Last updated:
4/25/2024
Years published: 1986, 1990, 1992, 1994, 1996, 1997, 1998, 2000, 2003, 2012, 2015, 2018, 2023, 2024
NORD gratefully acknowledges Isabelle Touitou, MD, PhD, Laboratoire des maladies rares et auto-inflammatoires, Hopital Arnaud de Villeneuve, Montpellier, France, for assistance in the preparation of this report.
Summary
Familial Mediterranean fever (FMF) is an inherited autoinflammatory disease characterized by recurrent episodes (attacks) of fever and acute inflammation of the membranes lining the abdomen, joints and lungs. Some affected individuals may develop skin rashes (erysipelas like erythema) affecting the lower legs. Less often, inflammation of the membrane lining the heart or covering the brain and spinal cord may occur. Some individuals may develop a serious condition known as amyloidosis, in which certain proteins called amyloid accumulates in various tissues of the body. In FMF, amyloid accumulates in the kidneys (renal amyloidosis) where it can impair kidney function potentially result in life-threatening complications such as kidney failure.
The specific symptoms and severity of FMF are highly variable. Some individuals develop amyloidosis but none of the other symptoms associated with FMF. These cases are sometimes referred to as FMF type 2. FMF is caused by changes (disease-causing variants) of the MEFV gene and is usually inherited in an autosomal recessive pattern. Some cases of dominant inheritance have been described.
Introduction
FMF is classified as an autoinflammatory syndrome. Autoinflammatory syndromes are a group of disorders characterized by recurrent episodes of inflammation due to an abnormality of the innate immune system. They are not the same as autoimmune syndromes, in which the adaptive immune system malfunctions and mistakenly attacks healthy tissue. FMF is the most common autoinflammatory syndrome. It is also classified as a hereditary periodic fever syndrome.
Disease Course
FMF usually occurs during childhood. The inflammatory attacks last 1-3 days. The outcome is good in patients treated early. Although episodes of FMF can occur spontaneously for no identifiable reason, certain triggers have been identified in some people. These triggers include infection, trauma, vigorous exercise and stress. In females, onset of their period (menses) can trigger an episode.
The symptoms and severity of FMF can vary greatly from one person to another, even among members of the same family.
Signs and symptoms of FMF may include:
Other symptoms may include:
Some individuals with FMF may develop a potentially serious complication known as amyloidosis. Amyloidosis is characterized by the accumulation of a fatty-like substance called amyloid in various parts of the body. In FMF, amyloid accumulates in the kidneys (renal amyloidosis), impairing kidney function. Renal amyloidosis can eventually progress to cause kidney failure. The prevalence of amyloidosis varies based upon ethnicity, gender and the specific variant of the MEFV gene. Certain ethnic populations including individuals of Turkish or Sephardic Jewish descent have a relatively high incidence of amyloidosis when compared to individuals from other ethnic groups. Individuals with FMF type 2 develop amyloidosis, but none of the other symptoms associated with FMF.
Untreated individuals with FMF have a risk of infertility. Individuals with severe FMF characterized by multiple frequent episodes and/or amyloidosis are particularly at risk if untreated. In males, inflammation of the testes (orchitis) may also occur. Orchitis is characterized by pain, redness and swelling.
According to the medical literature, some individuals with FMF have an increased risk of developing additional inflammatory disorders, especially those characterized by inflammation of the blood vessels (vasculitides), including Bechet’s disease, polyarteritis nodosa and Henoch-Schonlein purpura. Affected individuals may also be at greater risk of developing ulcerative colitis, Crohn’s disease and rheumatoid arthritis. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
FMF is caused by changes (disease-causing variants) of the MEFV gene. More than 400 different variants of the MEFV gene have been identified, although only four are clearly disease-causing (pathogenic). They are recorded on a dedicated website https://infevers.umai-montpellier.fr/web/.
The MEFV gene contains instructions for creating (encoding) a protein known as pyrin. Variants of the MEFV gene lead to deficient levels of functional pyrin. The exact role of pyrin in the body is being studied. Pyrin is critical for the proper function of the innate immune system by regulating or inhibiting the body’s inflammatory response. A pathogenic variant of the MEFV gene results in excessive release of interleukin-1B. Interleukin-1B is a pro-inflammatory cytokine (a specialized protein secreted from certain immune system cells that either stimulates or inhibits the function of other immune system cells). Drugs that inhibit the activity of interleukin-1B may have a role in treating FMF (see Investigational Therapies section below).
FMF is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Although FMF is an autosomal recessive disorder, some individuals who inherit only one pathogenic variant (heterozygotes) will develop symptoms of inflammatory disease very similar to FMF. These individuals are also a greater risk than the general population of developing other inflammatory diseases such as Bechet’s disease and Crohn’s disease. The severity of the disease in these individuals is often similar to individuals who inherit two disease genes (homozygotes) or individuals with two different pathogenic variants (compound heterozygotes) and these individuals usually require treatment (see Standard Therapies below). The reason that some individuals with one gene variant develop symptoms is not fully understood. More research is necessary to determine why this occurs and whether there is a specific disease pattern associated with these cases.
FMF can affect individuals of any ethnic group, but the rates are much higher for certain Mediterranean populations including individuals of Armenian, Turkish, Arabic and North African Jewish descent. In these populations, the prevalence is estimated to be 1 in 200.
In the United States, FMF is frequently found in Ashkenazi Jews and immigrants from the Middle East and Armenia.
FMF affects males and females in equal numbers, although some studies suggest that males are affected more than females.
A diagnosis of FMF is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. These tests can aid in obtaining a diagnosis of FMF or in assessing the extent of the disorder. Prompt diagnosis in FMF is important to avoid misdiagnosis and unnecessary surgery (as many children are misdiagnosed as having appendicitis).
Clinical Testing and Work-Up
During an episode, a blood test known as an erythrocyte sedimentation rate may be performed. Sedimentation rate measures how long it takes red blood cells (erythrocytes) to settle in a test tube over a given period. Many individuals with FMF have an elevated sedimentation rate, which is an indication of inflammation. Blood tests can also reveal elevated levels white blood cell levels, which are indicative of an immune system response, elevated C-reactive protein, which is elevated during periods of inflammation and/or elevated levels of fibrinogen (a substance that helps stop bleeding). However, these tests are only effective during an episode of FMF, and they return to normal or near normal when an episode ends.
Urine testing may reveal excess loss of a protein called albumin, which can be indicative of kidney disease.
A diagnosis of FMF can be confirmed by molecular genetic testing, which can identify the characteristic MEFV gene variants that cause the disorder. Molecular genetic testing is available through commercial and academic diagnostic laboratories.
Treatment
There is no cure for FMF but there are effective treatments. Specific treatments are aimed at the specific symptoms apparent in each individual.
Many individuals are treated with the mainstay medication is called colchicine, a complex compound that reduces inflammation. More than 90% affected individuals who take the medication show a marked improvement in the duration and frequency of episodes. Colchicine is also effective in preventing the accumulation of amyloid in the kidneys. However, colchicine requires strict daily adherence, and it does not treat an episode once an episode has begun. Therefore, increasing the dosage during an episode is not beneficial. In 2009, the U.S. Food and Drug Administration (FDA) approved the oral colchicine product Colcrys to treat FMF.
Colchicine can prevent the development of renal amyloidosis, even if it is ineffective in treating FMF attacks. Early-stage renal amyloidosis is reversible. Some individuals with FMF and amyloidosis eventually develop end stage renal disease (ESRD), ultimately requiring a kidney transplant. Initially, an affected individual may undergo dialysis. Dialysis is a procedure in which a machine is used to perform some of the functions of the kidney – filtering waste products from the bloodstream, helping to control blood pressure and helping to maintain proper levels of essential chemicals such as potassium. ESRD is not reversible so individuals will eventually require a kidney transplant. The rate of progressive of kidney dysfunction to ESRD can vary greatly from one individual to another. With the advent of colchicine therapy, the number of individuals with FMF requiring a kidney transplant has dropped. Most individuals with FMF who ultimately required a kidney transplant were unable to take colchicine or did not take the required daily dosage.
Nonsteroidal anti-inflammatory drugs (NSAIDs) and pain medications (analgesics) can be used to treat individuals during a febrile or inflammatory episode. NSAIDs are also used to treat joint and muscle pain which do not respond to colchicine.
In 2016, the monoclonal antibody Ilaris (canakinumab) that blocks the activity of interleukin-1 was approved by the FDA to treat FMF.
Genetic counseling is recommended for affected individuals and their families.
Some individuals who have not responded to colchicine therapy have been treated with anakinra (Kineret). Anakinra is an interkeukin-1 (IL1) receptor antagonist; it blocks the activity of interleukin-1. More research is necessary to determine the long-term safety and effectiveness of anakinra for individuals with FMF.
The drug rilonacept (Arcalyst) blocks the activity of interleukin-1 and is approved by the FDA for the treatment of autoinflammatory disorders such as cold autoinflammatory syndrome. It is being studied as a potential therapy for individuals with FMF. More research is necessary to determine the long-term safety and effectiveness of this medication in the treatment of individuals with FMF.
Additional drugs that have been used in individuals who are unresponsive to colchicine include thalidomide, etanercept, interferon alpha and sulphasalazine. More research is necessary to determine the long-term safety and effectiveness of these potential treatments for FMF.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://nord1dev.wpengine.com/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
RareConnect offers a safe patient-hosted online community for patients and caregivers affected by this rare disease. For more information, visit www.rareconnect.org.
TEXTBOOKS
El-Shanti H. Familial Mediterranean Fever. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:19.
JOURNAL ARTICLES
Cetin P, Sari I, Sozeri B, et al. Efficacy of interleukin-1 targeting treatments in patients with familial mediterranean Fever. Inflammation. 2015;38(1):27-31. doi:10.1007/s10753-014-0004-1
Giancane G, Ter Haar NM, Wulffraat N, et al. Evidence-based recommendations for genetic diagnosis of familial Mediterranean fever. Ann Rheum Dis. 2015;74(4):635-641. doi:10.1136/annrheumdis-2014-206844
Yanmaz MN, Özcan AJ, Savan K. The impact of familial Mediterranean fever on reproductive system. Clin Rheumatol. 2014;33(10):1385-1388. doi:10.1007/s10067-014-2709-9
Ozen S, Demirkaya E, Duzova A, et al. FMF50: a score for assessing outcome in familial Mediterranean fever. Ann Rheum Dis. 2014;73(5):897-901. doi:10.1136/annrheumdis-2013-204719
Hentgen V, Grateau G, Kone-Paut I, et al. Evidence-based recommendations for the practical management of Familial Mediterranean Fever. Semin Arthritis Rheum. 2013;43(3):387-391. doi:10.1016/j.semarthrit.2013.04.011
Savic S, Dickie LJ, Battellino M, McDermott MF. Familial Mediterranean fever and related periodic fever syndromes/autoinflammatory diseases. Curr Opin Rheumatol. 2012;24(1):103-112. doi:10.1097/BOR.0b013e32834dd2d5
Livneh A. Familial mediterranean fever: a continuously challenging disease. Isr Med Assoc J. 2011;13(4):197-198.
Henderson C, Goldbach-Mansky R. Monogenic autoinflammatory diseases: new insights into clinical aspects and pathogenesis. Curr Opin Rheumatol. 2010;22(5):567-578. doi:10.1097/BOR.0b013e32833ceff4
Gillespie J, Mathews R, McDermott MF. Rilonacept in the management of cryopyrin-associated periodic syndromes (CAPS). J Inflamm Res. 2010;3:1-8. doi:10.2147/jir.s8109
De Sanctis S, Nozzi M, Del Torto M, et al. Autoinflammatory syndromes: diagnosis and management. Ital J Pediatr. 2010;36:57. Published 2010 Sep 3. doi:10.1186/1824-7288-36-57
Ben-Chetrit E, Touitou I. Familial mediterranean Fever in the world. Arthritis Rheum. 2009;61(10):1447-1453. doi:10.1002/art.24458
Booty MG, Chae JJ, Masters SL, et al. Familial Mediterranean fever with a single MEFV mutation: where is the second hit?. Arthritis Rheum. 2009;60(6):1851-1861. doi:10.1002/art.24569
Chae JJ, Aksentijevich I, Kastner DL. Advances in the understanding of familial Mediterranean fever and possibilities for targeted therapy. Br J Haematol. 2009;146(5):467-478. doi:10.1111/j.1365-2141.2009.07733.x
Koné-Paut I, Hentgen V, Guillaume-Czitrom S, Compeyrot-Lacassagne S, Tran TA, Touitou I. The clinical spectrum of 94 patients carrying a single mutated MEFV allele. Rheumatology (Oxford). 2009;48(7):840-842. doi:10.1093/rheumatology/kep121
Milhavet F, Cuisset L, Hoffman HM, et al. The infevers autoinflammatory mutation online registry: update with new genes and functions. Hum Mutat. 2008;29(6):803-808. doi:10.1002/humu.20720
El-Shanti H, Majeed HA, El-Khateeb M. Familial mediterranean fever in Arabs. Lancet. 2006;367(9515):1016-1024. doi:10.1016/S0140-6736(06)68430-4
INTERNET
Meyerhoff JO. Familial Mediterranean Fever. Medscape. Updated Oct 10, 2023. Available at: https://emedicine.medscape.com/article/330284-overview Accessed April 23, 2024.
Garg S. Hereditary Periodic Fever Syndromes. Medscape. Updated: April 14, 2023. Available at: http://emedicine.medscape.com/article/952254-overview#aw2aab6b3 Accessed April 23, 2024.
Shohat M. Familial Mediterranean Fever. 2000 Aug 8 [Updated 2016 Dec 15]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1227/ Accessed April 23, 2024.
National Genome Research Institute. Learning About Familial Mediterranean Fever. June 29, 2017. Available at: http://www.genome.gov/12510679 Accessed April 23, 2024.
Mayo Clinic for Medical Education and Research. Familial Mediterranean Fever. Nov 11, 2021. Available at: http://www.mayoclinic.com/health/familial-mediterranean-fever/DS00766 Accessed April 23, 2024.
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