History
The preeminent feature of familial Mediterranean fever (FMF) is the paroxysm, the classic onset of which occurs without warning, although some patients may be able to detect premonitory symptoms. The paroxysms usually last 48-96 hours, with peak intensity occurring within the first 12 hours. A plateau with resolution follows, usually occurring more slowly than the onset of symptoms.
In paroxysms, the person's temperature rises rapidly to 38-40°C (100.4-104°F). Temperature increases may occur before other manifestations. In mild attacks, fever may be the only manifestation.
Peritoneal symptoms
Almost all patients with FMF experience abdominal episodes. Abdominal pain develops, and may progress to peritonitis. Frequently the clinical presentation is consistent with appendicitis or cholecystitis, so patients commonly undergo appendectomies and cholecystectomies because the abdominal episodes of FMF are not recognized as such. The symptoms may also mimic renal colic.
In many cases, patients develop constipation during the attack and diarrhea after the attack resolves.
Even with recurrent attacks, adhesions are rare.
Pleural and pericardial symptoms
The frequency of pleural and pericardial attacks varies among ethnic groups, with 25-80% of patients reporting pleuritic episodes. Effusions occasionally occur. Pericarditis may develop, but tamponade and constrictive pericarditis are rare.
Synovial symptoms
The rate of synovial symptoms varies from 25-75% in reported series. The episodes 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.
Arthritic symptoms tend to last several days longer than abdominal symptoms. Episodes can be protracted. The joints are normal between attacks, and permanent damage is unusual.
Arthritis may be the only manifestation of FMF. The diagnosis of FMF should be considered in patients who have a family history of FMF or live in an endemic area and experience episodes of arthritis. [14]
Other manifestations
The following may also be features of FMF:
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Dermatologic manifestations - As many as 50% of patients with FMF report erysipelaslike rashes on the lower extremities, particularly below the knees; rash and fever may be the only manifestations of attacks
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Muscle symptoms - Severe myalgia may last 3-6 weeks; symptoms are consistent with fibromyalgia; these episodes do not respond to colchicine therapy
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Pelvic symptoms - Female patients with FMF may have episodes of pelvic inflammatory disease
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Scrotal attacks - In males, inflammation of the tunica vaginalis testis may mimic episodes of testicular torsion
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Vasculitis - An increased frequency of Henoch-Schönlein purpura and polyarteritis nodosa is reported in persons with FMF, even in children; Behçet disease is also more common
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Neurologic manifestations - Headache is common. Other reported findings have included seizures, paresthesias, breath-holding, and ataxia. [15]
Amyloidosis
In a patient of the appropriate ethnic group, the typical progression of amyloidosis in FMF is proteinuria, followed by nephrotic syndrome, and, inevitably, death from renal failure.
One third of patients with amyloidosis develop renal vein thrombosis. Nephrotic syndrome is reported in patients as young as 14 years. Despite the frequency and extent of amyloid deposits in the renal system, deposits in other organs are only rarely reported as significant.
In a retrospective study of 170 Armenian patients with FMF and suspected nephropathy, biopsy-proven amyloid A (AA) amyloidosis was found in 102 (60%). Recurrent arthritis was significantly associated with an increased risk of AA amyloidosis, and involvement of the joint synovial membrane, which is capable of active serum amyloid A production, was the main predictor of renal amyloidosis. [16]
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.
Some patients with a family history of FMF present with amyloid nephropathy without ever having experienced an amyloid attack. Furthermore, some patients with otherwise typical FMF may develop renal failure without previous proteinuria.
Physical Examination
Temperatures can reach as high as 40°C (104°F), but, in most cases, rapid defervescence occurs within 12 hours. Other physical findings of FMF depend mostly on the serosal surface involved, as follows:
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A boardlike or surgical abdomen is present with typical findings of peritonitis (ie, abdominal tenderness, decreased bowel sounds). Splenomegaly is common in response to the inflammation. Patients with pleural involvement may have shallow breathing and chest-wall tenderness, but friction rubs are rare.
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Joints show typical inflammatory changes, with warmth, erythema, or swelling.
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A well-demarcated, erythematous, warm rash, particularly below the knee, ranging from 15-50 cm2 may develop and may be accompanied by swelling.
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Patients with painful myalgia syndrome may have tender muscles.
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Female patients with symptoms mimicking pelvic inflammatory syndrome may experience pain on cervical motion and may develop tender, enlarged ovaries.
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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.
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Amyloidosis is usually asymptomatic, with hypertension reported in 35% of patients late in the disease. Renal vein thrombosis may develop and manifests as loin pain.
Causes
FMF is a recessive genetic disease associated with missense and nonsense mutations in the MEFV gene, which is located on the short arm of chromosome 16. This gene codes for the protein known as pyrin or marenostrin.
More than 310 sequence variants in the MEFV gene have been identified, although not all not associated with a disease phenotype. [6] Most of the pathogenic mutations are in exon 10 of the gene between amino acids 680 and 761. One mutation, in exon 1 at amino acid 148, may represent as many as one quarter of the known mutations. Although certain mutations are more common in particular ethnic groups, patients usually inherit different mutations from each parent.
Homozygotes for M694V (valine for methionine at position 694) may experience more severe disease and may be more likely to develop amyloidosis. Patients with V726A (alanine for valine at position 726) may be at a lower risk of developing amyloidosis, although one study suggests that the combination of V726A and E148Q may be particularly amyloidogenic. [8]
Other genes may be involved in FMF. This possibility is supported by patients who meet criteria for FMF without identifiable mutations in MEFV and who have clinical manifestations that are indistinguishable from patients with MEFV mutations.
Diagnostic Considerations
Other problems to consider in the differential diagnosis of familial Mediterranean fever include the following:
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Familial Hibernian fever
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Hyperimmunoglobulin D and periodic fever syndrome
Differential Diagnoses
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Appendicitis
Laboratory Studies
Results of routine blood tests performed during the acute attacks of familial Mediterranean fever (FMF) are nonspecific. Levels of acute-phase reactants (ie, C-reactive protein, erythrocyte sedimentation rate, amyloid A protein, fibrinogen) are elevated. The white blood cell count is usually elevated during an attack. The elevated levels rapidly return to the reference range as the attack abates.
On urine studies, proteinuria should raise a concern about possible amyloidosis. For unknown reasons, hematuria occurs in 5% of patients.
In patients with arthritis during attack, synovial fluid is inflammatory, with cell counts as high as 100,000/µL.
Genetic Testing
Genetic testing is now available for FMF. Testing for a limited number of genes may be appropriate in patients with a known ethnic background. Complete gene sequencing may be more helpful in patients of mixed or unknown ethnicity. Symptomatic patients with at least one MEFV mutation should be considered to have FMF. Patients with no gene mutations who meet criteria for FMF should be offered a trial of colchicine. Given the high gene frequency and low penetrance in certain populations (eg, Ashkenazi Jews, Armenians), gene testing should be closely correlated to clinical findings to avoid false-positive results.
An expert committee of European pediatric rheumatologists has developed the following recommendations for genetic diagnosis of familial Mediterranean fever [17] :
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FMF is a clinical diagnosis; it can be supported but not excluded by genetic testing.
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FMF patients carrying two of the common mutated alleles (homozygotes or compound heterozygotes), especially for M694V mutation or mutations at position 680 to 694 on exon 10, must be considered at risk of having a more severe disease.
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Patients homozygous for M694V mutation are at risk for early-onset disease and at very high risk of developing a severe phenotype; those who are not reporting symptoms should be evaluated and followed closely in order to consider therapy.
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Patients with two pathogenic mutations for FMF who do not report symptoms but have risk factors for AA amyloidosis (eg, country of origin; family history; persistently elevated inflammatory markers, particularly serum amyloid A protein), should have close follow-up and be considered for treatment.
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The E148Q variant is common and of unknown pathogenic significance; its presence as the only MEFV variant does not support the diagnosis of FMF.
Imaging Studies
Findings during an acute attack in patients with peritonitis, pleuritis, and arthritis are as expected and include air-fluid levels, pleural effusions, and synovial effusions.
Histologic Findings
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.
Biopsy
Amyloidosis can be presumed in patients with FMF, particularly those of North African descent who have proteinuria. Renal biopsy or, alternatively, submucosal rectal biopsy, is indicated in these patients.
A recent retrospective review of kidney biopsies in FMF patients found that 40% of the patients had nonamyloid kidney disease (NAKD). While the patients with amyloid kidney disease (AKD) had more proteinuria and more of them had more than 3.5 g of proteinuria, all of these biopsies were in patients with greater than 500 mg of proteinuria. The AKD patients had more severe disease and were more likely to have hypertension. All patients with proteinuria of greater than 500 mg/24 h should have a biopsy. [18]
Medical Care
Colchicine
Colchicine is so effective in preventing attacks of familial Mediterranean fever (FMF) and preventing the development of amyloidosis that the most important aspects of medical care are to make the correct diagnosis and to institute therapy.
Administer colchicine therapy daily in patients at risk of developing amyloidosis (eg, North African Jewish people, Turkish people, Armenian people living in Armenia). Other Sephardic Jewish people and Arabic people are at lower risk but also probably require daily colchicine therapy.
Daily colchicine is customarily given in a dosage of 0.6 or 0.5 mg twice daily, depending on the dosage form available. However, a study in treatment-naive pediatric patients newly diagnosed with FMF found that a single 1-g daily dose was noninferior to 0.5 mg given twice daily. [19] Guidelines from the European League Against Rheumatism (EULAR) recommend the following starting dosages of colchicine [20] :
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Children < 5 years of age: ≤0.5 mg/day (≤0.6 mg/day if tablets contain 0.6 mg)
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Children 5–10 years: 0.5–1.0 mg/day (1.2 mg/day if tablets contain 0.6 mg)
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Children >10 years and adults:1.0–1.5 mg/day (1.8 mg/day if tablets contain 0.6 mg)
After colchicine has been started, EULAR recommends following patients closely for 3–6 months to observe the therapeutic effect.
In patients who do not respond to twice-a-day dosing, administer colchicine three, or even four, times a day. In patients who have difficulty tolerating colchicine, start therapy at once-a-day dosing and gradually increase the dose. In patients whose conditions were not responsive to oral colchicine, the addition of 1 mg IV once a week reduced the number of attacks in 10 of 13 patients and the severity of attacks in 6 of 13 patients. [21]
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 1.5 mg/d of colchicine.
Ashkenazi Jewish people and Armenian people living in the United States seem to be at extremely low risk of amyloidosis and may need treatment only to prevent attacks. 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.
Surgical Care
Before the advent of colchicine therapy, renal transplantation was performed in patients with end-stage renal disease due to amyloid nephropathy. Currently, renal failure develops only in patients who are not compliant with therapy or cannot tolerate it and those with disease refractory to therapy.
Consultations
Since the advent of colchicine therapy, most treated patients are asymptomatic and do not need consultation with a specialist.
Consultation with a rheumatologist is indicated in patients with the following conditions:
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Seronegative spondyloarthropathy not responsive to nonsteroidal anti-inflammatory drugs
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Fibromyalgia not responsive to the usual treatments
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Coexistent Henoch-Schönlein purpura, polyarteritis nodosa, or Behçet disease