Primer on the Rheumatic Diseases, 12th edition Order Your Copy Today!

Volume 51, Number 7

William P. Arend, MD
Division of Rheumatology
University of Colorado School of Medicine
Denver, CO

The two available TNF-a blockers are etanercept, a form of soluble TNF receptors, and infliximab, a monoclonal antibody to TNF. Etanercept is delivered by subcutaneous (SC) injections of 25 mg twice weekly each whereas infliximab is given by intravenous infusion at 0, 2, and 6 weeks and every 8 weeks thereafter. The indications for use of these biologic agents in the treatment of RA are unresponsiveness to the usual disease-modifying drugs, including methetrexate in high dose and in combination with other drugs, or intolerable side effects to these agents. Etanercept is approved for use with or without methotrexate whereas infliximab is approved for use only with methotrexate.

A series of publications over the past five years have described the results of clinical trials with etanercept in RA. The initial clinical trials are summarized in Table 1 (10,11,12). Either used alone or in combination with methotrexate, etanercept led to significant clinical improvement as measured by the ACR 20, 50, and 70. It was observed that stopping etanercept after 3 months led to a return of active synovitis. The major side effects to etanercept were injection site reactions and mild upper respiratory tract symptoms. In addition, 5% of treated patients developed anti-double-stranded DNA antibodies at 6 months.

In the most recent trial in RA, 632 patients with early RA (< 3 years) were treated either with etanercept at 10 or 25 mg SC twice weekly or with methotrexate (mean dose 19 mg/week) (13). Although the percentages of patients achieving ACR 20, 50, and 70 levels of improvement were no different at 12 months, the patients treated with 25 mg injections of etanercept exhibited slightly more rapid responses over the first 4 months. In addition, 72% of the patients who received the higher dose of etanercept exhibited no increase in radiographic erosions at 1 year in comparison to 60% of the patients who received methotrexate. Etanercept also has been shown to be effective in the treatment of polyarticular juvenile rheumatoid arthritis (14).

A monoclonal antibody to TNF-a, infliximab, also has been shown to be effective in the treatment of RA (15). In the original controlled trial, patients receiving a single or multiple infusions of infliximab demonstrated early efficacy (16,17). However, human antibodies to the murine IgG developed in over half of these patients and possibly were associated with reduced clinical responses.

Infliximab was next evaluated in combination therapy with methotrexate (18). A trial carried out over 4 months described a Paulus 20 or 50 response in 50% to 60% of patients treated with 5 infusions of infliximab at 1, 3, or 10 mg/kg combined with methotrexate, compared to up to 10% of patients treated with methotrexate alone. Patients receiving infliximab alone at the higher 2 doses exhibited lower percentages of Paulus 50 responses. However, the development of human antibodies to murine IgG was greatly reduced by the concomitant treatment with methotrexate.

The results of more recent clinical trials of infliximab given in combination with methotrexate are summarized in Table 2 (19,20). In studies carried out over 7 to 12 months, significantly higher ACR 20, 50, and 70 responses were observed in patients receiving infliximab 3 or 10 mg/kg every 4 to 8 weeks, along with methotrexate at a median dose of 15 mg/wk, in comparison to methotrexate alone. In addition, patients treated with the combination of infliximab and methotrexate over 12 months demonstrated an absence of radiographic evidence of progressive joint damage whether or not they exhibited a clinical response.

Side effects to treatment with infliximab included the development of antinuclear antibodies in up to 68% of patients and of anti-DNA antibodies in 10% (21). A few patients treated with infliximab developed clinical symptoms of systemic lupus erthematosus (SLE), with these manifestations responding to discontinuation of the agent. Other adverse events observed in patients treated with the combination of infliximab and methotrexate, compared with methotrexate alone, included upper respiratory infections, sinusitis, pharyngitis, and headache. Infusion reactions have also occurred with infliximab.

Recent publications have described the appearance of additional serious side effects to treatment with TNF-blocking agents.  Whether these therapeutic agents predispose to the development of malignancy will require longer-term follow-up studies.

Voluntary reporting to the FDA described the reactivation of latent tuberculosis in 70 patents treated with infliximab (22). Tuberculosis also has developed after treatment with etanercept, but whether this complication occurs equally with both forms of anti-TNF therapy is not known. Both anti-TNF agents may predispose to other infectious complications, primarily with intracellular pathogens such as listeria and fungi.

In addition, demyelination has been described in 19 patients after TNF blockade, 17 following etanercept and 2 after infliximab (23). Thus, anti-TNF therapy should not be used in patients with known infections, or should be stopped should infections develop, and these therapies should be avoided in patients with SLE, multiple sclerosis, or poorly defined neurological syndromes.