Introduction

Familial Mediterranean fever (FMF) is the most common monogenic systemic autoinflammatory disease [1]. FMF is caused by point mutations in the Mediterranean Fever (MEFV) gene located on the short arm of chromosome 16 [2]. The mutated gene encodes the protein pyrin (also known as marenostrin), which is expressed in neutrophils, eosinophils, monocytes, dendritic cells, and synovial fibroblasts [3,4,5]. Pyrin mediates regulation of caspase-1 activation and NLRP3 inflammasome, an intracellular complex required for conversion of precursor IL-1β (pro IL-1β) into mature IL-1β [6,7,8,9]. IL-1β is a cytokine released by cells of the immune system that have potent inflammatory and immunomodulatory effects, and is the key mediator of the immune response. IL-1β plays a role in T-cell activation, chemotaxis of polymorphonuclear leukocytes and monocytes, release of proteases from tissue macrophages, stimulation of fibroblast proliferation, and activation of chondrocytes [9,10,11,12]. Mutated forms of pyrin cause oversecretion of Il-1β, leading to inappropriate neutrophil activation and a burst of systemic inflammation [11, 12]. Furthermore, IL-1 is an inducer of serum amyloid A (SAA), which contributes to the development of amyloidosis, the most serious complication of FMF [12, 13]. Recent advances in our understanding of the pathogenesis of FMF have led to the discovery of new drugs specific to the pathogenesis. As IL-1β is the primary factor in the process of inflammation, inhibition of IL-1β by newly discovered biological agents that block IL-1β signaling may provide significant advantages in the targeted treatment of FMF [12, 15,16,17]. Canakinumab is a complete human IL-1β monoclonal antibody that works via neutralization of IL-1β signaling. It binds to IL-1β with high selectivity, without interfering with other pathways activated by IL-1 [18, 19]. Few studies have investigated canakinumab treatment in patients with colchicine-resistant FMF (cr-FMF) and FMF-related amyloidosis, especially pediatric patients [17, 20, 21]. In addition, findings related to canakinumab use in patients with amyloidosis due to autoinflammatory diseases are unsatisfactory [22, 23].

The present study aimed to determine the clinical effects, safety, and tolerability of canakinumab in pediatric patients with cr-FMF, and FMF patients with coexisting amyloidosis, chronic renal insufficiency, and uveitis.

Materials and methods

The study was conducted at Dr. Sami Ulus Children’s Hospital, Pediatric Nephrology and Rheumatology Departments, Ankara, Turkey, between January 2012 and January 2017. The study included 11 pediatric cr-FMF patients aged 6–17 years (median 14 years) that had been followed-up for ≥ 3 months while receiving canakinumab treatment [subcutaneous dose 2 mg/kg, monthly (maximum dose 150 mg)]. Patients that had been using canakinumab for < 3 months were excluded from the study.

FMF was diagnosed according to Tel-Hashomer criteria [24], with the support of routine diagnostic genetic testing. FMF attacks were confirmed by the presence of fever (≥ 38 °C), clinical findings (peritonitis, pleuritis, or monoarthritis), and an elevated acute phase reactant level. The diagnosis of amyloidosis was confirmed via kidney biopsy. Demographic and clinical data, genetic analysis of MEFV mutations results, laboratory parameters, including acute phase reactants, and response to treatment and adverse reactions were recorded. All patients were treated with colchicine together with canakinumab at the maximal dose for age and weight.

Colchicine resistance was defined as ≥ 1 FMF attacks per month for three sequential months and/or a high level of any acute-phase reactant between attacks despite taking the maximum dose of colchicine according to the degree of renal insufficiency, age, and weight [25]. Lidar et al. [26] defined non-responders as patients that do not respond to colchicine, patients with > 1 FMF clinical attacks every 3 months despite treatment with colchicine 2 mg/day. In addition, the FMF50 score, which was improved and validated by Ozen et al. [27], was used to assess treatment outcome. The primary outcome measure was to evaluate the percentage of patients with ≥ 50% reduction in FMF 50 score during the treatment period. Secondary outcome measures were acute phase reactants of patients, and recovery of serum creatinine, albumin, urinary protein excretion and findings associated with FMF.

Statistical analysis

The Kolmogorov–Smirnov test was used to evaluate normality of data. Descriptive analyses were presented as median and range (minimum–maximum) for continuous variables.

Results

Among the patients, seven (cases 1–7) had cr-FMF, three (cases 8–10) had FMF and chronic kidney disease (CKD), FMF secondary amyloidosis, and nephrotic syndrome, of which one (case 10) also had bilateral uveitis, and one (case 11) had cr-FMF and bilateral uveitis. Patients aged between 6 and 17 years (median 14.0 years). The median duration of use of canakinumab was 21 months (5–49). Genetic analysis showed homozygous M694V mutations in exon 10 in all the patients. Demographic data, clinical and laboratory findings, attack frequency, and treatment response are shown in Table 1.

Table 1 Patients’ characteristics, attack frequency, and treatment response
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Complete clinical, laboratory, and FMF50 response to canakinumab treatment was achieved in all the cr-FMF patients. In all, three patients (case 8, 9, and 10) had FMF-associated amyloidosis, nephrotic syndrome, and CKD, of which two (case 9 and 10) had clinical improvement with canakinumab and one (case 8) had partial response. Among the patients only one case (case 8) died in 2014; 1 year after canakinumab cessation due to sepsis related with mixed fungal and staphylococcal peritonitis. Nine of our patients currently continue to receive canakinumab treatment. Demographic, clinical, and laboratory features of the patients with FMF-associated amyloidosis are given in Table 2.

Table 2 Patients’ characteristics with FMF-associated amyloidosis
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Only one patient developed pneumonia following upper respiratory tract infection as an adverse effect. Macrophage activation syndrome and anaphylactic reaction were not observed in any of the patients.

Discussion

In FMF patients inflammatory attacks that typically last 1–3 days are usually self-limiting, but in some FMF patients continuous chronic subclinical inflammation causes secondary amyloidosis, which has a negative effect on quality of life, and is associated with renal failure and death [1, 2, 28, 29]. Colchicine prevents both FMF attacks and amyloid deposition, but not in all patients [12, 28,29,30]. The majority of patients that do not get receive this benefit from colchicine have homozygous M694V mutations, which are also associated with a more severe FMF phenotype [13, 31]. The present study included 11 patients given canakinumab for the treatment of cr-FMF. All of the presented patients had homozygous M694V mutations, as reported earlier.

Amyloidosis, the most serious life-threatening complication of FMF, and is more common in FMF patients with homozygote M694V mutation; three of the present study’s patients with FMF associated amyloidosis had a homozygote M694V mutation. It is critically important to decrease the number and frequency of FMF attacks in patients that do not respond to colchicine, so as to avoid renal failure due to secondary amyloidosis [13, 32]. Elevated IL-1 secretion is correlated with both the number of MEFV mutated monocytes and a high-degree of mutation penetration [33, 34]; therefore, IL-1β blockers might be an option for achieving successful treatment in patients with cr-FMF and FMF-associated amyloidosis [17, 20, 35]. The first use of anti-IL-1 therapy for cr-FMF was reported in a pediatric patient in 2007 [15]. Subsequently, anti-IL1 treatment was shown to be highly successful in pediatric patients with cr-FMF by other researchers [16, 36, 37]. Canakinumab, which was first used in an adult FMF patient [19], is preferred over other IL-1 blockers due to its specificity to IL-1β and its long half-life. Moreover, canakinumab can improve renal function, decrease protein excretion, and partially decrease amyloid deposition [20,21,22,23, 35]. Clinical experience about canakinumab is particularly limited in childhood [20, 38, 39]. Canakinumab was used in the present study due to the important role of IL-1 in the pathogenesis of cr-FMF and FMF-associated amyloidosis.

Complete clinical remission and a decrease in the laboratory parameters of active inflammation were achieved using canakinumab in all seven of the presented patients with cr-FMF (without amyloidosis). Published findings regarding use of canakinumab to treat amyloidosis due to autoinflammatory diseases are inconsistent. Topaloğlu et al. [22] reported that amyloid deposition decreases in response to IL-1β blockade. Other studies reported that amyloidosis associated with FMF can be successfully treated with canakinumab in children [20, 21, 35]. In the present study adequate response to canakinumab was observed in two of three FMF patients with secondary renal amyloidosis and nephrotic syndrome. The progression of amyloidosis and nephrotic syndrome were arrested, and renal function improved in two (case 9 and 10) of three patients with FMF-related amyloidosis, nephrotic syndrome, and CKD in response to canakinumab treatment; during follow-up there were no subsequent FMF attacks and the decreases were observed in acute phase reactants. Complete response to canakinumab treatment was not achieved in case 8. She had underwent persistent continuous ambulatory peritoneal dialysis (CAPD) treatment due to end stage renal disease (ESRD) and severe multiorgan amyloidosis. She died due to sepsis and peritonitis 1 year after cessation of canakinumab treatment. Though the present study’s patient sample was small, we think the findings indicate that canakinumab treatment has favorable effects on FMF-associated amyloidosis. In our study; we detected pneumonia following an upper respiratory tract infection in patient 11 as an adverse effect; she was treated with appropriate antibiotics successfully and we did not have to stop treatment. In a recent study carried out in 13 adults revealed different adverse affects as anxiety (1/13), headache (4/13), hidradenitis (1/13), pruritis(1/13), tooth infection (1/13), upper respiratory tract infection (2/13) and vomiting (1/13) [40]. Based on our results and the aforementioned literature we concluded that canakinumab might be a safe and tolerable choice in the treatment of cr-FMF patients.

To our knowledge there are only few case reports in the literature about FMF-associated uveitis [41, 42]. Two of our patients with uveitis were evaluated for accompanying vasculitis, Behçet and also juvenile idiopathic arthritis; neither these diseases nor any other underlying condition responsible for uveitis could be detected. Also uveitis may be an idiopathic finding not associated with FMF. In a recent report of Salehzadeh the authors concluded that in the areas with high prevalence of FMF, it could be considered as an underlying cause of uveitis [41]. Because our country is an endemic area for FMF and there is no other possible causative disease; we thought that uveitis is associated with FMF in these two patients. It is already known that IL-1 inhibitors [43] and canakinumab therapy [44, 45] have been successfully used to treat uveitis in patients with Behcet’s disease. Brambill et al. [46] reported that canakinumab successfully treated idiopathic uveitis and juvenile idiopathic arthritis. Hirano et al. [47] reported that chronic, infantile neurologic, cutaneous, and articular syndrome (CINCA) was successfully treated using canakinumab, and Simonini et al. [48] noted that canakinumab successfully treated Blau syndrome-related uveitis. To the best of our knowledge the literature is devoid of any information regarding the efficacy of IL-1 inhibitors or canakinumab in the treatment of uveitis in pediatric FMF patients as well as adults.

Uveitis in case 10 was successfully treated using canakinumab, without reactivation. Unfortunately, in 1 cr-FMF patient with uveitis (case 11), uveitis reactivated during canakinumab treatment (after 10 months) despite full remission of clinical and laboratory manifestations of FMF and canakinumab was withdrawn due to uveitis reactivation. To the best of our knowledge, this is the first report to describe administration of canakinumab in an FMF patient with bilateral anterior uveitis. Inhibition of IL-1β via canakinumab might be another option for management of FMF with bilateral anterior uveitis.

The main limitations of this study are the retrospective design and the small sample size. We could also stop treatment at a certain time and evaluate the period between the discontinuation of treatment and attack. This could provide an important contribution to the literature for the duration of treatment.

Conclusion

Canakinumab has favorable results in the management of pediatric patients with cr-FMF, FMF-associated renal amyloidosis, and is well tolerated. The duration of the treatment is still a matter of debate so it warrants further investigations.