In this study, patients with familial Mediterranean fever who were treated with canakinumab and whose dose intervals were adjusted according to a standard protocol were evaluated. The study focused only on patients who followed the protocol, demonstrating that it is possible to successfully integrate this protocol with canakinumab therapy. Our study represents the largest number of patient evaluation of canakinumab dose interval extension using a standardized protocol. It is worth noting that the protocol used in this study was developed using the Delphi method, a consensus-building approach that involved pediatric rheumatologists from multiple centers, and this protocol has been implemented in their clinical practice [13, 18].

The use of anti-interleukin-1 therapies in patients with colchicine-resistant FMF is a relatively new concept that has gained significant attention in recent years. Currently, guidelines recommend the use of anti-IL-1 therapy for patients who do not respond adequately to colchicine [5, 17]. Randomized controlled studies have demonstrated the efficacy of canakinumab in managing and preventing flares of familial Mediterranean fever in children. Overall, the treatment is considered safe, with the most frequently reported side effects being mild infections, abdominal pain, headaches, and injection-site reactions. Serious side effects, on the other hand, have been rarely observed [10, 12, 19]. However, data on anti-IL-1 treatment duration are limited to case series, and there are no clear recommendations regarding treatment duration [5, 17]. Interestingly, in clinical practice, it has been observed that attacks do not recur after discontinuation of anti-IL-1 therapy in some patients. This phenomenon may be explained by the termination of the ‘autonomous’ state in patients with IL-1 blockade. An autonomous state within inflammatory diseases is related to a constitutively active and self-amplifying innate immune response, which is most prominently observed in individuals with cryopyrin-associated periodic syndrome (CAPS). Nonetheless, in some individuals with FMF, it is suggested that unexpectedly prolonged episodes or frequent recurrent attacks may be attributed to a vicious circle of pro-inflammatory cytokine production triggered by a stressful condition. The administration of biologic agents targeting IL-1 may interrupt this autonomous IL-1β production in some colchicine-refractory FMF patients, leading to a more stable disease course and a restored positive response to colchicine treatment [20]. Nonetheless, there are still only a limited number of studies on the cessation of canakinumab treatment in FMF patients.

In the randomized controlled CLUSTER trial evaluating the efficacy and safety of canakinumab, patients who achieved remission at week 16 had their dose interval extended to once every 8 weeks. The study found that an extended dosing interval of canakinumab every 8 weeks was effective in maintaining disease control in 46% of patients with colchicine-resistant FMF [12]. In the open-label extension of the study, it was found that 53.2% of the patients who received canakinumab once every 8 weeks were able to maintain the same dose and complete the 72-week follow-up period [21]. In another study, canakinumab treatment was initiated at baseline with a frequency of every 2 months for all patients. The study reported that if patients remained attack-free for at least 6 months, the treatment interval was extended to once every 3 months. At the last visit, 4 out of 28 patients were receiving canakinumab every 3 months. However, the study did not provide detailed information on the process of dose interval extension [22]. A more recent study retrospectively evaluated extending the canakinumab dosing interval in 58 pediatric patients undergoing various dose interval extension schedules. The interval was extended for a median of 6 months (3–18 months) after initiation of therapy, and among these patients, the interval was subsequently decreased in four cases due to an attack. The study also found that canakinumab was withdrawn in 12 patients, and among those patients, two experienced an attack after discontinuation of treatment [23]. In a study that evaluated a standard protocol for extending the canakinumab interval, the dose interval was increased to once every 2 months 6 months after the start of canakinumab treatment, and discontinued after the next 6 months. However, the sample size in this study was small, with only 7 patients completing the protocol. Among the 7 patients, 4 experienced relapses after the discontinuation of treatment [24]. In a retrospective study involving adult FMF patients examining the tapering and discontinuation of canakinumab, 22 out of 57 patients receiving canakinumab monthly had their dosing interval extended to 8–12 weeks after 6 months. Among these patients, 12 discontinued canakinumab after a 6-month attack-free follow-up period. It was noted that treatment was reinstated in 3 patients who had initially discontinued due to re-attacks, while the other 9 patients remained in remission with colchicine alone [25]. In a more recent pediatric study, researchers implemented a predefined schedule to discontinue canakinumab treatment in 25 colchicine-resistant FMF patients. Patients with clinically inactive disease adhered to the schedule, which involved doubling the dose interval at 6 months, tripling it at 12 months, and ultimately discontinuing treatment at 18 months. After the completion of the 18-month period, canakinumab treatment was discontinued in 18 out of the 25 patients (72%). A comparison was conducted with patients who did not follow a standardized protocol, and the results showed no significant difference in relapse rates between the two groups. The compared group in this study lacked a standardized protocol, leaving the schedule and dose intervals for each patient unspecified. Based on these findings, the authors concluded that implementing a standardized protocol for ceasing canakinumab treatment can be an effective approach, enabling the potential reduction of treatment duration [26].

Our study demonstrated the efficacy of the canakinumab dose interval extension protocol in a large series of pediatric patients. The dose interval was effectively extended to once every 3 months in 28 patients. The fact that success of dose interval extension was not associated with disease severity, attack frequency before treatment, acute phase marker levels, or disease duration indicates that this dose interval extension protocol can be considered in patients regardless of these factors. In fact, our study showed that even patients who had 24 attacks in 6 months prior to biologic treatment were able to successfully extend the interval to 1 in 3 months (Supplementary file 1). The study also demonstrated that patients who successfully tolerated switching from a monthly dose to once every 2 months also tolerated further extension to a 3-month interval. Hence, it seems reasonable to consider repeating the dose interval extension in patients who remain attack-free while receiving the drug every 2 months.

While our study offers valuable insights into the efficacy of the dose interval extension protocol, there are some limitations to our findings. Specifically, our study did not provide information on the discontinuation of the drug after the dosing interval was increased, and we lacked data on the follow-up period after the drug was stopped. Additionally, due to the retrospective design of our study, not all patients completed the full treatment schedule, as some had not yet reached the second dose interval extension point. Therefore, we are planning to provide long-term results of our protocol to further investigate the efficacy of the protocol. Another limitation of our study is the small number of patients who were unable to undergo a second dose interval extension, which may have limited our ability to thoroughly investigate the factors that influence the success of a second extension. For a more comprehensive understanding of the long-term effects of the protocol, it is essential to conduct larger and global multicenter clinical studies with extended follow-up periods.