available so far prevented the task force from setting specific treatment goals. While the recommendations underscore the importance of treating SpA patients with a goal of remission or inactive disease, and failing that, at least low disease activity, they fall short of giving clinicians guidance on how to best measure and define remission or low disease activity or how to achieve these goals.
For example, for axial SpA – the subtype that received the most specific recommendations – the panel advised clinicians to guide treatment decisions by using a "validated composite measure of disease activity" such as the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) plus acute phase reactants, or the Ankylosing Spondylitis Disease Activity Score (ASDAS) with or without functional measures such as the Bath Ankylosing Spondylitis Functional Index (BASFI). But the recommendations say nothing about what scores by these measures would define remission or low disease activity. The recommendations also talk about using other factors to further gauge axial SpA disease activity such as MRI analysis of inflammation and radiographic progression, but again Dr. Smolen provided no specific targets when using these measures.
For other, less well studied types of SpA, the new recommendations were even more nebulous. For psoriatic arthritis, the panel indicated that "validated measures of musculoskeletal disease activity" should be "performed and documented regularly" as should other factors such as spinal and extraarticular manifestations, imaging findings, and comorbidities, but the recommendations gave no specifics on what any of these measures might be or what level might equal remission or low disease. The same held true for peripheral SpA.
Other factors touched on by the new recommendations include the need for individualized and shared decision making between physicians and patients, the need for coordination of care among rheumatologists and other medical specialists who treat SpA patients (dermatologists, gastroenterologists, and ophthalmologists), and the need to take into account extraarticular manifestations of SpA diseases, comorbidities, and treatment risks along with the goal of low disease activity.
"I think it was important to document that there is a paucity of trials that have looked at strategies to treat" SpA. "For rheumatoid arthritis we have strategies, but not in spondyloarthritis, and I think it is important to say that," said Dr. Jürgen Braun, medical director of Rheumazentrum Ruhrgebiet in Herne, Germany.
SpA also lags behind rheumatoid arthritis by not having any treatments proven to slow radiographic progression. "Although we say that it is presumably important to treat inflammation [in patients with SpA], we are not sure," said Dr. Braun, who served as a member of the treat-to-target task force.
Even though the task force’s report highlights the absence of evidence for most facets of SpA management, "in the absence of evidence you need eminence, and that’s what was produced." Dr. Braun predicted that rheumatologists and other clinicians who care for patients with SpA would welcome these new recommendations despite their shortcomings. "What we say is what clinicians feel: If a patient’s CRP is elevated we must do something about it, but the evidence supporting this is limited. Presumably, it is important to treat inflammation, but we are not yet sure," he said in an interview.
"We don’t have trial results yet where you set up a quantifiable endpoint as your target, but that is coming," said Dr. Philip J. Mease, director of the rheumatology clinical research division at Swedish Medical Center in Seattle and a member of the task force. For example, the results from the Tight Control of Psoriatic Arthritis (TICOPA) trial "will tell us whether more aggressive treatment to a quantifiable target is appropriate and makes a difference. We anticipate that it will, but evidence is currently lacking." The primary endpoint of the TICOPA trial is change in the ACR20 response, but the trial includes several other clinical measures as secondary endpoints, including the Assessment in Ankylosing Spondylitis (ASAS), the BASDAI, and the psoriasis area severity index (PASI).
"The rheumatoid model is prompting us to develop quantifiable measures like the ASDAS and the new Psoriatic Arthritis Disease Activity Score (PASDAS) that we’ll start to see used. I just spoke with a colleague about the need to also develop a similar measure for peripheral SpA," Dr. Mease said in an interview.
The task force that developed the treat-to-target recommendations included 16 physicians and patients on its steering committee and 16 on an advisory committee. The majority came from various European locations, but about a quarter of the task force members were from the United States. To arrive at its recommendations, the task force used a comprehensive literature review that identified 22 published reports that addressed treatment targets for SpA (Ann. Rheum. Dis. 2013 June 10 [doi:10.1136/annrheumdis-2013-203860]). The treat-to-target recommendations were published online a few days before Dr. Smolen’s presentation at the meeting (Ann. Rheum. Dis. 2013 June 8 [doi:10.1136/annrheumdis-2013-203419]).
Dr. Smolen, Dr. Braun, and Dr. Mease said that they had no disclosures relevant to the topic.
On Twitter @mitchelzoler
AT THE EULAR CONGRESS 2013
Spinal MRI does not enhance spondyloarthropathy diagnosis
MADRID – There is no added benefit of performing spinal MRI in the diagnosis of spondyloarthritis, the results of an international, multicenter study suggest.
Around one-quarter of patients with nonradiographic axial spondyloarthritis (nr-axSpA) who had a negative MRI scan of the sacroiliac joints (SIJs) were reclassified as being positive for SpA by a combined evaluation of SIJ MRI and spinal MRI scans.
However, 17.5% of healthy volunteers and up to 26.8% of patients with mechanical back pain who had a negative SIJ MRI were also reclassified as having SpA. This false-positive result balances out the value of combined spinal and SIJ MRI.
"Combined MRI added little incremental value compared to SIJ MRI alone for diagnosis of nr-axSpA," said Dr. Ulrich Weber, who presented the findings at the annual European Congress of Rheumatology (Ann. Rheum. Dis. 2013;72:145).
"Although you get about 20% more patients – which is the good news – we found about the same magnitude of false-positive controls," he said in an interview. He added that he "was very disappointed with this result, and these data need confirming." Dr. Weber collected data for the study while at the Balgrist University Clinic in Zurich, and also as a visiting professor in the rheumatology department at the University of Alberta, Edmonton.
SIJ MRI is a major criterion of the Assessment of SpondyloArthritis classification criteria for ankylosing spondylitis (AS). If a patient is strongly suspected of having early SpA, but this is not yet visible on radiographs, then an SIJ MRI is often the next step. If this is negative, however, it may be unclear what to do next.
"Our question was, ‘Would it help to order an additional spinal MRI in this situation?’ " Dr. Weber explained. These data suggest that it is not.
The collaborative study included 130 individuals with newly diagnosed back pain and aged 50 years or younger who were recruited from clinics based in Canada, China, Denmark, and Switzerland, as well as 20 healthy control individuals in whom MRI scans of the SIJ and spine were available.
The investigators used a clinical examination and pelvic radiography to stratify patients into groups, with 50 found to have nr-axSpA, 33 with AS, and 47 with mechanical back pain.
Three separate researchers blinded to the initial stratification read the MRI of the SIJ. An MRI of the spine was then performed 6 months later, with a combined SIJ/spinal scan done 1-12 months later. The presence or absence of SpA was determined in these scans, and comparisons were made between the results for MRI of the SIJ alone versus spinal MRI alone, as well as for the SIJ alone versus a combined read of both the spinal and SIJ MRI scans.
Dr. Weber noted that he would not recommend changing current practice as a result of this study. Further data are eagerly awaited from an ongoing Danish initiative that hopes to scan and assess around 2,000 whole-body MRIs in patients with suspected spondyloarthropathy by the end of the year. "This study will be very informative and very important for us because this is a large sample size. Preliminary data on about 1,000 MRIs point in the same direction," he observed.
Other data from the study, which Dr. Weber presented separately at the meeting, looked at the frequency and possible reasons for false-positive results with spinal MRI in the control groups (Ann. Rheum. Dis. 2013;72:125).
"Patients with mechanical back pain and healthy volunteers may show spinal MRI lesions suggestive of spondyloarthritis, such as corner inflammatory lesions or corner fat lesions," he explained. "We found that about 30% of those controls were misclassified as having spondyloarthritis by evaluation of the spinal MRI alone, so without SIJ MRI," said Dr. Weber. Bone marrow edema and fat infiltration were the MRI lesions largely responsible for this misclassification.
Dr. Weber said that, at least in Switzerland, general practitioners were more likely to order a spinal MRI than an SIJ MRI to assess a young patient with nonspecific back pain. "We think that caution is needed if a classification of SpA is based on MRI of the spine alone," he concluded.
Dr. Weber had no disclosures.
MADRID – There is no added benefit of performing spinal MRI in the diagnosis of spondyloarthritis, the results of an international, multicenter study suggest.
Around one-quarter of patients with nonradiographic axial spondyloarthritis (nr-axSpA) who had a negative MRI scan of the sacroiliac joints (SIJs) were reclassified as being positive for SpA by a combined evaluation of SIJ MRI and spinal MRI scans.
However, 17.5% of healthy volunteers and up to 26.8% of patients with mechanical back pain who had a negative SIJ MRI were also reclassified as having SpA. This false-positive result balances out the value of combined spinal and SIJ MRI.
"Combined MRI added little incremental value compared to SIJ MRI alone for diagnosis of nr-axSpA," said Dr. Ulrich Weber, who presented the findings at the annual European Congress of Rheumatology (Ann. Rheum. Dis. 2013;72:145).
"Although you get about 20% more patients – which is the good news – we found about the same magnitude of false-positive controls," he said in an interview. He added that he "was very disappointed with this result, and these data need confirming." Dr. Weber collected data for the study while at the Balgrist University Clinic in Zurich, and also as a visiting professor in the rheumatology department at the University of Alberta, Edmonton.
SIJ MRI is a major criterion of the Assessment of SpondyloArthritis classification criteria for ankylosing spondylitis (AS). If a patient is strongly suspected of having early SpA, but this is not yet visible on radiographs, then an SIJ MRI is often the next step. If this is negative, however, it may be unclear what to do next.
"Our question was, ‘Would it help to order an additional spinal MRI in this situation?’ " Dr. Weber explained. These data suggest that it is not.
The collaborative study included 130 individuals with newly diagnosed back pain and aged 50 years or younger who were recruited from clinics based in Canada, China, Denmark, and Switzerland, as well as 20 healthy control individuals in whom MRI scans of the SIJ and spine were available.
The investigators used a clinical examination and pelvic radiography to stratify patients into groups, with 50 found to have nr-axSpA, 33 with AS, and 47 with mechanical back pain.
Three separate researchers blinded to the initial stratification read the MRI of the SIJ. An MRI of the spine was then performed 6 months later, with a combined SIJ/spinal scan done 1-12 months later. The presence or absence of SpA was determined in these scans, and comparisons were made between the results for MRI of the SIJ alone versus spinal MRI alone, as well as for the SIJ alone versus a combined read of both the spinal and SIJ MRI scans.
Dr. Weber noted that he would not recommend changing current practice as a result of this study. Further data are eagerly awaited from an ongoing Danish initiative that hopes to scan and assess around 2,000 whole-body MRIs in patients with suspected spondyloarthropathy by the end of the year. "This study will be very informative and very important for us because this is a large sample size. Preliminary data on about 1,000 MRIs point in the same direction," he observed.
Other data from the study, which Dr. Weber presented separately at the meeting, looked at the frequency and possible reasons for false-positive results with spinal MRI in the control groups (Ann. Rheum. Dis. 2013;72:125).
"Patients with mechanical back pain and healthy volunteers may show spinal MRI lesions suggestive of spondyloarthritis, such as corner inflammatory lesions or corner fat lesions," he explained. "We found that about 30% of those controls were misclassified as having spondyloarthritis by evaluation of the spinal MRI alone, so without SIJ MRI," said Dr. Weber. Bone marrow edema and fat infiltration were the MRI lesions largely responsible for this misclassification.
Dr. Weber said that, at least in Switzerland, general practitioners were more likely to order a spinal MRI than an SIJ MRI to assess a young patient with nonspecific back pain. "We think that caution is needed if a classification of SpA is based on MRI of the spine alone," he concluded.
Dr. Weber had no disclosures.
MADRID – There is no added benefit of performing spinal MRI in the diagnosis of spondyloarthritis, the results of an international, multicenter study suggest.
Around one-quarter of patients with nonradiographic axial spondyloarthritis (nr-axSpA) who had a negative MRI scan of the sacroiliac joints (SIJs) were reclassified as being positive for SpA by a combined evaluation of SIJ MRI and spinal MRI scans.
However, 17.5% of healthy volunteers and up to 26.8% of patients with mechanical back pain who had a negative SIJ MRI were also reclassified as having SpA. This false-positive result balances out the value of combined spinal and SIJ MRI.
"Combined MRI added little incremental value compared to SIJ MRI alone for diagnosis of nr-axSpA," said Dr. Ulrich Weber, who presented the findings at the annual European Congress of Rheumatology (Ann. Rheum. Dis. 2013;72:145).
"Although you get about 20% more patients – which is the good news – we found about the same magnitude of false-positive controls," he said in an interview. He added that he "was very disappointed with this result, and these data need confirming." Dr. Weber collected data for the study while at the Balgrist University Clinic in Zurich, and also as a visiting professor in the rheumatology department at the University of Alberta, Edmonton.
SIJ MRI is a major criterion of the Assessment of SpondyloArthritis classification criteria for ankylosing spondylitis (AS). If a patient is strongly suspected of having early SpA, but this is not yet visible on radiographs, then an SIJ MRI is often the next step. If this is negative, however, it may be unclear what to do next.
"Our question was, ‘Would it help to order an additional spinal MRI in this situation?’ " Dr. Weber explained. These data suggest that it is not.
The collaborative study included 130 individuals with newly diagnosed back pain and aged 50 years or younger who were recruited from clinics based in Canada, China, Denmark, and Switzerland, as well as 20 healthy control individuals in whom MRI scans of the SIJ and spine were available.
The investigators used a clinical examination and pelvic radiography to stratify patients into groups, with 50 found to have nr-axSpA, 33 with AS, and 47 with mechanical back pain.
Three separate researchers blinded to the initial stratification read the MRI of the SIJ. An MRI of the spine was then performed 6 months later, with a combined SIJ/spinal scan done 1-12 months later. The presence or absence of SpA was determined in these scans, and comparisons were made between the results for MRI of the SIJ alone versus spinal MRI alone, as well as for the SIJ alone versus a combined read of both the spinal and SIJ MRI scans.
Dr. Weber noted that he would not recommend changing current practice as a result of this study. Further data are eagerly awaited from an ongoing Danish initiative that hopes to scan and assess around 2,000 whole-body MRIs in patients with suspected spondyloarthropathy by the end of the year. "This study will be very informative and very important for us because this is a large sample size. Preliminary data on about 1,000 MRIs point in the same direction," he observed.
Other data from the study, which Dr. Weber presented separately at the meeting, looked at the frequency and possible reasons for false-positive results with spinal MRI in the control groups (Ann. Rheum. Dis. 2013;72:125).
"Patients with mechanical back pain and healthy volunteers may show spinal MRI lesions suggestive of spondyloarthritis, such as corner inflammatory lesions or corner fat lesions," he explained. "We found that about 30% of those controls were misclassified as having spondyloarthritis by evaluation of the spinal MRI alone, so without SIJ MRI," said Dr. Weber. Bone marrow edema and fat infiltration were the MRI lesions largely responsible for this misclassification.
Dr. Weber said that, at least in Switzerland, general practitioners were more likely to order a spinal MRI than an SIJ MRI to assess a young patient with nonspecific back pain. "We think that caution is needed if a classification of SpA is based on MRI of the spine alone," he concluded.
Dr. Weber had no disclosures.
AT THE EULAR CONGRESS 2013
Major finding: More than 25% of patients with nonradiographic axial spondyloarthritis who had a negative MRI scan of the sacroiliac joints (SIJs) were reclassified as being positive for spondyloarthritis by a combined evaluation of SIJ MRI and spinal MRI scans, but this was balanced by a similarly high rate of false-positive results.
Data source: An international, multicenter study of combined SIJ and spinal MRI in 130 patients with newly diagnosed back pain and 20 healthy controls.
Disclosures: Dr. Weber had no disclosures.