Familial Mediterranean Fever 

FMF

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.[1] 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.

Epidemiology• 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.[2] 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.[3, 4]

• 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.[5]

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.

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

AgeOf 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.

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.[2]

• 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.

Differential Diagnoses

• Acute Rheumatic Fever• Appendicitis• Calcium Pyrophosphate Deposition Disea

se• Gout• Lyme Disease• Nephrolithiasis• Pericarditis, Acute• Pleurodynia• Systemic Lupus Erythematosus

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, amyloid A protein, fibrinogen) are elevated, as is the erythrocyte sedimentation rate. The WBC 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.

• 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.

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

• 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.

Medical Care• 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 (0.6 mg bid or 0.5 mg bid, depending on the dosage form available) 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.

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 reduced the number of attacks in 10 of 13 patients and the severity of attacks in 6 of 13 patients.[6]

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-alpha, the tumor necrosis factor–blocking drug etanercept,[7] and the IL-1 receptor antagonist anakinra[8] may be effective. Rilonacept, a once-weekly subcutaneous injection IL-1 decoy receptor, has been shown, in combination with continuation of colchicine, to reduce the number of attacks in patients who did not respond optimally.[9] Interferon-alpha has been used in an intermittent fashion and as prophylaxis, with varying results.[10, 11,

12]

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.

Medication Summary

• The goals of therapy are to reduce morbidity and to prevent complications.

• Class Summary

• Colchicine is the drug of choice for familial Mediterranean fever (FMF).

Complications

• Patients with amyloidosis may develop an acute onset of renal failure if they are stressed by dehydration, infection, or both.

• Renal vein thrombosis may occur in nephrotic patients. This condition may manifest as abdominal or flank pain, increasing proteinuria, and worsening renal function. Acute anticoagulation may stabilize or improve renal function.

Prognosis

• Patients who are compliant with daily colchicine can probably expect to have a normal lifespan if colchicine is started before proteinuria develops.

• Even with amyloidosis, the use of colchicine, dialysis, and renal transplantation should extend a patient's life beyond age 50 years.

Patient Education

• Patients with FMF need to understand the importance of strict compliance with daily colchicine therapy.

THANK YOU

DR .KHALED AL AOUN