Rheumatology

Familial Mediterranean Fever (FMF)

Does this patient have Familial Mediterranean Fever?

History and symptoms

Familial Mediterranean Fever (FMF) is an autosomal recessive condition due to mutations in MEFV, the gene that encodes pyrin, and is the most common member of the family of monogenic autoinflammatory disorders. FMF is characterized by relapsing and remitting 1-3 day episodes of fever, sterile serositis, arthritis and an erysipeloid erythematous rash associated with elevations in serum inflammatory markers. Fever is universal with abdominal pain occurring in over 90% of patients.

Serositis is classically a sterile peritonitis. However, pleuritis and pericarditis may also occur. This peritonitis is frequently of adequate severity to result in an exploratory laparotomy with the concern for an acute abdomen. Pleuritis and pericarditis can present with chest pain on inspiration and may be associated with fluid collections on radiographic studies or on echocardiogram, respectively.

Arthritis in FMF is typically monoarticular or oligoarticular with the most commonly affected joints being knees, ankles, hips and elbows. Arthritis may persist longer than 1-3 days after the resolution of other clinical findings. Attacks occur with a regular periodicity, however, the frequency between attacks is variable from patient to patient, with ranges from once weekly to once every few years.

Other findings may include scrotal pain and even necrosis due to inflammation of the tunica vaginalis, an embryologic remnant of the peritoneal membrane. Aseptic meningitis may rarely occur. Most patients present early in life, with 90% of patients experiencing their first symptom before the age of 20.

Pediatric patients

The clinical presentation in children differs from that of adults. In infants and young children, fever may be the only presenting symptom. However, the constellation of symptoms tends to progress to that seen more typically in adults within 3 years.

Epidemiology

FMF occurs most frequently in patients from Mediterranean ethnic backgrounds. However, it has been observed in patients from less typical backgrounds and the lack of a Mediterranean background should not preclude the diagnosis in the appropriate clinical setting. The carrier rate for disease causing mutations can be as high as 1:3 in Armenian populations and is expected to be much lower in areas without a Mediterranean ethnic background. The exact prevalence of disease is unknown as it is highly variable based on ethnic background and the penetrance of disease causing mutations.

Physical exam

Fever is a hallmark of disease and may be present on vital signs. The abdominal exam may reveal signs of an acute abdomen including rebound tenderness, guarding, rigidity and decreased or absent bowel signs. A pericardial rub may exist, as may decreased breath sounds at the bases in the setting of pericarditis or pleuritis, respectively.

Patients may have findings of an acute arthritis including joint effusions, warmth, tenderness and decreased range of motion of affected joints. This occurs most commonly in the knees, ankles, hips and elbows. The classic rash is an erysipeloid erythematous rash of the lower extremities, usually below the knee. The dorsum of the foot and ankle are particularly common sites. This rash appears as a warm, tender, swollen, erythematous plaque with well-defined borders. Lesions are typically 10-15 cm in size and may be bilateral.

Other skin findings include localized edema and subcutaneous nodules. In children, purpuric papular lesions are frequently observed. Notably, physical exam findings should resolve within 3 days with the exception of arthritis, which may persist after the resolution of other symptoms.

Differential diagnosis

FMF may be confused with other fever syndromes exhibiting periodicity including hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) and TNF receptor-associated periodic syndrome (TRAPS). Helpful in distinguishing these disorders is the duration of symptoms which tends to be shorter in FMF (1-3 days) compared to 3-7 days in HIDS and 1-4 weeks in TRAPS. Organ manifestations also differ with FMF, affecting the skin, joints, peritoneum and pleura, while HIDS also presents with painful lymphadenopathy, and TRAPS also presents with myalgia, conjunctivitis and periorbital edema.

The severe abdominal pain in FMF may be confused with an acute abdomen due to appendicitis or other acute surgical pathologies. It is not infrequent that a patient undergoes an emergency appendectomy only to find that the appendix does not appear inflamed. This can be a clue to the correct diagnosis.

Hereditary angioedema may present as acute abdominal pain but does not typically cause a fever. Swelling may be more pronounced in hereditary angioedema. In children, systemic onset juvenile idiopathic arthritis (SoJIA) is also a consideration. However, these patients have a quotidian fever pattern and may also present with an evanescent skin rash, lymphadenopathy and polyarthritis, and patients do not typically develop abdominal pain.

Diagnostic criteria

The most widely used clinical criteria for the diagnosis of FMF are the Tel Hashomer criteria. These criteria are based on clinical findings and were developed before the widespread availability of a genetic testing to confirm the diagnosis.

A definite diagnosis is established based on the presence of two major, or one major and two minor criteria. A probable diagnosis is based on one major and one minor criterion.

Major criteria are:

  1. Recurrent febrile episodes accompanied by peritonitis, synovitis or pleuritis.

  2. Amyloidosis of the AA-type without predisposing disease.

  3. Favorable response to continuous colchicine treatment.

Minor criteria are:

  1. Recurrent febrile episodes.

  2. Erysipelas like erythema.

  3. FMF in a first degree relative.

In the pediatric population, these criteria are sensitive but not specific for the establishment diagnosis based on genetic testing. Using logistic regression to identify five criteria most predictive of disease in children, the presence of two of the following criteria discriminated FMF from controls with a 86.5% sensitivity and 93.6% specificity:

  1. Fever.

  2. Abdominal pain.

  3. Chest pain.

  4. Arthritis.

  5. Family history of FMF.

What tests to perform?

Laboratories

During an acute clinical attack, inflammatory markers including the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and serum amyloid A (SAA), should be elevated. These abnormalities may also persist in between attacks. Elevations of serum immunoglobulins, including IgD, may be present both during attacks and in between attacks. As with all autoinflammatory disorders, ANA, RF and ANCAs are typically absent. Synovial fluid obtained during an attack is frequently highly inflammatory with leukocyte values in the range of those seen in septic arthritis.

Genetic testing

Genetic testing for mutations in MEFV is now widely commercially available and may be covered by insurance companies. While FMF is an autosomal recessive disorder, patients with a single heterozygous mutation can develop typical disease and appear to have the same clinical presentation as those patients with two mutations. Thus, a single mutation is considered sufficient for a genetic diagnosis.

Genotype-phenotype correlations are well established with the most severe manifestations occurring in patients homozygous for M694V mutations. These patients present with an earlier onset, more frequent arthritis and skin findings and require higher doses of colchicine to control disease. Moreover, they are more likely to develop amyloidosis, one of the most severe consequences of disease. Other mutations, including R369S, R408Q and E148Q, are associated with atypical disease and even an asymptomatic state. The significance of these mutations remains an issue of controversy and further investigation.

Imaging

Radiographs of the joints may show fluid collections and soft tissue swelling. Joint destruction is rare, however case reports exist. On MRI, acute synovitis and synovial effusions may be present. Abdominal and chest CT scans can reveal peritoneal and pleural enhancement in the setting of an acute attack. Abdominal CT scan or ultrasound may also be helpful in the setting of potential amyloidosis, as kidneys may be enlarged early in the course of disease and may later be abnormally small after long-term damage and atrophy has occurred.

Biopsy

A biopsy for diagnostic purposes is rarely obtained as the diagnosis is based on clinical criteria and genetic confirmation. However, biopsies of the skin may show perivascular and interstitial inflammatory infiltrates with a predominance of neutrophils and lymphocytes in the dermis. Edema of the papillary dermis and superficial dermal capillary dilatation may be observed.

In the setting of a clinical concern for secondary (SAA) amyloidosis, a renal, skin, fat pad or rectal biopsy is essential to confirm the diagnosis. Biopsies should be stained with a Congo red dye with positivity establishing the presence of amyloid in the tissue specimen. Given the potential severe consequences of this finding, patients with amyloidosis should be referred to a tertiary care center with experience in the treatment of this condition.

How should patients with Familial Mediterranean Fever be managed?

Treatment

Colchicine is the mainstay of treatment in patients with FMF. It is highly efficacious with near complete remission occurring in 75% of patients with a marked improvement in 95% of patients. It is so effective that it is one of the major Tel Hashomer criteria for the diagnosis of FMF. Moreover, it has been shown to prevent the development of amyloidosis in the majority of patients.

Goal doses are between 1.2 and 1.8 mg orally daily in divided doses for adults and children ages five and older. The most frequent limiting side effect is gastrointestinal intolerance with the common occurrence of nausea and diarrhea. This may improve with time and with the initiation of a low initial dose with slow uptitration. Bloating and abdominal pain may be due to lactose intolerance which may be alleviated with lactase replacement products in the appropriate setting.

More severe but rare side effects include myopathy and neuropathy. These are seen more commonly in the elderly and in patients with renal impairment. In the small subset of patients that do not respond adequately to colchicine or who cannot tolerate the medication, IL-1 and TNF inhibitors are often effective. IL-1 inhibition may also be considered in the setting of persistently elevated inflammatory markers in an attempt to control systemic inflammation, which likely reduces the risk of developing amyloidosis.

Case reports and small series exist to support the effective treatment of FMF with anakinra and/or canakinumab. TNF inhibitors may also play a role in resistant patients, with case reports indicating successful treatment in this setting. Moreover, regression of proteinuria due to amyloidosis with TNF inhibition has been observed. These medications may be added as an adjuvant therapy or replacement therapy in the case of colchicine intolerance.

What happens to patients with Familial Mediterranean Fever?

Natural history

Prior to the use of colchicine, patients experienced relapsing and remitting symptoms with the eventual development of amyloidosis in up to 60% of Turkish patients with FMF. With the proper daily use of colchicine, most patients achieve a near remission of symptoms and amyloidosis occurs at much lower rates. Acute attacks typically resolve without permanent organ damage.

Amyloidosis

The most severe and feared complication of FMF is the development of amyloidosis. This may occur in the setting of inadequately controlled disease and/or persistently elevated serum inflammatory markers. SAA is produced by the liver in acute inflammatory states and AA amyloid deposits in tissues to result in pathology. Initial amyloid deposits may occur without consequence, however, once a critical burden is reached, the rate of further amyloid deposition rapidly increases with resultant organ damage.

Renal amyloid deposition was the most common cause of death in patients prior to colchicine and remains the organ contributing to the highest amount of clinical pathology. However, deposition may also occur in the GI tract, lungs, testes, thyroid, and adrenal glands. Amyloidosis usually occurs after long-standing inflammatory disease.

Other risk factors include homozygosity for the M694V mutation and country of residence, with Armenia, Turkey and Arab countries showing the highest risks of renal amyloidosis. Interestingly, patients with FMF and renal amyloidosis living in areas of lower risk for amyloidosis were of higher Armenian, Turkish and Arab ethnic backgrounds than was observed in FMF patients not developing amyloidosis.

Patients with FMF should be monitored periodically between attacks for the development of proteinuria. Renal failure typically develops between 3-5 years after the onset of proteinuria. SAA levels are a sensitive measure for predicting the progression of renal failure in patients with renal amyloidosis. Unfortunately, this test is not commercially available but it may be possible to obtain these results in a research setting.

In the absence of a serum SAA measurement, SAA and CRP are highly correlated and CRP levels may be used as a reasonable surrogate. A promising study of eprodisate, an amyloid fibril polymerization inhibitor, showed efficacy in slowing the decline of renal function in patients with renal amyloidosis. Unfortunately, a benefit in progression to end-stage renal disease or in death was not observed. This drug is not commercially available.

How to utilize team care?

Specialty consultations

Patients are typically co-managed with primary care physicians and a consulting rheumatologist. If proteinuria develops, a nephrology consultation may also be indicated. In patients with persistent symptoms despite colchicine, referral to a tertiary care center with experience in the treatment of FMF is advised.

Nurses

FMF is a chronic condition and the involvement of clinic nurses knowledgeable in this condition and with the individual patient is crucial for patient education and optimal care.

Pharmacists

Pharmacists can be helpful in evaluating for multiple drug interactions and in guiding changes in therapeutic doses when indicated due to renal insufficiency or other co-morbidities.

Therapists

Patients do not typically have special physical or occupational therapy needs as attacks tend to resolve without sequelae.

Are there clinical practice guidelines to inform decision making?

No clear clinical practice guidelines exist to inform decision making. The mainstay of therapy is colchicine with further treatment and work-up based on expert opinion in patients with resistant or atypical disease.

Other considerations

DRG codes

  • 240 Connective tissue disorders with complications, comorbidities.

  • 241 Connective tissue disorders without complications, comorbidities.

  • 256 Other musculoskeletal and connective tissue diagnosis.

Typical lengths of stay

FMF is managed in the outpatient setting with inpatient admissions required only in the event of complications.

What is the evidence?

Ben-Chetrit, E, Levy, M. "Familial Mediterranean fever". Lancet. vol. 351. 1998. pp. 659-64.

Masters, SL, Simon, A, Aksentijevich, I, Kastner, DL. "Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease". Annu Rev Immunol. vol. 27. 2009. pp. 621-68..

Ozen, S, Bilginer, Y. "A clinical guide to autoinflammatory diseases: familial Mediterranean fever and next-of-kin". Nat Rev Rheumatol. 2013.

Hentgen, V, Grateau, G, Kone-Paut, I, Livneh, A, Padeh, S, Rozenbaum, M. "Evidence-based recommendations for the practical management of Familial Mediterranean Fever". Semin Arthritis Rheum. vol. 43. 2013. pp. 387-91..

Meinzer, U, Quartier, P, Alexandra, JF, Hentgen, V, Retornaz, F, Kone-Paut, I. "Interleukin-1 targeting drugs in familial Mediterranean fever: a case series and a review of the literature". Semin Arthritis Rheum. vol. 41. 2011. pp. 265-71..

Yalcinkaya, F, Ozen, S, Ozcakar, ZB, Aktay, N, Cakar, N, Duzova, A. "A new set of criteria for the diagnosis of familial Mediterranean fever in childhood". Rheumatology (Oxford). vol. 48. 2009. pp. 395-8.

Touitou, I. "The spectrum of Familial Mediterranean Fever (FMF) mutations". Eur J Hum Genet. vol. 9. 2001. pp. 473-83..

Samuels, J, Aksentijevich, I, Torosyan, Y, Centola, M, Deng, Z, Sood, R. "Familial Mediterranean fever at the millennium. Clinical spectrum, ancient mutations, and a survey of 100 American referrals to the National Institutes of Health". Medicine (Baltimore). vol. 77. 1998. pp. 268-97..

Sohar, E, Gafni, J, Pras, M, Heller, H. "Familial Mediterranean fever. A survey of 470 cases and review of the literature". Am J Med. vol. 43. 1967. pp. 227-53..

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