Elsevier

The Lancet

Volume 359, Issue 9313, 6 April 2002, Pages 1187-1193
The Lancet

Articles
Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial

https://doi.org/10.1016/S0140-6736(02)08215-6Get rights and content

Summary

Background

Treatment options for patients with ankylosing spondylitis are few. We aimed to assess the effectiveness of infliximab, an antibody to tumour necrosis factor (TNF)-α, in treatment of such patients.

Methods

In this 12-week placebo-controlled multicentre study, we randomly assigned 35 patients with active ankylosing spondylitis to intravenous infliximab (5 mg/kg) and 35 to placebo at weeks 0, 2, and 6. One patient in the infliximab group was withdrawn from the study. Our primary outcome was regression of disease activity of at least 50%. To assess response, we used validated clinical criteria from the ankylosing spondylitis assessment working group, including disease activity (BASDAI), functional indices (BASFI), metrology (BASMI), and quality of life (short form 36). Analyses were done by intention to treat.

Findings

18 (53%) of 34 patients on infliximab had a regression of disease activity at week 12 of at least 50% compared with three (9%) of 35 on placebo (difference 44% [95% Cl 23–61], p<0·0001). Function and quality of life also improved significantly on infliximab but not on placebo (p<0·0001 and p<0·0001, respectively). Treatment with infliximab was generally well tolerated, but three patients had to stop treatment because of systemic tuberculosis, allergic granulomatosis of the lung, or mild leucopenia.

Interpretation

Our results show that treatment with infliximab is effective in patients with active ankylosing spondylitis. Since there are some potentially serious adverse effects, we recommend that this treatment mainly be used in co-operation with rheumatological centres.

Introduction

Ankylosing spondylitis, the prototype of spondyloarthritis, is a chronic inflammatory rheumatic disease with a prevalence of 0·5–1·9% for all types of spondyloarthritis.1 This prevalence is close to that of rheumatoid arthritis. Interaction between a strong genetic component, mainly by specific HLA-B27 subtypes,2 and bacteria3 seems to be crucial for development of disease. Ankylosing spondylitis is mostly characterised by inflammation of the sacroiliac joints, the entheses,4 and the spine.5 The disease affects both sexes, usually starting when the patient is 20–30 years old and remains underdiagnosed.6 Many patients with ankylosing spondylitis carry a heavy burden of disease, which does not seem to differ much from rheumatoid arthritis,6 although it lasts longer. The disease itself is responsible for substantial direct and indirect socioeconomic costs.7

By contrast with rheumatoid arthritis, few studies have been done on treatment of patients with ankylosing spondylitis with disease-modifying antirheumatic drugs, none of which have proved clearly effective in axial disease. Sulfasalazine has little effectiveness in peripheral arthritis and possibly in early stages of ankylosing spondylitis.8 Methotrexate has not proven effective in treatment of ankylosing spondylitis. At present, treatment for ankylosing spondylitis consists mainly of non-steroidal anti-inflammatory drugs and physiotherapy. By contrast with rheumatoid arthritis, systemic corticosteroids work only in selected patients, but controlled studies have yet to be done. Patients who have severe ankylosing spondylitis might need phenylbutazone and opioids for pain relief. Treatment options for ankylosing spondylitis are therefore few, and quality of life is reduced in many patients.9 Treatment of severe ankylosing spondylitis is therefore thought to be an unmet medical need.

In patients with rheumatoid arthritis, anti-tumour necrosis factor-α (TNF-α) therapy with the monoclonal antibody infliximab is highly effective.10 However, this disease is pathogenetically distinct from ankylosing spondylitis. Crohn's disease11 and the arthritic symptoms12 known to be associated with inflammatory bowel diseases can also be effectively treated with anti-TNF-α. Since patients with Crohn's disease can develop ankylosing spondylitis, and many patients with idiopathic ankylosing spondylitis have lesions in the intestine that resemble those seen in Crohn's disease, spondyloarthritis has been associated with chronic inflammatory bowel disease. Additionally, anti-TNF-α agents seem to work in patients with psoriatic arthritis.13, 14 However, not all chronic inflammatory diseases improve with infliximab treatment (eg, multiple sclerosis).15 Furthermore, only half of patients with rheumatoid arthritis who were treated in large trials showed significant benefit on anti-TNF treatment.10, 16

Using a sacroiliac biopsy technique that is guided by computed tomography, we have shown that TNF-α is expressed in inflamed sacroiliac joints of patients with ankylosing spondylitis.17 A small open pilot study done by our group suggested that infliximab could have a clinically relevant benefit in patients with severe ankylosing spondylitis.18 We aimed to assess the effectiveness of infliximab in such patients.

Section snippets

Patients

In this short-term study, we investigated whether administration of multiple infusions of infliximab at 5 mg/kg was effective treatment for severe ankylosing spondylitis. 5 mg/kg of infliximab was chosen on the basis of previous experience.12, 18 The exact number of patients screened was not assessed in all centres. We estimate that no more than 100 patients were screened. The main reasons for exclusion were severe comorbidity, insufficient disease activity, complete ankylosis, incorrect

Results

One patient who had already been randomly assigned to treatment failed to fulfil the radiographic criterion of the modified New York criteria for ankylosing spondylitis, and was thus excluded from analysis (figure 1). Table 1 shows baseline characteristics of the two treatment groups. All questionnaires, including the SF36, were completed at all time points apart from the missing visits of patients who withdrew and some individual missing items in the physical function and mental health SF36

Discussion

Our results show that patients with active ankylosing spondylitis, despite treatment with NSAIDs, respond favourably to immunosuppressive treatment with infliximab. More than half of patients in the infliximab group showed an improvement of 50% in the activity index compared with less than a tenth in the placebo group. Rheumatologists will now be able to effectively treat patients with severe ankylosing spondylitis. By contrast with rheumatoid arthritis, Crohn's disease, and psoriasis, in which

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