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Management of familial Mediterranean fever

Management of familial Mediterranean fever
Literature review current through: Jan 2024.
This topic last updated: Nov 23, 2021.

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 renal 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" and "Clinical manifestations and diagnosis of familial Mediterranean fever" and "The autoinflammatory diseases: An overview".)

INITIAL MANAGEMENT — 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 amyloidosis. Initial treatment of FMF is with colchicine.

Colchicine — Colchicine is primarily effective as a prophylactic treatment for the FMF attacks. It is recommended in all patients 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 since it does not protect from the development of amyloidosis resulting from low-grade inflammation that can occur during asymptomatic intervals [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 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 prior to colchicine cessation were more common among children who required restart 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 (ie, 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 dose into two divided daily 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 renal or liver impairment. Dose adjustments are found in the Lexicomp 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 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. For monitoring 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. Colchicine-induced myopathy occurs either when the patient has kidney failure (elevated creatinine) or when colchicine is given concomitantly with other medications inhibiting 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], 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 in response to inflammatory stimuli [16,17]. Additional mechanisms include various inhibitory effects on macrophages including the inhibition of NALP3 and pyrin inflammasomes and stimulation of dendritic cell maturation and antigen presentation [17,18]. 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".)

Efficacy — Colchicine has demonstrated efficacy in preventing acute inflammatory episodes as well as preventing or slowing the progression toward 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 of 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, up to 40 percent of the patients treated with colchicine had partial remission, approximately 5 percent were non-responders, and 2 to 5 percent did not tolerate the drug, mainly due to gastrointestinal side effects [19]. (See 'Safety' below.)

Prevention of amyloidosis — Colchicine, as preventive therapy, can markedly reduce the incidence of clinical renal disease and can prevent additional deterioration of renal function in patients with mild proteinuria due to amyloidosis [20,21].

Among FMF patients with the 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 amyloidosis, the rate of development of proteinuria was 1.7 percent after 11 years in the adherent patients. By contrast, proteinuria developed in 49 percent of nonadherent patients after nine years [20]. 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 renal failure, since irreversible glomerular injury is probably present [11,12]. However, it can prevent recurrent disease (as manifested by proteinuria) in the transplant 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 amyloidosis in native kidneys described improvement in proteinuria and the plasma creatinine level, and reduction in the frequency of peritonitis attacks with the addition of azathioprine to colchicine, although the mechanism of the azathioprine effect is unclear [22]. Anecdotal reports suggest that, in patients with established secondary (AA) amyloidosis, anti-interleukin (IL) 1 treatment can also reverse proteinuria [23]. However, in a study from Turkey including 39 transplant recipients due to end-stage kidney disease from FMF-induced secondary amyloidosis, de novo amyloid accumulation was observed during the treatment with IL-1 antagonists [24]. (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, hepatotoxicity, and myotoxicity. Chronic renal insufficiency leading 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) [25]. (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 [26]; however, a second smaller study found no change in sperm count over six months of therapy [27]. 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 [28].

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 with medications [29]. 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 [30]. (See "The autoinflammatory diseases: An overview".)

Patients who are nonadherent or incompletely adherent with therapy – Adherence with colchicine therapy must be confirmed [31]. In one study, more than 40 percent of the patients with apparent colchicine-resistant FMF (crFMF) actually had poor adherence [32]. 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 a three-month period] or persistently elevated CRP or serum amyloid A [SAA] in between attacks [depending on which is available locally]), in the absence of any other plausible explanation [33]. Patients with elevated acute phase reactants (any value above normal range in at least two successive tests) between attacks despite maximal or tolerable dose of colchicine are considered crFMF because of their risk of developing amyloidosis.

The characteristics of patients with FMF who are truly colchicine non-responders are incompletely understood. One report compared 59 patients who did not respond to colchicine with 51 responders [34]. Non-responders 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 non-responders 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 [35]. In addition, colchicine activity may be related to its concentration within leukocytes rather than plasma levels [36].

Colchicine resistance or intolerance — Approximately 5 percent of FMF patients are non-responders, and 2 to 5 percent do not tolerate the drug mainly due to gastrointestinal side effects [19]. Interleukin (IL) 1 inhibition is the preferred second-line therapy for these patients. Anecdotal reports suggest that IL-1 inhibition has a beneficial effect on 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) in order to prevent 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. Moreover, data from two observational studies suggest that canakinumab may be beneficial following failure of or intolerance to anakinra [37,38]. The most common side effects reported were site injection reaction and slightly increased mild infections in patients treated with anakinra and canakinumab, respectively.

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 [39-42]. 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 [41]. One patient treated with canakinumab had secondary (AA) amyloidosis, and a significant decrease in urinary protein excretion was recorded after canakinumab. Seven patients had previously been treated with anakinra. In four patients, anakinra was discontinued due of 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 which 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 [42]. Raising the dose to 300 mg 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 [43]. 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 IL-1 receptor antagonist. 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 [41]. 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 [44]. 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 [45,46].

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 [47]. 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.

Other agents — A few crFMF patients have shown responsiveness to thalidomide, etanercept, adalimumab, infliximab, and tocilizumab [48-52]. However, the true efficacy and safety of treatment with these agents remains uncertain because of the paucity of reports and absence of controlled trials. Several studies have also described a potential role for interferon alfa in aborting or preventing attacks [53-56], but this is hardly used given the efficacy and tolerability of the interleukin-1 inhibitors.

MANAGEMENT OF SPECIFIC FEATURES — Some patients with familial Mediterranean fever (FMF) may develop other related features that are not responsive to colchicine or interleukin (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) [57,58]. 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. (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. (See "Clinical manifestations and diagnosis of familial Mediterranean fever", section on 'Other manifestations'.)

Exertional myalgia — Exercise-induced myalgia (mainly in the calves) improves with resting or treatment with nonsteroidal antiinflammatory drugs (NSAIDs). NSAIDs may be given once the patient experiences muscle 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. (See "Clinical manifestations and diagnosis of familial Mediterranean fever", section on 'Other manifestations'.)

SPECIAL POPULATIONS

Pregnancy — 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, continued use of colchicine is recommended for pregnant patients with familial Mediterranean fever (FMF).

FMF has been associated with a higher-than-normal rate of miscarriage and infertility even in the absence of colchicine. One study of women on long-term colchicine therapy found a 25 percent miscarriage rate and a 36 percent infertility rate [59]. However, these rates were comparable to those reported in women 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. Furthermore, colchicine therapy has never been associated with an increased risk of fetal abnormalities. 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 [60-63].

Breastfeeding — Nursing is safe in women with FMF who continue to take colchicine [64]. One report serially measured the colchicine concentrations in serum and breast milk in four women [65]. 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.

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

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 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 'Colchicine' above and 'Efficacy' above.)

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. For monitoring 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.)

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, and myotoxicity. Chronic renal insufficiency 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.)

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 with medications. Patient 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.)

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 (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. Thus, colchicine should be continued in FMF patients who receive such treatment. (See 'Colchicine resistance or intolerance' above and 'Interleukin 1 inhibition' above.)

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 myalgia. (See 'Chronic arthritis' above and 'Protracted febrile myalgia' above and 'Exertional myalgia' above.)

Colchicine should be continued during pregnancy and breastfeeding. (See 'Pregnancy' above and 'Breastfeeding' 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.

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Topic 2574 Version 31.0

References

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