Elsevier

Joint Bone Spine

Volume 75, Issue 4, July 2008, Pages 504-505
Joint Bone Spine

Case report
Anakinra: New therapeutic approach in children with Familial Mediterranean Fever resistant to colchicine

https://doi.org/10.1016/j.jbspin.2008.04.001Get rights and content

Abstract

Familial Mediterranean fever (FMF), a recessively inherited autoinflammatory disorder, is the prototype of a group of disorders termed systemic autoinflammatory diseases. Such diseases are characterized by seemingly unprovoked episodes of inflammation without evidence of high-titer autoantibodies or antigen-specific T cell. Repeated bouts of inflammation may lead to systemic AA protein deposition, making FMF a potentially fatal disease. Pyrin, the protein mutated in FMF, regulates caspase-1 activation and consequently IL-1β production. Although colchicine is the standard prophylactic therapy for attacks and amyloid deposition, some patients fail to respond or cannot tolerate its side effects. Anticytokine therapies have shown promise in the treatment of autoinflammatory disorders in children. We report on the use of the recombinant interleukin 1 receptor antagonist anakinra in one child with therapy-resistant FMF. The patient experienced immediate, sustained resolution of symptoms and laboratory markers of inflammation, and also, possibly, a reduced long-term risk of AA amyloidosis.

Introduction

Familial Mediterranean Fever (FMF, MIM249100) is the prototype of a group of disorders termed “systemic autoinflammatory diseases” and characterized by seemingly unprovoked episodes of inflammation in the absence of high-titer autoantibodies or antigen-specific T cells [1], [2]. The clinical picture associated with FMF includes short episodes of fever, abdominal, thoracic, and joint pain, and erysipelas-like erythema. Repeated bouts of inflammation may lead to systemic amyloid (AA) protein deposition, especially in the kidney making FMF a potentially fatal disease.

The FMF gene (MEFV), which was discovered in 1997 [3], encodes a protein known as pyrin or marenostrin that is thought to modulate apoptosis, NF-κβ activation, and processing of the potent pyrogenic interleukin-1β (IL-1β) cytokine. More than 70 FMF gene mutations have been reported to date [4]. Although colchicine prophylaxis has dramatically changed the prognosis of FMF by preventing febrile attacks and the production of serum AA [5], some patients are unresponsive or cannot tolerate its side effects.

Knockdown experiments have demonstrated a net inhibitory effect of pyrin on IL-1β processing, and clinical data have substantiated the importance of IL-1β in the pathogenesis of FMF [6]. Therefore, it remains to be seen whether targeting IL-1 can be an effective approach to FMF. Anakinra, a recombinant nonglycosylated homolog of human IL-1 receptor (IL-1Ra), is at present the only drug that competitively inhibits binding of IL-1α and IL-1β to IL-1 receptor type I.

Section snippets

Case report

The patient's symptoms began when he was 9 years old and consisted of long inflammatory episodes recurring each 2–3 weeks characterized by high fever, urticarial rash, abdominal pain and headache, in addition to arthralgia, myalgia and arthritis. A biologic inflammatory syndrome was observed, with a C-reactive protein (CRP) level of 168 mg/l, an erythrocyte sedimentation rate (ESR) of 95 mm/h and a white blood cell (WBC) count of 16.970/mm3. Exhaustive explorations failed to establish any

Discussion

Daily administration of colchicine is the current therapy of choice for the prophylaxis of attacks and amyloid deposition in FMF. The effect of alternative treatments on patients not responding to prophylactic administration of colchicine (5–10%) has only been reported in individual patients or small series. Although some favourable effects have been obtained with additional thalidomide, interferon-alfa, infliximab and weekly intravenous colchicine, no effective alternative treatment appears to

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