Reports

Ankylosing Spondylitis with Extra-articular Symptoms: Inflammation as the Common Denominator
Rheumatoid Arthritis: Managing Rapidly Progressing Patients

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

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

According to Dr. Filip Van den Bosch, University Hospital Ghent, Belgium, “It is clear that biologics are finding their place in the management of patients with spondyloarthritis and are seen to have a particularly important role in patients with extra-articular manifestations. Biologics are the treatment of choice in patients with ankylosing spondylitis who also exhibit uveitis, Crohn’s disease or ulcerative colitis.”

The most recent data to support early intervention with biologics in patients with extra-articular manifestations of rheumatic diseases are derived from extended evaluation of the tumour necrosis factor alpha (TNFa) inhibitor infliximab in patients with psoriatic arthritis (PsA). While initial data of the Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT) published last year (Arthritis Rheum 2005; 52(4):1227-36) associated this agent with sustained improvement in articular and dermatologic manifestations out to week 50, findings presented here demonstrated protection against progression of disability out to year 2.

“For up to two years of follow-up with continued treatment, the proportion of patients experiencing clinically meaningful worsening continued to be low in the infliximab group,” reported Dr. Arthur Kavanaugh, Director, Center of Innovative Therapy and Clinical Professor of Medicine, Division of Rheumatology, Allergy, and Immunology, University of California-San Diego, La Jolla. Although he cautioned that further research is needed to demonstrate that this produces better long-term functional outcomes, such as for employment, he indicated that early treatment with the TNFa antagonist appears to favourably affect the natural history of PsA.

Extended Analysis of IMPACT and IMPACT 2

The data presented by Dr. Kavanaugh was an extended analysis of IMPACT after year 1 and at year 2, which randomized a total of 304 patients to infliximab or placebo. Patients were enrolled who had not achieved an adequate response on previous disease-modifying antirheumatic drugs (DMARDs). However, participants in both studies who were on a stable dose of methotrexate at baseline were allowed to remain on this therapy. An active treatment dose of 5 mg/kg or placebo was administered at weeks 0, 2, 6, and then every eight weeks. Placebo patients were allowed to cross over to active treatment at week 16 in IMPACT and at week 24 in IMPACT 2.

At week 16 in IMPACT, the American College of Rheumatology (ACR) criteria for a 20% improvement (ACR 20) was reached in 65% of infliximab patients vs. 10% of placebo patients. ACR 50 and ACR 70 responses were achieved in 46% and 29%, respectively, for infliximab even though no placebo patients reached this level of disease control. Similarly, a 75% improvement in the Psoriasis Area and Severity Index (PASI 75) score was achieved in 68% of the active treatment group but none of the placebo patients. Comparable relative benefits were observed in IMPACT 2 at week 14, which also associated the active treatment with significant protection against dactylitis and enthesopathy. However, the newest data, now following patients as long as two years after randomization, have demonstrated that symptom control and protection against disability persists with very little attrition.

“At week 96, in IMPACT patients on continued treatment, the proportion of patients with an ACR 20 or a PASI 75 remained at rates near those observed at week 16,” Dr. Kavanaugh told the audience. Specifically, 61.5% of patients continued to demonstrate an ACR 20 response at week 96; PASI 75 response at the same time point was 64%.

IMPACT 2 data are now available out to week 54. Again, benefits with infliximab were sustained. While 58% had an ACR 20 response at week 14 (11% in the placebo group), 58.9% of those initially randomized to the active treatment and 61.4% of the placebo patients crossed over to infliximab had an ACR 20 response at week 54. A PASI 75 response, observed in 63.9% of infliximab patients at week 14 (vs. 2.3% of placebo patients), was documented at week 54 in 50% of patients initially randomized to infliximab and in 60.3% of placebo patients crossed over to the active treatment.

When measured with the validated Health Assessment Questionnaire Disability Index (HAQ-DI), clinically significant worsening (a decline in ³0.3 points) was observed in 41.2% of placebo patients at week 16 in IMPACT and 41% of placebo patients at week 14 in IMPACT 2. In IMPACT patients randomized to infliximab, clinically meaningful worsening was not observed in any patients at week 16 and in 5.2% of patients at week 98. In IMPACT 2, 1% of the patients demonstrated worsening at week 14 and 4% at week 54.

In ADEPT (Adalimumab Effectiveness in Psoriatic Arthritis Trial) the TNFa inhibitor adalimumab also demonstrated sustained benefit against both the joint and skin disease components in PsA. This phase III trial randomized 313 PsA patients to adalimumab or placebo. At 24 weeks, benefit in both skin and joint manifestations of disease was observed across a variety of baseline severities as well as duration of symptoms, according to investigators led by Dr. Christopher T. Ritchlin, Allergy, Immunology, and Rheumatology, University of Rochester School of Medicine, New York.

Biologics at Different Sites of Inflammation

The sustained benefits of infliximab in PsA are attributed to the key role played by TNFa in orchestrating inflammation, both in the joints and at extra-articular sites. However, more data are needed to determine whether all TNFa antagonists offer comparable activity at different sites of inflammation. According to Dr. Van den Bosch, cross-study comparisons have suggested that although these agents may have similar anti-inflammatory effects in the joint, they do not appear to be interchangeable for extra-articular symptoms, including control of psoriasis.

“Monoclonal antibodies and soluble receptor constructs have different properties and different TNFa-binding profiles which result in some key differences in efficacy in regard to extra-articular manifestations,” observed Dr. Van den Bosch, singling out protection against inflammatory bowel disease (IBD) in particular. While he suggested that comparative studies are needed, he noted that etanercept, unlike infliximab or adalimumab, has shown very little activity against IBD in controlled trials.

The same point was made by Dr. Martin Rudwaleit, Charité, Campus Benjamin Franklin, Berlin, Germany, concerning psoriasis and uveitis. He indicated that both infliximab and adalimumab show greater activity than etanercept. In uveitis, adalimumab has not yet been well researched, but etanercept, although active, has failed to demonstrate a degree of benefit comparable to infliximab.

Extra-articular Manifestations

According to Dr. Rudwaleit, “It is critical to recognize and consider the presence of inflammatory extra-articular manifestations such as psoriasis, uveitis and IBD when selecting a therapy for patients with spondyloarthritis. This diagnosis and treatment approach ensures that the optimal therapy will be selected which will provide the best chance for complete control of inflammation.”

The ability of TNFa antagonists to control one of the central mediators of inflammation has led to interest of early use of these agents. They appear not only to offer broad control of symptoms, including extra-articular symptoms, but also to halt disease progression and tissue damage that may prove irreversible. When to offer these agents to individuals with spondyloarthritis limited to joint disease, particularly those responding to DMARDs, is still in debate. However, a consensus that patients with inflammatory diseases at extra-articular sites may benefit from early use of these agents to improve both control and long-term outcome is growing.

Summary

The shared mechanism of disease manifestations in patients with ankylosing spondylitis who have both articular and extra-articular manifestations, such as psoriasis, uveitis or IBD, is inflammation. Targeted biologic therapies, particularly the TNFa antagonists, have proven to be the most effective agents in controlling the inflammatory process. Most of these agents provide clinically significant activity at both articular and extra-articular sites, although the degree of activity at these sites may differ. New evidence that these agents prevent progression is driving growing consensus that they are appropriate for early use in disease control.

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