2024 EULAR‑PReS‑Endorsed Recommendations for the Management of Familial Mediterranean Fever (FMF)‑Update

Annals of the Rheumatic Diseases, 2025；PMID: 40234174 Multidisciplinary task‑force: adult‑paediatric‑rheumatologists, nephrologist, methodologists, patient‑representatives；modified‑Delphi‑voting；4 overarching principles + 12 formal‑recommendations；degree‑of‑agreement > 9/10 for every statementPubMed

Abstract

Objective Familial Mediterranean fever (FMF) is the most‑prevalent monogenic auto‑inflammatory disease, caused by pathogenic MEFV gain‑of‑function variants encoding pyrin‑inflammasome‑protein. This 2024 EULAR‑PReS update revises the 2016 consensus, addressing new definitions for colchicine‑resistance/intolerance, treat‑to‑target strategy, biologic‑therapy, AA‑amyloidosis, fertility‑pregnancy‑lactation and adolescent‑transition‑careanzfaid.or....

Methods Systematic‑literature‑review; multidisciplinary‑expert‑panel voting; implementation‑quality‑indicators were developed for real‑world‑clinical‑practice. Key‑novel‑domains: standardized‑definition‑of‑colchicine‑resistance, IL‑1‑inhibitor‑positioning, pregnancy‑reproductive‑safety, adolescent‑to‑adult‑transition‑programme, adherence‑improvement‑strategiesPubMed.

Conclusion Colchicine remains lifelong‑first‑line‑prophylaxis. For compliant patients with confirmed colchicine‑resistance‑or‑intolerance, IL‑1‑inhibitors are‑first‑line‑biologic‑therapy. Target‑is complete‑suppression‑of‑clinical‑attacks plus resolution‑of‑subclinical‑inflammation. AA‑amyloidosis requires intensified‑therapy. Structured‑transition‑care is mandatory for adolescents. Shared‑decision‑making, patient‑education and adherence‑monitoring are central‑components of carePubMed.

Keywords: familial‑mediterranean‑fever; FMF; MEFV‑gene; autoinflammatory‑disease; colchicine‑resistance; IL‑1‑inhibitor; AA‑amyloidosis; auto‑inflammation

Overarching‑Principles (4 core‑principles)

1. FMF‑care integrates clinical‑phenotype, laboratory‑inflammatory‑markers and MEFV‑genetic‑results; genetic‑testing alone cannot‑establish‑or‑exclude‑diagnosis.
2. Treatment‑goal: abolish clinical‑attacks and‑eliminate persistent‑subclinical‑inflammation to‑prevent‑AA‑amyloidosis‑and‑organ‑damage.
3. Adherence‑assessment is performed‑at‑every‑visit; non‑adherence must‑be‑ruled‑out before‑labelling‑a‑patient‑as colchicine‑resistant.
4. Multidisciplinary‑care model; structured‑paediatric‑to‑adult‑transition‑plan for adolescent‑patients; patient‑education and genetic‑counselling are‑essentialPubMed.

1. Diagnosis and baseline‑evaluation

1. Typical‑clinical‑picture: recurrent short‑duration fever + serositis (abdominal‑pain, pleuritis, synovitis), erysipelas‑like‑skin‑rash; attacks last 12‑72 h, inter‑attack‑periods‑with‑partial‑or‑full‑recovery.
2. Baseline‑work‑up: inflammatory‑markers (ESR, CRP, SAA‑serum‑amyloid‑A‑protein), renal‑function‑urinalysis‑protein‑screening.
3. MEFV‑genetic‑testing: detect biallelic / heterozygous‑pathogenic‑variants; VUS (variant‑of‑unknown‑significance) cannot‑confirm‑FMF‑diagnosis.
4. At‑risk‑relatives: offer‑clinical‑and‑genetic‑screening for‑symptomatic‑or‑presymptomatic‑family‑members to‑enable‑early‑prophylaxis‑initiationNational C....

2. Colchicine‑therapy‑‑first‑line‑prophylaxis

Lifelong‑oral‑colchicine‑prophylaxis for‑all‑confirmed‑FMF‑patients, start‑immediately‑after‑clinical‑diagnosis‑(do‑not‑wait‑genetic‑results)Annals of ....

Age‑stratified‑starting‑doses - < 5 years: ≤ 0.5 mg/day - 5‑10 years: 0.5‑1.0 mg/day - > 10 years‑and‑adults: 1.0‑1.5 mg/day

• Titrate‑gradually upward‑to‑individual‑maximal‑tolerated‑dose; adult‑upper‑limit 3 mg/day, paediatric‑upper‑limit 2 mg/day; monitor‑gastrointestinal‑and‑neuromuscular‑side‑effectsAnnals of ....

New‑consensus‑definition: Colchicine‑resistance

Despite good‑adherence to maximal‑tolerated‑colchicine‑dose:

1. Persistent‑recurrent‑typical‑FMF‑attacks; and/or
2. Persistently‑elevated‑SAA / CRP‑between‑attacks (subclinical‑inflammation).

Colchicine‑intolerance: unacceptable‑toxic‑side‑effects‑precluding‑therapeutic‑dose‑achievement, even‑if‑attacks‑would‑respond‑pharmacologicallyanzfaid.or....

3. Colchicine‑resistant /‑intolerant FMF‑‑biologic‑therapy

1. First‑line‑rescue‑therapy:‑IL‑1‑inhibitors (anakinra, canakinumab).
   • Canakinumab (anti‑IL‑1β‑mAb): preferred‑for‑most‑FMF‑resistant‑patients, convenient‑intermittent‑dosing‑schedule.
   • Anakinra (recombinant‑IL‑1Ra): daily‑subcutaneous‑injection‑alternative‑option.
2. Therapeutic‑target: zero‑clinical‑attacks + normalisation‑of‑SAA‑and‑CRP.
3. Continue‑background‑colchicine‑at‑best‑tolerated‑dose together‑with‑IL‑1‑blockade, unless‑absolute‑intolerance‑exists.
4. Other‑biologics (anti‑TNF‑agents etc.) are‑not‑first‑line‑for‑FMF‑(conditional‑only‑for‑comorbid‑overlap‑conditions)anzfaid.or....

4. Monitoring‑strategy‑treat‑to‑target

1. Visit‑frequency:
   • Active‑uncontrolled‑disease: every 2‑3 months.
   • Sustained‑complete‑remission: every 6‑12 months.
2. Core‑monitoring‑parameters:
   • Clinical: attack‑diary / AIDAI‑auto‑inflammatory‑disease‑activity‑index‑patient‑diary‑tool.
   • Laboratory: CRP,‑SAA‑(serum‑amyloid‑A‑protein),‑renal‑function‑and‑urine‑protein‑screening‑to‑detect‑early‑AA‑amyloidosis.
3. Treatment‑escalate‑if‑SAA‑remains‑persistently‑elevated‑even‑without‑overt‑clinical‑flare‑(subclinical‑inflammation‑confers‑amyloid‑risk)PMC.

5. AA‑amyloidosis‑management (major‑complication)

• AA‑amyloidosis‑is‑triggered‑by‑chronic‑persistent‑SAA‑elevation.
• Maximal‑tolerated‑colchicine‑plus‑prompt‑addition‑of‑IL‑1‑inhibitor‑biologic‑therapy.
• Nephrology‑co‑management‑mandatory; close‑renal‑and‑proteinuria‑surveillance.
• Biologic‑therapy‑must‑be‑continued‑long‑term‑to‑suppress‑SAA‑production;‑do‑not‑de‑escalate‑prematurely‑even‑after‑protein‑reduction‑improvementAnnals of ....

6. Reproduction, pregnancy and lactation

1. Colchicine: safe‑through‑pre‑conception,‑pregnancy‑and‑breast‑feeding;‑no‑pre‑pregnancy‑drug‑holiday‑required.
2. IL‑1‑inhibitors‑(canakinumab‑/‑anakinra): may‑be‑continued‑during‑pregnancy‑and‑lactation‑under‑risk‑benefit‑assessment‑for‑severe‑colchicine‑resistant‑FMF‑patients;‑multidisciplinary‑obstetric‑rheumatology‑joint‑follow‑up.
3. Pre‑conception‑target: achieve‑stable‑complete‑remission‑before‑conception‑attempt‑to‑reduce‑flare‑risk‑during‑gestation.
4. Male‑patients‑planning‑conception:‑colchicine‑and‑IL‑1‑inhibitors‑do‑not‑require‑discontinuation;‑no‑evidence‑of‑increased‑teratogenic‑risk‑via‑paternal‑exposureEULAR.

7. Special‑populations

7.1 Paediatric‑patients

• Start‑prophylaxis‑early‑upon‑clinical‑suspicion;‑weight‑and‑age‑adapted‑colchicine‑dosing;‑monitor‑growth‑and‑pubertal‑development.
• IL‑1‑inhibitors‑are‑valid‑treatment‑option‑for‑paediatric‑colchicine‑resistant‑FMF.

7.2 Adolescent‑transition‑care

• Formal‑structured‑transition‑program‑from‑paediatric‑to‑adult‑rheumatology‑care‑is‑strongly‑recommended.
• Transition‑coordinator,‑transfer‑summary‑document,‑patient‑autonomy‑education‑are‑key‑components;‑poor‑transition‑correlates‑with‑poorer‑disease‑outcomePMC.

8. Key‑updates compared‑with‑2016‑EULAR‑PReS‑guidance

1. Formal‑consensus‑operational‑definition‑for colchicine‑resistance‑and‑colchicine‑intolerance,‑emphasising‑adherence‑check‑prior‑to‑biologic‑switch.
2. IL‑1‑inhibitors‑established‑as‑first‑line‑biologic‑for‑resistant‑FMF.
3. Explicit‑treat‑to‑target‑objective:‑suppress‑both‑clinical‑attacks‑and‑subclinical‑SAA‑elevation.
4. Expanded‑reproductive‑safety‑guidance‑for‑colchicine‑and‑IL‑1‑inhibitors‑in‑pregnancy‑lactation.
5. Mandatory‑structured‑adolescent‑transition‑care‑pathway‑added.
6. Implementation‑quality‑indicators‑for‑clinical‑audit‑and‑real‑world‑practice‑improvement.