Version July 2025
INTRODUCTION —
Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disorder characterized by recurrent bouts of fever and serosal inflammation. Its major complication is the insidious development of secondary (AA) amyloidosis with eventual kidney failure in uncontrolled patients. This topic will review the management of FMF. The epidemiology, genetics, pathophysiology, and clinical manifestations of FMF and an overview of periodic fever syndromes and other autoinflammatory diseases can be found elsewhere:
●(See "Familial Mediterranean fever: Epidemiology, genetics, and pathogenesis".)
●(See "Clinical manifestations and diagnosis of familial Mediterranean fever".)
●(See "The autoinflammatory diseases: An overview".)
GOALS OF THERAPY —
The goals of therapy for familial Mediterranean fever (FMF) are to prevent acute attacks and minimize subclinical inflammation in between attacks. Controlling inflammation even during asymptomatic intervals can prevent the development and progression of secondary (AA) amyloidosis.
INITIAL MANAGEMENT WITH COLCHICINE —
The initial treatment of FMF is with colchicine. Colchicine is primarily effective as a prophylactic treatment for FMF attacks. It is recommended in all patients with FMF regardless of the frequency and intensity of attacks. Use of intermittent high-dose colchicine only for treatment of acute attacks of FMF is not recommended; it is not effective and does not protect from the development of secondary (AA) amyloidosis [1-5].
Dosing and administration — Treatment with colchicine should be started as soon as a diagnosis of FMF is established and should be continued indefinitely. However, in rare cases of heterozygous FMF patients who are asymptomatic for several (more than four or five) years and do not display elevated acute phase reactants, it may be possible to discontinue colchicine [6,7]. In one study, 59 children with FMF discontinued colchicine and were followed for an average of 5±3.05 years [8]. During the follow-up period, 11 (20 percent) patients had an attack (mostly fever) and required renewal of colchicine treatment. Myalgia and arthritis before colchicine cessation were more common among children who required restarting of colchicine, whereas a longer attack-free period prior to colchicine discontinuation predicted successful colchicine cessation.
We recommend the following starting dose of colchicine [9]:
●For children <5 years of age, ≤0.5 mg/day (≤0.6 mg/day in case tablets contain 0.6 mg).
●For children 5 to 10 years of age, 0.5 to 1 mg/day (0.6 to 1.2 mg/day in case tablets contain 0.6 mg).
●For children >10 years of age and adults, 1 to 1.5 mg/day (1.2 to 1.8 mg/day in case tablets contain 0.6 mg).
●In patients with preexisting complications (eg, renal amyloidosis) or greater disease activity (eg, high frequency of attacks, long duration of each attack, involvement of multiple sites during the attack, and joint involvement) [10], higher initial doses (up to 2 mg/day) are needed, provided that kidney and liver function are normal [11-13].
Adherence with colchicine is higher with once-daily dosing, and its efficacy is the same as with splitting the daily dose into two divided doses [14]. We do not split the colchicine dose unless the patient does not tolerate once-daily dosing due to side effects, which are most commonly gastrointestinal. We generally start with a lower dose and increase the dose by 0.5 to 0.6 mg according to the patient’s response and tolerance without exceeding the maximum recommended daily dose of colchicine, which is 2 mg for children under 12 years and 3 mg for adults. Dose adjustment of colchicine is necessary in patients with kidney or liver impairment. Dose adjustments are found in the drug information topic within UpToDate.
An oral solution of colchicine (0.6 mg/5 mL) is also available in some areas for gout prophylaxis and may be used off-label in FMF patients who have difficulty swallowing pills or who require small dose adjustments [15]. Patients or caregivers must be reliably capable of using an oral measuring syringe with mL markings.
Administering colchicine only during an acute FMF attack or increasing its dose during the acute attack usually has no impact on the attack symptoms. In addition, high-dose colchicine (ie, >3 mg/day) is associated with significant side effects. We do not administer colchicine intravenously because of the risk of serious adverse effects.
Monitoring — Following initiation of colchicine, patients with FMF should be followed closely for three to six months to observe its therapeutic effect on attack frequency and severity.
Once the appropriate colchicine dose has been established, patients should be monitored for toxicity and response to therapy approximately every six months. Laboratory testing for colchicine toxicity includes a complete blood count (CBC) to assess for leukopenia. To monitor disease response, we check erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and, when available, serum amyloid A (SAA). We also check the urine for proteinuria, which may be the first sign of renal amyloidosis. We check liver and kidney function tests annually to ensure that no modification of the colchicine dose is required. We do not routinely monitor muscle enzymes as an indication of toxicity. Colchicine-induced myopathy occurs either when the patient has kidney failure (elevated creatinine) or when colchicine is given concomitantly with other medications (eg, clarithromycin, ritonavir, ketoconazole) that can inhibit cytochrome P450 3A4 and/or the glycoprotein 1 pump. In these selected cases, we reduce the dose of colchicine and monitor muscle enzymes (creatine phosphokinase [CPK], and lactate dehydrogenase [LDH]).
Mechanism of action — The pathophysiology of FMF involves the recruitment and activation of neutrophils at serosal surfaces. Colchicine affects the motility of neutrophils by reducing their deformability and elasticity by tubulin disruption. These properties are crucial for their extravasation into the tissue in response to inflammatory stimuli [16,17]. Additional mechanisms involve various inhibitory effects on macrophages, such as suppression of the stimulation of dendritic cell maturation and antigen presentation, and inactivation of the NALP3 inflammasome [17,18]. Furthermore, colchicine's inhibition of microtubule assembly may enhance the release of guanine nucleotide exchange factor-H1. This peptide triggers RhoA activation, which promotes the phosphorylation of pyrin, ultimately inhibiting the activation of the pyrin inflammasome [19]. The ability of colchicine to cause mitotic arrest is unlikely to play a role in its therapeutic action because the dose required to suppress mitosis is in considerable excess of that used for FMF. (See "Familial Mediterranean fever: Epidemiology, genetics, and pathogenesis", section on 'Inflammasome dysregulation in FMF'.)
Efficacy — Colchicine has demonstrated efficacy in preventing acute inflammatory episodes as well as preventing or slowing the progression toward AA amyloidosis.
Decreasing the frequency of attacks — The efficacy of colchicine in decreasing the frequency of attacks in FMF has been demonstrated in three double-blind, placebo-controlled trials [2-4]. In one such trial that included 43 patients with FMF, treatment with colchicine resulted in a significant reduction in the number of attacks as compared with placebo (29 versus 178). Another trial showed that patients treated with colchicine are also more likely to have milder attacks as compared with placebo (70 versus 25 percent) [3].
In the long term, one study of 350 children with FMF treated with colchicine for 6 to 13 years found that 64 percent of patients achieved complete remission of febrile attacks, and 31 percent achieved partial remission [20]. In another study, up to 40 percent of the patients treated with colchicine had partial remission, approximately 5 percent were nonresponders, and 2 to 5 percent did not tolerate the drug, mainly due to gastrointestinal side effects [21]. (See 'Safety' below.)
Preventing AA amyloidosis — Colchicine, as a preventive therapy, can markedly reduce the incidence of clinical kidney disease and can prevent additional deterioration of kidney function in patients with mild proteinuria due to AA amyloidosis [22,23].
Among FMF patients with nephrotic syndrome, prevention of disease progression and a reduction in protein excretion can be achieved. However, a higher colchicine dose of 1.5 to 2.0 mg/day appears to be required, and therapy should be instituted before the plasma creatinine concentration reaches 1.5 mg/dL (132 micromol/L) [11,12]. Protein excretion in responders can be reduced to below 1 to 2 g/day with this regimen; the benefit is gradual, occurring over a one- to two-year period [11]. In one study that included 1070 patients with FMF, among 960 patients who initially had no evidence of AA amyloidosis, the rate of development of proteinuria was 1.7 percent after 11 years in the adherent patients [22]. By contrast, proteinuria developed in 49 percent of nonadherent patients after nine years. Among 86 patients who already had non-nephrotic proteinuria prior to therapy, colchicine led to resolution of proteinuria in five and stabilization in 68; 13 had progressive disease.
Colchicine is not likely to be effective in patients who already have chronic kidney failure, since irreversible glomerular injury is probably present [11,12]. However, it can prevent recurrent disease (as manifested by proteinuria) in the transplanted kidney [13]. The optimal colchicine dose in this setting is 1.5 to 2.0 mg/day; lower doses are less predictably effective. A report of three patients with AA amyloidosis in native kidneys described improvement in proteinuria and the plasma creatinine level, and a reduction in the frequency of peritonitis attacks with the addition of azathioprine to colchicine, although the mechanism of the azathioprine effect is unclear [24]. Anecdotal reports suggest that, in patients with established amyloidosis, anti-interleukin 1 (IL-1) treatment can also reverse proteinuria [25]. However, in a study from Turkey including 39 transplant recipients due to end-stage kidney disease from AA amyloidosis, de novo amyloid accumulation was observed during the treatment with IL-1 antagonists [26]. (See 'Interleukin 1 inhibition' below.)
Safety — At doses of 1 to 2 mg/day, colchicine is safe even when given continually over decades, provided that the kidney and liver functions are intact. Side effects, most commonly gastrointestinal (eg, diarrhea, nausea, vomiting), are uncommon at low doses (0.5 to 1.2 mg per day), even when given continuously over years. Less common (<1 percent) side effects include bone marrow suppression (leukopenia), hepatotoxicity, myotoxicity, and hair loss. Chronic kidney disease, which can lead to increased colchicine levels, is a major risk factor for side effects. In addition, colchicine has drug interactions and altered metabolism in certain patient populations. In particular, concomitant administration of drugs metabolized by cytochrome P450 3A4 or affecting the glycoprotein 1 pump (ATP-binding cassette sub-family B member 1 [ABCB1]) has been associated with a greater risk of colchicine toxicity due to the resulting increased serum and tissue concentration of colchicine (table 1) [27]. (For additional information on drug interactions, use the drug interactions program provided by UpToDate.)
Concerns about gonadal toxicity in males have been raised. One study found either azoospermia or abnormal sperm penetration in up to 20 percent of males treated with long-term colchicine therapy [28]; however, a second smaller study found no change in sperm count over six months of therapy [29]. Our experience shows that this complication is rare and in most cases reversible following cessation of colchicine. Azoospermia is more common among Behçet syndrome patients treated with colchicine than in FMF patients [30].
SUBSEQUENT MANAGEMENT —
Despite treatment with colchicine, some patients continue to have either symptoms of familial Mediterranean fever (FMF) or elevated acute phase reactants (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP]) between attacks.
Reassessment — Patients with continued symptoms while on colchicine should be carefully reassessed, paying specific attention to the type of persistent symptoms, the degree to which symptoms have improved or worsened, and adherence to medications [31]. Levels of acute phase reactants should also be monitored.
Patients who fail to respond to colchicine fall into one of the following categories:
●Patients whose symptoms are not due to FMF – These patients may have other hereditary autoinflammatory diseases that may mimic FMF: tumor necrosis factor (TNF) receptor-1 associated periodic syndrome (TRAPS); periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA); and mevalonate kinase deficiency (MKD, hyperimmunoglobulin D syndrome), none of which usually respond to this drug. Some patients with PFAPA, however, may respond to colchicine [32]. (See "The autoinflammatory diseases: An overview".)
●Patients who are nonadherent or incompletely adherent with therapy – Adherence with colchicine therapy must be confirmed [33]. Several studies have reported challenges with adherence [34,35]; as an example, one study reported that more than 40 percent of the patients with apparent colchicine-resistant FMF (crFMF) had poor adherence [34]. Patients with poor adherence related to side effects may benefit from divided doses.
●Colchicine-resistant FMF – Patients with FMF who still experience frequent attacks despite the maximal tolerable dose of colchicine (up to 3 mg daily in adults and 2 mg in children) are considered to have crFMF. In clinical practice, we do not use a specific threshold for defining crFMF, and it is largely based on poor patient tolerance of attacks rather than their frequency. Consensus recommendations for the management of FMF have defined crFMF as the occurrence of one or more attacks each month despite receiving the maximally tolerated dose for at least six months [9]. A revised definition of crFMF suggests that, for a patient receiving the maximum tolerated dose of colchicine, resistance to colchicine is defined as ongoing disease activity (as reflected by either recurrent clinical attacks [average one or more attacks per month over three months] or persistently elevated levels of CRP or serum amyloid A [SAA] in between attacks [depending on which is available locally]), in the absence of any other plausible explanation [36]. Patients with elevated acute phase reactants (any value above the normal range in at least two successive tests) between attacks despite maximal or tolerable doses of colchicine are also considered to have crFMF.
Approximately 5 percent of FMF patients are nonresponders, and 2 to 5 percent do not tolerate the drug mainly due to gastrointestinal side effects [21]. The characteristics of patients with FMF who are truly colchicine nonresponders are incompletely understood. One report compared 59 patients who did not respond to colchicine with 51 responders [37]. Nonresponders tended to be from lower socioeconomic backgrounds, have less education, and have a more severe form of disease. In addition, they had a statistically lower concentration of colchicine in mononuclear cells. The authors speculated that nonresponders may be genetically predisposed to have a lower colchicine concentrating ability. One factor might be poorer gastrointestinal absorption of the drug, which has a wide range of absorption (24 to 88 percent) after oral ingestion [38]. An additional study identified a link between ABCB1 polymorphism and the response to colchicine in patients with FMF [39]. Specifically, patients with the TT genotype of the ABCB1 3435C>T variant demonstrated a better response to colchicine compared with those with other genotypes.
Treatment of colchicine-resistant or -intolerant FMF patients — Following the discovery that FMF flares are mediated by the proinflammatory cytokine interleukin 1 (IL-1), IL-1 blockers have been proposed as a potential treatment for colchicine-resistant FMF. Consequently, IL-1 inhibition has become the preferred second-line therapy for patients who are resistant or intolerant to colchicine (see 'Interleukin 1 inhibition' below). Anecdotal reports suggest that IL-1 inhibition benefits secondary (AA) amyloidosis, but more data are needed to confirm this observation. Thus, for patients who are colchicine-resistant and on IL-1 inhibitors, we give concomitant colchicine at a tolerable dose (or approximately 1.5 to 2 mg daily) to prevent AA amyloidosis. In patients who do not respond to IL-1 inhibitors, we try therapy with TNF inhibitors (eg, adalimumab) or tocilizumab.
Interleukin 1 inhibition — Increasing data suggest that IL-1 inhibition seems to be a relatively safe and effective alternative for patients with FMF who do not respond to or cannot tolerate colchicine. The choice of IL-1 inhibitor is based on a combination of factors including regulatory or insurance requirements, route of administration, and cost. Canakinumab is generally preferred due to its efficacy and convenience since it is given as a subcutaneous injection every four to eight weeks. Anakinra is usually given as a once-daily subcutaneous injection. The most common side effects reported are site injection reaction and slightly increased mild infections in patients treated with anakinra and canakinumab, respectively. More information on the use of IL-1 inhibitors is provided elsewhere. (See "Interleukin 1 inhibitors: Biology, principles of use, and adverse events".)
Efficacy
●Decreasing the frequency of attacks – Data to support the use of IL-1 inhibition for crFMF are primarily observational but include several randomized, placebo-controlled trials. In a systematic review that included almost 1400 patients with FMF, complete remission was achieved on IL-1 inhibitors in 60 percent of adults (95% CI 49-72) and 81 percent of children (95% CI 72-89) [40]. The incidence of adverse effects ranged from 12 percent in children to 25 percent in adults; injection-site reactions were the most common, and only 7 percent of the adverse effects were considered serious. Additional studies supporting various types of IL-1 inhibitors are summarized below:
•Canakinumab – Canakinumab is a human immunoglobulin G (IgG) antibody directed against IL-1-beta. Several studies have demonstrated efficacy of canakinumab in patients with crFMF [41-44]. In a systematic review of eight studies that included 40 patients with crFMF, rates of complete and partial response to canakinumab were 68 and 32 percent, respectively [43]. One patient treated with canakinumab had AA amyloidosis, and a significant decrease in urinary protein excretion was recorded with this treatment. Seven patients had previously been treated with anakinra. In four patients, anakinra was discontinued due to side effects. None of these patients had side effects while on canakinumab. In two patients in whom anakinra was unsuccessful in controlling inflammation, treatment with canakinumab resulted in a complete response. In an industry-sponsored randomized trial that included 63 genetically confirmed FMF patients who were colchicine-resistant, 61 versus 6 percent of patients receiving monthly 150 mg canakinumab or placebo, respectively, had a complete response (defined as resolution of flare and no flare) at 16 weeks [44]. Raising the dose to 300 mg of canakinumab monthly increased the rate of complete response to 71 percent. After 16 weeks, a prolonged dosing interval of canakinumab (every eight weeks) maintained disease control in 46 percent of patients with crFMF. Three serious infections (one each of cellulitis, pelvic abscess, and pharyngotonsillitis) were reported in two crFMF patients receiving canakinumab within the first 16 weeks. However, no new safety findings or deaths were reported in canakinumab-treated patients throughout the 40-week study. In an extension of this study which included 60 patients who were followed for 72 weeks, 35 out of 60 (58.3 percent) patients experienced no flares, and 23 out of 60 (38.3 percent) had 1 flare, as compared with a median of 17.5 flares per year reported at baseline [45]. Median CRP concentrations were always in the normal range, while median SAA concentrations remained over the limit of normal (10 mg/L) but under the 30 mg/L threshold. There were no new or unexpected adverse events.
•Anakinra – Anakinra is a recombinant version of the human IL-1 (alpha and beta) receptor antagonist. Due to its mode of action, anakinra must be given daily. A systematic review of IL-1 inhibitors for FMF including 64 patients from case reports or series treated with anakinra found a complete response to therapy in 77 percent of patients [43]. A decrease in attack frequency and inflammation was noted in an additional 19 percent of patients. Three patients had no clinical response to anakinra. The only randomized trial to evaluate the use of anakinra in crFMF patients included 24 patients from a single center who received daily injections of either anakinra or placebo and were followed for four months [46]. Patients in the anakinra group had significantly fewer attacks per month and experienced a significant improvement in quality of life. There were no severe adverse events observed with anakinra. Local injection site reaction was the most common adverse event. The benefits of anakinra have been supported by larger subsequent observational studies [47,48].
•Rilonacept – Rilonacept is a dimeric fusion protein consisting of the extracellular portions of the human IL-1 receptor and the Fc region of human IgG1 that binds and neutralizes IL-1. In a small, randomized, double-blind study, 14 patients with FMF with one or more attacks per month were enrolled [49]. Each patient was scheduled to receive one of four treatment sequences that included two three-month courses of rilonacept, 2.2 mg/kg (maximum, 160 mg) by weekly subcutaneous injection, and two three-month courses of placebo. Among 12 participants who completed two or more treatment courses, the rilonacept-placebo attack risk ratio was 0.59. The median number of attacks per month was 0.77, and there were more treatment courses of rilonacept without attacks than with placebo. However, the duration of attacks did not differ between placebo and rilonacept. Thus, rilonacept reduces the frequency but not duration of FMF attacks and seems to be a treatment option for patients with colchicine-resistant or intolerant FMF.
Switching between anti-IL-1 agents is possible and successful in cases of treatment failure or intolerance [50]. Two observational studies suggest that canakinumab may be beneficial following the failure of or intolerance to anakinra and vice versa [50,51].
●Preventing AA amyloidosis – It is uncertain whether anti-IL-1 agents provide comparable benefits to colchicine in regard to the prevention of AA amyloidosis. A systematic review evaluating the long-term efficacy, safety, and tolerability of canakinumab in FMF included data from 121 patients across 11 studies. Among 97 patients without evidence of AA amyloidosis at therapy initiation, none developed the condition during treatment [41].
Evidence supporting the use of anti-IL-1 agents as monotherapy for amyloidosis prevention is particularly limited. While some reports describe positive outcomes with canakinumab or anakinra alone [52-54], these studies involved short follow-up periods, emphasizing the need for further research. As a result, the standard approach for FMF patients with AA amyloidosis typically includes anti-IL-1 agents alongside colchicine therapy.
●Treating AA amyloidosis – Observational studies suggest that anakinra and canakinumab may be effective in FMF patients who have developed AA amyloidosis, with potential improvements in proteinuria and kidney function [52,55-57]. Such improvements may reflect reduced progression of amyloid deposition and its associated toxic effects [58] or diminished IL-1-associated kidney inflammation [59]. As an example, one study reported on four FMF patients with AA amyloidosis treated with anakinra. One patient showed improved proteinuria and stabilized kidney function, while the other three, who had end-stage kidney disease (ESKD), experienced no change in kidney function but did experience improved overall health, making them eligible for kidney transplantation [52]. In another case series, 11 patients with FMF and related amyloidosis who were not on hemodialysis experienced reduced proteinuria and stabilized kidney function with anakinra therapy [55]. Finally, in a third paper that described 14 patients who underwent kidney transplantation due to renal amyloidosis, seven displayed amyloid deposition in their transplanted kidneys, leading to canakinumab treatment [60]. Although proteinuria or serum creatinine did not significantly worsen on canakinumab therapy, they also did not improve. Conversely, one study with histopathologic evidence indicated that anti-IL-1 therapy did not prevent de novo vascular amyloid deposition [26].
Use in patients with comorbid kidney disease — Anakinra is primarily excreted through the kidneys, and dose adjustments may be necessary for individuals with severe kidney impairment or ESKD. Hemodialysis has minimal impact on the drug's clearance. In ESKD patients undergoing hemodialysis, a 100 mg dose of anakinra may be administered three times per week [61]. For patients on dialysis, we prefer short-acting anakinra over longer-acting since such patients are prone to infection.
While data are limited, IL-1 inhibitors may help stabilize disease progression in patients with FMF and kidney disease related to AA amyloidosis. The efficacy might differ depending on the degree of kidney dysfunction, as evidenced by the following studies:
●In a longitudinal study that included 35 patients with FMF who were not on dialysis at baseline, kidney function was maintained or improved in 27 patients (79 percent) and worsened in the other 7 patients (21 percent) [57]. A subgroup analysis of all 40 patients (including 15 on dialysis) revealed stabilized progression of kidney disease among 24 patients with baseline creatinine levels of ≤1.5 mg/dL, including 21 patients with significantly decreased proteinuria. Conversely, among 16 patients with baseline creatinine levels >1.5 mg/dL, kidney disease improved in one, remained stable in five, and deteriorated in five.
●Another study evaluated 18 patients with FMF including 11 with preserved kidney function (glomerular filtration rate [GFR] ≥60 mL/min) and 7 with impaired kidney function (GFR <60 mL/min) at baseline [62]. After 12 months of canakinumab therapy, proteinuria levels (24-hour urine protein excretion >150 mg/day) were significantly lower in patients with baseline preserved versus impaired kidney function. All patients with preserved kidney function experienced a greater than 50 percent reduction in proteinuria at 12 months compared with baseline, whereas none of the patients with impaired kidney function achieved a similar result.
●Finally, one study described the use of canakinumab in four FMF patients with ESKD requiring dialysis; two patients exhibited improved kidney function, one discontinued treatment due to disease progression, and one proceeded to kidney transplantation without evidence of disease recurrence while continuing on canakinumab therapy [60].
Other agents — A few crFMF patients have shown responsiveness to etanercept, adalimumab, infliximab, and tocilizumab [63-67]. However, the exact efficacy and safety of treatment with these agents remain uncertain because of limited data. A review evaluating the efficacy of tocilizumab in FMF highlighted mixed results from multicenter, double-blinded randomized controlled trials. Conversely, retrospective studies suggest that tocilizumab may offer benefits for FMF patients with established renal AA amyloidosis, potentially slowing or preventing its progression [68]. Thus, tocilizumab may be of interest for FMF patients with amyloidosis who are resistant to colchicine and IL-1 blockers.
In addition, several studies have also described a potential role for interferon alfa in aborting or preventing attacks [68-71]. However, this approach is hardly used given the superior efficacy and tolerability of the IL-1 inhibitors.
"On-demand" treatment for flares — FMF flares can be excruciatingly painful, often necessitating opioid administration for relief. Increasing the colchicine dose during an attack is ineffective. However, anakinra may serve as an "on-demand" treatment when administered as a single dose either at the onset of the characteristic prodrome preceding a flare or at the very beginning of the episode. This approach can prevent the flare, shorten its duration, relieve symptoms, and/or normalize inflammatory markers. The rationale for this approach lies in patients' ability to identify characteristic prodromes or triggers, such as emotional or physical stress or exposure to cold [72].
In a retrospective analysis of 78 FMF patients treated with IL-1 inhibitors, 15 followed an “on-demand” anakinra protocol, resulting in a significant reduction in the frequency, duration, and severity of flares [72]. Another study similarly reported successful outcomes with anakinra administered exclusively at the onset of flares [73]. In both studies, patients continued their background colchicine therapy.
This strategy offers the dual benefit of reducing costs and minimizing side effects, particularly in well-selected patients with controlled disease and clearly identifiable prodromes. However, this approach does not address subclinical inflammation between flares, which may lead to renal amyloidosis as seen in type 2 FMF. Therefore, "on-demand" anti-IL-1 treatment should complement standard colchicine therapy rather than replace it.
MANAGEMENT OF SPECIFIC FEATURES —
Some patients with familial Mediterranean fever (FMF) may develop other related features that are not responsive to colchicine or interleukin 1 (IL-1) inhibitors and require additional therapy.
Chronic arthritis — Colchicine is not always an effective treatment for chronic arthritis associated with FMF, and patients may require nonbiologic or biologic disease-modifying antirheumatic drugs (DMARDs) [74,75]. In FMF patients with spondyloarthropathy (usually human leukocyte antigen [HLA]-B27-negative sacroiliitis), we may start with sulfasalazine and/or methotrexate, and if there is no response we add anti-tumor necrosis factor (TNF) agents. We do not use IL-1 inhibitors together with other biologic DMARDs (bDMARDs); however, they may be combined with conventional synthetic DMARDs (csDMARDs). (See "Clinical manifestations and diagnosis of familial Mediterranean fever", section on 'Joint pain'.)
Protracted febrile myalgia — Patients with protracted febrile myalgia typically require treatment of glucocorticoids for relief of symptoms. Usually, we start with prednisone 1 mg/kg daily for one to two weeks and then decrease the dose gradually over four to eight weeks.
If patients remain symptomatic despite glucocorticoids, we typically add an anti-IL-1 agent. In one study, two out of five patients with protracted febrile myalgia who had only a partial response to corticosteroids showed significant improvement after receiving their first dose of anakinra, including a rapid decrease in inflammatory markers, and were able to taper glucocorticoids within a month [76]. Similarly, case reports have described five pediatric patients with protracted febrile myalgia who responded to anakinra after prednisone treatment proved ineffective [77].
Exertional leg pain — Exercise-induced leg pain (mainly in the calves) improves with resting or treatment with nonsteroidal antiinflammatory drugs (NSAIDs). NSAIDs may be given once the patient experiences pain, and the symptoms typically resolve with a single dose. We do not advise prophylactic NSAID use prior to exercise. Any NSAID may be used, and in some cases, acetaminophen is effective too. In certain patients with FMF experiencing severe exertional leg pain, anakinra has been beneficial [46]. (See "Clinical manifestations and diagnosis of familial Mediterranean fever", section on 'Other manifestations'.)
SPECIAL POPULATIONS
Pregnancy
●Female patients – The benefits of continued colchicine therapy through pregnancy outweigh any risks to the fetus as well as prevent painful symptomatic attacks for the mother. Thus, we continue colchicine therapy for pregnant patients with familial Mediterranean fever (FMF). Four large studies involving a total of more than 1000 colchicine-exposed pregnancies have shown no evidence of an increase in cytogenetic or congenital abnormalities and suggest that colchicine treatment does not confer a risk of preterm delivery [78-81]. More information on the use of colchicine during pregnancy is provided elsewhere. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Colchicine'.)
We do not initiate canakinumab or anakinra during pregnancy, based on our experience, available data, and guidelines for the use of medications during pregnancy for patients with rheumatic diseases [82,83]. However, for FMF patients already receiving anakinra at the time of conception, continuing treatment is reasonable after a thorough discussion of its potential risks and benefits. We prefer anakinra over canakinumab during pregnancy due to its shorter half-life, which provides greater flexibility for abrupt discontinuation if necessary (eg, for infections or other complications). This preference, however, is not evidence-based and may pose challenges for patients already stabilized on canakinumab. Further research is essential to develop more definitive guidelines for the use of IL-1 blockers in pregnant FMF patients. Data on the use of anakinra during pregnancy are discussed in detail elsewhere. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Anakinra'.)
FMF has been associated with a higher-than-normal rate of miscarriage and infertility even in the absence of colchicine. One study of females on long-term colchicine therapy found a 25 percent miscarriage rate and a 36 percent infertility rate [84]. However, these rates were comparable to those reported in females with FMF prior to the introduction of colchicine therapy. The same study found that all the infants born to mothers with FMF on colchicine were healthy.
●Male patients – For males exposed to anakinra who father children, data on pregnancy outcomes are scarce. However, in six reported cases with follow-up periods ranging from four weeks to eight years, no congenital or developmental abnormalities were observed in the offspring [85].
Breastfeeding — Nursing is safe in lactating patients with FMF who continue to take colchicine [86]. One report serially measured the colchicine concentrations in serum and breast milk in four mothers [87]. The concentrations in breast milk were low (1.9 to 8.6 ng/mL) and similar to those in serum; the low values reflect extensive peripheral tissue binding of colchicine. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Colchicine'.)
Several infants have been breastfed during maternal anakinra therapy, occasionally in conjunction with colchicine, with no obvious adverse effects [88]. If anakinra is required by the mother, it is not a reason to discontinue breastfeeding [89]. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Anakinra'.)
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Familial Mediterranean fever".)
SUMMARY AND RECOMMENDATIONS
●Initial management with colchicine – The goals of therapy for familial Mediterranean fever (FMF) are to prevent acute attacks and minimize subclinical inflammation in between attacks, and to prevent the development and progression of secondary (AA) amyloidosis. For all patients with FMF, we recommend initial treatment with colchicine (Grade 1B). The maximum recommended daily dose of colchicine is 2 mg for children under 12 years and 3 mg for adults. (See 'Initial management with colchicine' above and 'Dosing and administration' above.)
•Monitoring – After initiation of colchicine, patients with FMF should be followed closely for three to six months to observe its therapeutic effect on attack frequency and severity. Laboratory testing for colchicine toxicity includes a complete blood count (CBC) to assess for leukopenia. To monitor disease response, we check erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and, when available, serum amyloid A (SAA). We also check the urine for proteinuria, which may be the first sign of renal amyloidosis. We check liver and kidney function tests annually to ensure that no modification of the colchicine dose is required. (See 'Monitoring' above.)
•Safety – At doses of 1 to 2 mg/day, colchicine is safe even when given continually over decades, provided that the liver and kidney functions are normal. Side effects, most commonly gastrointestinal (eg, diarrhea, nausea, vomiting), are uncommon at low doses (0.5 to 1.2 mg per day). Less common (<1 percent) side effects include bone marrow suppression, hepatotoxicity, myotoxicity, and hair loss. Chronic kidney disease or liver cirrhosis leading to increased colchicine levels is a major risk factor for side effects. Colchicine also has drug interactions and altered metabolism in certain patient populations. (See 'Safety' above.)
•Pregnancy and breastfeeding – Colchicine should be continued during pregnancy and breastfeeding. (See 'Pregnancy' above and 'Breastfeeding' above.)
●Reassessment – Patients with continued symptoms despite treatment with colchicine should be carefully reassessed, paying specific attention to the type of persistent symptoms, the degree to which symptoms have improved or worsened, and adherence to medications. Patients who fail to respond to therapy with colchicine may have an alternative diagnosis (eg, another hereditary autoinflammatory disease), may be nonadherent or incompletely adherent, or may be colchicine-resistant. (See 'Reassessment' above.)
●Colchicine resistance or intolerance – Approximately 5 percent of FMF patients are colchicine-resistant, and 2 to 5 percent do not tolerate the drug mainly due to gastrointestinal side effects. Interleukin 1 (IL-1) inhibition is the preferred second-line therapy for these patients. It is unknown whether IL-1 inhibitors have a beneficial effect on amyloidosis, although some anecdotal reports are promising. Thus, colchicine should be continued in FMF patients who receive IL-1 blockers. (See 'Treatment of colchicine-resistant or -intolerant FMF patients' above and 'Interleukin 1 inhibition' above.)
●Management of specific features – Some patients with FMF may develop other related features that are not responsive to colchicine or IL-1 inhibitors and require additional therapy. These features include a chronic form of arthritis, protracted febrile myalgia, and exertional leg pain. (See 'Chronic arthritis' above and 'Protracted febrile myalgia' above and 'Exertional leg pain' above.)
ACKNOWLEDGMENT —
The UpToDate editorial staff acknowledges Peter M Rosenberg, MD, and Stephen E Goldfinger, MD, who contributed to an earlier version of this topic review.
