Effectiveness of Canakinumab Treatment in Colchicine Resistant Familial Mediterranean Fever Cases

Abstract

Anti-interleukin 1 agents are used successfully in colchicine-resistant or intolerant Familial Mediterranean Fever (FMF) patients. Sixty-five patients with FMF who received canakinumab treatment for at least 6 months due to colchicine resistance or intolerance between 2016 and 2020 in our department were retrospectively analyzed. Canakinumab treatment was given subcutaneously every 4 weeks. After completing monthly canakinumab therapy over 12 months, in patients with complete remission, the dosing interval was extended to every 1.5 months for 6 months, then every 2 months for 6 months, and finally every 3 months for a year. In patients without disease activation, canakinumab treatment was discontinued at the end of 3 years and followed up with colchicine treatment. Patients who had a flare switched to the previous dosing interval. In patients with renal amyloidosis, monthly canakinumab treatment was continued without extending the dose intervals. The mean duration of canakinumab use in our patients was 31.4 ± 10.57 months (6–52 months). The mean age at onset of symptoms was 4.65 ± 3.84 (range, 1–18) years, and the mean age at diagnosis was 5.59 ± 3.9 (range, 4–19) years. Complete remission was achieved in 57 (87.6%) and partial remission in seven (10.7%) patients. One patient was unresponsive to treatment. Canakinumab treatment was discontinued in three patients with complete remission and one patient with drug resistance. Erythrocyte sedimentation rate (ESR) (51.85 ± 15.7 vs. 27.80 ± 13.73 mm/h) and C-reactive protein (CRP) [26 (3-73) vs. 5 (1–48) mg/L] values were compared before and after canakinumab treatment in attack-free periods, a significant decrease was found after canakinumab treatment (p < 0.001, p < 0.001, respectively). Bodyweight Z-scores (respectively −0.80 ± 0.86 vs. −0.49 ± 0.92) were compared, similarly, a statistically significant increase after canakinumab treatment (p < 0.001), but no significant increase in height Z scores (−1.00 ± 0.88 vs. −0.96 ± 0.94) (p = 0.445) was detected. Four patients had FMF-related renal amyloidosis. The decrease in proteinuria with canakinumab treatment was not statistically significant (p = 0.068). Cervical lymphadenitis developed in one and local reactions in two patients. No severe adverse effects requiring discontinuation of canakinumab treatment were observed. Our study showed that canakinumab treatment was highly effective, well-tolerated in pediatric FMF patients, and controlled extension of the canakinumab dose interval was safe.

Effect of interleukin-1 antagonist on growth of children with colchicine resistant or intolerant FMF

“…One patient reported an injection site skin reaction, and two additional patients complained of abdominal pain. These results are in-line with published data regarding canakinumab safety [17,22,27]. It is worth noting that in a randomized, placebo-controlled trial of canakinumab in autoinflammatory diseases in children, a somewhat higher rate of adverse events was recorded, including infections (23.8%), injection site reactions, (6.0%), headache (3.9%) and abdominal pain (3.6%) [26].…”

“…In the study of Balci et al of 11 children with FMF, despite a median follow-up of only 1.5 years, canakinumab treatment had a positive effect on both height and body weight Z-scores [18]. Yücel et al, however, have failed to demonstrate a positive effect of canakinumab on linear growth and reported an improvement in body weight Z-scores only [17]. This lack of improvement in height percentiles in this study was attributed by the authors for late initiation of treatment and a relatively short duration of follow-up.…”

“…Anti-IL-1 agents are highly effective and safe in patients with colchicine-resistant FMF [17,21,22]. However, the efficacy and safety profile of these drugs in the treatment of pediatric FMF is largely limited to a relatively short duration of follow-up.…”

“…Both drugs are currently prescribed to colchicine-resistant or -intolerant FMF patients, although colchicine is still used in these patients to prevent amyloidosis, as the two biological drugs have not been consistently shown to have this effect. Both anakinra and canakinumab have a relatively favorable safety profile, with the most common side effects being injection site reactions and infections (typically of the upper respiratory tract) [16,17]. Despite the growing use in anti-IL1 drugs in FMF among children, data is still lacking in regard to long-term follow up.…”

Feasibility of canakinumab withdrawal in colchicine-resistant familial Mediterranean fever

“…In addition, colchicine cannot be used at effective doses in some patients due to its side effects or intolerance [ 10 ]. Therapeutic blockage of IL-1β is highly effective in the treatment of FMF patients with colchicine resistance or intolerance [ 11 , 12 ]. Among the anti-IL-1 agents, anakinra (recombinant antagonist of the IL-1 receptor), canakinumab (human monoclonal antibody against IL-1β) and rilonacept (a soluble decoy receptor ‘trap’, binding both IL-1α and IL-1β) can be used in the treatment of FMF [ 13 ].…”