Evidence-based recommendations for the practical management of Familial Mediterranean Fever
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.
References (62)
- et al.
Familial Mediterranean fever
Lancet
(1998) Colchicine update: 2008
Semin Arthritis Rheum
(2009)- et al.
Colchicine: 1998 update
Semin Arthritis Rheum
(1998) - et al.
Colchicine nonresponsiveness in familial Mediterranean fever: clinical, genetic, pharmacokinetic, and socioeconomic characterization
Semin Arthritis Rheum
(2004) - et al.
Colchicine is a safe drug in children with familial Mediterranean fever
J Pediatr
(2012) - et al.
Double-blind, placebo-controlled, randomized, pilot clinical trial of ImmunoGuard—a standardized fixed combination of Andrographis paniculata Nees, with Eleutherococcus senticosus Maxim, Schizandra chinensis Bail. and Glycyrrhiza glabra L. extracts in patients with Familial Mediterranean Fever
Phytomedicine
(2003) - et al.
Interleukin-1 targeting drugs in familial Mediterranean fever: a case series and a review of the literature
Semin Arthritis Rheum
(2011) - et al.
Familial Mediterranean fever. A survey of 470 cases and review of the literature
Am J Med
(1967) Clinical and genetic aspects of the hereditary periodic fever syndromes
Rheumatology (Oxford)
(2004)Colchicine for familial Mediterranean fever
N Engl J Med
(1972)
Once-daily use of colchicine in children with familial Mediterranean fever
Clin Pediatr (Phila)
A new approach to the treatment of periodic fever
Med Bull Istanbul Med Fac
EULAR standardised operating procedures for the elaboration, evaluation, dissemination, and implementation of recommendations endorsed by the EULAR standing committees
Ann Rheum Dis
Consensus procedures and their role in pediatric rheumatology
Curr Rheumatol Rep
A controlled trial of colchicine in preventing attacks of familial Mediterranean fever
N Engl J Med
Colchicine therapy for familial Mediterranean fever. A double-blind trial
N Engl J Med
Prophylactic colchicine therapy in familial Mediterranean fever. A controlled, double-blind study
Ann Intern Med
Colchicine in the prevention and treatment of the amyloidosis of familial Mediterranean fever
N Engl J Med
The prevention of amyloidosis in familial Mediterranean fever with colchicine
Proc Eur Dial Transplant Assoc Eur Ren Assoc
Colchicine inhibition of the first phase of amyloid synthesis in experimental animals
Br J Exp Pathol
Colchicine treatment of AA amyloidosis of familial Mediterranean fever. An analysis of factors affecting outcome
Arthritis Rheum
Colchicine prevents kidney transplant amyloidosis in familial Mediterranean fever
Nephron
Regression of nephrotic syndrome due to amyloidosis secondary to familial Mediterranean fever following colchicine treatment
Nephrol Dial Transplant
Colchicine use in children and adolescents with familial Mediterranean fever: literature review and consensus statement
Pediatrics
Therapeutic approach to familial Mediterranean fever: a review update
Clin Exp Rheumatol
Evidence basis of a novel colchicine dose reduction algorithm to predict & prevent colchicine toxicity in the presence of P-gp/CYP P450 3A4 inhibitors
Arthritis Rheum
Familial Mediterranean fever (recurrent hereditary polyserositis) in children: analysis of 88 cases
Eur J Pediatr
Long-term colchicine treatment in children with familial Mediterranean fever
Arthritis Rheum
About colchicine compliance, resistance and virulence.
Clin Exp Rheumatol
Therapeutic approach to patients with familial Mediterranean fever-related amyloidosis resistant to colchicine
Clin Exp Rheumatol
30
Anti-interleukin 1 treatment for patients with familial Mediterranean fever resistant to colchicine
J Rheumatol
Cited by (127)
Colchicine-intolerant familial mediterranean fever patients: A comparative study between different colchicine doses and IL-1 inhibitor monotherapy
2024, International ImmunopharmacologyAdherence to colchicine prophylaxis among patients with familial Mediterranean fever treated with interleukin-1 inhibitors
2023, Seminars in Arthritis and RheumatismImmune Dysfunction and Drug Targets in Autoinflammatory Syndromes
2022, Comprehensive PharmacologyManagement of autoinflammatory syndromes and periodic fevers
2022, Allergic and Immunologic Diseases: A Practical Guide to the Evaluation, Diagnosis and Management of Allergic and Immunologic Diseases
Financial source: Association Française de la fièvre Méditerranéenne Familiale et des autres fièvres récurrentes héréditaires (AFFMF), 20 rue de Madrid, 75008 Paris