Familial Mediterranean fever.

ABSTRACT

Background. The pathogenesis of familial Mediterranean fever (FMF) is unknown, and since no specific laboratory test is yet available, the diagnosis of FMF remains clinical. The purpose of this study was to review clinical characteristics of patients with FMF.

Methods. A total of 96 patients with FMF were evaluated either retrospectively (for those diagnosed before 1997) or prospectively (for those after 1997).

Results. The records of 54 male and 42 female patients were studied. All patients were Turks. Family history was positive in 72 patients (75%). Involved site was peritoneum in 73 (76%),joints in 65 (68%), and pleura in 16 (17%). Febrile myalgia occurred in 3 patients (3%), and erysipelas-like skin lesions were observed in 2 (2%). Fever was found in 93 patients (97%). Reactive systemic (AA) amyloidosis was found in 38 patients (40%).

Conclusions. Diagnostic problems persist despite increased understanding of the of FMF. Amyloidosis, the most important complication of FMF, is often seen.

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FAMILIAL MEDITERRANEAN FEVER (FMF) is an autosomal recessive hereditary disease that primarily affects populations surrounding the Mediterranean basin. It is characterized by recurrent attacks of fever and peritonitis, pleuritis, arthritis, or erysipelas-like skin disease. It is often complicated by reactive systemic (AA) amyloidosis. (1) The pathogenesis of FMF is unknown, and in the absence of any confirmatory test, diagnosis has hitherto rested on characteristic clinical features and exclusion of other pathologic findings. Diagnosis can be especially difficult in patients without the typical ethnic background or in those with unusual clinical manifestations, a poor response to colchicine, or no family history. About 25% of affected patients have a form of renal AA amyloidosis. The amyloidosis usually progresses over a period of years to renal failure, and almost all deaths attributable to FMF result from this complication. (1,2) Otherwise, the disease is compatible with normal survival, but the quality of life is seriously impaired by the frequent and incapacitating episodes of inflammation. (3) The only effective treatments are prophylactic colchicine, which reduces the frequency of attacks and can prevent amyloidosis, and transplantation for renal failure. The purpose of this analysis was to review clinical characteristics of patients with FMF seen in our facility.

PATIENTS AND METHODS

This study was done in our hospital, situated in the east of Turkey. It included 96 patients who had evaluation and follow-up for FMF at the hospital over the past 8 years. The diagnosis of FMF was based on typical clinical and laboratory features. The same parameters were used for both retrospectively and prospectively evaluated patients. All patients fulfilled the criteria of Livneh et al (4) for diagnosis of FMF requiring one major or two minor criteria. Major criteria included peritonitis, unilateral pleurisy or pericarditis, monoarthritis (knee, hip, ankle), or fever alone. Minor criteria included incomplete attacks involving the chest or joints, exertional leg pain, and favorable response to colchicine.

Biopsies of kidney or rectum were done in proteinuric patients. The histologic diagnosis of AA amyloidosis was made by the demonstration of amyloid deposits by Congo red staining on light microscopy. Potassium permanganate test for bleaching was done on all amyloid-positive materials. Samples sensitive to potassium permanganate were evaluated as AA amyloid.

RESULTS

The records of 54 male patients (56%) and 42 female patients (44%) were studied. All patients were Turks. Family history was positive in 72 patients (75%). Involved site was peritoneum in 73 (76%),joints in 65 (68%), and pleura in 16 (17%). Three patients had febrile myalgia, and 2 had erysipelas-like skin lesions. Fever was found in 93 patients (97%) and AA amyloidosis in 38 (40%) of the patients. Hepatomegaly, splenomegaly, and edema were found in 21(22%), 52 (54%), and 18 (19%) of the patients, respectively. Testicular involvement was observed in only 1 patient.

Arthritis was the presenting symptom in 28 patients (29%), and 59 patients (61%) had definite arthritis during the course of the disease. It was monoarticular in 26, oligoarticular in 15, and polyarticular (similar to rheumatic fever) in 18 patients. The arthritis was acute and self-limiting and accompanied an acute FMF attack in the majority of cases. Three patients had chronic protracted arthritis, and 1 patient had diffuse erosions and destruction of the hip necessitating total hip replacement. Demographic and clinical characteristics of the 96 patients are shown in the Table.

DISCUSSION

Familial Mediterranean fever is an autosomal recessive inherited disorder characterized by periodic episodes of fever, peritonitis, pleurisy, rashes, or arthritis, and associated with an intense acute phase response. It has been identified chiefly in Sephardic Jews, Armenians, Turks, and Middle Eastern Arab populations. It is frequentiy complicated by AA amyloidosis. (1)

Fever is a feature of every acute attack. The temperature may rise to 38[degrees] to 40[degrees]C, though. mild attacks may be accompanied by lowgrade fever. In 20% to 30% of patients, the fever is preceded by chills. The fever usually lasts between 12 hours and 3 days. (1,4,5) Of our 96 patients, 92 (96%) had recurrent fever during every acute attack. The remaining patients did not report fever.

Abdominal pain is present in 75% to 95% of patients, the clinical picture being typical of acute peritonitis. Abdominal pain usually precedes the fever by a few hours and persists for 1 or 2 days after the temperature returns to normal. (1) The typical chest pain is another frequent manifestation of FMF. In our patient group, signs and symptoms of peritonitis were observed in 82 patients (85%) and pleurisy in 14 (14%). Eleven patients had appendectomy before the diagnosis of FMF.

Myalgia is a classical manifestation of FMF and occurs in about 10% to 25% of patients. (6,7) Usually the pain is not severe, appears in the lower extremities after physical exertion, occurs mostly in the evenings, lasts from a few hours to 2 or 3 days, and subsides with rest, though sometimes treatment with nonsteroidal anti-inflammatory drugs is needed. Only rarely are the short attacks of muscle pain severe and accompanied by high fever. (8,9) Three of our 96 patients had a history of typical myalgia attacks of FMF. Two of them had myalgia accompanied by high fever. All 3 patients had a history of typical febrile attacks of FMF, and 1 was treated successfully with colchicine before the appearance of prolonged febrile myalgia. Two patients with severe and prolonged febrile myalgia improved promptly and dramatically after treatment with prednisone was started, though they continued to take the same dosage of colchicine as before.

Arthritis is the common and important feature of FMF in some patients, and sometimes it remains as the only major manifestation of the disorder. Although the most common type of arthritis is recurrent, self-limited, and short-lived acute inflammation of the joints, chronic forms with protracted joint effusion have occasionally been seen. Joint involvement in Jews originating from northern Africa is more common than it is in other ethnic groups. (1,2,4,10) Currently, no criteria have been established for the definition or differential diagnosis of arthritis associated with FMF. Therefore, diagnostic delay or misdiagnosis is not uncommon in the Mediterranean countries. Migratory polyarthritis, resembling acute rheumatic fever, is often misdiagnosed as rheumatic fever. Fifteen of our patients had migratory polyarthritis, which led to a misdiagnosis of rheumatic fever at other hospitals. These patients were referred to our hospital after the development of AA amyloidosis. The hip is the most vulnerable joint and is likely to be affected by the protracted attacks, which may result in destruction of the articular cartilage and in some cases, aseptic necrosis of the femoral head. (1,10) Three patients with hip involvement had protracted attacks in this joint, one requiring total hip replacement. In a review of the records of 1,140 Israeli patients with FMF, Sneh et al (11) found that only 57 (5%) had protracted attacks involving a total of 84 joints, 36 of them knees and 25 hips.

Erysipelas-like skin lesions are seen in 7% to 40% of cases of FMF. It appears almost invariably on the extensor surfaces of the leg, over the ankle joint, or on the dorsum of the foot, and it is most commonly unilateral. (1) In two of our patients (2%), we observed erysipelas-like skin lesions accompanied by a sudden rise in temperature. The lesions rapidly disappeared within 12 to 48 hours.

Familial Mediterranean fever can also cause enlargement of the spleen without amyloid deposition. Splenomegaly has been described in 30% to 50% of patients with FMF. In most of them, rectal biopsy was negative for amyloidosis, suggesting that the spleen enlargement was not the result of amyloid deposition. (1,5) Among our patients, 52 (54%) had splenomegaly, 36 with amyloidosis and 16 without evidence of amyloidosis.

Amyloidosis is the most significant complication of FMF, usually affecting the kidneys and resulting in renal insufficiency that progresses to end-stage renal disease. Amyloidosis may also affect the gastrointestinal tract, liver, spleen, and at a later stage the heart and testes. The amyloid is of the AA type. The frequency of amyloidosis differs among various ethnic groups and depends on whether patients are taking colchicine. (1,5,12) In our series, 38 patients (40%) had AA amyloidosis and renal involvement. In 4 of them, end-stage renal disease was diagnosed when they first applied to our clinic. The diagnosis was made by rectal biopsy in 63% of the patients and by renal biopsy in the remaining 37%. For most of the patients with amyloidosis, onset of disease occurred before the age of 12. Disease duration in most cases was more than 10 years, and family history was positive in all but 4 cases. Three patients had taken colchicine irregularly, and 35 patients had taken no colchicine. No amyloidosis was foun d in the 58 patients who took colchicine regularly. According to reports, amyloidosis occurs in 20% to 60% of Turkish patients, in 27% of the non-Ashkenazi Jews, and in only 1% to 2% of Armenians living in the United States. (1,13) The frequency of AA amyloidosis in our patients was high. There is no close link between the severity of the inflammatory crisis and the outcome of amyloidosis. However, it was clearly shown that colchicine prevents the development of amyloidosis in every patient, whereas the inflammatory crises were not completely suppressed. (1,14)

Some patients present with renal amyloidosis but no history of typical FMF attacks; however, questioning often reveals that other family members have characteristic manifestations of FMF. This presentation of amyloidosis without the attacks of serositis has been called "phenotype II." (2,15) Three patients had the phenotype II form of FMF, and all of them had a positive family history. Typical symptoms of FMF became apparent 1 year after onset of amyloidosis in 1 patient. The reported incidence of phenotype II ranges from 7% to 25% of patients with FMF and amyloidosis. The largest case series to have the phenotype II form was reported by Saatci et al (15) from a pediatric unit. Their analysis was of 425 FMF patients without amyloidosis and 180 with amyloidosis. Of the 180 patients, 123 had amyloidosis phenotype I, and 57 had amyloidosis phenotype II. Majed et al (7) observed no case of phenotype II in their series of 476 patients.

Several newly described manifestations of FMF are vasculitis, various types of glomerulonephritis, and Mollaret's meningitis. (1,16-18) In our series, none of these manifestations were observed.

Of our 96 patients, all but 1 achieved complete remission with colchicine. That patient's response was incomplete. Colchicine did reduce the severity and frequency of the attacks.

The gene for FMF has been localized on the short arm of chromosome 16. Designated MEFV, this gene has been identified by two independent teams using positional cloning techniques. It is approximately 10 kilobases, with 10 exons expressing a transcript coding a 781-amino-acid protein known as pyrin, or marenostrin. (19,20) The gene is expressed in neutrophils but not in lymphocytes or monocytes. Missense mutations in the gene are considered capable of causing structural changes in the protein that subsequently interrupt the normal pyrin-mediated feedback loop, resulting in an uninhibited escalation of the inflammatory response. The identification of the MEFV gene and its various mutations has led to the application of an accessible, noninvasive, and sensitive molecular genetic test for an accurate diagnosis of FMF. However, some authors believe there was no need for a genetic analysis to make the diagnosis. (21) The genetic test can be useful in atypical cases of FMF and for genetic counseling, but the diagnos is is usually based on clinical grounds only.

TABLE

Demographic and Clinical Characteristics of 96 Patients With Familial
Mediterranean Fever

                                      No. (Range)         Percent

Age (years)
 Male                          23.5 [+ or -] 4.8 (16-33)   56.2
 Female                        23.7 [+ or -] 5.2 (15-34)   43.7
Age at first attack            10.0 [+ or -] 5.3 (4-22)
Family history of FMF          75                          78.0
Disease duration at diagnosis  13.4 [+ or -] 4.1 (5-20)
 (years)

Clinical findings
  Arthritis                               59               61.4
  Peritonitis                             82               85.4
  Fever                                   92               95.8
  Erysipelas-like skin lesion              2                2.0
  Protracted febrile myalgia               2                2.0
  Amyloidosis                             38               40.0

References

(1.) Ben-Chetrit E, Levy M: Familial Mediterranean fever. Lancet 1998; 351:659-664

(2.) Sohar E, Gafni J, Pras M, et al: Familial Mediterranean fever. a survey of 470 cases and review of the literature. Am J Med 1967; 43:227-253

(3.) Matzner Y, Ayesh SK, Hochner-Celniker D, et al: Proposed mechanism of the inflammatory attacks in familial Mediterranean fever. Arch Intern Med 1990; 150:1289-1291

(4.) Livneh A, Langevitz P. Zemer D, et al: criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum 1997; 40:1879-1885

(5.) Ozel AM, Demirturk L, Yazgan Y, et al: Familial Mediterranean fever. a review of the disease and clinical and laboratory findings in 105 patients. Dig Liver Dis 2000; 32:504-509

(6.) Majeed HA, Al-Qudah AK, Qubain H, et al: The clinical patterns of myalgia in children with familial Mediterranean fever. Semin Arthritis Rheum 2000; 30:138-143

(7.) Majeed HA, Rawashdeh M, el-Shanti H, et al: Familial Mediterranean fever in children: the expanded clinical profile. QJ Med 1999; 92:309-318

(8.) Sidi G, Shinar Y, Livneh A, et al: Protracted febrile myalgia of familial Mediterranean fever. mutation analysis and clinical correlations. Scand J Rheumatol 2000; 29:174-176

(9.) Odabas AR, Cetinkaya R, Selcuk Y, et al: Severe and prolonged febrile myalgia in familial Mediterranean fever. Scand J Rheumatol 2000; 29:394-395

(10.) Uthman I, Hajj-Ali RA, Arayssi T, et al: Arthritis in familial Mediterranean fever. Rheumatol Int 2001; 20:145-148

(11.) Sneh E, Pras M, Michaeli D, et al: Protracted arthritis in familial Mediterranean fever. Rheumatol Rehahil 1977; 16:102-106

(12.) Majeed HA, Ghandour K, Shahin HM: The acute scrotum in Arab children with familial Mediterranean fever. Pediatr Surg Int 2000; 16:72-74

(13.) Pras M, Bronshpigel N, Zemer D, et al: Variable incidence of amyloidosis in familial Mediterranean fever among different ethnic groups. Johns Hopkins Med J 1982; 150:22-26

(14.) Grateau G: Familial Mediterranean fever: from inflammation to amyloidosis. Nephrol Dial Transplant 1998; 13:1919-1920

(15.) Saatci U, Ozen S, Ozdemir S, et al: Familial Mediterranean fever in children: report of a large series and discussion of the risk and prognostic factors of amyloidosis. Eur J Pediatr 1997; 156:619-623

(16.) Flatau E, Kohn D, Schiller D, et al: Schonlein-Henoch syndrome in patients with FMF. Arthritis Rheum 1982; 25:42-47

(17.) Tekin M, Yalcinkaya F, Tumer N, et al: Familial Mediterranean fever. renal involvement by diseases other than amyloid. Nephrol Dial Transplant 1999; 14:475-479

(18.) Arisoy N, Kasapcapur O, Sever L, et al: Vasculitis in familial Mediterranean fever. Ozdogan J Rheumatol 1997; 24:323-327

(19.) The International FMF consortium: Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 1997; 90:797-807

(20.) The French FMF Consortium: A candidate gene for familial Mediterranean fever. Nat Genet 1997; 17:25-31

(21.) Nir-Paz R, Ben-Chetrit E: Molecular diagnosis of familial Mediterranean fever. N Engl J Med 2000; 342:360

KEY POINTS

* Familial Mediterranean fever (FMF) is an inherited inflammatory disease and is frequently complicated by reactive amyloidosis.

* Since no specific laboratory test is yet available, the diagnosis of FMF remains clinical.

* The genetic test can be useful in atypical cases of FMF.

From the Department of Nephrology, Ataturk University School of Medicine, Erzurum, Turkey.

Reprint requests to Ali Riza Odabas, Ataturk Universitesi Postanesi, PK: 26; 25171 Erzurum, Turkey.