Familial Mediterranean fever (FMF) is a disease of people with genetic origins in the Mediterranean basin, predominantly Sephardic Jews, North African Arabs, Armenians, Turks, Greeks, and Italians. However, cases have occurred among enough other groups (eg, Ashkenazi Jews, Cubans, Japanese) to caution against excluding the diagnosis solely on the basis of ancestry. Up to 50% of patients have a family history of the disorder, usually involving siblings.
Familial Mediterranean fever is caused by
Mutations in the MEFV gene on the short arm of chromosome 16
The mutation is inherited in an autosomal recessive Autosomal Recessive Genetic disorders determined by a single gene (Mendelian disorders) are easiest to analyze and the most well understood. If expression of a trait requires only one copy of a gene (one allele)... read more manner. FMF mutations are gain-of-function, that is, they confer new or enhanced activity on a protein, with a gene dosage effect (ie, more copies of the abnormal gene convey a greater effect). The MEFV gene normally codes a protein named pyrin, which is expressed in circulating neutrophils.
Pyrin is part of the innate immune system Innate immunity The immune system distinguishes self from nonself and eliminates potentially harmful nonself molecules and cells from the body. The immune system also has the capacity to recognize and destroy... read more and guards against bacterial toxins that depolymerize actin and activate inflammasomes. Bacteria that produce such toxins include Clostridioides difficile, Burkholderia cenocepacia, and Vibrio cholerae ( 1 Etiology references Familial Mediterranean fever is an autosomal recessive disorder characterized by recurrent bouts of fever and peritonitis, sometimes with pleuritis, skin lesions, arthritis, and, rarely, pericarditis... read more ). Pyrin is presumed to blunt the inflammatory response, possibly by inhibiting neutrophil activation and chemotaxis. Gene mutations result in altered pyrin molecules that do not inhibit inflammasome activation and thus cannot suppress minor, unknown triggers to inflammation that are normally checked by intact pyrin. The clinical consequence is spontaneous bouts of neutrophil-predominant inflammation in the abdominal cavity as well as in other sites. There is strong evidence that Yersinia pestis, the cause of bubonic plague, led to the positive selection of FMF-associated MEFV mutations. These mutations confer a survival advantage to certain people who harbor Yersinia pestis ( 2 Etiology references Familial Mediterranean fever is an autosomal recessive disorder characterized by recurrent bouts of fever and peritonitis, sometimes with pleuritis, skin lesions, arthritis, and, rarely, pericarditis... read more ).
1. Park YH, Wood G, Kastner DL, Chae JJ: Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS. Nat Immunol 17(8):914–921, 2016. doi: 10.1038/ni.3457
2. Park YH, Remmers EF, Lee W, et al: Ancient familial Mediterranean fever mutations in human pyrin and resistance to Yersinia pestis. Nat Immunol 21(8):857–867, 2020. doi: 10.1038/s41590-020-0705-6
Symptoms and Signs
Onset of familial Mediterranean fever is usually between the ages of 5 and 15 years but may be much later or earlier, even during infancy. Attacks have no regular pattern of recurrence. They usually last 24 to 72 hours but may last longer. Frequency ranges from 2 attacks/week to 1 attack/year (most commonly, once every 2 to 6 weeks). Severity and frequency tend to decrease during pregnancy and in patients with amyloidosis. Spontaneous remissions may last years.
Fever as high as 40° C, usually accompanied by peritonitis, is the major manifestation. Abdominal pain (usually starting in one quadrant and spreading to the whole abdomen) occurs in about 95% of patients and can vary in severity with each attack. Decreased bowel sounds, distention, guarding, and rebound tenderness are likely to occur at the peak of an attack and cannot be differentiated from a perforated viscus by physical examination. Consequently, some patients have undergone urgent laparotomy before the correct diagnosis was made. With diaphragmatic involvement, splinting of the chest and pain in one or both shoulders may occur.
Other manifestations of FMF include acute pleurisy (in 30%); arthritis (in 25%), usually involving the knee, ankle, and hip; an erysipelas-like rash of the lower leg; and scrotal swelling and pain caused by inflammation of the tunica vaginalis of the testis. Pericarditis Pericarditis Pericarditis is inflammation of the pericardium, often with fluid accumulation in the pericardial space. Pericarditis may be caused by many disorders (eg, infection, myocardial infarction, trauma... read more occurs rarely. The pleural, synovial, and skin manifestations of FMF vary in frequency among different populations and are less frequently encountered in the US than elsewhere.
Despite the severity of symptoms during acute attacks, most patients recover swiftly and remain free of illness until their next attack.
Autoinflammatory periodic fever disorders
CAPS = cryopyrin-associated periodic syndromes; FMF = familial Mediterranean fever; NOMID = neonatal-onset multisystem inflammatory disease; PFAPA = periodic fevers with aphthous stomatitis, pharyngitis, and adenitis; TRAPS = tumor necrosis factor receptor–associated periodic syndrome.
Adapted from Sag E, Bilginer Y, Ozen S: Autoinflammatory diseases with periodic fevers. Curr Rheumatol Rep 19(7):41, 2017. doi: 10.1007/s11926-017-0670-8
Complications of familial Mediterranean fever
The most significant long-term complication of FMF is
Chronic renal failure caused by deposition of amyloid protein in the kidneys
Amyloid may also be deposited in the gastrointestinal tract, liver, spleen, heart, testes, and thyroid.
FMF causes infertility or spontaneous abortion in about one third of women because peritoneal pelvic adhesions form, interfering with conception. In women with FMF, about 20 to 30% of pregnancies end in fetal loss.
FMF increases the risk of other inflammatory disorders, such as ankylosing spondylitis Ankylosing Spondylitis Ankylosing spondylitis is the prototypical spondyloarthropathy and a systemic disorder characterized by inflammation of the axial skeleton, large peripheral joints, and digits; nocturnal back... read more , immunoglobulin A–associated (IgA) vasculitis Immunoglobulin A–Associated Vasculitis (IgAV) Immunoglobulin A–associated vasculitis (formerly called Henoch-Schönlein purpura) is vasculitis that affects primarily small vessels. It occurs most often in children. Common manifestations... read more (formerly Henoch-Schönlein purpura), juvenile idiopathic arthritis Juvenile Idiopathic Arthritis (JIA) Juvenile idiopathic arthritis is a group of rheumatic diseases that begins by age 16. Arthritis, fever, rash, adenopathy, splenomegaly, and iridocyclitis are typical of some forms. Diagnosis... read more , polyarteritis nodosa Polyarteritis Nodosa (PAN) Polyarteritis nodosa is a systemic necrotizing vasculitis that typically affects medium-sized muscular arteries and occasionally affects small muscular arteries, resulting in secondary tissue... read more , multiple sclerosis Multiple Sclerosis (MS) Multiple sclerosis (MS) is characterized by disseminated patches of demyelination in the brain and spinal cord. Common symptoms include visual and oculomotor abnormalities, paresthesias, weakness... read more , and Behçet disease Behçet Disease Behçet disease is a multisystem, relapsing, chronic vasculitic disorder with mucosal inflammation. Common manifestations include recurrent oral ulcers, ocular inflammation, genital ulcers, and... read more ( 1 Symptoms and signs reference Familial Mediterranean fever is an autosomal recessive disorder characterized by recurrent bouts of fever and peritonitis, sometimes with pleuritis, skin lesions, arthritis, and, rarely, pericarditis... read more ).
Symptoms and signs reference
1. Balcı-Peynircioğlu B, Kaya-Akça Ü, Arıcı ZS, et al: Comorbidities in familial Mediterranean fever: Analysis of 2000 genetically confirmed patients. Rheumatology (Oxford) 59(6):1372–1380, 2020. doi: 10.1093/rheumatology/kez410. PMID: 31598713
Diagnosis of familial Mediterranean fever is mainly clinical based on Tel HaShomer criteria (see table Tel HaShomer Criteria for the Diagnosis of Familial Mediterranean Fever Tel HaShomer Criteria for the Diagnosis of Familial Mediterranean Fever* ; 1 Diagnosis references Familial Mediterranean fever is an autosomal recessive disorder characterized by recurrent bouts of fever and peritonitis, sometimes with pleuritis, skin lesions, arthritis, and, rarely, pericarditis... read more ), but genetic testing is available and is particularly useful in evaluation of atypical cases. However, current genetic testing is not infallible; some patients with phenotypically unmistakeable FMF have only a single mutated gene or occasionally no evident mutations in the MEFV gene. About 10 to 20% of patients who meet the diagnostic criteria for FMF do not have MEFV mutations, which suggests epigenetic and environmental factors contribute to the disease pathogenesis ( 2 Diagnosis references Familial Mediterranean fever is an autosomal recessive disorder characterized by recurrent bouts of fever and peritonitis, sometimes with pleuritis, skin lesions, arthritis, and, rarely, pericarditis... read more ).
Nonspecific findings include elevations in white blood cells with neutrophil predominance, erythrocyte sedimentation rate, C-reactive protein, and fibrinogen. Urinary excretion of > 0.5 g protein/24 hours suggests renal amyloidosis.
Differential diagnosis includes acute intermittent porphyria Acute Porphyrias Acute porphyrias result from deficiency of certain enzymes in the heme biosynthetic pathway, resulting in accumulation of heme precursors that cause intermittent attacks of abdominal pain and... read more , hereditary angioedema Hereditary angioedema Hereditary angioedema and acquired angioedema (acquired C1 inhibitor deficiency) are caused by deficiency or dysfunction of complement 1 (C1) inhibitor, a protein involved in the regulation... read more with abdominal attacks, relapsing pancreatitis Overview of Pancreatitis Pancreatitis is classified as either acute or chronic. Acute pancreatitis is inflammation that resolves both clinically and histologically. Chronic pancreatitis is characterized by histologic... read more , and other hereditary relapsing fevers.
1. Livneh A, Langevitz P, Zemer D, et al: Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum 40(10):1879–1885, 1997. doi: 10.1002/art.1780401023
2. Booty MG, Chae JJ, Masters SL, et al: Familial Mediterranean fever with a single MEFV mutation: Where is the second hit? Arthritis Rheum 60(6):1851–1861, 2009. doi: 10.1002/art.24569
Sometimes canakinumab, anakinra, or rilonacept
Prophylactic colchicine 0.6 mg orally 2 times a day (some patients require dosing 4 times a day; others a single daily dose) provides complete remission or distinct improvement in about 85% of patients. If attacks or subclinical inflammation persist, the colchicine dose should be increased. For patients with infrequent attacks that have a gradual onset, colchicine can be reserved until initial symptoms occur and then begun at 0.6 mg orally every hour for 4 hours, then every 2 hours for 4 hours, then every 12 hours for 48 hours. Initiation of colchicine at the peak of an attack is unlikely to be beneficial. Children often require adult dosages for effective prophylaxis. Widespread use of prophylactic colchicine has led to a dramatic reduction in the incidence of amyloidosis and subsequent renal failure.
Colchicine does not add to the increased risk of infertility and miscarriage among affected women; when taken during pregnancy, it does not increase the risk of teratogenic events. Lack of response to colchicine is often caused by poor adherence to the drug regimen, but a correlation has also been noted between poor response and diminished colchicine concentration in circulating monocytes.
Alternative subcutaneous therapies for nonresponders include anakinra 100 mg once a day, rilonacept 2.2 mg/kg weekly, or canakinumab 150 mg every 4 weeks ( 1 Treatment references Familial Mediterranean fever is an autosomal recessive disorder characterized by recurrent bouts of fever and peritonitis, sometimes with pleuritis, skin lesions, arthritis, and, rarely, pericarditis... read more , 2 Treatment references Familial Mediterranean fever is an autosomal recessive disorder characterized by recurrent bouts of fever and peritonitis, sometimes with pleuritis, skin lesions, arthritis, and, rarely, pericarditis... read more ).
Opioids are sometimes needed for pain relief but should be used prudently to avoid addiction.
1. Ozen S, Demirkaya E, Erer B, et al: EULAR recommendations for the management of familial Mediterranean fever. Ann Rheum Dis 75(4):644–651, 2016. doi: 10.1136/annrheumdis-2015-208690
2. De Benedetti F, Gattorno M, Anton J, et al: Canakinumab for the treatment of autoinflammatory recurrent fever syndromes. N Engl J Med 378(20):1908–1919, 2018. doi: 10.1056/NEJMoa1706314
Familial Mediterranean fever is caused by an autosomal recessive mutation in a protein that helps modulate the inflammatory response in neutrophils.
People with genetic origins in the Mediterranean basin are more commonly (but not exclusively) affected.
Patients have brief episodes of fever, abdominal pain, and sometimes other symptoms such as pleuritis, arthritis, and rash.
Renal amyloidosis, sometimes causing renal failure, is the most common complication, but prophylactic colchicine provides protection against amyloidosis.
Diagnose clinically, but consider genetic testing for atypical cases.
Daily colchicine results in significant protection against attacks in most patients, but a few require an immunomodulator such as anakinra, rilonacept, or canakinumab.
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