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Update on the management of colchicine resistant Familial Mediterranean Fever (FMF)



Familial Mediterranean Fever (FMF), an autoinflammatory disease, is characterized by self-limited inflammatory attacks of fever and polyserositis along with high acute phase response. Although colchicine remains the mainstay in treatment, intolerance and resistance in a certain portion of patients have been posing a problem for physicians.

Main body

Like many autoimmune and autoinflammatory diseases, many colchicine-resistant or intolerant FMF cases have been successfully treated with biologics. In addition, many studies have tested the efficacy of biologics in treating FMF manifestations.


Since carriers of FMF show significantly elevated levels of serum TNF alpha, IL-1, and IL-6, FMF patients who failed colchicine were successfully treated with anti IL-1, anti IL-6, or TNF inhibitors drugs. It is best to use colchicine in combination with biologics.


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.

Main text

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].


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.


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].


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


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

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].


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

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

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

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.


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.

Availability of data and materials

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.



Autoinflammatory disease


Cryopyrin-associated periodic syndrome


European League Against Rheumatism


Familial cold-induced autoinflammatory syndrome


Familial Mediterranean fever


Juvenile Idiopathic Arthritis


Muckle-Wells syndrome


Peripheral blood mononuclear cells


Rheumatoid arthritis


Secondary amyloidosis


Serum Amyloid A




Systemic lupus erythematosus




Tumor necrosis factor


Visual analog scale


  1. 1.

    Sönmez HE, Batu ED, Özen S. Familial mediterranean fever: current perspectives. J Inflamm Res. 2016;9:13–20.

  2. 2.

    El-Shanti H, Majeed HA, El-Khateeb M. Familial mediterranean fever in Arabs. Lancet. 2006;367(9515):1016–24.

  3. 3.

    Tunca M, Ozdogan H, Kasapcopur O, Yalcinkaya F, Ozen S, Topaloglu R, et al. Familial mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study. Medicine (Baltimore). 2005;84(1):1–11.

  4. 4.

    Ben-Chetrit E, Touitou I. Familial mediterranean fever in the world. Arthritis Care Res. 2009;61(10):1447–53.

  5. 5.

    Bernot A, Clepet C, Dasilva C, Devaud C, Petit JL, Caloustian C, et al. A candidate gene for familial mediterranean fever. Nat Genet. 1997;7(8):1317–25.

  6. 6.

    Aksentijevich I, Centola M, Deng Z, Sood R, Balow J, Wood G, et al. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell. 1997;90(4):797–807.

  7. 7.

    Georgin-Lavialle S, Hentgen V, Stankovic Stojanovic K, Bachmeyer C, Rodrigues F, Savey L, et al. Familial mediterranean fever. Rev Med Interne. 2018;39(4):240–55.

  8. 8.

    Sari I, Birlik M, Kasifoglu T. Familial mediterranean fever: an updated review. Eur J Rheumatol. 2014;1(1):21–33.

  9. 9.

    Lidar M, Yaqubov M, Zaks N, Ben-Horin S, Langevitz P, Livneh A. The prodrome: a prominent yet overlooked pre-attack manifestation of familial mediterranean fever. J Rheumatol. 2006;33(6):1089–92.

  10. 10.

    Sohar E, Gafni J, Pras M, Heller H. Reviews familial mediterranean fever* a Suruey of 470 cases and review of the literature. Am J Med. 1967;43(2):227–53.

  11. 11.

    Kees S, Langevitz P, Zemer D, Padeh S, Pras M, Livneh A. Attacks of pericarditis as a manifestation of familial Mediterranean fever (FMF). Q J Med. 1997;90(10):643–7.

  12. 12.

    Lidar M, Kedem R, Mor A, Levartovsky D, Langevitz P, Livneh A. Arthritis as the sole episodic manifestation of familial Mediterranean fever. J Rheumatol. 2005;32(5):859–62.

  13. 13.

    Lidar M, Doron A, Barzilai A, Feld O, Zaks N, Livneh A, et al. Erysipelas-like erythema as the presenting feature of familial Mediterranean fever. J Eur Acad Dermatol Venereol. 2013;27(7):912–5.

  14. 14.

    Kukuy O, Livneh A, Ben-David A, Kopolovic J, Volkov A, Shinar Y, et al. Familial Mediterranean fever (FMF) with proteinuria: clinical features, histology, predictors, and prognosis in a cohort of 25 patients. J Rheumatol. 2013;40(12):2083–7.

  15. 15.

    Kasifoglu T, Bilge SY, Sari I, Solmaz D, Senel S, Emmungil H, et al. Amyloidosis and its related factors in turkish patients with familial mediterranean fever: a multicentre study. Rheumatol U K. 2014;53(4):741–5.

  16. 16.

    van der Hilst JC, Simon A, Drenth JP. Hereditary periodic fever and reactive amyloidosis. Clin Exp Med. 2005;5(3):87–98.

  17. 17.

    Stoffels M, Szperl A, Simon A, Netea MG, Plantinga TS, Van Deuren M, et al. MEFV mutations affecting pyrin amino acid 577 cause autosomal dominant autoinflammatory disease. Ann Rheum Dis. 2014;73(2):455–61.

  18. 18.

    de Torre-Minguela C, del Castillo PM, Pelegrín P. The NLRP3 and pyrin inflammasomes: implications in the pathophysiology of autoinflammatory diseases. Front Immunol. 2017;8:43.

  19. 19.

    Shinar Y, Obici L, Aksentijevich I, Bennetts B, Austrup F, Ceccherini I, et al. Guidelines for the genetic diagnosis of hereditary recurrent fevers. Ann Rheum Dis. 2012;71(10):1599–605.

  20. 20.

    Majeed HA, El-Shanti H, Al-Khateeb MS, Rabaiha ZA. Genotype/phenotype correlations in Arab patients with familial mediterranean fever. Semin Arthritis Rheum. 2002;31(6):371–6.

  21. 21.

    Giancane G, Haar NMT, Wulffraat N, Vastert SJ, Barron K, Hentgen V, et al. Evidence-based recommendations for genetic diagnosis of familial Mediterranean fever. Ann Rheum Dis. 2015;74(4):635–41.

  22. 22.

    Livneh A, Langevitz P, Zemer D, Zaks N, Kees S, Lidar T, et al. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum. 1997;40(10):1879–85.

  23. 23.

    Demirkaya E, Saglam C, Turker T, Koné-Paut I, Woo P, Doglio M, et al. Performance of different diagnostic criteria for familial Mediterranean fever in children with periodic fevers: results from a multicenter international registry. J Rheumatol. 2016;43(1):154–60.

  24. 24.

    Alghamdi M. Familial Mediterranean fever, review of the literature. Clin Rheumatol. 2017;36(8):1707–13.

  25. 25.

    Ozen S, Demirkaya E, Erer B, Livneh A, Ben-Chetrit E, Giancane G, et al. EULAR recommendations for the management of familial Mediterranean fever. Ann Rheum Dis. 2016;75(4):644–51.

  26. 26.

    Dinarello CA, Wolfe SM, Goldfinger SE, Dale DC, Alling DW. Colchicine therapy for familial Mediterranean fever. N Engl J Med. 1974;291(18):934–7.

  27. 27.

    Ravelli RBG, Gigant B, Curmi PA, Jourdain I, Lachkar S, Sobel A, et al. Insight into tubulin regulation from a complex with colchicine and a stathmin-like domain. Nature. 2004;428(6979):198–202.

  28. 28.

    Taskiran EZ, Cetinkaya A, Balci-Peynircioglu B, Akkaya YZ, Yilmaz E. The effect of colchicine on pyrin and pyrin interacting proteins. J Cell Biochem. 2012;113(11):3536–46.

  29. 29.

    Livneh A, Zemer D, Siegal B, Laor A, Sohar E, Pras M. Colchicine prevents kidney transplant amyloidosis in familial Mediterranean fever. Nephron. 1992;60(4):418–22.

  30. 30.

    Jayaprakash V, Ansell G, Galler D. Colchicine overdose: the devil is in the detail. N Z Med J. 2007;120(1248):U2402.

  31. 31.

    Varughese GI, Varghese AI, Tahrani AA. Colchicine: time to rethink [1]. N Z Med J. 2007;120(1249):U2429.

  32. 32.

    Merlin HE. Azoospermia caused by colchicine--a case report. Fertil Steril. 1972;23(3):180–1.

  33. 33.

    American Academy of Periatrics - Comitee on Drugs. The transfer of drugs and other chemicals into human milk. Pediatrics. 1994;93(1):137–50.

  34. 34.

    Ben-Chetrit E, Ben-Chetrit A, Berkun Y, Ben-Chetrit E. Pregnancy outcomes in women with familial Mediterranean fever receiving colchicine: is amniocentesis justified? Arthritis Care Res. 2010;62(2):143–8.

  35. 35.

    Diav-Citrin O, Shechtman S, Schwartz V, Avgil-Tsadok M, Finkel-Pekarsky V, Wajnberg R, et al. Pregnancy outcome after in utero exposure to colchicine. Am J Obstet Gynecol. 2010;203(2):144.e1–6.

  36. 36.

    Finkelstein Y, Aks SE, Hutson JR, Juurlink DN, Nguyen P, Dubnov-Raz G, et al. Colchicine poisoning: the dark side of an ancient drug. Clin Toxicol. 2010;48(5):407–14.

  37. 37.

    Kallinich T, Haffner D, Niehues T, Huss K, Lainka E, Neudorf U, et al. Colchicine use in children and adolescents with familial Mediterranean fever: literature review and consensus statement. Pediatrics. 2007;119(2):e474–83.

  38. 38.

    Barut K, Sahin S, Adrovic A, Sinoplu AB, Yucel G, Pamuk G, et al. Familial Mediterranean fever in childhood: a single-center experience. Rheumatol Int. 2018;38(1):67–74.

  39. 39.

    Kiraz S, Ertenli I, Arici M, Calgüneri M, Haznedaroglu I, Çelik I, et al. Effects of colchicine on inflammatory cytokines and selectins in familial Mediterranean fever. Clin Exp Rheumatol. 1998;16(6):721–4.

  40. 40.

    Terreri MTRA, Bernardo WM, Len CA, da Silva CAA, de Magalhães CMR, Sacchetti SB, et al. Guidelines for the management and treatment of periodic fever syndromes familial Mediterranean fever. Rev Bras Reumatol. 2016;56(1):37–43.

  41. 41.

    Hawkins PN, Lachmann HJ, McDermott MF. Interleukin-1–receptor antagonist in the Muckle–Wells syndrome. N Engl J Med. 2003;348(25):2583–4.

  42. 42.

    Chae JJ, Wood G, Masters SL, Richard K, Park G, Smith BJ, et al. The B30.2 domain of pyrin, the familial Mediterranean fever protein, interacts directly with caspase-1 to modulate IL-1β production. Proc Natl Acad Sci U S A. 2006;103(26):9982–7.

  43. 43.

    Belkhir R, Moulonguet-Doleris L, Hachulla E, Prinseau J, Baglin A, Hanslik T. Treatment of familial Mediterranean fever with anakinra. Ann Intern Med. 2007;146(11):825–6.

  44. 44.

    Calligaris L, Marchetti F, Tommasini A, Ventura A. The efficacy of anakinra in an adolescent with colchicine-resistant familial Mediterranean fever. Eur J Pediatr. 2008;167(6):695–6.

  45. 45.

    Gattringer R, Lagler H, Gattringer KB, Knapp S, Burgmann H, Winkler S, et al. Anakinra in two adolescent female patients suffering from colchicine-resistant familial Mediterranean fever: effective but risky. Eur J Clin Investig. 2007;37(11):912–4.

  46. 46.

    Kuijk LM, Govers AMAP, Hofhuis WJD, Frenkel J. Effective treatment of a colchicine-resistant familial Mediterranean fever patient with anakinra. Ann Rheum Dis. 2007;66(11):1545–6.

  47. 47.

    Mitroulis I, Papadopoulos VP, Konstantinidis T, Ritis K. Anakinra suppresses familial Mediterranean fever crises in a colchicine-resistant patient. Neth J Med. 2008;66(11):3.

  48. 48.

    Roldan R, Ruiz AM, Miranda MD, Collantes E. Anakinra: new therapeutic approach in children with familial Mediterranean fever resistant to colchicine. Joint Bone Spine. 2008;75(4):504–5.

  49. 49.

    Moser C, Pohl G, Haslinger I, Knapp S, Rowczenio D, Russel T, et al. Successful treatment of familial Mediterranean fever with Anakinra and outcome after renal transplantation. Nephrol Dial Transplant Off Publ Eur Dial Transpl Assoc - Eur Ren Assoc. 2009;24(2):676–8.

  50. 50.

    Petropoulou AD, Robin M, Socié G, Galicier L. Transmission of familial Mediterranean fever mutation after bone marrow transplantation and successful treatment with Anakinra. Transplantation. 2010;90(1):102–3.

  51. 51.

    Özen S, Bilginer Y, Ayaz NA, Calguneri M. Anti-interleukin 1 treatment for patients with familial Mediterranean fever resistant to colchicine. J Rheumatol. 2011;38(3):516–8.

  52. 52.

    Alpay N, Şumnu A, Çalışkan Y, Yazıcı H, Türkmen A, Gül A. Efficacy of anakinra treatment in a patient with colchicine-resistant familial Mediterranean fever. Rheumatol Int. 2012;32(10):3277–9.

  53. 53.

    Bilginer Y, Ayaz NA, Ozen S. Anti-IL-1 treatment for secondary amyloidosis in an adolescent with FMF and Behçet’s disease. Clin Rheumatol. 2009;29(2):209.

  54. 54.

    Hennig S, Bayegan K, Uffmann M, Thalhammer F, Winkler S. Pneumonia in a patient with familial Mediterranean fever successfully treated with anakinra—case report and review. Rheumatol Int. 2012;32(6):1801–4.

  55. 55.

    Stankovic Stojanovic K, Delmas Y, Ureña Torres P, Peltier J, Pelle G, Jéru I, et al. Dramatic beneficial effect of interleukin-1 inhibitor treatment in patients with familial Mediterranean fever complicated with amyloidosis and renal failure. Nephrol Dial Transplant. 2012;27(5):1898–901.

  56. 56.

    Estublier C, Stankovic Stojanovic K, Bergerot J-F, Broussolle C, Sève P. Myositis in a patient with familial Mediterranean fever and spondyloarthritis successfully treated with anakinra. Jt Bone Spine Rev Rhum. 2013;80(6):645–9.

  57. 57.

    Soriano A, Verecchia E, Afeltra A, Landolfi R, Manna R. IL-1β biological treatment of familial Mediterranean fever. Clin Rev Allergy Immunol. 2013;45(1):117–30.

  58. 58.

    Celebi ZK, Kucuksahin O, Sengul S, Tuzuner A, Keven K. Colchicine-resistant familial Mediterranean fever in a renal transplantation patient: successful treatment with anakinra. Clin Kidney J. 2014;7(2):219–20.

  59. 59.

    Mercan R, Turan A, Bitik B, Tufan A, Haznedaroglu S, Goker B. Rapid resolution of protracted febrile myalgia syndrome with anakinra: report of two cases. Mod Rheumatol. 2016;26(3):458–9.

  60. 60.

    Sevillano ÁM, Hernandez E, Gonzalez E, Mateo I, Gutierrez E, Morales E, et al. Anakinra induce la remisión completa del síndrome nefrótico en un paciente con fiebre mediterránea familiar y amiloidosis. Nefrología. 2016;36(1):63–6.

  61. 61.

    Ben-Zvi I, Kukuy O, Giat E, Pras E, Feld O, Kivity S, et al. Anakinra for colchicine-resistant familial Mediterranean fever: a randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol Hoboken NJ. 2017;69(4):854–62.

  62. 62.

    Pecher A-C, Igney-Oertel A, Kanz L, Henes J. Treatment of familial Mediterranean fever with anakinra in patients unresponsive to colchicine. Scand J Rheumatol. 2017;46(5):407–9.

  63. 63.

    İlgen U, Küçükşahin O. Anakinra use during pregnancy: report of a case with familial Mediterranean fever and infertility. Eur J Rheumatol. 2017;4(1):66–7.

  64. 64.

    Venhoff N, Voll RE, Glaser C, Thiel J. IL-1-Blockade mit Anakinra in der Schwangerschaft. Z Für Rheumatol. 2018;77(2):127–34.

  65. 65.

    Laskari K, Boura P, Dalekos GN, Garyfallos A, Karokis D, Pikazis D, et al. FRI0497 the Interleukin-1 inhibitor Canakinumab for familial Mediterranean fever: long-term beneficial effect in a cohort of 14 patients. Ann Rheum Dis. 2016;75(Suppl 2):618–9.

  66. 66.

    Babaoglu H, Varan O, Kucuk H, Atas N, Satis H, Salman R, et al. On demand use of anakinra for attacks of familial Mediterranean fever (FMF). Clin Rheumatol. 2019;38(2):577–81.

  67. 67.

    Hausmann JS. Targeting cytokines to treat autoinflammatory diseases. Clin Immunol. 2018;206:23–32.

  68. 68.

    Mitroulis I, Skendros P, Oikonomou A, Tzioufas AG, Ritis K. The efficacy of canakinumab in the treatment of a patient with familial Mediterranean fever and longstanding destructive arthritis. Ann Rheum Dis. 2011;70(7):1347–8.

  69. 69.

    Hacihamdioglu DO, Ozen S. Canakinumab induces remission in a patient with resistant familial Mediterranean fever. Rheumatology. 2012;51(6):1041.

  70. 70.

    Brik R, Butbul-Aviel Y, Lubin S, Dayan EB, Rachmilewitz-Minei T, Tseng L, et al. Canakinumab for the treatment of children with colchicine-resistant familial Mediterranean fever: a 6-month open-label, single-arm pilot study. Arthritis Rheumatol. 2014;66(11):3241–3.

  71. 71.

    Alpa M, Roccatello D. Canakinumab as rescue therapy in familial Mediterranean fever refractory to conventional treatment. Drug Des Devel Ther. 2015;9:1983–7.

  72. 72.

    Gül A, Ozdogan H, Erer B, Ugurlu S, Kasapcopur O, Davis N, et al. Efficacy and safety of canakinumab in adolescents and adults with colchicine-resistant familial Mediterranean fever. Arthritis Res Ther. 2015;17:243.

  73. 73.

    Sozeri B, Gulez N, Ergin M, Serdaroglu E. The experience of canakinumab in renal amyloidosis secondary to familial Mediterranean fever. Mol Cell Pediatr. 2016;3(1):33.

  74. 74.

    Ozkan S, Atas B. Canakinumab treatment in four children with colchicine resistant familial mediterranean fever. JPMA J Pak Med Assoc. 2017;67(6):945–7.

  75. 75.

    Yazılıtaş F, Aydoğ Ö, Özlü SG, Çakıcı EK, Güngör T, Eroğlu FK, et al. Canakinumab treatment in children with familial Mediterranean fever: report from a single center. Rheumatol Int. 2018;38(5):879–85.

  76. 76.

    Jesenak M, Hrubiskova K, Kapustova L, Kostkova M, Banovcin P. Canakinumab as monotherapy for treatment of familial Mediterranean fever – first report in central and Eastern Europe region. Bratisl Med J. 2018;119(04):198–200.

  77. 77.

    De Benedetti F, Gattorno M, Anton J, Ben-Chetrit E, Frenkel J, Hoffman HM, et al. Canakinumab for the treatment of autoinflammatory recurrent fever syndromes. N Engl J Med. 2018;378(20):1908–19.

  78. 78.

    Trabulus S, Korkmaz M, Kaya E, Seyahi N. Canakinumab treatment in kidney transplant recipients with AA amyloidosis due to familial Mediterranean fever. Clin Transpl. 2018;32(8):e13345.

  79. 79.

    Meinzer U, Quartier P, Alexandra J-F, Hentgen V, Retornaz F, Koné-Paut I. Interleukin-1 targeting drugs in familial Mediterranean fever: a case series and a review of the literature. Semin Arthritis Rheum. 2011;41(2):265–71.

  80. 80.

    Cetin P, Sari I, Sozeri B, Cam O, Birlik M, Akkoc N, et al. Efficacy of Interleukin-1 targeting treatments in patients with familial Mediterranean fever. Inflammation. 2015;38(1):27–31.

  81. 81.

    Başaran Ö, Uncu N, Çelikel BA, Taktak A, Gür G, Cakar N. Interleukin-1 targeting treatment in familial Mediterranean fever: an experience of pediatric patients. Mod Rheumatol. 2015;25(4):621–4.

  82. 82.

    Eroglu FK, Beşbaş N, Topaloglu R, Ozen S. Treatment of colchicine-resistant familial Mediterranean fever in children and adolescents. Rheumatol Int. 2015;35(10):1733–7.

  83. 83.

    Özçakar ZB, Özdel S, Yılmaz S, Kurt-Şükür ED, Ekim M, Yalçınkaya F. Anti-IL-1 treatment in familial Mediterranean fever and related amyloidosis. Clin Rheumatol. 2016;35(2):441–6.

  84. 84.

    Köhler BM, Lorenz H-M, Blank N. IL1-blocking therapy in colchicine-resistant familial Mediterranean fever. Eur J Rheumatol. 2018;5(4):230–4.

  85. 85.

    Kucuksahin O, Yildizgoren MT, Ilgen U, Ates A, Kinikli G, Turgay M, et al. Anti-interleukin-1 treatment in 26 patients with refractory familial mediterranean fever. Mod Rheumatol. 2017;27(2):350–5.

  86. 86.

    Varan O, Kucuk H, Babaoglu H, Atas N, Salman RB, Satis H, et al. Effect of interleukin-1 antagonists on the quality of life in familial Mediterranean fever patients. Clin Rheumatol. 2019;38(4):1125–30.

  87. 87.

    Varan Ö, Kucuk H, Babaoglu H, Guven SC, Ozturk MA, Haznedaroglu S, et al. Efficacy and safety of interleukin-1 inhibitors in familial Mediterranean fever patients complicated with amyloidosis. Mod Rheumatol. 2019;29(2):363–6.

  88. 88.

    McDermott MF. Rilonacept in the treatment of chronic inflammatory disorders. Drugs Today Barc Spain 1998. 2009;45(6):423–30.

  89. 89.

    Hashkes PJ, Spalding SJ, Giannini EH, Huang B, Johnson A, Park G, et al. Rilonacept for colchicine-resistant or -intolerant familial Mediterranean fever: a randomized trial. Ann Intern Med. 2012;157(8):533–41.

  90. 90.

    Hashkes PJ, Spalding SJ, Hajj-Ali R, Giannini EH, Johnson A, Barron KS, et al. The effect of rilonacept versus placebo on health-related quality of life in patients with poorly controlled familial Mediterranean fever. Biomed Res Int. 2014;2014:854842.

  91. 91.

    Sakallioglu O, Duzova A, Ozen S. Etanercept in the treatment of arthritis in a patient with familial Mediterranean fever. Clin Exp Rheumatol. 2006;24(4):435–7.

  92. 92.

    Schattner A, Lachmi M, Livneh A, Pras M, Hahn T. Tumor necrosis factor in familial mediterranean fever. Am J Med. 1991;90(4):434–8.

  93. 93.

    Schattner A, Gurevitz A, Zemer D, Hahn T. Induced TNF production in vitro as a test for familial Mediterranean fever. QJM Mon J Assoc Physicians. 1996;89(3):205–10.

  94. 94.

    Drenth JP, van Deuren M, van der Ven-Jongekrijg J, Schalkwijk CG, van der Meer JW. Cytokine activation during attacks of the hyperimmunoglobulinemia D and periodic fever syndrome. Blood. 1995;85(12):3586–93.

  95. 95.

    Mege JL, Dilsen N, Sanguedolce V, Gul A, Bongrand P, Roux H, et al. Overproduction of monocyte derived tumor necrosis factor alpha, interleukin (IL) 6, IL-8 and increased neutrophil superoxide generation in Behçet’s disease. A comparative study with familial Mediterranean fever and healthy subjects. J Rheumatol. 1993;20(9):1544–9.

  96. 96.

    Baykal Y, Saglam K, Yilmaz MI, Taslipinar A, Akinci SB, Inal A. Serum sIL-2r, IL-6, IL-10 and TNF-alpha level in familial Mediterranean fever patients. Clin Rheumatol. 2003;22(2):99–101.

  97. 97.

    Gang N, Drenth JP, Langevitz P, Zemer D, Brezniak N, Pras M, et al. Activation of the cytokine network in familial Mediterranean fever. J Rheumatol. 1999;26(4):890–7.

  98. 98.

    Centola M, Wood G, Frucht DM, Galon J, Aringer M, Farrell C, et al. The gene for familial Mediterranean fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators. Blood. 2000;95(10):3223–31.

  99. 99.

    Ozgocmen S, Akgul O. Anti-TNF agents in familial Mediterranean fever: report of three cases and review of the literature. Mod Rheumatol. 2011;21(6):684–90.

  100. 100.

    Aldea A, Campistol JM, Arostegui JI, Rius J, Maso M, Vives J, et al. A severe autosomal-dominant periodic inflammatory disorder with renal AA amyloidosis and colchicine resistance associated to the MEFV H478Y variant in a Spanish kindred: an unusual familial Mediterranean fever phenotype or another MEFV-associated periodic inflammatory disorder? Am J Med Genet A. 2004;124A(1):67–73.

  101. 101.

    Metyas S, Arkfeld D, Forrester D, Ehresmann G. Infliximab treatment of familial Mediterranean fever and its effect on secondary AA amyloidosis. Jcr J Clin Rheumatol. 2004;10(3):134–7.

  102. 102.

    Kaya S, Kaptanoglu E, Elden H, Hizmetli S. Coexistence of familial Mediterranean fever and juvenile idiopathic arthritis with osteoporosis successfully treated with etanercept. Intern Med Tokyo Jpn. 2010;49(6):619–22.

  103. 103.

    Ozgocmen S, Özçakar L, Ardicoglu O, Kocakoc E, Kaya A, Kiris A. Familial Mediterranean fever responds well to infliximab: single case experience. Clin Rheumatol. 2006;25(1):83–7.

  104. 104.

    Daysal S, Akcil G, Goker B, Haznedaroglu S, Ercan N, Ozturk MA. Infliximab therapy in a patient with familial Mediterranean fever and chronic hip arthritis. Arthritis Care Res. 2005;53(1):146–7.

  105. 105.

    Mor A, Pillinger M, Kishimoto M, Abeles A, Livneh A. Familial Mediterranean fever successfully treated with Etanercept. Jcr J Clin Rheumatol. 2007;13(1):38–40.

  106. 106.

    Nakamura A, Matsuda M, Tazawa K-I, Shimojima Y, Ikeda S-I. Successful treatment with infliximab and low-dose methotrexate in a Japanese patient with familial Mediterranean fever. Intern Med Tokyo Jpn. 2007;46(15):1247–9.

  107. 107.

    Bilgen SA, Kilic L, Akdogan A, Kiraz S, Kalyoncu U, Karadag O, et al. Effects of anti-tumor necrosis factor agents for familial mediterranean fever patients with chronic arthritis and/or sacroiliitis who were resistant to colchicine treatment. J Clin Rheumatol. 2011;17(7):358–62.

  108. 108.

    Erten S, Erten SF, Altunoglu A. Successful treatment with anti-tumor necrosis factor (anti-TNF)-alpha of proteinuria in a patient with familial mediterranean fever (FMF) resistant to colchicine: anti-TNF drugs and FMF. Rheumatol Int. 2012;32(4):1095–7.

  109. 109.

    Kosmidou M, Mpolotsis V, Christou L, Tsianos EV. Late onset of Crohn’s disease in familial Mediterranean fever: the necessity of anti-TNF treatment. J Dig Dis. 2014;15(2):102–4.

  110. 110.

    Fujikawa K, Migita K, Tsukada T, Umeda M, Nonaka F, Kawakami A, et al. Interleukin-6 targeting therapy in familial Mediterranean fever. Clin Exp Rheumatol. 2013;31(3 Suppl 77):150–1.

  111. 111.

    Hamanoue S, Suwabe T, Hoshino J, Sumida K, Mise K, Hayami N, et al. Successful treatment with humanized anti–interleukin-6 receptor antibody (tocilizumab) in a case of AA amyloidosis complicated by familial Mediterranean fever. Mod Rheumatol. 2016;26(4):610–3.

  112. 112.

    Umeda M, Aramaki T, Fujikawa K, Iwamoto N, Ichinose K, Terada K, et al. Tocilizumab is effective in a familial Mediterranean fever patient complicated with histologically proven recurrent fasciitis and myositis. Int J Rheum Dis. 2017;20(11):1868–71.

  113. 113.

    Yilmaz S, Cinar M, Simsek I, Erdem H, Pay S. Tocilizumab in the treatment of patients with AA amyloidosis secondary to familial Mediterranean fever. Rheumatol Oxf Engl. 2015;54(3):564–5.

  114. 114.

    Nikiphorou E, Neocleous V, Phylactou LA, Psarelis S. Successful use of tocilizumab in two cases of severe autoinflammatory disease with a single copy of the Mediterranean fever gene. Rheumatology. 2017;56(9):1627–8.

  115. 115.

    Aikawa E, Shimizu T, Koga T, Endo Y, Umeda M, Hori T, et al. Atypical familial Mediterranean fever complicated with gastrointestinal amyloidosis diagnosed due to paroxysmal arthralgia and intractable diarrhea, successfully treated with Tocilizumab. Intern Med. 2019;1:2277–18.

  116. 116.

    Norman P. Selective JAK inhibitors in development for rheumatoid arthritis. Expert Opin Investig Drugs. 2014;23(8):1067–77.

  117. 117.

    Bodenmiller B, Zunder ER, Finck R, Chen TJ, Savig ES, Bruggner RV, et al. Multiplexed mass cytometry profiling of cellular states perturbed by small-molecule regulators. Nat Biotechnol. 2012;30(9):858–67.

  118. 118.

    Gök K, Cengiz G, Erol K, Ozgoçmen S. Tofacitinib suppresses disease activity and febrile attacks in a patient with coexisting rheumatoid arthritis and familial Mediterranean fever. Acta Reumatol Port. 2017;42(1):88–90.

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GEH performed the literature review, and wrote the initial version of this manuscript. AJ revised the manuscript. IU revised the manuscript. All authors read and approved the final manuscript.

Correspondence to Imad Uthman.

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El Hasbani, G., Jawad, A. & Uthman, I. Update on the management of colchicine resistant Familial Mediterranean Fever (FMF). Orphanet J Rare Dis 14, 224 (2019).

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  • Familial Mediterranean fever
  • Autoinflammatory diseases
  • Colchicine resistance
  • Biologics