I read with interest the results of the phase II study by Schumacher et al on the use of rilonacept (interleukin-1 Trap) during the first few months of urate-lowering therapy in patients with gout (1). New therapeutic agents, and particularly biologic agents, should be tested against active comparators that are considered standard of care rather than against placebo, as was done in the trial by Schumacher and colleagues. For preventing gouty flares, proving the effectiveness of rilonacept versus placebo may be appropriate to demonstrate proof of concept but falls short of determining clinical usefulness. Rilonacept should be compared, in a randomized double-blinded manner, with colchicine at standard dosages (0.6 mg or 0.5 mg twice a day) in a population of patients who have not previously received colchicine. It is paramount that active comparators be used so that the strength of the experimental drug under study is not overestimated. In the case of rilonacept in this phase II study, the drug afforded a relative risk (RR) reduction of 68% (RR 0.32) for sustaining an acute gouty flare over the first 12 weeks of urate-lowering therapy and of 54% (RR 0.46) for sustaining an acute flare over the course of the 16 weeks of the study. Only one randomized trial specifically investigated the effectiveness of colchicine for prophylaxis of gout flares during urate-lowering therapy, in which colchicine (0.6 mg twice daily) was compared to placebo for the prevention of gout attacks during initiation of allopurinol therapy (2). Patients receiving colchicine had a relative risk reduction of 57% (RR 0.43) for sustaining a gout attack during the first 6 months of urate-lowering treatment. At low doses, colchicine is tolerated by most patients, is rarely absolutely contraindicated, and has long been considered the standard of care for prevention of gout flares when initiating urate-lowering therapy. Without comparing rilonacept to the standard-of-care treatment, clinicians will have a difficult time judging the drug's potential merit. Particularly when considering economic factors, the cost-effectiveness of a biologic agent cannot be ignored.
Infection is also a concern with interleukin-1 antagonists. A study of rheumatoid arthritis patients demonstrated that over the long term (up to 3 years of treatment), anakinra-treated patients not receiving concomitant steroid therapy had a 74% increased relative risk of developing a serious infection versus placebo-treated patients. (2.87 events/100 patient-years versus 1.65 events/100 patient-years) (3). Because the phase II rilonacept study by Schumacher and colleagues was a 16-week trial with 41 patients in the active-treatment arm, the resulting data are too few to enable one to reasonably conclude anything regarding the safety of the drug, as the cumulative number of patient-years in the study totaled only 12.62. Of course, the phase III trial(s) will be larger and should help answer safety concerns. Nevertheless, initiating long-term treatment with immunosuppressive agents for gouty arthritis—when colchicine remains an option for most patients—might be cause for concern.