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Familial Mediterranean Fever FMF is an inherited autoinflammatory disorder characterized by unprovoked episodes of fever and inflammation. The mechanism by which mutations in pyrin alter protein function to cause episodic inflammation is controversial. To address this question, we have generated a mouse line lacking the Mefv gene by removing a 21 kb fragment containing the entire Mefv locus. Caspase-1 activity, however, did not change under identical conditions. Editor: David M.
Home » Decision Support in Medicine » Rheumatology. Familial Mediterranean Fever FMF is an autosomal recessive condition due to mutations in MEFV, the gene that encodes pyrin, and is the most common member of the family of monogenic autoinflammatory disorders. FMF is characterized by relapsing and remitting day episodes of fever, sterile serositis, arthritis and an erysipeloid erythematous rash associated with elevations in serum inflammatory markers. Serositis is classically a sterile peritonitis.
However, pleuritis and pericarditis may also occur. This peritonitis is frequently of adequate severity to result in an exploratory laparotomy with the concern for an acute abdomen. Pleuritis and pericarditis can present with chest pain on inspiration and may be associated with fluid collections on radiographic studies or on echocardiogram, respectively.
Arthritis in FMF is typically monoarticular or oligoarticular with the most commonly affected ts being knees, ankles, hips and elbows.
Arthritis may persist longer than days after the resolution of other clinical findings. Attacks occur with a regular periodicity, however, the frequency between attacks is variable from patient to patient, with ranges from once weekly to once every few years. Other findings may include scrotal pain and even necrosis due to inflammation of the tunica vaginalis, an embryologic remnant of the peritoneal membrane. Aseptic meningitis may rarely occur. The clinical presentation in children differs from that of adults. In infants and young children, fever may be the only presenting symptom.
However, the constellation of symptoms tends to progress to that seen more typically in adults within 3 years. FMF occurs most frequently in patients from Mediterranean ethnic backgrounds. However, it has been observed in patients from less typical backgrounds and the lack of a Mediterranean background should not preclude the diagnosis in the appropriate clinical setting.
Familial mediterranean fever (fmf)
The carrier rate for disease causing mutations can be as high as in Armenian populations and is expected to be much lower in areas without a Mediterranean ethnic background. The exact prevalence of disease is unknown as it is highly variable based on ethnic background and the penetrance of disease causing mutations. Fever is a hallmark of disease and may be present on vital s. The abdominal exam may reveal s of an acute abdomen including rebound tenderness, guarding, rigidity and decreased or absent bowel s. A pericardial rub may exist, as may decreased breath sounds at the bases in the setting of pericarditis or pleuritis, respectively.
Patients may have findings of an acute arthritis including t effusions, warmth, tenderness and decreased range of motion of affected ts. This occurs most commonly in the knees, ankles, hips and elbows. The classic rash is an erysipeloid erythematous rash of the lower extremities, usually below the knee. The dorsum of the foot and ankle are particularly common sites.
This rash appears as a warm, tender, swollen, erythematous plaque with well-defined borders. Lesions are typically cm in size and may be bilateral. Other skin findings include localized edema and subcutaneous nodules. In children, purpuric papular lesions are frequently observed. Notably, physical exam findings should resolve within 3 days with the exception of arthritis, which may persist after the resolution of other symptoms.
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Organ manifestations also differ with FMF, affecting the skin, ts, peritoneum and pleura, while HIDS also presents with painful lymphadenopathy, and TRAPS also presents with myalgia, conjunctivitis and periorbital edema. The severe abdominal pain in FMF may be confused with an acute abdomen due to appendicitis or other acute surgical pathologies. It is not infrequent that a patient undergoes an emergency appendectomy only to find that the appendix does not appear inflamed.
This can be a clue to the correct diagnosis. Hereditary angioedema may present as acute abdominal pain but does not typically cause a fever. Swelling may be more pronounced in hereditary angioedema.
In children, systemic onset juvenile idiopathic arthritis SoJIA is also a consideration. However, these patients have a quotidian fever pattern and may also present with an evanescent skin rash, lymphadenopathy and polyarthritis, and patients do not typically develop abdominal pain. These criteria are based on clinical findings and were developed before the widespread availability of a genetic testing to confirm the diagnosis. A definite diagnosis is established based on the presence of two major, or one major and two minor criteria. A probable diagnosis is based on one major and one minor criterion.
In the pediatric population, these criteria are sensitive but not specific for the establishment diagnosis based on genetic testing. Using logistic regression to identify five criteria most predictive of disease in children, the presence of two of the following criteria discriminated FMF from controls with a These abnormalities may also persist in between attacks.
Elevations of serum immunoglobulins, including IgD, may be present both during attacks and in between attacks. Synovial fluid obtained during an attack is frequently highly inflammatory with leukocyte values in the range of those seen in septic arthritis. Genetic testing for mutations in MEFV is now widely commercially available and may be covered by insurance companies. While FMF is an autosomal recessive disorder, patients with a single heterozygous mutation can develop typical disease and appear to have the same clinical presentation as those patients with two mutations.
Thus, a single mutation is considered sufficient for a genetic diagnosis. Genotype-phenotype correlations are well established with the most severe manifestations occurring in patients homozygous for MV mutations. These patients present with an earlier onset, more frequent arthritis and skin findings and require higher doses of colchicine to control disease.
Moreover, they are more likely to develop amyloidosis, one of the most severe consequences of disease. Other mutations, including RS, RQ and EQ, are associated with atypical disease and even an asymptomatic state. The ificance of these mutations remains an issue of controversy and further investigation.
Radiographs of the ts may show fluid collections and soft tissue swelling. t destruction is rare, however case reports exist. On MRI, acute synovitis and synovial effusions may be present. Abdominal and chest CT scans can reveal peritoneal and pleural enhancement in the setting of an acute attack. Abdominal CT scan or ultrasound may also be helpful in the setting of potential amyloidosis, as kidneys may be enlarged early in the course of disease and may later be abnormally small after long-term damage and atrophy has occurred.
A biopsy for diagnostic purposes is rarely obtained as the diagnosis is based on clinical criteria and genetic confirmation. However, biopsies of the skin may show perivascular and interstitial inflammatory infiltrates with a predominance of neutrophils and lymphocytes in the dermis.
Edema of the papillary dermis and superficial dermal capillary dilatation may be observed. In the setting of a clinical concern for secondary SAA amyloidosis, a renal, skin, fat pad or rectal biopsy is essential to confirm the diagnosis.
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Biopsies should be stained with a Congo red dye with positivity establishing the presence of amyloid in the tissue specimen. Given the potential severe consequences of this finding, patients with amyloidosis should be referred to a tertiary care center with experience in the treatment of this condition. Colchicine is the mainstay of treatment in patients with FMF. Moreover, it has been shown to prevent the development of amyloidosis in the majority of patients. Goal doses are between 1. The most frequent limiting side effect is gastrointestinal intolerance with the common occurrence of nausea and diarrhea.
This may improve with time and with the initiation of a low initial dose with slow uptitration. Bloating and abdominal pain may be due to lactose intolerance which may be alleviated with lactase replacement products in the appropriate setting. More severe but rare side effects include myopathy and neuropathy. These are seen more commonly in the elderly and in patients with renal impairment.
Familial mediterranean fever (fmf)
In the small subset of patients that do not respond adequately to colchicine or who cannot tolerate the medication, IL-1 and TNF inhibitors are often effective. IL-1 inhibition may also be considered in the setting of persistently elevated inflammatory markers in an attempt to control systemic inflammation, which likely reduces the risk of developing amyloidosis.
TNF inhibitors may also play a role in resistant patients, with case reports indicating successful treatment in this setting. Moreover, regression of proteinuria due to amyloidosis with TNF inhibition has been observed. These medications may be added as an adjuvant therapy or replacement therapy in the case of colchicine intolerance.
With the proper daily use of colchicine, most patients achieve a near remission of symptoms and amyloidosis occurs at much lower rates. Acute attacks typically resolve without permanent organ damage. The most severe and feared complication of FMF is the development of amyloidosis. SAA is produced by the liver in acute inflammatory states and AA amyloid deposits in tissues to result in pathology.
Initial amyloid deposits may occur without consequence, however, once a critical burden is reached, the rate of further amyloid deposition rapidly increases with resultant organ damage.
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Renal amyloid deposition was the most common cause of death in patients prior to colchicine and remains the organ contributing to the highest amount of clinical pathology. However, deposition may also occur in the GI tract, lungs, testes, thyroid, and adrenal glands. Amyloidosis usually occurs after long-standing inflammatory disease.
Other risk factors include homozygosity for the MV mutation and country of residence, with Armenia, Turkey and Arab countries showing the highest risks of renal amyloidosis. Interestingly, patients with FMF and renal amyloidosis living in areas of lower risk for amyloidosis were of higher Armenian, Turkish and Arab ethnic backgrounds than was observed in FMF patients not developing amyloidosis. Patients with FMF should be monitored periodically between attacks for the development of proteinuria.
Renal failure typically develops between years after the onset of proteinuria. SAA levels are a sensitive measure for predicting the progression of renal failure in patients with renal amyloidosis. Unfortunately, this test is not commercially available but it may be possible to obtain these in a research setting.