Guideline sources The following summarized guidelines for the evaluation and management of familial Mediterranean fever (FMF) are prepared by our editorial team based on guidelines from the Egyptian Expert Group on Familial Mediterranean Fever (FMF-EEG 2022), the European League Against Rheumatism (EULAR 2016), the Brazilian Society of Rheumatology (BSR 2016), the Single Hub and Access Point for Pediatric Rheumatology in Europe (SHARE initiative 2015), and the American Academy of Allergy, Asthma & Immunology (AAAAI/ACAAI 2015). 1 2 3 4 5 Calculator Calculator Calculat Simplified Livneh diagnostic crit Tel-Hashomer diagnostic criteri Yalcink Guidelines 1. Screening and diagnosis Diagnosis: as per AAAAI 2015 guidelines, suspect FMF in patients presenting with recurrent and often prolonged fever attacks associated with serosal, cutaneous, and synovial https://web.pathway.md/diseases/recam5wEC5aGsxnfs 1/6 6/29/23, 4:01 AM Familial Mediterranean fever Pathway manifestations. B Diagnosis (RBR): Recognize that FMF is a genetic disease presenting an autosomal recessive trait and caused by a mutation in the MEFV gene. E Diagnose FMF based on clinical manifestations, characterized by recurrent febrile episodes associated with abdominal and chest pain, or arthritis of large joints. E 2. Diagnostic investigations Clinical assessment: assess for persistent systemic signs of inflammation in patients with suspected FMF in the absence of demonstrable infection or autoimmune disease. B Laboratory tests: Recognize that laboratory tests are not specific, with high serum levels of inflammatory proteins in the acute phase, but often, high levels are found even between attacks. E Consider assessing serum amyloid A levels for the monitoring of treatment effectiveness. E Genetic testing: as per SHARE initiative 2015 guidelines, consider supporting, but not excluding, the clinical diagnosis of FMF by genetic testing. C Show 7 more Genetic testing (RBR): Regard patients with p.Met694V mutation as being at risk of more severe disease with a high risk for amyloidosis. E Recognize that mutations and polymorphisms in genes other than MEFV may have an impact on the development of FMF or even on the severity of the disease. E 3. Medical management General principles (EEG-FMF): consider identifying possible triggers to help in preventing possible attacks by temporarily increasing the colchicine dose. C General principles: As per EULAR 2016 guidelines: Diagnose and treat FMF initially by a physician with experience in FMF. B Set a goal to reach complete control of unprovoked attacks and minimize subclinical inflammation in between attacks. B Colchicine: As per EULAR 2016 guidelines: Initiate colchicine therapy, in single or divided doses depending on tolerance and compliance, B as soon as a clinical diagnosis is made. A Take other possible causes into consideration when suspecting an attack. Continue the usual dose of colchicine during the attacks. B As per AAAAI 2015 guidelines, initiate colchicine as the mainstay of treatment for FMF. B https://web.pathway.md/diseases/recam5wEC5aGsxnfs 2/6 6/29/23, 4:01 AM Familial Mediterranean fever Pathway Colchicine (RBR): initiate colchicine to prevent acute inflammatory episodes and progression toward amyloidosis in patients with FMF. E Colchicine (EEG-FMF): initiate treatment of FMF at the time of clinical diagnosis, without waiting for genetic testing. Offer a period of 3-month observation if the attacks are not severe or frequent to confirm the pattern of the attacks before initiating treatment. A Show 3 more Nonsteroidal anti-inflammatory drugs: as per EULAR 2016 guidelines, adminisyer NSAIDs during FMF attacks. B Nonsteroidal anti-inflammatory drugs (EEG-FMF): Administer NSAIDs during acute attacks. B Consider administering NSAIDs for the treatment of leg pain. C Management of protracted febrile myalgia: As per EULAR 2016 guidelines: Administer corticosteroids for symptom relief in patients with protracted febrile myalgia. Consider administering NSAIDs and IL-1 inhibitors as a treatment option. B Consider administering NSAIDs for the management of exertional leg pain. C Management of protracted febrile myalgia (EEG-FMF): Administer low-dose corticosteroids for the management of symptoms in patients with protracted febrile myalgia. Consider administering NSAIDs and IL-1 inhibitors as another treatment option. B Consider administering NSAIDs for the management of leg pain. C Management of resistant disease: as per EULAR 2016 guidelines, initiate alternative biological treatments in compliant patients not responding to the maximum tolerated dose of colchicine. B Management of resistant disease (RBR): consider administering biologics as an alternative option in patients with FMF not responding or intolerant to colchicine. E Management of resistant disease (EEG-FMF): ensure optimal patient compliance and adherence to therapy in patients with colchicine resistance and failure. Increase the dose of colchicine up to a maximum tolerated (up to 2 mg in pediatric and 3 mg in adult patients). B Show 3 more Management of chronic arthritis: as per EULAR 2016 guidelines, consider initiating additional medications, such as DMARDs, intra-articular corticosteroid injections, or biologics, for chronic arthritis in patients with FMF. C Management of chronic arthritis (EEG-FMF): consider initiating DMARDs (such as methotrexate), biologics (anti-TNF), or administering intra-articular corticosteroid injections for the management of chronic arthritis in patients with FMF. C Management of AA amyloidosis: ensure good control of FMF and maintain normal serum amyloid A protein concentration between attacks in order to prevent amyloidosis. B Show 2 more https://web.pathway.md/diseases/recam5wEC5aGsxnfs 3/6 6/29/23, 4:01 AM Familial Mediterranean fever Pathway 4. Specific circumstances Pregnant patients: As per EULAR 2016 guidelines: Do not discontinue colchicine during conception, pregnancy, or lactation. Do not perform amniocentesis. D Do not discontinue colchicine before conception in male patients. Consider reducing the dose or discontinuing temporarily in the rare case of azoospermia or oligospermia proven to be related to colchicine. D Pregnant patients (EEG-FMF): Do not discontinue colchicine before conception, during pregnancy, or during lactation. D Do not discontinue colchicine in males before conception, except if conception is delayed. D Pediatric patients: Initiate colchicine with the following doses (not exceeding 2 mg/day, in single or divided doses depending on tolerance - divide if diarrhea or related abdominal pain - and patient compliance) in pediatric patients with FMF: Situation Guidance 0.5 mg/day < 5 years old 0.5-1.0 mg/day 5-10 years old 1.0-1.5 mg/day. B > 10 years old 5. Follow-up and surveillance Assessment of treatment response: Monitor patients for 3-6 months to assess for the therapeutic effect on attack frequency and severity (clinical diary and acute phase reactants). B Consider extending the follow-up frequency up to 1-year in controlled compliant patients. C Assessment of treatment compliance: recognize that there is a high rate of poor compliance with colchicine therapy because of concerns about lifelong use of the drug, adverse effects (such as bloating and diarrhea), fertility, embarrassment, and laziness. B Show 3 more Dose adjustments (EEG-FMF): increase the colchicine dose in patients with persistent attacks and/or of subclinical inflammation. B Show 2 more Dose adjustments: as per EULAR 2016 guidelines, increase the colchicine dose in case of the persistence of attacks or subclinical inflammation. B Show 3 more Monitoring for treatment-related adverse effects: as per EULAR 2016 guidelines, monitor response, toxicity, and compliance every 6 months. B Show 3 more https://web.pathway.md/diseases/recam5wEC5aGsxnfs 4/6 6/29/23, 4:01 AM Familial Mediterranean fever Pathway Monitoring for treatment-related adverse effects (EEG-FMF): recognize that diarrhea and vomiting are the most common side effects of treatment, and these effects are dose-dependent and more common at higher doses. B Show 3 more Clinical findings Patient demographics Symptoms Mediterranean countries Abdominal pain Anxiety Past medical history Arthralgia Chest pain CKD Fatigue Glomerulonephritis Fever Cardiac exam Hematuria Increased appetite Pericarditis Irritability Myalgia Abdominal exam Restlessness Peritoneal findings Scrotal pain Splenomegaly Ocular exam Genitourinary exam Scleritis Scrotal erythema Uveitis Scrotal swelling Respiratory exam Integument exam Pleuritis Palmar erythema Musculoskeletal exam Raynaud's phenomenon Subcutaneous nodules Arthritis Urticaria Polyarticular synovitis Imaging findings Lymphatic exam Atelectasis Lymphadenopathy Pericardial effusion Pericardial thickening Lab findings ESR serum CRP serum amyloid A serum fibrinogen urine protein Genetic testing Mefv gene mutation https://web.pathway.md/diseases/recam5wEC5aGsxnfs 5/6 6/29/23, 4:01 AM Familial Mediterranean fever Pathway References 1. Seza Ozen, Erkan Demirkaya, Burak Erer et al. EULAR recommendations for the management of familial Mediterranean fever. Ann Rheum Dis. 2016 Apr;75 4 644 51. Open 2. S. Salah, H. Lotfy, M. H. Abu-Zaid et al. Egyptian evidence-based consensus on clinical practice recommendations for the management of familial Mediterranean fever. Egypt Rheumatol Rehabil. 2022 Jun 21;49 39 . Open 3. Gabriella Giancane, Nienke M Ter Haar, Nico Wulffraat et al. Evidence-based recommendations for genetic diagnosis of familial Mediterranean fever. Ann Rheum Dis. 2015 Apr;74 4 635 41. Open 4. Maria Teresa R A Terreri, Wanderley Marques Bernardo, Claudio Arnaldo Len et al. Guidelines for the management and treatment of periodic fever syndromes familial Mediterranean fever. Rev Bras Reumatol Engl Ed. 2016 Jan-Feb;56 1 37 43. Open 5. Francisco A Bonilla, David A Khan, Zuhair K Ballas et al. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol. 2015 Nov;136 5 1186 205.e1 78. Open 6. V ronique Hentgen, Gilles Grateau, Isabelle Kone-Paut et al. Evidence-based recommendations for the practical management of Familial Mediterranean Fever. Semin Arthritis Rheum. 2013 Dec;43 3 387 91. Open 7. M Pras. Familial Mediterranean fever: from the clinical syndrome to the cloning of the pyrin gene. Scand J Rheumatol. 1998;27 2 92 7. Open 8. A Livneh, P Langevitz, D Zemer et al. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum. 1997 Oct;40 10 1879 85. Open 9. Fatos Yal inkaya, Seza Ozen, Zeynep Birsin Oz akar et al. A new set of criteria for the diagnosis of familial Mediterranean fever in childhood. Rheumatology Oxford). 2009 Apr;48 4 395 8. Open https://web.pathway.md/diseases/recam5wEC5aGsxnfs 6/6