Cytokines are crucial mediators of the inflammatory response in rheumatoid arthritis. Interleukin-1 (IL-1) is one such cytokine that promotes inflammation. Interleukin-1 receptor antagonist (IL-1Ra) is a naturally occurring protein that blocks the binding of IL-1 to its receptors, thereby diminishing the inflammatory response. Anakinra is a recombinant human form of IL-1Ra and is approved for the treatment of rheumatoid arthritis.
Treatment with anakinra as monotherapy has been shown to be clinically effective in rheumatoid arthritis patients (Bresnihan et al Arthritis Rheum 41:2196, 1998). The current study by Cohen et al (Arthritis Rheum 46(3):614-624, 2002) examined the safety and efficacy of anakinra in combination with methotrexate compared to methotrexate alone.
In this study 419 subjects were studied who had moderate-to-severe RA and had been receiving methrotrexate for six consecutive months and had been on a stable dose for three or more months. All subjects had disease duration greater than six months but less than twelve years. Subjects were randomized to receive either placebo or anakinra in one of the following doses: 0.04, 0.1, 0.4, 1.0, or 2.0 mg/kg in a daily subcutaneous injection.
The primary endpoint was a twenty percent clinical improvement according to the American College of Rheumatology criteria (ACR20 criteria). A dose response relationship was found when the ACR20 response of the placebo group was compared with the ACR20 response of the anakinra group (p=0.0001). Most pronounced were the differences in the 1 mg/kg and the 2 mg/kg groups of which 46% (p=0.001) and 38% (p=0.007) achieved an ACR20 response, respectively, as opposed to the placebo group of which 19% achieved an ACR20 response. These results remained consistent at 24 weeks.
The most common side effect was an injection site reaction, which occurred in 70% of subjects at the higher doses and led to a 7% dropout rate in the 1 mg/kg group and a 10% dropout rate in the 2 mg/kg group. No other dose-related adverse events were reported.
Anakinra in combination with methotrexate is safe and well-tolerated. The efficacy of the combination therapy is better than methotrexate monotherapy.
Anakinra (Kineret® is the newest FDA approved agent for the treatment of rheumatoid arthritis. The ACR20 responses for anakinra are, in general, more modest than for the TNF inhibitors. This is true in the current study as well as when anakinra is added to background methotrexate. Nonetheless, it is clearly efficacious. Its short halflife necessitates daily administration. However, this may be an advantage in the patient who develops serious infection since the drug will “wash out” quickly upon discontinuation. It will be interesting to see, as post-approval experience with the drug increases, whether serious and opportunistic infections are less of a problem with anakinra than with the TNF inhibitors.