​FMF – Familial Mediterranean Fever

Genetics

FMF is a genetic disease and the gene responsible for most cases of FMF, designated as MEFV, was identified on chromosome 16p13AE3. The MEFV gene controls a protein called pyrin plays a role in controlling inflammation. When this gene has a defect, the inflammation is dysregulated, and patients experience episodes of fever (high or low-grade temperatures), pain and other symptoms that may impact joints and organs.

FMF is inherited as an autosomal recessive disease, but de novo (spontaneous) mutations are also possible. Patients may be heterozygous (one mutation), compounded heterozygous (two different single mutations) or homozygous (have two of the same mutations). People may be carriers of FMF mutations and may be asymptomatic (no symptoms).

Often, in families where there is someone with FMF, there are more affected members. Sometimes it’s not so obvious because they might have a less severe form. It is always good to ask the parents and have not only symptomatic but also asymptomatic family members tested.

Patients with only one mutation consist of 20-25% of the population. There are also patients without any mutations (negative genetics for the MEFV gene) that make up 20% of the FMF population. In the literature, there are at least 100 papers that describe genetic findings in cohorts of patients. From these descriptions, it may be observed that only 50% of patients carry 2 mutations.

For more information on this topic, please refer to this article: Marek-Yagel D, Berkun Y, Padeh S, Abu A, Reznik-Wolf H, Livneh A, Pras M, Pras E. Clinical disease among patients heterozygous for familial Mediterranean fever. Arthritis Rheum. 2009 Jun;60(6):1862-6. doi: 10.1002/art.24570. PMID: 19479871.

Epidemiology

FMF can affect individuals of any ethnic group, but it is more prevalent in Mediterranean populations (despite where they may live) including individuals of Armenian, Turkish, Arabic, Sephardic and Ashkenazi Jewish, Greek, Italian, and Spanish descent. FMF patients are also found in these countries to name but a few: United States, Melungeons (southern Appalachia), Canada, Germany, Belgium, France, Netherlands, UK, Sweden, Argentina, Brazil, Georgia, Russia, Australia, Eastern European countries, Japan, China, etc.

Symptoms

FMF patients usually present with recurrent attacks of severe abdominal pain (in 95% of patients). Although the most common symptoms involve abdominal pain and fever, the inflammatory targets of FMF are the “serous” membranes, which line the body cavities, joints and surround the major organs. Inflammatory episodes can involve any of these membranes resulting in pleuritis (thoracic pain), pericarditis (pain around the heart), synovitis (joint pain), and as stated above, peritonitis (abdominal pain). Other common symptoms are painful headaches (aseptic meningitis), skin rashes (erysipelas-like, psoriasis-like, eczema), diarrhea/constipation, vomiting, dizziness, fainting, fatigue, tachycardia, elevated blood pressure, hot flashes & chills, and breathing difficulties. Articular involvement is one of the significant features of FMF. Arthritis in FMF is typically monoarticular or oligoarticular and most commonly affects joints of the knees, ankles, hips, and wrists. Spondylitis is another feature of musculoskeletal involvement often seen in FMF.

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Erysipelas-like Erythema

It’s a skin manifestation of familial Mediterranean fever (FMF) which usually appears in the lower extremities and can be brought on by physical exertion. It is a very painful red discoloration of the ankles usually lasting 3 days with accompanying fever and affects approximately 7% to 40% of FMF patients. The rash appears as tender, raised, erythematous (red) lesions that mimic acute infectious cellulitis and usually occur unilaterally on the lower leg, ankle, or foot.

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Peritonitis

Almost all patients with FMF present with painful abdominal attacks. The pain and tenderness initially may be focal, usually the lower abdomen, and it may progress to become more generalized. Exploratory laparotomy or even appendectomy is sometimes unnecessarily performed. Recurrent attack of peritonitis may lead to adhesions and potentially cause small bowel obstructions or infertility in female patients.

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Clinically, FMF can be distinguished into three phenotypes:

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Type 1, which is commonly associated with recurrent short episodes of inflammation and serositis, including fever, peritonitis, synovitis, pleuritis, but also pericarditis, orchitis or meningitis episodes. The symptoms and severity vary among affected individuals, and even among members of the same family who have FMF.

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Type 2, characterized by the evidence of reactive amyloid-associated (AA) amyloidosis, the most severe complication of FMF, as the first clinical manifestation of the disease in an otherwise asymptomatic individual. Amyloidosis, which can lead to renal failure, is the most severe complication, if untreated.

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Type 3, referred to the 'silent' homozygous or compound heterozygote state, in which two MEFV mutations are detected without any signs or symptoms of FMF nor of AA amyloidosis. In recent years, it has been observed that also heterozygous mutation carriers can suffer from FMF.

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Flares

FMF flares usually last between 1–3 days. Other types of flares or abdominal attacks vary in frequency and can be as often as once per week, lasting on average 3 to 7 days or as infrequent as a few times per year or less. The duration and severity of episodes can vary even within the same family. Temperature ranges may run high or low during episodes and may occur before, during, after or independently of other symptoms. There are atypical cases where patients never present with fever or develop them later in life.

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Most patients during a flare will have elevated acute phase reactants and may have elevated white blood cells, liver enzymes, etc. There are cases of FMF patients who do not present with elevated inflammatory markers (CRP, ESR, WBC).

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Triggers

Infection, accidents, menstruation, physical effort (i.e. sports), climate changes (temperature, humidity, cold/hot, rain, etc.), stress, illness, emotions (positive or negative), certain foods (dairy, gluten), lack of sleep.

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It is important to remember that no matter what supplements a patient may trial, prescribed treatment should NEVER be discontinued (i.e. colchicine, biological medications).

FMF is often determined based on the clinical symptoms especially when genetic testing is not available. Patients should be offered colchicine even if they only carry a heterozygous mutation.

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Livneh diagnostic criteria for diagnosis of familial Mediterranean fever

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The requirements for diagnosis of FMF are ≥1 major criterion, or ≥2 minor criteria, or 1 minor criterion plus 2.5 supportive criteria, or I minor criterion plus ≥4 of the first 5 supportive criteria.

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Major criteria:

• Peritonitis (generalized)

• Pleurisy (unilateral) or pericarditis

• Monoarthritis (hip, knee or ankle)

• Isolated fever

Minor criteria:

Incomplete attacks affecting one or more sites:

• Abdomen

• Lungs

• Joints

• Exertion-related leg pain

• Response to colchicine

Supportive criteria:

• Family history of FMF

• Appropriate ethnic origin

• Age <20 years at disease onset

• Features of attacks

• Severe, requiring bed rest

• Spontaneous remission

• Symptom-free interval

• Transient inflammatory response, with 1 or more abnormal test result(s) for white blood cell count, erythrocyte sedimentation rate, serum amyloid A, and/or fibrinogen

• Episodic proteinuria/hematuria

• Unproductive laparotomy or removal of white appendix

• Consanguinity of parents

Reference: Livneh A, Langevitz P, Zemer D, Zaks N, Kees S, Lidar T, Migdal A, Padeh S, Pras M. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum. 1997 Oct;40(10):1879-85. doi: 10.1002/art.1780401023. PMID: 9336425.

There is no cure for Familial Mediterranean Fever. However, treatments including colchicine and biologics can help relieve symptoms, prevent attacks, and reduce complications caused by inflammation.

Colchicine

Colchicine is the gold standard treatment for FMF and is recommended for all patients regardless of the frequency and intensity of attacks. Treatment with colchicine should be started as soon as clinical diagnosis is established and be continued indefinitely. Patients should discuss all medication reactions or side effects with their physician.

The treatment of FMF aims to achieve these two goals:

• To prevent the patient from flaring or minimizing the clinical attacks

• To suppress chronic subclinical inflammation (elevated inflammatory markers, in particular SAA protein), and the development of secondary amyloidosis, as well as other long-term complications.

The main target is to improve the patients’ quality of life by reducing the frequency and intensity of the flares. However, complete cessation of attacks may not be possible in patients with more severe forms of FMF.

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According to the EULAR recommendations for the management of Familial Mediterranean Fever, the starting colchicine dose should be of 0.5 mg or 0.6 mg (American dosing). For more information, see the Colchicine brochure.

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Biologics

Patients who continue to have one or more flares each month despite receiving the maximum tolerated dose for at least 6 months are considered resistant to colchicine. Alternative biological treatments are indicated in these patients. Biological treatment such as anti-interleukin 1 (anakinra, canakinumab and rilonacept USA only) therapy must be considered and is the second line of therapy for patients who are intolerant or resistant to colchicine. It is recommended that colchicine should be co-administered with alternative biological therapies, should the patient tolerate the medication at any dose, as it may further reduce the risk of amyloidosis despite persistence of attacks.

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Interleukin 6 (IL-6) therapy (tocilizumab), is found to be efficient in improvement of amyloidosis and decreasing the frequency of recurrent attacks in patients with FMF, should IL-1 biologics not be effective or tolerated by the patient.

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Additional medications

Additionally, medications such as corticosteroids, painkillers, antihistamines, opioids, and antibiotics, are often required to manage inflammatory symptoms of FMF.

Laboratory tests are recommended to monitor liver enzymes, complete cell blood count, kidney function, creatinine phosphokinase (CPK) and to identify proteinuria. The preferred APR are SAA protein and CRP. See under documents: “Lab tests for patients with AID”.

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If a biologic is used as a treatment, it is important to receive antibiotic treatment, should a patient present with sinus, respiratory or other major infection. Patients who are on biologics are more susceptible to having an infection that requires prompt treatment.

MEFV patients who may become pregnant may require further information with regards to the safety of colchicine treatment during conception, pregnancy and breastfeeding.

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For more information, see the Pregnancy brochure.

On average, it takes ca. 17 years from the onset of the disease until the development of AA amyloidosis. The most noticeable clinical manifestation of AA amyloidosis is renal dysfunction (acute kidney failure), with the majority of patients presenting with protein-uric kidney disease. Renal biopsy is required to confirm the diagnosis of amyloidosis in patients with FMF with proteinuria. Please discuss further details of this with the treating physician.

Ozen S, Demirkaya E, Erer B, et al, EULAR recommendations for the management of familial Mediterranean fever. Annals of the Rheumatic Diseases 2016; 75: 644-651. https://ard.bmj.com/content/75/4/644

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Livneh A, Langevitz P, Zemer D, Zaks N, Kees S, Lidar T, Migdal A, Padeh S, Pras M. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum. 1997 Oct;40(10):1879-85. doi: 10.1002/art.1780401023. PMID: 9336425.

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Zemer, Deborah, Pras, Mordechai, Sohar, Ezra, Modan, Michaela, Cabili, Shaltiel, Gafni, Joseph. Colchicine in the Prevention and Treatment of the Amyloidosis of Familial Mediterranean Fever. N Engl J Med 1986; 314:1001-1005. DOI: 10.1056/NEJM198604173141601

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Prof Eldad Ben-Chetrit and Prof Micha Levy. Familial Mediterranean fever. The Lancet, VOLUME 351, ISSUE 9103, P659-664, FEBRUARY 28, 1998. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(97)09408-7/fulltext

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Shohat M. Familial Mediterranean Fever. 2000 Aug 8 [Updated 2016 Dec 15]. In: Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1227

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Roldan R, Ruiz AM, Miranda MD, Collantes E. Anakinra: new therapeutic approach in children with Familial Mediterranean Fever resistant to colchicine. Joint Bone Spine. 2008 Jul;75(4):504-5. doi: 10.1016/j.jbspin.2008.04.001. Epub 2008 Jun 9. PMID: 18541452.

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Ben-Zvi I, Livneh A. Colchicine failure in familial Mediterranean fever and potential alternatives: embarking on the anakinra trial. Isr Med Assoc J. 2014 May;16(5):271-3. PMID: 24979828. https://pubmed.ncbi.nlm.nih.gov/24979828

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Booty, M.G., Chae, J.J., Masters, S.L., Remmers, E.F., Barham, B., Le, J.M., Barron, K.S., Holland, S.M., Kastner, D.L. and Aksentijevich, I. (2009), Familial mediterranean fever with a single MEFV mutation: Where is the second hit? Arthritis & Rheumatism, 60: 1851-1861. https://doi.org/10.1002/art.24569

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Marek-Yagel, D., Berkun, Y., Padeh, S., Abu, A., Reznik-Wolf, H., Livneh, A., Pras, M. and Pras, E. (2009), Clinical disease among patients heterozygous for familial mediterranean fever. Arthritis & Rheumatism, 60: 1862-1866. https://doi.org/10.1002/art.24570

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Soriano A, Manna R. Familial Mediterranean fever: new phenotypes. Autoimmun Rev. 2012 Nov;12(1):31-7. doi: 10.1016/j.autrev.2012.07.019. Epub 2012 Aug 2. PMID: 22878273.

Selda SARIKAYA, Şenay ÖZDOLAP, Erdem MARAŞLI. Spondylitis and Arthritis in Familial Mediterranean Fever. Archives of Rheumatology, Issue: Volume 27 - Issue 4 - December 2012; Page: 241-247. DOI: 10.5606/tjr.2012.043