Familial Mediterranean Fever: Perspective and Round on Uncertainties

Published date: Dec 31 2025

Journal Title: Dubai Medical Journal

Issue title: Dubai Medical Journal (DMJ): Volume 8, Issue 4

Pages: 454-468

DOI: 10.18502/dmj.v8i4.20485

Haifa Ali Bin DahmanBin_Dahman.H@hotmail.comPediatric Department, Hadharmout University College of Medicine and Health Sciences, Mukalla, Hadhramout

Adel Mohammed Al-WahadnehPediatric Allergy, Immunology and Rheumatology, Al-Saudi Hospital, Amman

Mohammed Elian Abu-ShukairPediatric Allergy, Immunology and Rheumatology, Al-Saudi Hospital, Amman

Introduction: Familial Mediterranean fever (FMF) is a hereditary periodic fever characterized by its autosomal recessive nature. The complexity of its presentation and response to treatment poses significant challenges in diagnosing and managing FMF patients. This article aims to shed light on the primary disagreements concerning FMF diagnosis and management, presenting them in a more accessible format through a simplified flowchart based on existing FMF recommendations.

Methods: To conduct this review, we scoured several electronic databases, including PubMed, Google Scholar, and connected papers focusing on FMF recommendations, guidelines, challenges, and conflicting viewpoints. Our search terms included ‘familial Mediterranean fever’ and ‘recommendation’; ‘familial Mediterranean fever’ and ‘guideline’; ‘familial Mediterranean fever’ and ‘update’; ‘familial Mediterranean fever’ and ‘controversies’; ‘familial Mediterranean fever’ and ‘difficulty’. Additionally, we checked the reference lists of relevant journals for further information.

Results: To facilitate understanding, we utilized four algorithmic graphics to summarize the recommendations.

Conclusion: The diagnosis of FMF patients demands a high level of suspicion, particularly in unusual presentations. By highlighting conflicting points and offering a simplified algorithmic flow chart, physicians can better assess the likelihood of FMF, initiate appropriate treatment, and adjust medication dosages as necessary.

Keywords: amyloidosis, colchicine, familial Mediterranean fever, genetic, periodic fever

[1] Ben-Chetrit E, Touitou I. Familial Mediterranean fever in the world. Arthritis Rheum. 2009;61(10):1447– 1453.

[2] Maggio MC, Corsello G. FMF is not always “fever”: From clinical presentation to “treat to target”. Ital J Pediatr. 2020;46(7):1–5.

[3] Ben-Chetrit E, Yazici H. Familial Mediterranean fever: Different faces around the world. Clin Exp Rheumatol. 2019;37 Suppl 121(6):18–22.

[4] Ben-Chetrit E, Levy M. Enigmas in familial Mediterranean fever (FMF). Clin Exp Rheumatol. 2001;19(5 Suppl 24):S1–S5.

[5] Giancane G, Ter Haar NM, Wulffraat N, Vastert SJ, Barron K, Hentgen V, et al. Evidencebased recommendations for genetic diagnosis of familial Mediterranean fever. Ann Rheum Dis. 2015;74(4):635–641.

[6] Hentgen V, Grateau G, Kone-Paut I, Livneh A, Padeh S, Rozenbaum M, et al. Evidence-based recommendations for the practical management of familial Mediterranean fever. Semin Arthritis Rheum. 2013;43(3):387–391.

[7] Ozen S, Demirkaya E, Erer B, Livneh A, Ben-Chetrit E, Giancane G, et al. EULAR recommendations for the management of familial Mediterranean fever. Ann Rheum Dis. 2016;75(4):644–651.

[8] Salah S, Lotfy H, Abu-Zaid MH, El Gaafary M, Abdulhady H, Salah H, et al. Egyptian evidence-based consensus on clinical practice recommendations for the management of familial Mediterranean fever. Egypt Rheumatol Rehabil. 2022;49(39):1–15.

[9] Terreri MT, Bernardo WM, Len CA, da Silva CA, de Magalhães CM, Sacchetti SB, et al. Guidelines for the management and treatment of periodic fever syndromes familial Mediterranean fever. Rev Bras Reumatol Engl Ed. 2016;56(1):37–43.

[10] Chetrit EB. Management of familial Mediterranean fever. UpToDate. 2023.

[11] Akyol Onder EN, Ozcan KE, Sahin FI, Gulleroglu KS, Baskin E. Comparison of diagnostic criteria for children with familial Mediterranean fever. Eur J Pediatr. 2022;181(4):1661–1667.

[12] Ozdogan H, Ugurlu S. Familial Mediterranean fever. Presse Med. 2019;48(1 Pt 2):e61–e76.

[13] Heydari S, Namdar H, Behzadnia MJ. Familial Mediterranean fever (FMF): Mysterious presentations and challenging points from diagnosis to management in acute care settings; A literature review. Int J Travel Med Glob Health. 2019;7(4):118–122.

[14] Soriano A, Manna R. Familial Mediterranean fever: New phenotypes. Autoimmun Rev. 2012;12(1):31–37.

[15] El-Shanti H, Majeed HA, El-Khateeb M. Familial Mediterranean fever in Arabs. Lancet. 2006;367(9515):1016–1024.

[16] Assouad E, El Hage S, Safi S, El Kareh A, Mokled E, Salameh P. Familial Mediterranean fever research activity in the Arab world: The need for regional and international collaborations. East Mediterr Health J. 2021;27(10):984–992.

[17] Sönmez HE, Esmeray P, Batu ED, Arιcι ZS, Demir S, Sağ E, et al. Is age associated with disease severity and compliance to treatment in children with familial Mediterranean fever? Rheumatol Int. 2019;39(1):83–87.

[18] Altamimi E, Samara DN, Bani Issa D, Jaradat S, Hayajneh W. Genotype-phenotype correlation in Jordanian children with genetically-proven familial Mediterranean fever: The effect of R202Q mutation. Pediatr Neonatol. 2023;64(2):183–191.

[19] Shohat M, Halpern GJ. Familial Mediterranean fever—A review. Genet Med. 2011;13(6):487–498.

[20] Majeed HA, Ghandour K, Shahin HM. The acute scrotum in Arab children with familial Mediterranean fever. Pediatr Surg Int. 2000;16(1–2):72–74.

[21] Yalçinkaya F, Ozen S, Ozçakar ZB, Aktay N, Cakar N, Düzova A, et al. A new set of criteria for the diagnosis of familial Mediterranean fever in childhood. Rheumatology (Oxford). 2009;48(4):395–398.

[22] Livneh A, Langevitz P, Zemer D, Zaks N, Kees S, Lidar T, et al. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum. 1997;40(10):1879–1885.

[23] Ozen S, Kone-Paut I, Gül A. Colchicine resistance and intolerance in familial Mediterranean fever: Definition, causes, and alternative treatments. Semin Arthritis Rheum. 2017;47(1):115–120.

[24] Batu ED, Şener S, Arslanoglu Aydin E, Aliyev E, Bagrul İ, Türkmen Ş, et al. A score for predicting colchicine resistance at the time of diagnosis in familial Mediterranean fever: Data from the TURPAID registry. Rheumatology (Oxford). 2024;63(3):791–797.

[25] Özen S, Sag E, Ben-Chetrit E, Gattorno M, Gül A, Hashkes PJ, et al. Defining colchicine resistance/intolerance in patients with familial Mediterranean fever: A modified-Delphi consensus approach. Rheumatology (Oxford). 2021;60(8):3799–3808.

[26] Sag E, Akal F, Atalay E, Akca UK, Demir S, Demirel D, et al. Anti-IL1 treatment in colchicineresistant paediatric FMF patients: Real life data from the HELIOS registry. Rheumatology (Oxford). 2020;59(11):3324–3329.

[27] Georgin-Lavialle S, Stankovic Stojanovic K, Bachmeyer C, Sellam J, Abbara S, Awad F, et al. Spondyloarthritis associated with familial Mediterranean fever: Successful treatment with anakinra. Rheumatology (Oxford). 2017;56(1):167–169.

[28] Majeed HA, El-Shanti H, Al-Khateeb MS, Rabaiha ZA. Genotype/phenotype correlations in Arab patients with familial Mediterranean fever. Semin Arthritis Rheum. 2002;31(6):371–376.

[29] Karacan İ, Uğurlu S, Tolun A, Tahir Turanlι E, Ozdogan H. Other autoinflammatory disease genes in an FMF-prevalent population: A homozygous MVK mutation and a novel heterozygous TNFRSF1A mutation in two different Turkish families with clinical FMF. Clin Exp Rheumatol. 2017;35 Suppl 108(6):75-81.

[30] Ozen S, Bilginer Y. A clinical guide to autoinflammatory diseases: Familial Mediterranean fever and next-of-kin. Nat Rev Rheumatol. 2014;10(3):135–147.