Treatment of systemic-onset juvenile arthritis with canakinumab

Abstract

Treatment of systemic-onset juvenile idiopathic arthritis is challenging, but the availability of cytokine antagonists targeting interleukin-1 and interleukin-6 have markedly advanced the therapeutic options. In this review, we focus on the current experience with canakinumab, an interleukin-1 monoclonal human antibody for the treatment of systemic-onset juvenile idiopathic arthritis and describe its efficacy and safety. Canakinumab is an important, safe, and valid drug in the treatment of systemic-onset juvenile idiopathic arthritis.

Keywords: anakinra; canakinumab; interleukin-1; interleukin-6; systemic-onset juvenile idiopathic arthritis.

Figure 1

Interaction of IL-1 and IL-1 receptor antagonist with the IL-1 receptor molecules. Notes: The binding of IL-1 leads the IL-1 receptor to a steric approximation of the two chains of the receptor (IL1-R1 and IL1RacP) and triggers activation of the T-cell. The natural IL-1 RA binds to the IL-1R1, with no association with IL-1RAcP. Thus, anakinra, a recombinant modified IL1RA, inhibits the activation of IL-1α and IL-1β. IL-1β is specifically bound by canakinumab. Rilonacept inhibits IL-1α and IL-1β. Abbreviations: IL, interleukin; IL1RA, IL-1 receptor antagonist; IL1RacP, IL-1 receptor accessory protein.

Figure 2

Flow diagram of the study for the open-label and withdrawal design. Notes: (A) Trial 1 was a head-to-head, placebo-controlled study. Patients with persistent fever after day 1 had the option to switch to open-label canakinumab (entering trial 2). (B) Trial 2 was a three-phase trial. In the first phase, attempts were made to decrease the dosage of oral corticosteroids or even to discontinue corticosteroids. Next, patients were entered into a withdrawal phase in which they were randomized to receive canakinumab or placebo, with disease flare as the primary outcome parameter. The third phase of trial 2 was an open-label extension study. Abbreviation: SC, subcutaneous.

Figure 3

Response according to PedACR30, PedACR50, and PedACR100 criteria in a double-blind study in patients with systemic-onset juvenile idiopathic arthritis. Notes: The primary endpoint was PedACR30 and resolution of fever, and was achieved significantly more often in the canakinumab group. (A) Fourteen patients had a PedACR100 response on day 15. (B) The effect was unchanged until the 29th day. *P<0.0001, **P=0.0001. Abbreviation: PedACR, American College of Rheumatology Pediatric Criteria.

Figure 4

Occurrence of relapses during second double blind study phase. Notes: Disease relapses in the double-blind “withdrawal” phase of the study was significantly more frequent in the placebo group than in the canakinumab group (Kaplan-Meier analysis). Twenty-two percent of patients in the canakinumab group and 52% in the placebo group showed a flare (P=0.0043), meaning that the probability of a disease flare with canakinumab was about three times lower.

Figure 5

Responses to canakinumab therapy in trial 2. Abbreviation: PedACR, American College of Rheumatology Pediatric Criteria.