Anti-TNF agents for rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory, autoimmune disease with a prevalence of approximately 1% and an annual incidence of 0.04%. Up to 50% of patients with RA are unable to work 10 years after diagnosis. The disease is associated with significant morbidity and mortality with associated medical costs to the UK of between £240 m and £600 m per year.

Non steroidal anti-inflammatory drugs (NSAIDs) have little effect on the underlying course of RA, but they have some anti-inflammatory and analgesic properties. Disease modifying antirheumatic drugs (DMARDs) have been shown to slow progression of RA and are currently recommended early in the course of treatment of RA which is when disease progression is most rapid.

Etanercept and infliximab belong to a new group of parentally administered antitumour necrosis factor (TNF) drugs.

Etanercept is licensed in the UK for the treatment of active rheumatoid arthritis in patients who have not responded to other DMARDs and in children with polyarticular-course juvenile arthritis who have not responded to or are intolerant of methotrexate. In adults it produces significant improvements in all measures of rheumatic disease activity compared to placebo. In patients whose disease remains active despite methotrexate treatment, further improvement in control is obtained with the addition of etanercept without an increase in toxicity. In one small trial, etanercept was found to be more effective than placebo in a selected group of children.

Infliximab is a monoclonal antibody which is currently licensed in the UK for Crohn's disease and, in combination with methotrexate for the treatment of rheumatoid arthritis in patients with active disease when the response to disease-modifying drugs, including methotrexate, has been inadequate. In clinical trials infliximab produced significant improvements in all measures of rheumatic disease activity compared with placebo. Infliximab in combination with methotrexate was shown to be superior to methotrexate or infliximab alone.

There are currently no predictors of a good response to anti-TNF drugs and a percentage of patients fail to respond to treatment (25% to 38% of etanercept patients; 21% to 42% of infliximab patients). Infliximab monotherapy induces the production of anti-infliximab antibodies, which may reduce its effectiveness. Adding methotrexate to infliximab therapy may prevent this response.

Anti-TNF drugs may affect host defences against infection and malignancy; whether these agents affect the development and course of malignancies and chronic infections is unknown and safety and efficacy in patients with immunosuppression or chronic infections has not been investigated. With infliximab, upper respiratory tract infections, general infections and those requiring antimicrobial treatment were more common in patients than placebo. Likewise, upper respiratory tract infections were more common in patients treated with etanercept than with placebo. Injection site reactions occur with both infliximab (16%–20%) and etanercept (37%).

There are approximately 600 000 patients with RA in the UK, and of these between 2% and 3.5% may have severe disease which has failed to respond to conventional treatment and who might be eligible for anti-TNF therapy. If between 50% and 70% of patients treated with anti-TNF drugs respond and continue on long-term treatment then the recurrent annual cost to the NHS could be between £48 m and £129 m.