Background
Familial Mediterranean fever (FMF) is also called recurrent polyserositis. The salient 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 than in persons of any other ethnicity.
Pathophysiology
Nonsense or missense mutations in the MEFV (Mediterranean fever) gene appear to cause the disease. This gene 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, but its exact function is not known. The protein may function as an inhibitor of chemotactic factor (C5a) or perhaps of interleukin 8. Patients 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, and this results in uninhibited activity of the chemotactic factor and episodes of inflammation (with associated 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
Frequency in any location is a function of the ethnic background of the patient. To survive ethnic and religious persecution, Mediterranean families may have converted to other religions or intermarried members of other ethnic groups and, thus, carried the gene with them.
• Ashkenazi Jewish people (descended from Eastern European Jewish people and also including most European and American Jewish people) have a prevalence of 1 case per 73,000 population, with a gene frequency of 1:135.
• Sephardic Jewish people (descended from Jewish people who were expelled from Spain, largely to North Africa, and also including other Middle Eastern Jewish populations) have a prevalence of 1 case per 250-1000 population, with a gene frequency of 1:8-16.
• Armenian persons (based on epidemiology among Armenian populations in Lebanon and Southern California) have an estimated prevalence of 1 case per 500 population and a gene frequency of 1:7.
• 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 1:50.
Mortality/Morbidity
• Nephrotic syndrome: Before the institution of colchicine therapy, mortality from 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 undiagnosed FMF patients had appendectomies because the severity of the peritoneal episodes seemed to indicate appendicitis.
• Chronic arthritis: Approximately 5% of patients may 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 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. FMF is rare in persons older than 40 years.


History
The preeminent feature of 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

o Temperatures rise rapidly to 38-40°C (100.4-104°F). Temperature increases may occur before other manifestations.
o In mild attacks, fever may be the only manifestation.
• Peritoneal symptoms

o Almost all patients with FMF experience abdominal episodes. Patients develop abdominal pain that may progress to peritonitis, resembling a surgical abdomen.
o Patients frequently have symptoms consistent with appendicitis or cholecystitis, and they frequently have appendectomies and cholecystectomies because the abdominal episodes of FMF are not recognized as such.
o The symptoms may also mimic renal colic.
o Often, patients develop constipation during the attack and diarrhea after the attack resolves.
o Even with recurrent attacks, adhesions are rare.
• Pleural and pericardial symptoms

o The frequency of pleural and pericardial attacks varies among ethnic groups, with 25-80% of patients reporting pleuritic episodes.
o Effusions may occasionally occur. Pericarditis may develop, but tamponade and constrictive pericarditis are rare.
• Synovial symptoms

o 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.
o The joints are normal between attacks, and permanent damage does not usually occur.
o Arthritic symptoms tend to last several days longer than abdominal symptoms. Episodes can be protracted.

o 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

o As many as 50% of patients report erysipelaslike rashes on the lower extremities, particularly below the knees.
o Rash and fever may be the only manifestations of attacks.
• Muscle symptoms

o Recent descriptions more often include reports of severe myalgia lasting 3-6 weeks. These episodes do not respond to colchicine therapy.
o Symptoms are consistent with fibromyalgia.
• Pelvic symptoms: Female patients may have episodes of pelvic inflammatory disease.
• Scrotal attacks: In males, inflammation of the tunica vaginalis testis may mimic episodes of torsion of the testis.
• 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

o In a patient of the appropriate ethnic group, the typical progression is proteinuria, followed by nephrotic syndrome, and, inevitably, death from renal failure.
o One third of patients with amyloidosis may 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.
o 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.
o Some patients with a family history of FMF may 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 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 be accompanied by swelling.
• Patients with painful myalgia syndrome may have tender muscles.
• 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 likely caused by missense and nonsense mutations in the MEFV gene that 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 less likely to develop amyloidosis.

DIFFERENTIALS
Acute Rheumatic Fever
Appendicitis
Calcium Pyrophosphate Deposition Disease
Gout
Lyme Disease
Nephrolithiasis
Pericarditis, Acute
Pleurodynia
Systemic Lupus Erythematosus
Other Problems to be Considered
Familial Hibernian fever
Hyperimmunoglobulin D and periodic fever syndrome


Lab Studies
• Results of routine blood tests performed during the acute attacks are nonspecific. 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. The elevated levels rapidly return to the reference range as the attack abates.
• 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/µL.
• From the successful cloning of the MEFV gene, researchers have developed a rapid test for the most common mutations. Compared with gene sequencing, the test has a sensitivity and specificity of 100%. However, not every patient with FMF based on clinical criteria has a mutation as determined by testing for specific mutations. One explanation for this is that, although at least 30 identified mutations exist, 5 of them account for 99% of FMF cases, so testing for all 30 mutations, particularly in defined populations, is not cost-effective.
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.
Procedures
• 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.
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.

TREATMENT
Medical Care
Colchicine is so effective in preventing attacks of 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 (0.6 mg bid) 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.
• Ashkenazi Jewish people and Armenian people living in America 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 therapy.
• The regimen for acute attacks in patients not taking daily colchicine is 0.6 mg every hour for 4 doses, then 0.6 mg every 2 hours for 2 doses and then 0.6 mg every 12 hours for 4 doses. Colchicine should be started as soon as the patient recognizes that an attack is occurring. If the initial doses are effective, patients may be able to do without the later doses, but this varies from patient to patient.
• In patients who do not respond to twice-a-day dosing, administer colchicine 3, or even 4, 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 was effective in reducing the number of attacks in 10 of 13 patients and the severity of attacks in 6 of 13 patients.
• 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. However, 2 recent studies from Turkey reached opposite conclusions about the effectiveness of interferon alfa therapy.
• 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.
• Hemodialysis can be used for patients who develop renal failure. Peritoneal dialysis tends to increase the number of abdominal attacks.
• 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 with exertional lower extremity muscle pain respond to rest.
• Treat patients with fibromyalgia with the usual agents for this condition.
• Patients who develop seronegative spondyloarthropathy are treated with nonsteroidal anti-inflammatory drugs. Some of these patients require remission-type drugs (as used in rheumatoid arthritis) and receive follow-up care by a rheumatologist.
Surgical Care
Before the advent of colchicine therapy, renal transplantation was performed in patients with end-stage renal disease due to amyloid nephropathy. Now, renal failure develops only in patients who are not compliant with therapy or those who cannot tolerate adequate doses of colchicine.
Consultations
• With the advent of colchicine therapy, most patients are asymptomatic and do not need consultation with a specialist.
• Consider consultation with a nephrologist for patients with proteinuria that is not responsive to colchicine.
• Consultation with a rheumatologist is indicated in patients with the following conditions:

o Seronegative spondyloarthropathy not responsive to nonsteroidal anti-inflammatory drugs
o Fibromyalgia not responsive to the usual treatments
o Coexistent Henoch-Schönlein purpura, polyarteritis nodosa, or Behçet disease

MEDICATION
The goals of therapy are to reduce morbidity and to prevent complications.
Drug Category: Anti-inflammatory agents
Colchicine is the DOC for FMF.

Drug Name Colchicine
Description Decreases leukocyte motility and phagocytosis in inflammatory responses.
Adult Dose 1.2-2 mg PO in divided doses
Pediatric Dose Administer as in adults
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 C - Safety for use during pregnancy has not been established.
Precautions 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