Familial Mediterranean fever, from pathogenesis to treatment: a contemporary review

Abstract

Familial Mediterranean fever (FMF) (OMIM #249100) is the most common hereditary autoinflammatory disease in the world. FMF is caused by gain of function mutations of MEFV gene which encodes an immune regulatory protein, pyrin. Over the last few years, we have witnessed several new developments in the pathogenesis, genetic testing, diagnosis, comorbidities, disease related damage and treatment approaches to FMF. Elucidation of some of the pathogenic mechanisms has led to the discovery of pathways involved in inflammatory, metabolic, cardiovascular and degenerative diseases. The use of next generation sequencing in FMF has revealed many new gene variants whose clinical significance may be clarified by developing functional assays and biomarkers. Clinically, although FMF is considered an episodic disease characterized by brief attacks, recent systematic studies have defined several associated chronic inflammatory conditions. Colchicine is the mainstay of FMF treatment, and interleukin (IL)-1 antagonists are the treatment of choice in refractory or intolerant cases. Experience of IL-1 antagonists, anakinra and canakinumab, is now available in thousands of colchicine resistant or intolerant FMF patients. In this contemporary review, we surveyed current FMF knowledge in the light of these recent advances.

Keywords: Clinical features; Diagnosis; Familial Mediterranean fever; Genetics; Pathogenesis; Prognosis; Treatment.

Figure 1

(A) A patient with scars from multiple abdominal surgeries, (B) chest X-ray showing massive pericardial effusion, (C) chest X-ray of the same patient after treatment with anakinra.

Figure 2

(A) A patient with acute knee arthritis, (B) chronic deforming arthritis involving both knees, (C) joint aspirate showing sterile inflammatory effusion.

Figure 3

(A) Acute right hip joint arthritis, (B) permanent destruction in the same joint in the long term.

Figure 4

(A) Coronal and (B) axial T2-weighted fat saturation magnetic resonance images of the right calf muscles showing increased intensity and severe swelling due to muscular inflammation.

Figure 5

Skin manifestations of familial Mediterranean fever. (A) Erysipelas like erythema (ELE) on the dorsum of the foot, and (B) painful purpura.

Figure 6

Side effects of anakinra (A) injection site reaction, (B) lipoatrophy, (C) toxic epidermal necrolysis.