Familiäres Mittelmeerfieber – aktuelle Aspekte der Diagnostik und Therapie

Zusammenfassung

Das familiäre Mittelmeerfieber (FMF) ist die häufigste monogenetische autoinflammatorische Erkrankung und betrifft vor allem Menschen mit mediterranem Migrationshintergrund. Ursache sind meist Mutationen im MEFV-Gen, die zu einer überschießenden Interleukin-1-vermittelten Entzündungsreaktion führen. Typisch sind wiederkehrende Fieberschübe, Serositis, Arthralgien und erysipelähnliche Hautveränderungen. Die schwerwiegendste Komplikation ist die AA-Amyloidose. Die Diagnose basiert auf klinischen Kriterien und genetischer Testung. Colchicin ist die Standardtherapie, bei Colchicin-Resistenz stehen mit Anakinra und Canakinumab zwei effektive IL-1-Inhibitoren zur Verfügung. Neue Therapieansätze wie IL-6-Inhibition (z. B. Tocilizumab) zeigen vielversprechende Ergebnisse. Eine frühzeitige Diagnose und konsequente Therapie sind entscheidend zur Vermeidung schwerer Komplikationen.

Schlüsselwörter

Familiäres Mittelmeerfieber (FMF) - Autoinflammation - Colchicin-Resistenz - IL-1-Inhibition - AA-Amyloidose

Publication History

Article published online:
29 August 2025

• Literatur

• 1 Ben-Chetrit E, Touitou I. Familial Mediterranean fever in the world. Arthritis Rheum 2009; 61: 1447-1453
• 2 Ozdogan H, Ugurlu S. Familial Mediterranean fever. Presse Med 2019; 48: e61-e76
• 3 Ben-Zvi I, Herskovizh C, Kukuy O. et al. Familial Mediterranean fever without MEFV mutations: a case-control study. Orphanet J Rare Dis 2015; 10: 34
• 4 Sohar E, Gafni J, Pras M, Heller H. Familial Mediterranean fever. A survey of 470 cases and review of the literature. Am J Med 1967; 43: 227-253
• 5 Bodur H, Yurdakul FG, Cay HF. et al. Familial mediterranean fever: assessment of clinical manifestations, pregnancy, genetic mutational analyses, and disease severity in a national cohort. Rheumatol Int 2020; 40: 29-40
• 6 Ebrahimi-Fakhari D, Schönland SO, Hegenbart U. et al. Familial Mediterranean fever in Germany: clinical presentation and amyloidosis risk. Scand J Rheumatol 2013; 42: 52-58
• 7 Blank N, Schönland SO. [Autoinflammatory syndromes and AA amyloidosis]. Z Rheumatol 2020; 79: 649-659
• 8 Kallinich T, Blank N, Braun T. et al. [Evidence-based treatment recommendations for familial Mediterranean fever : A joint statement by the Society for Pediatric and Adolescent Rheumatology and the German Society for Rheumatology]. Z Rheumatol 2019; 78: 91-101
• 9 Ozen S, Demirkaya E, Erer B. et al. EULAR recommendations for the management of familial Mediterranean fever. Ann Rheum Dis 2016; 75: 644-651
• 10 Lainka E, Bielak M, Lohse P. et al. Familial Mediterranean fever in Germany: epidemiological, clinical, and genetic characteristics of a pediatric population. Eur J Pediatr 2012; 171: 1775-1785
• 11 Tamir N, Langevitz P, Zemer D. et al. Late-onset familial Mediterranean fever (FMF): a subset with distinct clinical, demographic, and molecular genetic characteristics. Am J Med Genet 1999; 87: 30-35
• 12 Touitou I. The spectrum of Familial Mediterranean Fever (FMF) mutations. Eur J Hum Genet 2001; 9: 473-483
• 13 Shinar Y, Obici L, Aksentijevich I. et al. Guidelines for the genetic diagnosis of hereditary recurrent fevers. Ann Rheum Dis 2012; 71: 1599-1605
• 14 Booty MG, Chae JJ, Masters SL. et al. Familial Mediterranean fever with a single MEFV mutation: where is the second hit?. Arthritis Rheum 2009; 60: 1851-1861
• 15 Toplak N, Frenkel J, Ozen S. et al. An international registry on autoinflammatory diseases: the Eurofever experience. Ann Rheum Dis 2012; 71: 1177-1182
• 16 Papadopoulos VP, Giaglis S, Mitroulis I, Ritis K. The population genetics of familial mediterranean fever: a meta-analysis study. Ann Hum Genet 2008; 72: 752-761
• 17 Yilmaz E, Ozen S, Balci B. et al. Mutation frequency of Familial Mediterranean Fever and evidence for a high carrier rate in the Turkish population. Eur J Hum Genet 2001; 9: 553-555
• 18 Kallinich T, Orak B, Wittkowski H. [Role of genetics in familial Mediterranean fever]. Z Rheumatol 2017; 76: 303-312
• 19 Federici S, Sormani MP, Ozen S. et al. Evidence-based provisional clinical classification criteria for autoinflammatory periodic fevers. Ann Rheum Dis 2015; 74: 799-805
• 20 Ben-Zvi I, Brandt B, Berkun Y. et al. The relative contribution of environmental and genetic factors to phenotypic variation in familial Mediterranean fever (FMF). Gene 2012; 491: 260-263
• 21 Chae JJ, Cho YH, Lee GS. et al. Gain-of-function Pyrin mutations induce NLRP3 protein-independent interleukin-1beta activation and severe autoinflammation in mice. Immunity 2011; 34: 755-768
• 22 Park H, Bourla AB, Kastner DL. et al. Lighting the fires within: the cell biology of autoinflammatory diseases. Nat Rev Immunol 2012; 12: 570-580
• 23 Yang J, Xu H, Shao F. Immunological function of familial Mediterranean fever disease protein Pyrin. Sci China Life Sci 2014; 57: 1156-1161
• 24 Park YH, Wood G, Kastner DL, Chae JJ. Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS. Nat Immunol 2016; 17: 914-921
• 25 Omenetti A, Carta S, Delfino L. et al. Increased NLRP3-dependent interleukin 1beta secretion in patients with familial Mediterranean fever: correlation with MEFV genotype. Ann Rheum Dis 2014; 73: 462-469
• 26 Apostolidou E, Skendros P, Kambas K. et al. Neutrophil extracellular traps regulate IL-1beta-mediated inflammation in familial Mediterranean fever. Ann Rheum Dis 2016; 75: 269-277
• 27 Heller H, Gafni J, Michaeli D. et al. The arthritis of familial Mediterranean fever (FMF). Arthritis Rheum 1966; 9: 1-17
• 28 Padeh S, Livneh A, Pras E. et al. Familial Mediterranean Fever in the first two years of life: a unique phenotype of disease in evolution. J Pediatr 2010; 156: 985-989
• 29 Reissman P, Durst AL, Rivkind A. et al. Elective laparoscopic appendectomy in patients with familial Mediterranean fever. World J Surg 1994; 18: 139-41 discussion 141–142
• 30 Salah S, Hegazy R, Ammar R. et al. MEFV gene mutations and cardiac phenotype in children with familial Mediterranean fever: a cohort study. Pediatr Rheumatol Online J 2014; 12: 5
• 31 Majeed HA, Barakat M. Familial Mediterranean fever (recurrent hereditary polyserositis) in children: analysis of 88 cases. Eur J Pediatr 1989; 148: 636-641
• 32 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges 2011; 9: 232-246
• 33 Ben-Chetrit E, Levy M. Familial Mediterranean fever. Lancet 1998; 351: 659-664
• 34 Bakkaloglu A, Duzova A, Ozen S. et al. Influence of Serum Amyloid A (SAA1) and SAA2 gene polymorphisms on renal amyloidosis, and on SAA/C-reactive protein values in patients with familial mediterranean fever in the Turkish population. J Rheumatol 2004; 31: 1139-1142
• 35 Akpolat T, Ozkaya O, Ozen S. Homozygous M694V as a risk factor for amyloidosis in Turkish FMF patients. Gene 2012; 492: 285-289
• 36 Asan G, Derin ME, Dogan HO. et al. Can calprotectin show subclinical inflammation in familial Mediterranean fever patients?. J Korean Med Sci 2020; 35: e63
• 37 Giancane G, Ter Haar NM, Wulffraat N. et al. Evidence-based recommendations for genetic diagnosis of familial Mediterranean fever. Ann Rheum Dis 2015; 74: 635-641
• 38 Yalcinkaya F, Ozen S, Ozcakar ZB. et al. A new set of criteria for the diagnosis of familial Mediterranean fever in childhood. Rheumatology (Oxford) 2009; 48: 395-398
• 39 Federici S, Vanoni F, Ben-Chetrit E. et al. An International Delphi Survey for the Definition of New Classification Criteria for Familial Mediterranean Fever, Mevalonate Kinase Deficiency, TNF Receptor-associated Periodic Fever Syndromes, and Cryopyrin-associated Periodic Syndrome. J Rheumatol 2019; 46: 429-436
• 40 Demirkaya E, Erer B, Ozen S, Ben-Chetrit E. Efficacy and safety of treatments in Familial Mediterranean fever: a systematic review. Rheumatol Int 2016; 36: 325-331
• 41 Hentgen V, Grateau G, Kone-Paut I. et al. Evidence-based recommendations for the practical management of Familial Mediterranean Fever. Semin Arthritis Rheum 2013; 43: 387-391
• 42 Lidar M, Kedem R, Langevitz P. et al. Intravenous colchicine for treatment of patients with familial Mediterranean fever unresponsive to oral colchicine. J Rheumatol 2003; 30: 2620-2623
• 43 Varan O, Kucuk H, Babaoglu H. et al. Effect of interleukin-1 antagonists on the quality of life in familial Mediterranean fever patients. Clin Rheumatol 2019; 38: 1125-1130
• 44 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: 854-862
• 45 Laskari K, Boura P, Dalekos GN. et al. Longterm beneficial effect of canakinumab in colchicine-resistant familial Mediterranean fever. J Rheumatol 2017; 44: 102-109
• 46 Kacar M, Savic S, van der Hilst JCH. The efficacy, safety and tolerability of canakinumab in the treatment of familial Mediterranean fever: A systematic review of the literature. J Inflamm Res 2020; 13: 141-149
• 47 Ugurlu S, Hacioglu A, Adibnia Y. et al. Tocilizumab in the treatment of twelve cases with aa amyloidosis secondary to familial mediterranean fever. Orphanet J Rare Dis 2017; 12: 105
• 48 Colak S, Tekgoz E, Cinar M, Yilmaz S. The assessment of tocilizumab therapy on recurrent attacks of patients with familial Mediterranean fever: A retrospective study of 15 patients. Mod Rheumatol 2021; 31: 223-225
• 49 Henes JC, Saur S, Kofler DM. et al. Tocilizumab for the treatment of familial Mediterranean fever. A randomized, double-blind, placebo-controlled phase II study. J Clin Med 2022; 11: 5360
• 50 Sag E, Demirel D, Demir S. et al. Performance of the new ‘Eurofever/PRINTO classification criteria’ in FMF patients. Semin Arthritis Rheum 2020; 50: 172-175