Evidence-based recommendations for the practical management of Familial Mediterranean Fever

https://doi.org/10.1016/j.semarthrit.2013.04.011Get rights and content

Abstract

Aim

Familial Mediterranean Fever (FMF) is the most common recurrent autoinflammatory fever syndrome. Still, many issues—e.g.: colchicine dosage adjustment, maximum dosage of colchicine in children and adults, definition of colchicine resistance, alternative treatment solutions in colchicine-resistant patients, and genetic screening for asymptomatic siblings—have not yet been standardized. The current paper aims at summarizing consensus recommendations to approach these issues.

Methods

A literature review concerning these practical management questions was performed through PubMed. On the basis of this analysis, expert recommendations were developed during a consensus meeting of caregivers from France and Israel.

Results

A patient experiencing more than four FMF attacks a year needs colchicine dose adjustment. In case of persistent attacks (≥6 per year) in patients with maximum doses of colchicine (2 mg in children; 3 mg in adults), alternative treatment to colchicine with IL1 inhibitors should be considered. Routine genetic testing for MEFV mutations in asymptomatic siblings of an index case is not recommended.

Conclusion

This is a first attempt to resolve practical questions in the daily management of FMF patients.

Introduction

Familial Mediterranean Fever (FMF), the most common autoinflammatory hereditary fever disease, is characterized by recurrent self-limited attacks of fever and serositis [1], [2]. Colchicine is the standard treatment for the prophylaxis of FMF attacks, and to fend off the development of secondary amyloidosis—the main devastating complication of this disease [3], [4], [5]. However, many issues in FMF management are not yet standardized and lack consensus recommendations such as guidelines for optimal disease control and follow-up. Moreover new effective biologic agents are available for the most difficult-to-treat patients, especially those who do not respond (or are intolerant) to optimal dosage of colchicine.

We (an interdisciplinary group of French and Israeli physicians and geneticists) analyzed the published data on practical questions on management of Familial Mediterranean Fever and developed practical consensus recommendations in order to standardize the clinical management of FMF patients.

We summarize herein the consensus statements our group was able to reach.

Section snippets

Methods

  • A preliminary questionnaire with case presentations was sent by the scientific organizer (VH) of the meeting to all the participants. The scientific organizer of the meeting:

    • Identified the main points of controversies in FMF patient management

    • Established and submitted to the group the questions to be debated by the experts i.e.:

      • Colchicine dosage adjustment

      • Maximum dosage of colchicine in children and adults

      • Definition of colchicine resistance

      • Alternative treatment solutions in colchicine-resistant

Literature review

Colchicine undoubtedly has a beneficial role in the prevention of FMF attacks in adults and children and thus improves their quality of life (evidence 1A) [3], [8], [9], [10]. Furthermore, colchicine is the only current treatment for the prevention of secondary amyloidosis in FMF (evidence 2A) [11], [12], [13], [14], [15], [16]. Consensus exists for the starting dose of colchicine in children and adults, with the recommendation to adjust the dosage according to disease activity as judged by

Literature review

The literature suggests that the minimum daily dose for preventing the development of amyloidosis in adult FMF patients is 1 mg/d, even if the attacks may be suppressed with a lower dose (evidence 2A) [11], [15]. However, detailed information about the maximal dose of colchicine in patients with the most severe FMF phenotypes is not available. Though defining the maximal dose of colchicine in children and adults seems to be an important issue, this task was found to be quite difficult. The

Literature review

Treatment with colchicine according to the recommendations developed above is effective in reducing the frequency of attacks in most patients and prevents the development of amyloidosis in nearly all patients (evidence 2A) [18]. However, 30–40% of FMF cases are only partially responsive and about 5% are considered resistant [24], [25], [26]. Literature review could not find an agreement to define “colchicine resistance” [22], [26], [27], [28], [29], [30], [31], [32], [33], [34], although it is

Literature review

Once the definition of resistance to colchicine has been established, the next problem concerns the therapeutic choices in such patients. Up to the consensus meeting, placebo-controlled trials for alternative treatments in FMF have failed to prove their effectiveness [32], [33], [34], [36], [37], [38] and the major hope is now placed on understanding the function of marenostrin/pyrin in the inflammatory pathways [39], [40]. Functional studies suggest that interleukin IL1 is implicated in the

Literature review

Following the identification of the gene associated with Familial Mediterranean Fever (FMF), a question was raised as to the justification for population screening for carriers of MEFV mutations [54]. The conclusion was that there is no justification to perform whole-population screening. However, an additional question arose regarding the need for screening families in whom at least one member suffers from FMF. The main reason for such screening is the concern that some of these siblings may

Conclusion

We hope that these guidelines and recommendations will be of help for FMF-caring physicians in coping with the problems raised in this paper. Future studies are needed in order to confirm or refute

  • The use of IL1 inhibitors in colchicine-resistant or -intolerant patients.

  • The presence of phenotype II FMF and thus minimize screening the siblings of an index FMF patient.

Key Points

  • FMF attacks more frequent than every 3 months and/or persistent elevation of inflammatory markers, regardless of the frequency of the symptoms, require colchicine dose adjustment.

  • Maximum colchicine dose should not exceed 3 mg/d in adults without comorbidity or 2 mg/d in children before puberty.

  • A fully compliant patient should be considered resistant to colchicine on a clinical basis if he/she suffers from more than six typical FMF attacks per year.

  • IL1 inhibitors should be the first-choice

Role of the funding source

The French patients' association for FMF and other hereditary recurrent fever syndromes (AFFMF) was the only funding source for the organization of the consensus conference held in Safed, Israel. The conference sponsor had no other role in the elaboration of this paper.

Acknowledgments

The authors thank the French Patients' association for Familial Mediterranean Fever and other hereditary recurrent fever syndromes (AFFMF) for its financial support and its substantial contribution to the running of the consensus meeting.

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