This week's recommended article, Canakinumab for the Treatment of Autoinflammatory Recurrent Fever Syndromes, was published last May on NEJM.

SUMMARY:
Familial Mediterranean fever, mevalonate kinase deficiency, and the tumor necrosis factor receptor–associated periodic syndrome (TRAPS) are monogenic autoinflammatory diseases, that are characterized by recurrent fever episodes, with variable skin, joint, and serosal involvement, which affect functional capacity and quality of life. Colchicine is the standard treatment for familial Mediterranean fever, but it is ineffective or associated with unacceptable side effects in 5 to 10% of patients. No standard treatments are available for mevalonate kinase deficiency or TRAPS. Excessive interleukin (IL)-1β production has been reported in these three diseases, and small studies have suggested that its inhibition improves clinical and laboratory features of patients affected by these diseases. The authors reported the results of a phase 3 Canakinumab Pivotal Umbrella Study in Three Hereditary Periodic Fevers (CLUSTER), in which they evaluated the efficacy and safety of canakinumab, an anti–IL-1β monoclonal antibody, in patients with colchicine-resistant familial Mediterranean fever, mevalonate kinase deficiency, and TRAPS.
Patients ≥ 2 years, at their first flare were randomly assigned, in a 1:1 ratio, to receive subcutaneous canakinumab or placebo every 4 weeks. A flare was defined as a C-reactive protein (CRP) > 10 mg/L and a physician’s global assessment (PGA) score ≥ 2. All the patients were eligible for a blinded dose increase, if they had a persistent baseline flare between days 8 and 14. After day 29, patients were eligible for an open-label increase in the dose if they had a flare. 
A total of 63 patients with colchicine-resistant familial Mediterranean fever, 72 with mevalonate kinase deficiency, and 46 with TRAPS underwent randomization.
At week 16, significantly more patients, of all the three groups, receiving canakinumab had a complete response compared to those receiving placebo. The proportion of patients who had a complete response was higher with canakinumab than with placebo. Significantly more patients in the canakinumab group had a PGA score of < 2, and a CRP ≤ 10 mg/L compared to the placebo group.
In epoch 3, an extended dosing regimen was evaluated: an absence of flares was maintained in approximately half the patients with colchicine-resistant familial Mediterranean fever and TRAPS. Among patients, who had a complete response in epoch 2, all the patients with colchicine-resistant familial Mediterranean fever, 82% of those with mevalonate kinase deficiency, and 83% of those with TRAPS maintained an absence of flares up to week 40. Also patients who did not have a complete response benefited from canakinumab: they had a lower number of days of fever per year than reported in the literature.
No opportunistic infections, cases of tuberculosis, or deaths occurred. Overall, the most frequently reported adverse events were infections, which were more numerous in the canakinumab group than in the placebo group. The authors concluded that CLUSTER, which used a novel approach of grouping separate diseases with different genetic causes on the basis of a common targetable pathogenic mediator, provided evidence of a pathogenic role of IL-1β in colchicine-resistant familial Mediterranean fever, mevalonate kinase deficiency, and TRAPS, and showed that the inhibition of IL-1β with canakinumab was efficacious in controlling and preventing flares.

ARTICLE: Fabrizio De Benedetti, Marco Gattorno, Jordi Anton, et al.