- FAMILIAL MEDITERRANEAN FEVER.

FAMILIAL MEDITERRANEAN FEVER

Def: Autosomal recessive autoinflammatory disease usually characterized by recurrent 1-3 day self-limited episodes of fever, serositis, mono- or pauciarticular arthritis, or an erysipeloid rash, sometimes complicated by AA amyloidosis.

Etiology:-

Caused by mutations in MEFV, a 10 exon gene located on the short arm of chromosome 16 encoding a 781 amino acid protein denoted pyrin.

FMF occurs primarily among ethnic groups of Mediterranean ancestry, most commonly Jews, Turks, Armenians, Arabs, and Italians.

Most patients present with symptoms in childhood, with 90% of patients presenting prior to the age of 20 yr.

Clinical Manifestations:-

Attacks occur irregularly, precipitated by minor physical or emotional stress, menstrual cycle, diet or infection. Attacks resolve within 72 hours.

Between flares, patients are generally symptom-free but may have persistent elevation of their inflammatory markers.

The attack frequency can vary from weekly to 1-2 flares/year.  

Clinical features includes:

•  Fever :- Temperatures rise rapidly to 38–40 °C (100.4–104 °F)..
• Serositis presenting as pleuritic chest pain or severe abdominal pain (peritonitis in 90% of patients and may mimic an acute surgical abdomen), arthritis, and rash. The pleural pain is typically unilateral, whereas the abdominal pain can be generalized or localized to 1 quadrant, similar to other forms of peritonitis.
• During an episode they often complain of constipation, secondary to the peritoneal inflammation leading to a temporary paralytic ileus, followed by diarrhea as the inflammation fades.
• Arthritis occurs primarily in the large joints, may be accompanied by large, neutrophil-rich effusions, and is usually nonerosive and nondestructive.
• The hallmark cutaneous finding is an erysipeloid erythematous rash that overlies the ankle or dorsum of the foot .
• Scrotal pain caused by inflammation of the tunica vaginalis testis,
• febrile myalgia,
• Exerciseinduced myalgia (particularly common in children),
• Association with various forms of vasculitis, including Henoch-Schönlein purpura in as many as 5% of pediatric patients.

Diagnosis:-

-The diagnosis of FMF can often be made clinically by Tel-Hashomer criteria:

Major criteria

• Recurrent febrile episodes associated with peritonitis, pleuritis or synovitis
• Amyloidosis of AA-type without a predisposing disease
• Favorable response to daily colchicine

Minor criteria

• Recurrent febrile episodes
• Erysipelas-like erythema
• Positive history of familial Mediterranean fever in a first degree relative

Definite Diagnosis: 2 major or 1 major + 2 minor criteria.

Probable Diagnosis: 1 major + 1 minor criteria .

-Genetic testing can be used as adjunctive evidence in ambiguous cases.

- ESR, CRP, fibrinogen, and White blood counts (WBCs) may be elevated during the episodes of fever then normalize in between flares.

Treatment

• Prophylactic daily oral colchicine decreases the frequency, duration, and intensity of FMF flares. This regimen also prevents the development of systemic AA amyloidosis.
• Colchicine should be started as soon as the patient recognizes that an attack is occurring.
•  Colchicine is generally well-tolerated and safe in children, with the most common side effects being diarrhea and other gastrointestinal complaints.
• Some patients develop lactose intolerance while taking colchicine.
• Gastrointestinal side effects can be minimized by initiating therapy at a low dose (for young children, (0.3 mg/day) and slowly titrating upward.
•  A dose-related transaminitis may also be observed.
• Bone marrow suppression is rarely seen at the dosages prescribed for FMF.
• Pediatric patients may require doses of colchicine similar to those needed in adults (1-2 mg/day), reflecting the fact that children metabolize the drug more rapidly than adults.
• It is not always possible to find a tolerated dose of colchicine at which all symptoms are suppressed, but approximately 90% of patients have a marked improvement in disease-related symptoms.
• Colchicine is generally continued during pregnancy and lactation.
• Periodic monitoring of CBC, liver and renal function is necessary.
•  A small percentage of FMF patients are either unresponsive to or intolerant of therapeutic doses of colchicine.
• Based on the role of pyrin in IL-1β activation, a randomized placebo-controlled trial demonstrated the safety and effectiveness of rilonacept, an IL-1 inhibitor, in FMF, and there are case reports of the effectiveness of anakinra, a recombinant IL-1 receptor antagonist.

Complications and Prognosis

Amyloidosis is the most serious complication of FMF.

Amyloidosis may develop when serum AA, an acute-phase reactant found at extremely high levels in the blood during FMF attacks, most commonly develop in the kidneys, gastrointestinal tract, spleen, lungs, testes, thyroid, and adrenals. Rarely, cardiac amyloidosis may develop; macroglossia and amyloid neuropathy are generally not seen with the amyloidosis of FMF.

The most common presenting sign of AA amyloidosis is proteinuria.

The diagnosis is then usually confirmed by rectal or renal biopsy.

Risk factors for the development of amyloidosis in FMF include:-

•    homozygosity for the M694V MEFV mutation,
•    polymorphisms of the serum AA gene (encoding AA),
•    noncompliance with colchicine treatment,
•   male gender,
•   positive family history of AA amyloid.
•   patients raised in the Middle East having a much higher risk than genotypically identical patients raised in the West.

Aggressive lifelong suppression of the acute phase reactants should be the goal in patients with FMF amyloidosis, and there are documented cases in which this may result in resorption of amyloid deposits.

The natural history of untreated amyloidosis in FMF is the inexorable progression to renal failure, often within 3–5 yr.

Ibrahim Samaha

References:-

• Amanda K. Ombrello and Daniel L. Kastner , Hereditary Periodic Fever Syndromes and Other Systemic Autoinflammatory Diseases,Chapter 163,NELSON TEXTBOOK OF PEDIATRICS, TWENTIETH EDITION 2016
• Clarissa Pilkington, Kiran Nistala, Helen Lachman and Paul Brogan, Rheumatology , GREAT ORMOND STREET HANDBOOK OF PAEDIATRICS, 2nd  ed
• Osama Naga,Rheumatologic Disorders, Periodic Fever ,190-192 Pediatric Board Study Guide, A Last Minute Review
• Sujata Sawhney and Amita Aggarwal, Autoinflammatory Syndromes in Children, Pediatric Rheumatology,546-554 A Clinical Viewpoint,2017
• Ronald M. Laxer ,David D. Sherry  and Philip J. Hashkes,CH10 Autoinflammatory Syndromes,189-208 Pediatric Rheumatology in Clinical Practice,2nd ed 2016