Sources & References

36 published sources for Familial Mediterranean Fever, each with evidence grades and key findings.

36 total sourcesGrade A: 16Grade B: 20diagnostics (6)reviews (6)treatment (10)genetics (6)pathophysiology (5)epidemiology (2)clinical (1)

diagnostics

6 sources

Grade Aclinical guideline

EULAR/PReS endorsed recommendations for the management of familial Mediterranean fever (FMF): 2024 update

Ozen S, Batu ED, Demir S, et al. · Ann Rheum Dis · 2025

●4 overarching principles and 12 recommendations
●Colchicine should be initiated immediately upon clinical diagnosis
●IL-1 inhibitors recommended for inadequate colchicine response
●Colchicine safe in pregnancy

Details DOI ↗

Grade Adiagnostic criteria

Classification criteria for autoinflammatory recurrent fevers

Gattorno M, Hofer M, Federici S, et al. · Ann Rheum Dis · 2019

●Eurofever/PRINTO criteria combining genetic and clinical variables
●Sensitivity 85-89%, specificity 94-100% for FMF
●First evidence-based classification criteria for hereditary recurrent fevers

Details DOI ↗

Grade Aclinical guideline

EULAR recommendations for the management of familial Mediterranean fever

Ozen S, Demirkaya E, Erer B, et al. · Ann Rheum Dis · 2016

●Colchicine as first-line lifelong treatment
●IL-1 blockers for colchicine-resistant cases
●Regular monitoring of SAA/CRP to assess subclinical inflammation

Details DOI ↗

Grade Bvalidation studyn=716

Performance of different diagnostic criteria for familial Mediterranean fever in children with periodic fevers

Demirkaya E, Saglam C, Turker T, et al. · J Rheumatol · 2016

●Compared Yalcinkaya-Ozen, Tel-Hashomer, and Livneh criteria performance
●Eurofever registry data from 339 FMF patients

Details DOI ↗

Grade Bdiagnostic criterian=311

A new set of criteria for the diagnosis of familial Mediterranean fever in childhood

Yalcinkaya F, Ozen S, Ozcakar ZB, et al. · Rheumatology (Oxford) · 2009

●Five criteria: fever, abdominal pain, chest pain, arthritis, family history
●Sensitivity 86.5%, specificity 93.6% with 2+ criteria
●Higher specificity than Tel-Hashomer in children

Details DOI ↗

Grade Bdiagnostic criterian=211

Criteria for the diagnosis of familial Mediterranean fever

Livneh A, Langevitz P, Zemer D, et al. · Arthritis Rheum · 1997

●Established Tel-Hashomer diagnostic criteria
●Sensitivity >95%, specificity >97% in adults
●Defined major, minor, and supportive criteria

Details DOI ↗

reviews

6 sources

Grade Bnarrative review

Familial Mediterranean Fever; Recent Advances, Future Prospectives

Recent Advances Group · Diagnostics · 2025

●JAK inhibitors (tofacitinib) showing promise in case series
●Updated pipeline of emerging therapies

Details PubMed ↗

Grade Bnarrative review

Update in familial Mediterranean fever

Ozen S · Curr Opin Rheumatol · 2021

●Recent developments in FMF genetics, criteria, and treatment
●Discussion of factors contributing to phenotype variation

Details DOI ↗

Grade Bnarrative review

Familial Mediterranean fever, from pathogenesis to treatment: a contemporary review

Alghamdi M · Turk J Med Sci · 2020

●FMF is most common hereditary autoinflammatory disease worldwide
●>200 MEFV variants identified
●Comprehensive pathogenesis-to-treatment review

Details DOI ↗

Grade Bnarrative review

Familial Mediterranean fever, review of the literature

Alghamdi M · Clin Rheumatol · 2017

●Comprehensive review of FMF clinical features, genetics, and treatment
●MEFV gene encodes mutated protein pyrin

Details DOI ↗

Grade Bnarrative review

A clinical guide to autoinflammatory diseases: familial Mediterranean fever and next-of-kin

Ozen S, Bilginer Y · Nat Rev Rheumatol · 2014

●Comprehensive clinical guide to FMF and related autoinflammatory diseases
●Flowcharts for mutation analysis interpretation

Details DOI ↗

Grade Bnarrative review

Familial Mediterranean fever: an updated review

Sari I, Birlik M, Kasifoglu T · Eur J Rheumatol · 2014

●Updated clinical review covering epidemiology, genetics, and management
●Splenomegaly in 10-60% depending on series

Details PubMed ↗

treatment

10 sources

Grade Asystematic review

Efficacy and safety of anti-interleukin-1 treatment in familial Mediterranean fever patients: a systematic review and meta-analysis

Grattagliano V, et al. · Clin Exp Rheumatol · 2023

●Anti-IL-1 agents significantly reduce attack frequency and inflammatory markers
●Both anakinra and canakinumab effective in colchicine-resistant FMF

Details PubMed ↗

Grade Asystematic review

Interventions for reducing inflammation in familial Mediterranean fever

Cochrane Collaboration · Cochrane Database Syst Rev · 2022

●10 RCTs with 312 participants
●Colchicine may reduce people experiencing attacks
●Includes assessment of rilonacept, anakinra, canakinumab

Details PubMed ↗

Grade Bcohort

Canakinumab is effective in patients with familial Mediterranean fever resistant and intolerant to colchicine and/or anakinra treatment

Cetin P, et al. · Int J Rheum Dis · 2021

●Mean attacks reduced from 8.3 to 1.56 per 24 weeks (P<0.001)
●Mean attack duration reduced from 67.2 to 18.3 hours
●Effective after colchicine and/or anakinra failure

Details PubMed ↗

Grade Bcohort

IL-1-blocking therapy in colchicine-resistant familial Mediterranean fever

Kucuksahin O, et al. · Clin Exp Rheumatol · 2018

●Rapid (2-3 days) and persistent suppression of FMF symptoms
●Significant reduction in attack frequency (P<0.003)
●Well tolerated over median 2 years

Details PubMed ↗

Grade ARCT

Anakinra for colchicine-resistant familial Mediterranean fever: a randomized, double-blind, placebo-controlled trial

Ben-Zvi I, Kukuy O, Giat E, et al. · Arthritis Rheumatol · 2017

●Anakinra significantly reduced attack frequency (1.7 vs 3.5/month, P=0.037)
●6 anakinra patients vs 0 placebo had <1 attack/month (P=0.005)
●First RCT of anakinra in colchicine-resistant FMF

Details DOI ↗

Grade Asystematic review

Efficacy and safety of treatments in familial Mediterranean fever: a systematic review

Demirkaya E, Erer B, Ozen S, Ben-Chetrit E · Rheumatol Int · 2016

●Systematic review of colchicine and alternative treatments
●Colchicine remains main lifelong treatment

Details DOI ↗

Grade Bsystematic review

Efficacy of anti-IL-1 treatment in familial Mediterranean fever: a systematic review of the literature

van der Hilst JCH, Moutschen M, Breitscheidel L, et al. · Biologics · 2016

●Complete response in 76.5% on anakinra, 67.5% on canakinumab
●5-10% colchicine resistant, 5-10% intolerant

Details PubMed ↗

Grade ARCT

Prophylactic colchicine therapy in familial Mediterranean fever: a controlled, double-blind study

Goldstein RC, Schwabe AD · Ann Intern Med · 1974

●Demonstrated colchicine prophylaxis significantly reduces FMF attacks
●One of three seminal 1974 colchicine RCTs

Details DOI ↗

Grade ARCTn=11

Colchicine therapy for familial Mediterranean fever: a double-blind trial

Dinarello CA, Wolff SM, Goldfinger SE, et al. · N Engl J Med · 1974

●38 attacks per 60 placebo courses vs 7 per 60 colchicine courses (P<0.001)
●Landmark NEJM trial establishing colchicine efficacy

Details DOI ↗

Grade ARCTn=22

A controlled trial of colchicine in preventing attacks of familial Mediterranean fever

Zemer D, Revach M, Pras M, et al. · N Engl J Med · 1974

●Colchicine 0.5mg twice daily significantly reduced attack frequency vs placebo
●4-month double-blind crossover study

Details PubMed ↗

genetics

6 sources

Grade Abasic research

Ancient familial Mediterranean fever mutations in human pyrin and resistance to Yersinia pestis

Park YH, et al. · Nat Immunol · 2020

●FMF-associated pyrin mutations confer resistance to Yersinia pestis
●Explains high carrier frequencies via heterozygote advantage

Details DOI ↗

Grade Bsystematic review

Lack of clear and univocal genotype-phenotype correlation in familial Mediterranean fever patients: a systematic review

Shinar Y, Obici L, Gattorno M, et al. · Rheumatology (Oxford) · 2018

●M694V associated with severe clinical course
●E148Q and V726A heterozygosity correlate with milder disease
●No univocal consensus on genotype-phenotype correlation

Details DOI ↗

Grade Bcohortn=220

The differential contribution of MEFV mutant alleles to the clinical profile of familial Mediterranean fever

Giaglis S, Papadopoulos V, Kambas K, et al. · J Mol Med · 2002

●M694V homozygosity most severe: highest amyloidosis risk
●V726A-E148Q complex allele also severe
●E148Q is not a benign polymorphism

Details PubMed ↗

Grade Bpopulation geneticsn=1173

The spectrum of familial Mediterranean fever (FMF) mutations

Touitou I · Eur J Hum Genet · 2001

●Carrier rates extremely high: 1 in 3.5 to 1 in 5 in affected populations
●Suggests heterozygote advantage or genetic drift

Details DOI ↗

Grade Agene discovery

Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever

International FMF Consortium · Cell · 1997

●Identified MEFV gene on chromosome 16p13.3
●Found M694V, V726A, and M680I mutations in exon 10

Details DOI ↗

Grade Agene discovery

A candidate gene for familial Mediterranean fever

French FMF Consortium · Nature Genetics · 1997

●Independently identified MEFV gene
●Named the protein 'marenostrin'
●Found 4 sequence variations correlating with FMF

Details DOI ↗

pathophysiology

5 sources

Grade Bnarrative review

The pyrin inflammasome in health and disease

Schnappauf O, Chae JJ, Kastner DL, Aksentijevich I · Front Immunol · 2019

●Comprehensive review of pyrin guard mechanism for RhoA GTPases
●Covers all pyrin-associated autoinflammatory diseases

Details DOI ↗

Grade Bnarrative review

Function and mechanism of the pyrin inflammasome

Heilig R, Broz P · Eur J Immunol · 2018

●Pyrin responds to homeostasis-altering molecular processes (HAMPs)
●Does not directly recognize molecular patterns

Details DOI ↗

Grade Abasic research

Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS

Park YH, Wood G, Kastner DL, Chae JJ · Nat Immunol · 2016

●RhoA activates PKN1/PKN2 which phosphorylate pyrin at Ser208 and Ser242
●Phosphorylated pyrin binds 14-3-3 proteins keeping inflammasome inactive
●FMF mutations decrease PKN/14-3-3 binding

Details DOI ↗

Grade Abasic research

Familial Mediterranean fever mutations lift the obligatory requirement for microtubules in Pyrin inflammasome activation

Van Gorp H, Sber P, Van Hauwermeiren F, et al. · Proc Natl Acad Sci USA · 2016

●FMF mutations render pyrin activation independent of microtubules
●Colchicine efficacy likely via leukocyte motility effects, not direct inflammasome block

Details DOI ↗

Grade Abasic research

Gain-of-function Pyrin mutations induce NLRP3 protein-independent interleukin-1beta activation and severe autoinflammation in mice

Chae JJ, Cho YH, Lee GS, et al. · Immunity · 2011

●Pyrin inflammasome is ASC-dependent but NLRP3-independent
●FMF knock-in mice show spontaneous inflammation ablated by IL-1R deficiency
●Provides evidence for distinct pyrin inflammasome in FMF

Details DOI ↗

epidemiology

2 sources

Grade Bcohort

Familial Mediterranean Fever (FMF): a single centre retrospective study in Amsterdam

Lidar M, Yaqubov M, Giat E, et al. · Rheumatol Int · 2019

●Mean diagnostic delay 8.2 years in non-endemic setting
●Mean onset age 13.8 years

Details PubMed ↗

Grade Bcohortn=2838

Familial Mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study

Tunca M, Akar S, Onen F, et al. · Medicine (Baltimore) · 2005

●Largest FMF cohort: 2838 patients
●Male:female ratio 1.2:1
●Mean diagnostic delay 6.9 years
●Peritonitis 93.7%, fever 92.5%, arthritis 47.4%

Details DOI ↗

clinical

1 sources

Grade Bnarrative review

Familial Mediterranean fever and renal AA amyloidosis — phenotype-genotype correlation, treatment and prognosis

Ben-Chetrit E, Levy M · J Nephrol · 2003

●AA amyloidosis is most severe complication
●M694V homozygosity and SAA1 alpha/alpha genotype increase risk
●Colchicine prevents amyloidosis development

Details PubMed ↗