Interleukin-1 Targeting Drugs in Familial Mediterranean Fever: A Case Series and a Review of the Literature

Division of Paediatric Rheumatology, CEREMAI, Hôpital de Bicêtre, University of Paris Sud, Le Kremlin Bicêtre Cedex, France.
Seminars in arthritis and rheumatism (Impact Factor: 3.93). 10/2011; 41(2):265-71. DOI: 10.1016/j.semarthrit.2010.11.003
Source: PubMed


Familial Mediterranean fever (FMF) is an autosomal-recessive autoinflammatory disorder common in Mediterranean populations. FMF is associated with mutations of the MEFV gene, which encodes pyrin. Functional studies suggest that pyrin is implicated in the maturation and secretion of IL-1. The IL-1 receptor antagonist or anti-IL1 monoclonal antibody may therefore represent a new approach to treat FMF. The aim of this report was to evaluate and discuss treatment of FMF with interleukin-1 targeting drugs.
Electronic mailing lists of French pediatric and adult rheumatologist associations were used to call for FMF patients treated with interleukin-1 antagonists. A search for published FMF patients treated with interleukin-1 targeting drugs was performed by screening PubMed.
Here, we report 7 cases of FMF patients treated with anakinra and/or canakinumab and discuss the clinical situations that may indicate the use of IL-1 blocking agents in FMF. The use of interleukin-1 targeting drugs was beneficial to all patients. The reasons for using interleukin-1 targeting drugs in FMF patients were as follows: (1) incomplete control of disease activity despite colchicine treatment; (2) high serum amyloid A levels despite colchicine treatment; (3) impossibility to use colchicine treatment because of severe side effects; (4) FMF in association with vasculitis.
Interleukin-1 targeting drugs may be good candidates when looking for an alternative or supplementary treatment to colchicine. These observations highlight the need for controlled trials to further evaluate the safety and efficacy of interleukin-1 antagonists in FMF patients.

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    • "The inhibitory effect on IL-1 release operated by colchicine and its prophylactic role on the recurrence of FMF attacks were discovered serendipitously, however alternative medications as IL-1 blockers have shown to be highly effective in colchicine-poor responders [21]. Children with colchicine-resistant FMF have been treated with the recombinant IL-1 receptor antagonist anakinra, while adult patients have been treated with the fully human anti-IL-1β monoclonal antibody canakinumab, which has reduced frequency of FMF attacks and normalized SAA in seemingly refractory patients [22]. In 1982 a large family from Scotland and Ireland was described with a newly recognized syndrome, initially termed familial Hibernian (meaning " Irish " in Latin) fever, characterized by recurrent fevers, skin rash, monocytic fasciitis, and abdominal pain [23], but only in 1998 the genetic basis of this autosomal dominant condition was discovered: its name became tumor necrosis factor receptor-associated periodic syndrome (TRAPS) due to its relationship with TNF receptor 1 (TNFR1), encoded by TNFRSF1A gene [24]. "
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    • "Recently, in agreement with the more recent studies about the pathogenetic origin of FMF, given that high levels of IL-1β (and NF-κB) were considered responsible for most disease manifestations, IL-1 inhibitors, such as anakinra, a competitive IL-1 receptor antagonist, canakinumab, a fully humanized IgG1 monoclonal antibody specifically acting against IL-1β, and rilonacept, a dimeric glycoprotein consisting of human IL-1 receptor extracellular domains and the Fc portion of human IgG1, have been effective in colchicine-resistant patients and are actually regarded as the most valid therapeutic option for FMF patients unresponsive or intolerant to colchicine as well as those with concomitant vasculitis [56–58]. Accordingly, data from the Eurofever registry showed that 3 patients were treated with anakinra, with a complete response in all cases, including 1 patient who failed to respond to colchicine [34]. "
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