Interleukin-1RA in Rheumatoid Arthritis: Antagonizing Mother Nature?

Abstract & Commentary

Synopsis: A bio-engineered version of a naturally occurring human protein, interleukin-1 receptor antagonist (IL-1RA), was more efficacious than placebo in reducing symptoms and signs of synovitis and was associated with less radiographically apparent new joint damage.

Source: Bresnihan B, et al. Arthritis Rheum 1998;41: 2196-2204.

Tumor necrosis factor (tnf) and interleukin-1 (IL-1) are two cytokines that are present in increased amounts in synovial fluid of patients with rheumatoid arthritis (RA).1 Logical targets for RA therapy, there are currently two FDA-approved agents that act by binding TNF, etanercept (Embrel) and infliximab (Remicade). Etanercept is indicated for treatment of RA refractory to disease modifying drugs (DMARDs), while infliximab, currently approved as an intravenous infusion for Crohn’s disease, has shown promise in RA in a recent trial.2 Currently, there is no FDA-approved agent that acts primarily by binding to IL-1 or by blocking IL-1 receptors. IL-1RA is a naturally occurring protein that antagonizes the pro-inflammatory effects of IL-1 by competitively binding to receptors. Bresnihan and colleagues compared three doses of a human recombinant IL-RA to injections of placebo in adults with RA, in a multicenter, randomized, controlled trial. Six weeks after withdrawing from any DMARDs, the active treatment groups received 30 mg, 75 mg, or 150 mg of IL-1RA subcutaneously daily for 24 weeks. The 119 placebo subjects were compared pair-wise with each active treatment group (119, 115, and 115 subjects respectively). (See Figure.) The changes from baseline to 24 weeks for the 11 clinical and laboratory variables measured have been normalized in order to represent them together. The change in each variable is divided by the standard error of the mean at baseline for that measurement. Almost all measures improved (decreased) for the placebo and active treatment groups. Radiographic measures of joint damage, the Larsen score and the number of new joints with erosions, both increased over the 24 weeks of study. A mean of 2.6 new joints with erosions were noted in the placebo group vs. 1.4 joints with new erosions in all the subjects receiving IL-1RA (P = 0.004 placebo vs IL-1RA groups combined). At 24 weeks, the IL-1RA treated groups had fewer swollen and tender joints and more improvement than the placebo group as assessed by physician and patient global scores. Pain, disability, morning stiffness, erythrocyte sedimentation rate (ESR), and c-reactive protein (CRP) all declined more in the IL-1RA treated than placebo groups. When compared using ACR composite criteria, 43% of those in the IL-1RA 150 mg/d group were improved at 24 weeks vs. 27% of those receiving placebo (P = 0.02 placebo vs IL1-RA-treated subjects). Using Paulus criteria, 44% of the IL-1RA high-dose group was improved vs. 21% of those receiving placebo (P = 0.0002 placebo vs IL-1RA subjects).

Injection site reactions were more common in the active treatment groups and increased in frequency along with the dose of IL-1RA (25% of placebo vs 81% of 150 mg/d IL-1RA). They were described as "mild and transient." Infections for which antibiotics were prescribed occurred in 12% of the placebo group and 15-17% of those receiving IL-1RA. Six infections resulted in hospitalization (1 each in the placebo and 75 mg/d IL-1RA groups and 4 in the 150 mg/d IL-1RA group). Neutropenia resulting in withdrawal developed in two subjects in the 150 mg/d and one subject in the 30 mg/d IL-1RA groups but was not seen in any of the placebo subjects. Neutropenia resolved when IL-1RA was withdrawn.

Comment by Jerry M. Greene, MD, FACR

Joint damage in patients with RA often progresses despite symptomatic improvement with anti-inflammatory therapy. Damage to cartilage and bone is at least in part due to release of proteolytic enzymes. The production of metalloproteinases by rheumatoid synovium is increased by IL-1 binding.3 The IL-1 receptor is, therefore, a natural target for RA therapy. The results of the study by Bresnihan et al, especially the radiographic evidence of less cumulative joint damage in the groups receiving IL-1RA than in the placebo groups, is very encouraging. However, optimism needs to be offset with some concern about the risks of interfering with IL-1 mediated signaling. The difference in rates of adverse events related to infection does not appear to be statistically significant in this trial, but the clustering of subjects requiring hospitalization because of infections in the high-dose group is worrisome. The results of this trial are sufficiently encouraging; one can anticipate there will be larger, phase III trials in the future. Hopefully, it will be possible to antagonize the action of IL-1 in RA enough to get a significant therapeutic benefit without seriously upsetting the balance between host defenses and pathogenic microbial flora.

References

    1. Firestein GS, et al. Arthritis Rheum 1994;37:644-652.

    2. Maini RN, et al. Arthritis Rheum 1998;41:1552-1563.

    3. Firestein GS, et al. Arthritis Rheum 1991;34:1094-1105.