To the Editor:

In recent years, it has been shown that tumor necrosis factor α (TNFα) plays an important role in the pathogenesis of rheumatoid arthritis (RA). TNFα blockers represent a new generation of treatments for both RA and juvenile RA (JRA). These agents induce a rapid and sustained decrease in symptoms and slow progression of joint damage in both disorders (1–4).

The efficacy of disease-modifying antirheumatic drugs (DMARDs) for the treatment of extraarticular manifestations of RA (e.g., tenosynovitis, rheumatoid nodules) has not yet been demonstrated. Some reports are encouraging, such as that of the beneficial effect of etanercept in a patient with rheumatoid lymphedema (5).

Etanercept, a recombinant human soluble TNF receptor, is a dimeric fusion protein resulting from the association of the human p75 TNF receptor and the Fc portion of IgG1. It belongs to the family of TNFα blockers. We attempted to determine whether etanercept has efficacy in either the treatment of the extraarticular features of RA or prevention of their occurrence.

We assessed 82 patients with RA and 5 with JRA (70 female, 17 male). The median age was 51 years (range 7–76), and the median duration of RA was 11 years (range 2–32). Rheumatoid factor was positive in 64 patients. The median number of previously used DMARDs was 5 (range 1–10). We examined all patients for the presence of tenosynovitis and rheumatoid nodules on day 0, before treatment with etanercept was started. We then observed the evolution of tenosynovitis and rheumatoid nodules during a 6-month period.

All patients received 25 mg of etanercept subcutaneously twice a week. They were seen once monthly during the first 3 months and then once every 3 months. The presence or absence of tenosynovitis and rheumatoid nodules was systematically registered.

When etanercept treatment began, 66% of the 87 patients who were assessed had tenosynovitis. After 90 days of treatment, some or all tenosynovitis disappeared in 23% of these patients, new tenosynovitis appeared in 7%, and in 2% of patients tenosynovitis disappeared from some sites but appeared in others. No change was observed in the remaining 68% of patients.

On day 180, 73 patients were available for assessment, 57 of whom had tenosynovitis on day 90. In contrast to the findings on day 90, no change was observed in 87% of these patients, 8% had either less or no increase in tenosynovitis, new tenosynovitis appeared in 4%, and in 1% of patients tenosynovitis disappeared in some sites but appeared in new ones.

Throughout the study period, no new rheumatoid nodules appeared, and none disappeared. On day 0 and on day 180, 22 nodules were observed in 10 patients. Overall, after 6 months of etanercept treatment, very few patients had a change in their tenosynovitis assessment, and no one had a change of rheumatoid nodule status.

Although tenosynovitis disappeared in some patients at the beginning of etanercept therapy, this occurrence was probably independent of treatment, because tenosynovitis could simultaneously disappear from one site and appear at other locations in the same individuals. In the majority of cases, etanercept was not efficacious for tenosynovitis, and surgery remains the only possibility for helping people who are handicapped by this disorder.

Nodules neither appeared nor disappeared during treatment, and we can conclude similarly that their evolution might be completely independent of treatment. However, in contrast with methotrexate, which can induce rheumatoid nodules (6, 7), etanercept seemed to have neither an efficacious nor a deleterious effect on nodules. Currently, no DMARD has proven efficacy for the treatment of spontaneously occurring rheumatoid nodules. Apparently, only colchicine, hydroxychloroquine, and D-penicillamine can reduce nodules induced by methotrexate, and only in some cases (8, 9). Surgery is also disappointing, because nodules often recur.

No other extraarticular manifestation of RA appeared in our patients during the period of assessment. The role of etanercept for the treatment of other extraarticular features of RA remains to be elucidated.


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M.-J. Kaiser MD*, M.-C. Bozonnat MD†, C. Jorgensen MD, PhD‡, J.-P. Daurès MD, PhD§, J. Sany MD¶, * Hôpital Lapeyronie, † Institut Universitaire de Recherche Clinique, ‡ Hôpital Lapeyronie, § Institut Universitaire de Recherche Clinique, ¶ Hôpital Lapeyronie Montpellier, France