History
The preeminent feature of familial Mediterranean fever (FMF) is the paroxysm—a recurrent episode of peritonitis, pleuritis, and arthritis, usually with accompanying fever. Classically, the onset occurs without warning, although some patients may be able to detect premonitory symptoms. The 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.
A minority of patients with FMF have attacks without fever. These patients tend to have onset later in childhood (median age 7 years) and to have attacks with predominantly musculoskeletal symptoms (eg, exercise-induced leg pain, myalgia) along with erysipelas-like skin rash. [15]
Paroxysms usually last 48-96 hours, with peak intensity occurring within the first 12 hours. The manifestations plateau and then resolve, usually more slowly than they appeared.
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. [16] 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. [17]
Other manifestations
These include the following:
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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. [18]
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 kidney 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. [21]
Prolonged survival resulting from colchicine therapy, dialysis, and kidney 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 kidney 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.
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.
Joints show typical inflammatory changes, with warmth, erythema, or swelling. Patients with painful myalgia syndrome may have tender muscles.
A well-demarcated, erythematous, warm rash, particularly below the knee, ranging from 15-50 cm2 may develop and may be accompanied by swelling.
Female patients with symptoms mimicking pelvic inflammatory syndrome may experience pain on cervical motion and may develop tender, enlarged ovaries.
Unilateral, erythematous, and tender swelling of the scrotum occurs in scrotal attacks. The typical manifestations of Behçet disease or IgA vasculitis (Henoch-Schönlein purpura) may be observed. Behçet disease and FMF share ethnic distribution, and some individuals may suffer from both disorders. [22]
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.
