Vasculitides induced by TNFα antagonists: a study in 39 patients in France

doi:10.1016/j.jbspin.2006.02.010

Joint Bone Spine

Volume 73, Issue 6, December 2006, Pages 710-713

https://doi.org/10.1016/j.jbspin.2006.02.010 Get rights and content

Abstract

TNFα antagonists are effective in the treatment of chronic inflammatory joint disease. Despite a good overall safety profile, they can induce a number of adverse effects, including autoimmunity and infections. A link between TNFα antagonists and vasculitides has been suggested.

Methods

Between December 2004 and January 2005, a nationwide survey was conducted among 1200 hospital-based rheumatologists and internists in France, who were asked to report cases of vasculitis in patients taking TNFα antagonists.

Results

The survey identified 39 cases (32 women) of vasculitis during TNFα antagonist therapy. The joint disease was rheumatoid arthritis (RA) in 34 patients (including four without rheumatoid factor), juvenile idiopathic arthritis in two patients, ankylosing spondylitis in two patients, and psoriatic arthritis in one patient. Mean disease duration was 14.1 ± 8.7 years. The TNFα antagonist was etanercept in 21 patients, infliximab in 15, adalimumab in 2, and another drug in 1; mean treatment duration was 9.6 months. The manifestations of vasculitis involved the skin (n = 32); peripheral nervous system (n = 9); kidney (n = 7); central nervous system (n = 3); pleura (n = 2), pericardium (n = 2); and the lung, gallbladder, and heart (n = 1 each). Antinuclear factor (ANF) was present in 22 patients, hypocomplementemia in 6, and antineutrophil cytoplasmic antibody in 5. Histology (30 biopsies from 27 patients) showed nonnecrotizing vasculitis in 12 patients, necrotizing vasculitis in 7, an inflammatory dermal infiltrate without vasculitis in 3, extravascular necrotic granulomas in 2, chilblain lupus in 1, and cicatricial fibro-inflammatory changes in 1. Renal biopsy in three patients showed extracapillary glomerulonephritis with IgA deposits (n = 2) or active floccular necrosis against a background of glomerular sclerosis (n = 1). TNFα antagonist therapy was stopped in 33 patients, among whom 18 recovered without further treatment and 14 required high-dose glucocorticoids and/or immunosuppressant therapy, which ensured symptom resolution within a few weeks. The remaining patient died with multiple organ failures.

Discussion

The relative contributions of TNFα antagonist therapy and of the underlying disease to the development of vasculitis cannot be determined. Features that suggest a causal link between TNFα antagonists and vasculitis include the short time from TNFα antagonist initiation to vasculitis onset; the favorable response to discontinuation of TNFα antagonist therapy; and the development of systemic vasculitis in patients with rheumatoid factor-negative RA, in adults with juvenile-onset arthritis, and in patients with spondyloarthropathies.

Introduction

TNFα antagonists are effective in the treatment of rheumatoid arthritis (RA) [1], [2] and are used in an estimated 750,000 patients worldwide. Adverse effects include autoimmunity and infections. Reports of vasculitis in patients on TNFα antagonist therapy provide limited information on clinical features, outcomes, and histological findings. In addition, the fact that TNFα antagonists are used to treat diseases that can induce vasculitis is a major obstacle to causality assessments.

A permanent committee of the French Society for Rheumatology (the Club Rhumatismes et Inflammation) conducted a nationwide survey to collect data on systemic vasculitis developing during TNFα antagonist therapy for chronic inflammatory joint disease. The survey identified 39 cases.

Section snippets

Methods

Between December 2004 and January 2005, the committee collected retrospective data on histologically documented cases of vasculitis in patients on TNFα antagonist therapy for chronic inflammatory joint disease. Several methods were used to raise awareness of the survey among rheumatologists and internists throughout France: the survey was described at the committee meetings, in the committee's newsletter, and on the committee's website (http://www.CRI-net.com). A letter was sent three times at

Results

Thirty-nine cases were identified. Typical signs of vasculitis were consistently present, and we therefore included all the patients in the study, although histological documentation was missing for 12 patients. Table 1 reports the main characteristics. There were 32 women and seven men. The diagnoses and mean disease durations were as follows: RA, n = 34, 14.1 ± 8.7 years; juvenile idiopathic arthritis, n = 2, 26.2 years; ankylosing spondylitis, n = 2, 23 and 15 years, respectively; and psoriatic

Discussion

We report the results of a nationwide survey conducted in France to collect data on vasculitides in patients taking TNFα antagonists. Only 39 cases were identified, indicating that this is a rare event. Fewer than 50 cases have been reported in the literature [3], [4], [5], [6], [7], [8], [9], [10], [11]. The largest case-series includes 35 cases seen in Canada, 20 with etanercept and 15 with infliximab therapy [3]. Histological evidence of leukocytoclastic vasculitis was obtained in 17 (48%)

Acknowledgments

We thank the physicians who supplied information about patients with vasculitis during TNFα antagonist therapy: S. Steinfeld, J.M. Berthelot, Ch. Roux, P. Richette, D. Mulleman, D. Wendling, B. Moura, C. Gabay, O. Meyer, L. Euler Ziegler, Ch. Marcelli, C. Job Deslandres, C. Richez, X. Puechal, J. Sibilia, M. Dougados, J. Morel, and S. Guignard.

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¹: On behalf of the CRI (Club Rhumatismes et Inflammation).

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Original articleVasculitides induced by TNFα antagonists: a study in 39 patients in France

Abstract

Methods

Results

Discussion

Introduction

Section snippets

Methods

Results

Discussion

Acknowledgments

Joint Bone Spine

Hypersensitivity vasculitis with leukocytoclastic vasculitis secondary to infliximab

J. Clin. Gastroenterol.

Etanercept and infliximab associated with cutaneous vasculitis

Rheumatology (Oxford)

Leukocytoclastic vasculitis associated with tumor necrosis factor-alpha blocking agents

J. Rheumatol.

Immunology of cutaneous vasculitis associated with both etanercept and infliximab

Scand. J. Immunol.

Proliferative lupus nephritis and leukocytoclastic vasculitis during treatment with etanercept

J. Rheumatol.

Anti-tumor necrosis factor-alpha therapy-induced vasculitis: case series

J. Rheumatol.

Anti-tumour necrosis factor therapy associated with cutaneous vasculitis

Rheumatology (Oxford)

Original article
Vasculitides induced by TNFα antagonists: a study in 39 patients in France