Management of familial Mediterranean fever
- Eldad Ben-Chetrit, MD
Eldad Ben-Chetrit, MD
- Professor of Medicine
- Hadassah-Hebrew University Medical School
- Section Editors
- David S Pisetsky, MD, PhD
David S Pisetsky, MD, PhD
- Section Editor — Lupus
- Professor of Medicine and Immunology
- Duke University Medical Center
- J Thomas Lamont, MD
J Thomas Lamont, MD
- Editor-in-Chief — Gastroenterology and Hepatology
- Section Editor — Anorectal Disorders and Misc. Lower GI Disease; Nutrition, Malabsorption, and Misc. Upper GI Disease
- Professor of Medicine
- Harvard Medical School
- Deputy Editors
- Monica Ramirez Curtis, MD, MPH
Monica Ramirez Curtis, MD, MPH
- Deputy Editor — Rheumatology
- Instructor of Medicine, Part-time
- Harvard Medical School
- Shilpa Grover, MD, MPH, AGAF
Shilpa Grover, MD, MPH, AGAF
- Deputy Editor — Gastroenterology/Hepatology
- Assistant Professor of Medicine, Part-time
- Harvard Medical School
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 "Periodic fever syndromes and other autoinflammatory diseases: An overview".)
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 does not protect against 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 clinical diagnosis 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].
We recommend the following starting dose of colchicine :To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Goldfinger SE. Colchicine for familial Mediterranean fever. N Engl J Med 1972; 287:1302.
- Zemer D, Revach M, Pras M, et al. A controlled trial of colchicine in preventing attacks of familial mediterranean fever. N Engl J Med 1974; 291:932.
- Dinarello CA, Wolff SM, Goldfinger SE, et al. Colchicine therapy for familial mediterranean fever. A double-blind trial. N Engl J Med 1974; 291:934.
- Goldstein RC, Schwabe AD. Prophylactic colchicine therapy in familial Mediterranean fever. A controlled, double-blind study. Ann Intern Med 1974; 81:792.
- Wright DG, Wolff SM, Fauci AS, Alling DW. Efficacy of intermittent colchicine therapy in familial Mediterranean fever. Ann Intern Med 1977; 86:162.
- Hentgen V, Grateau G, Stankovic-Stojanovic K, et al. Familial Mediterranean fever in heterozygotes: are we able to accurately diagnose the disease in very young children? Arthritis Rheum 2013; 65:1654.
- Ben-Zvi I, Krichely-Vachdi T, Feld O, et al. Colchicine-free remission in familial Mediterranean fever: featuring a unique subset of the disease-a case control study. Orphanet J Rare Dis 2014; 9:3.
- Ozen S, Demirkaya E, Erer B, et al. EULAR recommendations for the management of familial Mediterranean fever. Ann Rheum Dis 2016; 75:644.
- Mor A, Shinar Y, Zaks N, et al. Evaluation of disease severity in familial Mediterranean fever. Semin Arthritis Rheum 2005; 35:57.
- Livneh A, Zemer D, Langevitz P, et al. Colchicine treatment of AA amyloidosis of familial Mediterranean fever. An analysis of factors affecting outcome. Arthritis Rheum 1994; 37:1804.
- Zemer D, Livneh A, Langevitz P. Reversal of the nephrotic syndrome by colchicine in amyloidosis of familial Mediterranean fever. Ann Intern Med 1992; 116:426.
- Livneh A, Zemer D, Siegal B, et al. Colchicine prevents kidney transplant amyloidosis in familial Mediterranean fever. Nephron 1992; 60:418.
- Polat A, Acikel C, Sozeri B, et al. Comparison of the efficacy of once- and twice-daily colchicine dosage in pediatric patients with familial Mediterranean fever--a randomized controlled noninferiority trial. Arthritis Res Ther 2016; 18:85.
- Paschke S, Weidner AF, Paust T, et al. Technical advance: Inhibition of neutrophil chemotaxis by colchicine is modulated through viscoelastic properties of subcellular compartments. J Leukoc Biol 2013; 94:1091.
- Leung YY, Yao Hui LL, Kraus VB. Colchicine--Update on mechanisms of action and therapeutic uses. Semin Arthritis Rheum 2015; 45:341.
- Ter Haar N, Lachmann H, Özen S, et al. Treatment of autoinflammatory diseases: results from the Eurofever Registry and a literature review. Ann Rheum Dis 2013; 72:678.
- Zemer D, Pras M, Sohar E, et al. Colchicine in the prevention and treatment of the amyloidosis of familial Mediterranean fever. N Engl J Med 1986; 314:1001.
- Saatci U, Bakkaloglu A, Ozen S, Besbas N. Familial Mediterranean fever and amyloidosis in children. Acta Paediatr 1993; 82:705.
- Sayarlioglu H, Erkoc R, Sayarlioglu M, et al. Successful treatment of nephrotic syndrome due to FMF amyloidosis with azathioprine: report of three Turkish cases. Rheumatol Int 2006; 27:197.
- Sevillano ÁM, Hernandez E, Gonzalez E, et al. Anakinra induces complete remission of nephrotic syndrome in a patient with familial mediterranean fever and amyloidosis. Nefrologia 2016; 36:63.
- Ehrenfeld M, Levy M, Margalioth EJ, Eliakim M. The effects of long-term colchicine therapy on male fertility in patients with familial Mediterranean fever. Andrologia 1986; 18:420.
- Bremner WJ, Paulsen CA. Colchicine and testicular function in man. N Engl J Med 1976; 294:1384.
- Haimov-Kochman R, Ben-Chetrit E. The effect of colchicine treatment on sperm production and function: a review. Hum Reprod 1998; 13:360.
- Lidar M, Scherrmann JM, Chetrit A, et al. Clinical, genetic, pharmacokinetic and socioeconomical characterization of colchicine nonresponsiveness in FMF (abstract). Clin Exp Rheumatol 2003; 29 (Suppl 26):88.
- Peters, RS. Non-response to daily colchicine attack suppression in familial Mediterranean fever. Proceedings, 1st International Conference on FMF, Jerusalem, Israel 1997. p.8.
- Ben-Chetrit E, Aamar S. About colchicine compliance, resistance and virulence. Clin Exp Rheumatol 2009; 29(Suppl 5):S1.
- Lidar M, Scherrmann JM, Shinar Y, et al. Colchicine nonresponsiveness in familial Mediterranean fever: clinical, genetic, pharmacokinetic, and socioeconomic characterization. Semin Arthritis Rheum 2004; 33:273.
- Niel E, Scherrmann JM. Colchicine today. Joint Bone Spine 2006; 73:672.
- Tufan A, Babaoglu MO, Akdogan A, et al. Association of drug transporter gene ABCB1 (MDR1) 3435C to T polymorphism with colchicine response in familial Mediterranean fever. J Rheumatol 2007; 34:1540.
- Gül A, Ozdogan H, Erer B, et al. Efficacy and safety of canakinumab in adolescents and adults with colchicine-resistant familial Mediterranean fever. Arthritis Res Ther 2015; 17:243.
- Brik R, Butbul-Aviel Y, Lubin S, 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; 66:3241.
- van der Hilst JCh, Moutschen M, Messiaen PE, et al. Efficacy of anti-IL-1 treatment in familial Mediterranean fever: a systematic review of the literature. Biologics 2016; 10:75.
- Ben-Zvi I, Kukuy O, Giat E, et al. Anakinra for Colchicine-Resistant Familial Mediterranean Fever: A Randomized, Double-Blind, Placebo-Controlled Trial. Arthritis Rheumatol 2017; 69:854.
- Hashkes PJ, Spalding SJ, Giannini EH, et al. Rilonacept for colchicine-resistant or -intolerant familial Mediterranean fever: a randomized trial. Ann Intern Med 2012; 157:533.
- Seyahi E, Ozdogan H, Celik S, et al. Treatment options in colchicine resistant familial Mediterranean fever patients: thalidomide and etanercept as adjunctive agents. Clin Exp Rheumatol 2006; 24:S99.
- Ozgocmen S, Ozçakar L, Ardicoglu O, et al. Familial Mediterranean fever responds well to infliximab: single case experience. Clin Rheumatol 2006; 25:83.
- Metyas S, Arkfeld DG, Forrester DM, Ehresmann GR. Infliximab treatment of Familial Mediterranean fever and its effect on secondary AA amyloidosis. J Clin Rheumatol 2004; 10:134.
- Fujikawa K, Migita K, Tsukada T, et al. Interleukin-6 targeting therapy in familial Mediterranean fever. Clin Exp Rheumatol 2013; 31:150.
- Akgul O, Kilic E, Kilic G, Ozgocmen S. Efficacy and safety of biologic treatments in Familial Mediterranean Fever. Am J Med Sci 2013; 346:137.
- Tunca M, Tankurt E, Akbaylar Akpinar H, et al. The efficacy of interferon alpha on colchicine-resistant familial Mediterranean fever attacks: a pilot study. Br J Rheumatol 1997; 36:1005.
- Tunca M, Akar S, Soytürk M, et al. The effect of interferon alpha administration on acute attacks of familial Mediterranean fever: A double-blind, placebo-controlled trial. Clin Exp Rheumatol 2004; 22:S37.
- Tweezer-Zaks N, Rabinovich E, Lidar M, Livneh A. Interferon-alpha as a treatment modality for colchicine- resistant familial Mediterranean fever. J Rheumatol 2008; 35:1362.
- Calguneri M, Apras S, Ozbalkan Z, et al. The efficacy of continuous interferon alpha administration as an adjunctive agent to colchicine-resistant familial Mediterranean fever patients. Clin Exp Rheumatol 2004; 22:S41.
- Langevitz P, Livneh A, Zemer D, et al. Seronegative spondyloarthropathy in familial Mediterranean fever. Semin Arthritis Rheum 1997; 27:67.
- Sakallioglu O, Duzova A, Ozen S. Etanercept in the treatment of arthritis in a patient with familial Mediterranean fever. Clin Exp Rheumatol 2006; 24:435.
- Ehrenfeld M, Brzezinski A, Levy M, Eliakim M. Fertility and obstetric history in patients with familial Mediterranean fever on long-term colchicine therapy. Br J Obstet Gynaecol 1987; 94:1186.
- 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 (Hoboken) 2010; 62:143.
- Diav-Citrin O, Shechtman S, Schwartz V, et al. Pregnancy outcome after in utero exposure to colchicine. Am J Obstet Gynecol 2010; 203:144.e1.
- Berkenstadt M, Weisz B, Cuckle H, et al. Chromosomal abnormalities and birth defects among couples with colchicine treated familial Mediterranean fever. Am J Obstet Gynecol 2005; 193:1513.
- Yasar O, Iskender C, Kaymak O, et al. Retrospective evaluation of pregnancy outcomes in women with familial Mediterranean fever. J Matern Fetal Neonatal Med 2014; 27:733.
- Herscovici T, Merlob P, Stahl B, et al. Colchicine use during breastfeeding. Breastfeed Med 2015; 10:92.
- Ben-Chetrit E, Scherrmann JM, Levy M. Colchicine in breast milk of patients with familial Mediterranean fever. Arthritis Rheum 1996; 39:1213.
- INITIAL MANAGEMENT
- - Dosing and administration
- - Monitoring
- - Mechanism of action
- - Efficacy
- Decreasing the frequency of attacks
- Prevention of amyloidosis
- - Safety
- SUBSEQUENT MANAGEMENT
- Colchicine resistance or intolerance
- - Interleukin-1 inhibition
- - Other agents
- MANAGEMENT OF SPECIFIC FEATURES
- Chronic arthritis
- Febrile myalgia
- Exertional myalgia
- SPECIAL POPULATIONS
- SUMMARY AND RECOMMENDATIONS