Background

Familial Mediterranean fever (FMF) (OMIM #249100) is the most common autoinflammatory disease (AID) worldwide [1]. The condition was first described in 1945 as “benign paroxysmal peritonitis” [2]. The typical phenotype of FMF includes self-limited inflammatory attacks of fever and polyserositis, arthritis, and dermal manifestations along with high acute phase response [3]. Although it has been classically known to affect people in the Mediterranean region like the Arabs, Armenians, Turks, Greeks, Italians, Persians, and Jews, FMF is seen worldwide due to travel and immigration that happened mainly in the twentieth century [4]. Clinically, FMF is highly heterogenous depending on the sequence variants in MEFV gene which is located on the short (p) arm of chromosome 16 encoding for a pyrin protein [5, 6]. Colchicine has been the mainstay of treatment for FMF since 1972 [7]. However, the molecular and genetic advancements have introduced new targeted drugs that could be used as an add-on to colchicine in certain circumstances such as resistance, which is defined as having 1 or more attacks per month despite receiving the maximally tolerated dose for ≥3 months. The objective of this review is to describe the different treatment modalities that have been successfully used in the course of management of colchicine resistant FMF patients.

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Clinical picture and pathogenesis of FMF

FMF is characterized by self-limiting episodes of fever associated with serositis, arthritis, and dermal manifestations which last 12–72 h. The interval between the episodes is variable [8]. FMF has prodromal symptoms that occur 1–2 days prior to the onset of symptoms. These include constitutional, neuropsychiatric or physical signs, appetite and taste alterations, and pain in the region where the flare will appear [9]. The fever of FMF is high grade (> 38 °C), and is typically recurrent. It tends to rise rapidly followed by a plateau and rapid decrease over 1 to 3 days [9]. The peritoneal inflammation causes an abdominal pain that is initially localized and becomes generalized to resolve in 12 to 48 h. Pleuritis or pericarditis can cause chest pain. Pleuritic pain is unilateral, and lasts 12 to 48 h [10]. Pericarditis lasts longer than pleuritic plain for up to 14 days [11]. Arthritis is a common symptom that accompanies FMF attacks. It is usually monoarticular typically involving large joints of the lower limbs (knees and ankles) and develops in childhood [12]. The dermatological manifestations of FMF include painful and warm erysipelas-like skin lesion occurring on the lower limb about 10–35 cm2 in size with sharp boundaries. In children, those lesions may be the presenting feature of FMF [13]. Proteinuria can be developed in FMF patients. Kidney biopsy is recommended whenever the urinary protein is more than 0.5 g/24 h [14]. Renal amyloidosis is the major complication of FMF which leads to end-stage renal disease. Some of the risk factors for the development of amyloidosis are: Male gender, arthritis, delay in diagnosis, M694 V homozygous genotype, and family history of amyloidosis [15, 16].

In 1997, FMF was found to be associated with the MEFV gene on chromosome 16 [5, 6, 17]. The MEFV gene encodes for the protein pyrin/marenostrin which is an immunoregulatory molecule made up of 781 amino acids which interacts with caspase-1 and other inflammasome components to regulate interleukin IL-1β production. Inflammasomes are mutiprotein complexes that play a major role in both innate and adaptive immune systems [18]. 85% of FMF cases in the Mediterranean basin have genetic mutations encoded from exon 10 and exon 2 [4]. There are 9 clearly pathogenic variants of FMF which are: M694 V, M694I, M680I, V726A, R761H, A744S, I692del, E167D, and T267I. Other variants of unknown significance include: E148Q, K695R, P369S, F479 L, and I591T [19]. M694 V is the most common mutation in the Eastern Mediterranean populations, although less common among Arabs [20]. Since M694 V is associated with a severe disease phenotype, patients homozygous for M694 V are considered at a high risk for early disease [21].

Diagnosis

The diagnosis of FMF is based on the Tel-Hashomer clinical criteria. Livneh et al. [22] noted that the Tel-Hashomer criteria includes typical, incomplete, and supportive cases. The diagnostic criterion for Yalcinkaya-Ozen has a better sensitivity than other criteria for FMF in children [23]. FMF attacks are classified into typical or incomplete. Typical attacks are defined as recurrent (≥3 of the same type), febrile (rectal temperature of 38 °C or higher), and short (lasting between 12 h and 3 days). Incomplete attacks are defined as painful and recurrent attacks that differ from typical attacks in one or two features, as follows:

  1. 1.

    The temperature is normal or lower than 38 °C

  2. 2.

    The attacks are longer or shorter than specified (but not shorter than 6 h or longer than a week)

  3. 3.

    No signs of peritonitis during the abdominal attacks

  4. 4.

    The abdominal attacks are localized

  5. 5.

    The arthritis involves joints other than those specified

The attacks that do not fulfill the definition for a typical or incomplete attack are not considered as FMF attack [24]. Mediterranean fever genetic testing can be useful to detect at least two heterozygote mutations or a homozygous mutation.

Management

In January 2016, The European League Against Rheumatism (EULAR) recommendation set for the management of FMF has been published supported by the best available evidence [25]. The goal of FMF treatment, as per the EULAR recommendations, is to obtain the control of acute attacks, minimize the chronic and subclinical inflammation, prevent complications, and provide an acceptable quality of life.

Colchicine: diagnostic and therapeutic limitations

Colchicine has been the main treatment of FMF since 1972 [26]. Colchicine is related to pyrin through altering the organization of actin cytoskeleton by binding to tubulin monomers and inhibiting polymer formation [27, 28]. Although colchicine cannot completely prevent febrile episodes, its use may halt the progression of amyloidosis, reversing proteinuria in the absence of irreversible glomerular damage [29]. Colchicine has a narrow therapeutic index. Sometimes, its maximum tolerated dose may not be adequate to control disease activity. Gastrointestinal disturbance may be seen in up to 10% of patients in the first month of treatment which might lead to increased fecal excretion of starch, fat, and bile acids and decreased absorption of D-xylose and vitamin B12 [30, 31]. Merlin et al. [32] case report suggested that colchicine is associated with azoospermia at high doses. However, men need not stop colchicine prior to conception [25]. In women, colchicine use is safe during pregnancy and lactation [33,34,35]. Nevertheless, it should be used cautiously in patients with impaired renal or hepatic functions [36]. Compliance with colchicine is very important for the proper management of FMF. Although colchicine is effective for FMF, approximately one-third of the patients treated with colchicine have a partial remission, and about 5–10% are non-responders; another 2–5% do not tolerate the drug mainly due to gastrointestinal symptoms [37]. Barut et al. recent study showed that the frequency of M694 V homozygosity might be associated with non-responding to colchicine [38]. Because FMF is the most common autoinflammatory disease, colchicine resistance or unresponsiveness posed a problem for physicians. Since carriers of FMF show significantly elevated levels of serum TNF, IL-1, IL-6 and IL-8, new biological drugs targeting those cytokines were used in colchicine non-responders or resistant [39].

Proper management of FMF includes trying colchicine up to 2 mg a day until the flare settles. The dose is reduced to 0.5 or 1 mg daily in the time when CRP or preferably serum AA protein is checked weekly for at least 8 weeks to see whether the acute-phase response is high. In that case, treatment is escalated with a higher dose of colchicine. If there is no control of FMF manifestations, other treatments are added to a low dose of colchicine [25]. Patients who continue to have ≥1 attacks per month despite receiving the maximally tolerated dose for ≥3 months might be considered non-responder or resistant to colchicine [25]. In those patients, biologics and maximal tolerated dose of colchicine are recommended [25]. In cases of AA amyloidosis secondary to FMF addition, the treatment also should be intensified with biologics and maximal tolerated dose of colchicine [25].

Anti Il-1 drugs

Because elevated levels of IL-1 are related to inflammatory activity, the use of drugs targeting IL-1 have been proposed. Three different types of IL-1 receptor antagonists are available. Anakinra is a human recombinant un-glycosylated analog of the IL-1 receptor antagonist. Rilonacept is a fusion protein that contains the extracellular portions of type I IL-1receptor and IL-1 receptor accessory protein. Canakinumab is a fully humanized monoclonal antibody of the class IgG1 that acts specifically against IL-1 beta [40].

Anakinra

Before 2003, Anakinra was successfully tested for the treatment of multiple autoimmune diseases including rheumatoid arthritis and systemic lupus erythematosus (SLE). In 2003, 5 patients with Muckle-Wells Syndrome which is a milder form of FMF responded successfully to a trial of Anakinra [41]. The first quantitative study discussing the efficacy of blocking IL-1 receptors in FMF came by Chae et al. [42]. Anakinra suppressed the acute-phase proteins in a patient with FMF and amyloidosis supporting a direct effect of the mutated protein in FMF pyrin on IL-1beta activation suggesting a heightened IL-1 responsiveness as one factor selecting for pyrin mutations. Shortly after that, the efficacy of Anakinra in the treatment of a colchicine resistant 68 year old woman homozygous for the M694 V mutation of the MEFV gene [43] and a 15 year-old colchicine resistant girl was reported [44]. Table 1 summarizes all case reports and studies describing the use of Anakinra in treating the manifestations of FMF.

Table 1 Studies and case reports that discussed the use of Anakinra in FMF
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Canakinumab

Canakinumab is the only FDA-approved cytokine blocker for the treatment of colchicine-resistant FMF in the United States [67]. The first report in the literature of the successful administration of Canakinumab in a patient with FMF and chronic arthritis after failing Anakinra, Etanercept and low dose prednisone, and Methotrexate was published in 2011 by Mitroulis et al. [68]. Table 2 summarizes all case reports and studies describing the efficacy of Canakinumab in the treatment of FMF.

Table 2 Studies and case reports that discussed the use of Canakinumab in FMF
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There has been some relatively large randomized studies that tested the efficacy of Canakinumab and/or Anakinra in treating FMF attacks. Meizner et al. treated 7 patients with recurrent FMF attacks with Anakinra or Cankinumab along with colchicine on board. The regimen was beneficial to all patients (complete remission in 6 patients, partial remission in 1 patient) [79].

A study by Cetin et al. included 20 patients in whom Colchicine was considered ineffective. Twelve patients received anakinra, and 8 patients were treated with canakinumab. Only 1 patient did not respond to the Anakinra. A significant decrease in proteinuria in the amyloidosis complicated FMF patients was observed [80]. Basaran et al. analyzed the MEFV gene in 8 patients having refractory FMF. They found homozygous mutations in 6 patients. All patients were successfully treated with anakinra and/or canakinumab [81]. Fourteen patients were included in Eroglu et al. study, 11 of which were treated with anakinra. Nine patients responded to the treatment at the third month, but 4 of them switched to canakinumab because of noncompliance, local side effects, and active arthritis. Nine patients in total were treated with canakinumab. All patients treated with canakinumab responded well [82]. Thirteen patients were included in the study by Ozcakar et al. 7 of them received anti-IL-1 therapy due to colchicine resistance and 6 due to FMF-related amyloidosis. In all treated patients, attacks completely disappeared or decreased in frequency [83]. Anakinra and canakinumab showed a rapid (2 ± 3 days) and persistent suppression of FMF symptoms and inflammatory parameters in 31 colchicine resistant FMF patients. The frequency of FMF attacks was significantly reduced [84]. Kucuksahin et al. followed up patients using colchicine for 4 months to 30 years. In some patients, the treatment was switched to anti-IL-1 treatment for various reasons. Twenty-four patients used anakinra and 2 used canakinumab. Sixteen patients with colchicine resistance had no attacks under anti-IL-1 treatment, and 4 had decreased frequency and duration of attacks [85]. Varan et al. treated 33 patients with anakinra and 11 with canakinumab. Striking improvements were detected in frequency, duration, and visual analog scale (VAS) severity of attacks [86]. Also, Varan et al. identified 17 patients with colchicine resistant FMF-amyloidosis. Background colchicine therapy was continued in all patients in maximal-tolerated dose along with IL-1 inhibitors. All patients benefited from IL-1 antagonists assessed by patient and physician global assessments. Inflammatory markers and the amount of proteinuria were reduced in all patients [87].

Rilonacept

In February 2008, rilonacept received the approval from the FDA for the treatment of two Cryopyrin-associated periodic syndrome (CAPS) disorders, namely, familial cold-induced autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS), for children and adults 12 years and older [88]. As a primary study to assess the efficacy and safety of rilonacept in treating patients with colchicine-resistant FMF, Hashkes et al. [89] performed a randomized, double blind, placebo-controlled trial including 14 patients. The complete remission was observed in two patients during the 3-month treatment course, while eight patients had a partial response. The remaining four had no significant reduction in attack frequency [89]. There was no reported serious side effect for rilonacept in this study. Table 3 lists the 3 studies that discussed the successful treatment of FMF with rilonacept.

Table 3 Studies and case reports that discussed the use of Rilonacept in FMF
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Anti TNF drugs

In 1991, Schattner et al. [92] studied the levels of tumor necrosis factor (TNF) in the plasma and in supernatants of peripheral blood mononuclear cells (PBMC) incubated alone or with an inducer in 36 asymptomatic and 24 patients with acute FMF and compared with 20 matched healthy subjects. No TNF was found in plasma and non-induced PBMC supernatants. Induced TNF production was markedly decreased in patients with acute FMF and increased in asymptomatic FMF patients to levels over those of control subjects. Re-testing of patients first studied during an acute episode when their disease was quiescent revealed a fivefold increase in TNF production. The capacity of PBMC to respond to TNF inducers may more accurately reflect its synthesis. The marked decrease in the response of PBMC to TNF inducers in acute FMF suggested that cells were already exhausted and highly activated to produce TNF possibly contributing to the pathogenesis of FMF. Later on, other quantitative studies have been published on the role of TNF-α in FMF. Those studies reported a decreased/slightly increased TNF-α levels during acute attacks or normal/increased levels between the attacks [93,94,95,96]. Gang et al. [97] found increased levels of soluble TNF receptor fusion protein p55 and p75 during attacks. Then, it was found out that the MEFV gene is upregulated by TNF-α [98]. Lachman et al. reported the first case, where a 38-year-old FMF patient with protracted arthritis responded favorably to infliximab. Sakallioglu et al. [91] presented a case of successful use of etanercept on a pediatric FMF patient resistant to colchicine, steroid, and methotrexate. Another report by Ozgocmen et al. [99] described the successful use of adalimumab in 3 patients with FMF. Table 4 summarizes all case reports and studies describing the use of anti-TNF drugs in treating the manifestations of FMF.

Table 4 Studies and case reports that discussed the use of Anti-TNF drugs in FMF
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Anti IL6 drugs

In clinical settings, tocilizumab (TCZ), an IL-6 receptor blocker, has been widely used for the treatment of rheumatoid arthritis (RA). The first cases reported on the success of tocilizumab in the treatment of FMF came from Japan [110,111,112]. Yilmaz et al. [113] reported 11 cases with AA amyloidosis secondary to FMF successfully treated by TCZ. Among these 11 patients, 10 patients did not experience any attack during the course of treatment, and no major adverse events were observed. Even though 8 patients had the decreased level of the proteinuria after treatment, there was no case where the deposition of amyloid in any organ have been confirmed to be reduced by biopsy. Table 5 summarizes all the case reports and studies which discuss the successful treatment of FMF manifestations with TCZ.

Table 5 Studies and case reports that discussed the use of toclizumab in FMF
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Januse kinase inhibitors

Januse kinase inhibitors have been well studied for the treatment of RA [116]. Tofacitinib (Xeljanz) is specific to the JAK-STAT pathway with preferential inhibition of JAK1 and JAK3 [117]. Recently, Gok et al. [118] described recently the case of a 27-year-old woman with RA and FMF resistant to colchicine who presented for morning stiffness. She had elevated inflammatory markers, and was started on sulfasalazine, hydroxychloroquine, methotrexate, and steroid. After 3 months of the regimen, the patient continued to have the attacks. The patient was followed for 12-months under treatment with tofacitinib and colchicine. She was completely attack free, and no adverse events occurred. This case report is promising for the use of janus kinase inhibitors to control colchicine-resistant FMF attacks.

Conclusions

Familial Mediterranean Fever (FMF) is the most common autoinflammatory disease. A mutation of the MEFV gene on chromosome 16, which codes for protein pyrin, is associated with the disease pathogenesis. Colchicine, which has been prescribed to treat FMF since 1972, remains the mainstay for treatment although its use has been complicated by resistance and intolerance in a minority of patients. Since FMF patients have high levels of certain cytokines, practitioners have found in biologics a solution for colchicine resistant and intolerant cases given the success that biologics have shown in other autoimmune and auto-inflammatory diseases. Anti-interleukin 1, anti-interleukin 6, anti-TNF, and Janus Kinase inhibitors drugs, can be beneficial add-on to colchicine in treating FMF manifestations.