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Progress in Control of Psoriatic Arthritis: Addressing Articular and Extra-articular Manifestations

Ankylosing Spondylitis with Extra-articular Symptoms: Inflammation as the Common Denominator

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

7th Annual European Congress of Rheumatology (EULAR)

Amsterdam, The Netherlands / June 21-24, 2006

In a survey of 458 rheumatologists in six countries, Canadian physicians were most likely to ask patients with ankylosing spondylitis (AS) whether they had non-joint symptoms. At 81%, they exceeded the average of 66% and were almost twice as likely to ask about non-joint symptoms as rheumatologists in France, of whom only 46% routinely ask about symptoms in sites other than joints. While these figures demonstrate encouraging awareness of the relationship between joint and extra-articular symptoms, such as uveitis, inflammatory bowel disease (IBD), or psoriatic arthritis (PsA), experts now suggest that all patients should be routinely questioned about non-joint symptoms because of the importance of comprehensive control of disease manifestations.

Joint and Non-joint Symptoms: A Common Mechanism

According to Dr. Filip Van den Bosch, Department of Rheumatology, University Hospital, Ghent University, Belgium, joint and non-joint symptoms can be considered as different phenotypical manifestations of a common underlying inflammatory pathway, resulting in organ damage and increased morbidity and mortality. “The knowledge that joint and non-joint symptoms share the same underlying inflammatory pathogenesis has led to novel treatment approaches designed to address the treatment of the whole patient with AS,” he indicated.

The most recent evidence that AS is frequently complicated by non-joint symptoms was generated by ASPECT (Ankylosing Spondylitis Patients Epidemiological Cross-sectional Trial) in which 42% of 887 AS patients evaluated in Belgium had non-joint symptoms. Dr. Van den Bosch told the audience that 26.5% of the ASPECT population had uveitis, 10.5% had psoriasis, 10% had IBD, and 5% had more than one extra-articular manifestation. He indicated, “This analysis clearly highlights the importance of recognizing and treating comorbid inflammatory diseases [in AS patients].”

The common pathophysiologic feature in joint and non-joint symptoms of AS is inflammation. This central role of inflammation has not only been demonstrated in mechanistic studies but also in clinical trials with inhibitors of tumour necrosis factor alpha (TNFa), a dominant cytokine in the inflammatory process. The TNFa inhibitors are often called biologics. In Canada, infliximab is already indicated for the treatment of IBD and it has demonstrated efficacy against PsA. The TNFa inhibitor adalimumab has not been extensively studied in non-joint inflammatory diseases, but preliminary studies also suggest activity.

Extra-articular Manifestations

“It is clear that biologics are finding their place in the management of patients with AS, but it is important to evaluate each of these drugs independently. Monoclonal antibodies and soluble receptor constructs have different properties and different TNFa binding profiles, and as such, they have the potential to result in substantial differences across these inflammatory processes,” explained Dr. Van den Bosch.

One of the benefits of biologics in the treatment of AS is that symptom control appears to be durable. In new two-year data from ASSERT (Ankylosing Spondylitis Study for the Evaluation of Recombinant infliximab Therapy), prolonged benefit has been observed in both the patients who initiated therapy on infliximab and the placebo arm participants who were crossed over at week 24. In this multicentre study, 61% of 200 active-treatment patients vs. 19% of 75 placebo patients achieved an ASAS 20 (20% improvement in the Assessment of Ankylosing Spondylitis criteria) at week 24. At week 102, 72% of patients randomized to active treatment and 74% of placebo patients crossed over to infliximab experienced this level of response. Most of the remaining patients in both groups (27% in the placebo group and 23% of the active treatment group) had discontinued therapy at this time point. Only 9% of the patients in the active treatment group discontinued therapy due to side effects.

“The study demonstrates that infliximab sustained improvement over a two-year period with acceptable safety,” reported Dr. Jürgen Braun, Medical Director, Rheumazentrum Ruhrgebiet, St-Josefs-Krankenhaus, Herne, and Professor of Rheumatology, Free University of Berlin, Germany.

Five-year Data now Available

Results of this study are consistent with open-label extensions which assessed efficacy and safety of infliximab in the treatment of AS. Other controlled trials used a variety of clinical measures, such as the BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) and the BASFI (Bath Ankylosing Spondylitis Functional Index) scores. Citing unpublished three-year extension data (two-year data were published in 2004: Braun et al. Ann Rheum Dis 2005;64:229-34) that evaluated patients who continued to receive infliximab 5 mg/kg every 6 weeks up to week 102. With BASDAI, Dr. Braun noted very little attrition from year 1, when 63% of patients had a 50% improvement, to year 3, when 61% remained with this degree of improvement over baseline. He indicated that 39% of patients had a 70% improvement in BASDAI score at the end of year 3.

In an extension of a study first published in 2002 ( Braun et al. Lancet 2002;359:1187-93) that now has data out to year 5, the same persistency of benefit and acceptable tolerability profile was documented. Tracing the five-year study population back to the initial three-month trial, Dr. Xenophon Baraliakos, a colleague of Dr. Braun’s at St-Josefs-Krankenhaus, reported that 65 of the 69 patients entered into the open phase. Fifty-four finished the first year, 49 the second year, 43 the third year, and 42 entered into an additional two-year extension. At the end of five years, 41 were still on therapy, which represents almost 60% of those who entered the initial three-month trial. At this time, 28 (68.3%) had a 50% improvement over their initial baseline BASDAI score. An ASAS 40 response was observed in 63.4%. While there were few dropouts due to adverse events at any time during the five years of study, no major side effects were observed in year 5 on therapy, commented Dr. Baraliakos. He added, “The data from this study demonstrate persistent benefit over a period of five years with no evidence of a cumulative increase in adverse events.”

Although Dr. Braun cautioned that there are no major trials directly comparing the TNFa inhibitors, he did indicate that the most clinical data evaluating these agents in both joint and non-joint AS symptomatology has been generated by studies employing infliximab. According to Dr. Braun, “Infliximab has now been associated with a reduction in the signs, symptoms and flares of psoriasis, IBD-associated colitis, and anterior uveitis in AS patients. There are even some encouraging early reports that this agent can decelerate radiographic progression.”

Other TNFa inhibitors do show significant activity against joint-related symptoms. In ATLAS (Adalimumab Trial evaluating Long-term Efficacy and Safety in Ankylosing Spondylitis), 315 patients with AS who had failed on at least one NSAID were randomized to adalimumab or placebo in a 2:1 ratio. At 12 weeks, patients were allowed to “escape” to open- label active treatment if response was inadequate, a step taken by more than half of the placebo patients. By week 24, when all patients were switched to open-label active treatment, 69.2% of placebo patients had switched to the TNFa inhibitor. Overall, 58% of active treatment patients had a partial remission, as defined by an ASAS 20 by week 12, and 46% by week 52.

Summary

In the survey of rheumatologists in Canada and five European countries, 97% of respondents agreed that the goal of therapy in AS is to control inflammation. This demonstrates a strong awareness of the key pathophysiologic process that drives both articular and extra-articular manifestations. Although not all patients require TNFa inhibitors as first-line therapy, they are particularly attractive in patients with both articular and non-joint symptoms “because they address the central inflammatory component of the disease that drives multiple manifestations,” reported Dr. Martin Rudwaleit, Charité-Campus Benjamin Franklin, Free University of Berlin. “Choosing the most appropriate patients for TNFa is critical because appropriate patient selection will maximize patient outcomes.”

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