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Mediterranean Fever Familial. Background. Familial Mediterranean fever (FMF) is also called recurrent polyserositis.
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Background • Familial Mediterranean fever (FMF) is also called recurrent polyserositis. • Features of this disease include brief recurrent episodes of peritonitis, pleuritis, and arthritis, which are usually associated with fever. The disease occurs within families and is much more common in individuals of Mediterranean descent. • FMF is more prevalent in men than women (2:1). • 80-95% are younger than 20 years. Rare in persons older than 40.
Pathophysiology • Nonsense or missense mutations in the MEFV (Mediterranean fever) gene appear to cause the disease. • This gene produces a protein called pyrin or marenostrin. • This protien probably functions as an inhibitor of chemotactic factor C5a or of IL8. • Thus in patients with FMF , there is uninhibited activity of chemotactic factor and episodes of inflammation in peritoeneum, pleura, joints. • These inflammatory episodes lead to the excess production of amyloid A protein with subsequent deposition in the kidney.
Frequency • Ashkenazi Jewish people have a prevalence of 1 case per 73,000 population. • Armenian persons have an estimated prevalence of 1 case per 500 population. • Turkish people (from one study) may have a prevalence of approximately 1 case per 1000 population. • Arabic people (from one study) may have a prevalence of 1 case per 2600 population in children and a gene frequency of 1:50.
Mortality/Morbidity • Nephrotic syndrome. • Appendectomies in undiagnosed FMF cases. • Chronic arthritis (5%) that sometimes leads to destructive arthritis of hips or knees and may necessitate joint replacements. • 10% of patients with chronic arthritis develop seronegative spondyloarthropathy. • Approximately one third of female patients are infertile, and 20-30% of pregnancies result in fetal loss .
History • The preeminent feature of FMF is the paroxysm, the classic onset of which occurs without warning. • The paroxysms usually last 48-96 hours, with peak intensity occurring within the first 12 hours.
History • Fever • Temperatures rise rapidly to 38-40°C . May be the only manifestation. • Peritoneal symptoms • Abdominal pain that may progress to peritonitis, resembling a surgical abdomen. • Symptoms consistent with appendicitis or cholecystitis, and they frequently have appendectomies and cholecystectomies. • The symptoms may also mimic renal colic. • Constipation during the attack and diarrhea after the attack resolves.
History • Pleural and pericardial symptoms • pleuritic episodes. • Effusions. • Pericarditis. • Tamponade and constrictive pericarditis arerare. • Synovial symptoms May resemble gout in their acute onset and intensity. Knees, ankles, and wrists are the joints most commonly affected. An arthritis that resembles seronegative spondyloarthritis may also occur.
History • Dermatologic manifestations • Erysipelas like rashes on the lower extremities. • Muscle symptoms • Severe myalgia lasting 3-6 weeks. • Pelvic symptoms • Female patients may have episodes of PID. • Scrotal attacks • Inflammation of the tunica vaginalis may mimic episodes of torsion of the testis. • Vasculitis • An increased frequency of Henoch-Schönlein purpura ,polyarteritis nodosa and Behçet disease.
History • Amyloidosis • The typical progression is proteinuria, followed by nephrotic syndrome, and, inevitably, death from renal failure. • One third of patients may develop renal vein thrombosis. • Prolonged survival resulting from colchicine therapy, dialysis, and renal transplantation allows additional manifestations of amyloidosis to develop. Some patients have intestinal involvement, which may lead to malabsorption and death.
Physical • Fever as high as 40°C. • A boardlike or surgical abdomen. • Splenomegaly. • Shallow breathing and chest-wall tenderness (pleural involvement). • Joints show typical inflammatory changes, with warmth, erythema, or swelling. • Erythematous, warm rash, particularly below the knee. • Tender muscles (painful myalgia syndrome). • Pain upon cervical motion and tender, enlarged ovaries( pelvic inflammatory syndrome). • Unilateral, erythematous, and tender swelling of the scrotum occurs in scrotal attacks. • The typical manifestations of Behçet disease and Henoch-Schönlein purpura may be observed. • Amyloidosis is usually asymptomatic. • Renal vein thrombosis may develop and manifests as loin pain.
WORKUP • Lab Studies: • Levels of acute phase reactants (ie, C-reactive protein, amyloid A protein, fibrinogen) are elevated, as is the erythrocyte sedimentation rate. The white blood cell count is usually elevated during an attack. • Proteinuria should raise a concern about possible amyloidosis. For unknown reasons, hematuria occurs in 5% of patients. • Synovial fluid is inflammatory, with cell counts as high as 100,000/mL. • From the successful cloning of the MEFV gene, researchers have developed a rapid test for the most common mutations. The test has a sensitivity and specificity of 100%.
WORKUP • Imaging Studies: • Findings during an acute attack include air-fluid levels, pleural effusions, and synovial effusions. • Procedures: • Renal biopsy or, alternatively, submucosal rectal biopsy, is indicated in patients who have proteinuria. • Histologic Findings: • A massive amyloid infiltration of the blood vessels and of the endothelial side of the glomerular basement membrane occurs in the kidneys. In the rectal submucosa, the amyloid is found near the blood vessels.
Medical Care • The most important aspects of medical care are to make the correct diagnosis and to institute therapy . • Administer colchicine therapy daily (0.6 mg bid) in patients at risk of developing amyloidosis (eg, North African Jewish people, Turkish people, Armenian people living in Armenia). Other Jewish people and Arabic people are at lower risk but also probably require daily colchicine therapy. • If attacks are rare and patients can determine when they are beginning, treatment with intermittent colchicine therapy at the onset of attacks may be sufficient therapy.
Medical Care • Some patients develop lactose intolerance and may respond to a lactose-free diet. • In patients whose conditions do not respond to colchicine, the use of interferon alfa or the tumor necrosis factor–blocking drug etanercept may be effective. • Colchicine also stabilizes the amount of proteinuria in patients with amyloid nephropathy. Renal disease may resolve in patients with a creatinine level of less than 1.5 mg/dL who are treated with more than 1.5 mg/d of colchicine.
Medical Care • Hemodialysis can be used for patients who develop renal failure. • Patients who experience episodes of prolonged myalgia with fever and severe pain may need treatment with prednisone (1 mg/kg) for as long as 6 weeks. • Patients who develop seronegative spondyloarthropathy are treated with nonsteroidal anti-inflammatory drugs and receive follow-up care by a rheumatologist.
MEDICATION • Colchicine is the DOC for FMF. • Action: • Decreases leukocyte motility and phagocytosis in inflammatory responses. • Dose • 1.2-2 mg PO in divided doses • Contraindications: • Documented hypersensitivity; severe renal, hepatic, GI, or cardiac disorders; blood dyscrasias . • Interactions: • Sympathomimetic agent toxicity and effect of CNS depressants are significantly increased • Pregnancy: • Safety for use during pregnancy has not been established • Precuations: • In pregnant patients with FMF, treatment may improve infertility and miscarriage rates; no evidence of teratogenic effects in males or females; may be excreted in breast milk (no evidence of adverse effects in breastfed children); may cause both myopathy and neuropathy in elderly persons and people with renal insufficiency
Out-patient care • Perform a urinalysis at every visit, particularly in patients at risk of developing amyloidosis. If proteinuria is confirmed, increase the daily dose of colchicine. • For unknown reasons, hematuria occurs in approximately 5% of patients. Its presence, along with prolonged abdominal or muscle pain, suggests the development of polyarteritis nodosa.
Complication • Patients with amyloidosis may develop an acute onset of renal failure if they are stressed by dehydration, infection, or both. • Renal vein thrombosis may occur in nephrotic patients. This condition may manifest as abdominal or flank pain, increasing proteinuria, and worsening renal function. Acute anticoagulation may stabilize or improve renal function.
Prognosis • Patients who are compliant with daily colchicine can probably expect to have a normal lifespan if colchicine is started before proteinuria develops. • Even with amyloidosis, the use of colchicine, dialysis, and renal transplantation should extend a patient's life beyond age 50 years.
