eMedicine Specialties > Rheumatology > Miscellaneous Inflammatory Arthritis

Mediterranean Fever, Familial

Author: John O Meyerhoff, MD, Assistant Professor, Department of Internal Medicine, Johns Hopkins University School of Medicine; Clinical Scholar in Rheumatology, Department of Medicine, Sinai Hospital of Baltimore
Contributor Information and Disclosures

Updated: Nov 13, 2009

Introduction

Background

Familial Mediterranean fever (FMF) is also called recurrent polyserositis. The salient features of FMF include brief recurrent episodes of peritonitis, pleuritis, and arthritis, usually with accompanying fever. FMF occurs within families and is much more common in individuals of Mediterranean descent than in persons of any other ethnicity.

Pathophysiology

Nonsense or missense mutations in the MEFV (Mediterranean fever) gene appear to cause the disease in many cases. MEFV produces a protein called pyrin (derived from the association with predominant fever) or marenostrin (derived from the phrase "our sea," because of the Mediterranean heritage of most patients).

The protein is expressed mostly in neutrophils. Its exact function is unknown, but it may function as an inhibitor of chemotactic factor (C5a) or perhaps of interleukin (IL)–8. Individuals with normal pyrin/marenostrin levels may have the ability to deactivate the target chemotactic factor when it is produced in response to an inflammatory stimulus. However, patients with FMF lack this ability, resulting in uninhibited activity of the chemotactic factor and episodes of inflammation (with accompanying fever) in the peritoneum, pleura, and joints. Presumably, these inflammatory episodes lead to the excess production of amyloid A protein from the acute phase and reactant serum amyloid A with subsequent deposition in the kidneys; however, only patients with specific MEFV haplotypes develop amyloidosis.

Frequency

International

The frequency of FMF in any location depends on the ethnic background of the population. To survive ethnic and religious persecution, many Mediterranean families converted to other religions or intermarried members of other ethnic groups, thus carrying the MEFV gene with them.

• In Ashkenazi Jewish people (descended from Eastern European Jewish people and including most European and American Jewish people), the prevalence of FMF is 1 case per 73,000 population, with a MEFV gene frequency now estimated at perhaps 1 per 5, in contrast to previous estimates of 1 per 135.¹ This suggests that not all mutations have equal penetrance.
• In Sephardic Jewish people (descended from Jewish people who were expelled from Spain, largely to North Africa, and including other Middle Eastern Jewish populations), the prevalence of FMF is 1 case per 250-1000 population, with a gene frequency of 1 per 8-16.
• In Armenian persons (based on epidemiology among Armenian populations in Lebanon and southern California), the estimated prevalence of FMF is 1 case per 500 population, with a gene frequency of 1 per 7.
• 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 per 50.
• Since the development of gene testing, which allows confirmation of FMF in some cases, the disease has been reported in unexpected locations, including by two Japanese groups.^2,3
• Migrations of guest workers around the world have highlighted the need for physicians to think about formerly uncommon illnesses in their home countries and the need for review articles in national journals.⁴

Mortality/Morbidity

• Nephrotic syndrome: Before the institution of colchicine therapy, mortality due to nephrotic syndrome was almost universal by age 50 years in North African Sephardic Jewish patients. Among other Sephardic Jewish, Ashkenazi Jewish, and Armenian patients, amyloidosis was extremely rare. The mortality rate among Turkish patients was high, but this high rate may have represented selection bias. No pre–colchicine-therapy data are available from Arabic patients.
• Appendectomies: Many patients with undiagnosed FMF have undergone appendectomy because the severity of the peritoneal episodes seemed to indicate appendicitis.
• Chronic arthritis: Approximately 5% of patients with FMF develop chronic arthritis that sometimes leads to destructive arthritis of hips or knees and may necessitate joint replacements. Approximately 10% of patients with chronic arthritis develop seronegative spondyloarthropathy.
• Fertility and pregnancy: Approximately one third of female patients with FMF are infertile, and 20-30% of pregnancies result in fetal loss.

Sex

• In adults, FMF is more prevalent in men than in women, with a male-to-female ratio of 1.5-2:1.

Age

• Of all persons with FMF, 50-60% are younger than 10 years, 80-95% are younger than 20 years, and 5-10% are older than 20 years at onset. Onset in persons older than 40 years is rare.

Clinical

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.

• Fever
  • Temperatures rise 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. Patients develop abdominal pain that may progress to peritonitis, resembling a surgical abdomen.
  • Patients with FMF frequently have symptoms consistent with appendicitis or cholecystitis and 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.
  • The joints are normal between attacks, and permanent damage is unusual.
  • Arthritic symptoms tend to last several days longer than abdominal symptoms. Episodes can be protracted.
  • Arthritis may be the only manifestation. FMF should be considered in patients with a family history of FMF or who live in an endemic area.
• 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.
• Muscle symptoms
  • Recent descriptions more often include reports of severe myalgia lasting 3-6 weeks. These episodes do not respond to colchicine therapy.
  • Symptoms are consistent with fibromyalgia.
• Pelvic symptoms: Female patients with FMF may have episodes of pelvic inflammatory disease.
• Scrotal attacks: In males, inflammation of the tunica vaginalis testis may mimic episodes of testicular torsion.
• 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.
• Amyloidosis
  • In a patient of the appropriate ethnic group, the typical progression 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.
  • 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

Physical findings of FMF depend mostly on the serosal surface involved.

• Temperatures can reach as high as 40°C (104°F), but, in most cases, rapid defervescence occurs within 12 hours.
• 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.
• A well-demarcated, erythematous, warm rash, particularly below the knee, ranging from 15-50 cm² may develop and may be accompanied by swelling.
• Patients with painful myalgia syndrome may have tender muscles.
• Female patients with symptoms mimicking pelvic inflammatory syndrome may experience pain upon 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 and Henoch-Schönlein purpura may be observed.
• 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.

• Multiple mutations are located on the MEFV gene. Most of the 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.¹
• Other genes may be involved in FMF. This 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.

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