6Approach to the patients with inadequate response to colchicine in familial Mediterranean fever
Section snippets
Terminology
Familial Mediterranean fever (FMF), the most common type of hereditary autoinflammatory disorders, is characterized by recurrent episodes of inflammation in serosal and synovial membranes and a tendency for secondary amyloidosis [1], [2]. FMF is more prevalent in Jews, Arabs, Armenians, and Turks, and analysis of the typical patients revealed an autosomal recessive mode of inheritance pattern [2]. Variations in the MEFV gene encoding pyrin protein were identified through positional cloning in
Assessment of disease severity in FMF
FMF may run a variable course in terms of its severity, and the MEFV variations have been shown to be the most important factor affecting its inflammatory characteristics and phenotypic variability [16]. Contributions of environmental factors and other modifier genes were estimated as 12% and 17% on an average, respectively [16].
Penetrance of the disease-associated MEFV variants, especially p.Met694Val, has been considered as the main factor determining the severity of inflammatory response,
Optimum use of colchicine and compliance
Colchicine has a prophylactic activity in FMF patients, and its efficacy can be observed when it is used regularly at stable doses. Colchicine treatment should aim to prevent both the recurrence of inflammatory episodes and the development of amyloidosis, and effective doses required for the latter goal may be higher [9]. Colchicine is usually given at tolerable doses to children and adults [31], and the doses need to be adjusted according to the ongoing disease activity determined by number
Evaluation of response to treatment
There is no universally accepted tool to evaluate the efficacy of colchicine or other treatments in FMF patients, and recent attempts to develop criteria for the evaluation of the treatment response have usually been praised with reservations [26], [36]. The FMF50 score developed by Özen and colleagues requires observing a 50% improvement in five of the six criteria without worsening of the sixth criterion, which are determined by two rounds of Delphi exercise, followed by a consensus
Efficacy of biologic agents in inadequate colchicine responders
MEFV-encoded pyrin is an important component of multiprotein inflammasome platforms, which regulates caspase 1 activity and processing of pro-IL-1β and pro-IL-18 into their active forms. Despite its identification in 1997, physiological functions of pyrin has recently been clarified by studies showing a specific function in sensing the virulence of certain exogenous threats by detecting downstream effects of decreased RhoA GTPase activity [41], [42], [43]. Exposure to glucosylating TcdB toxin
Conclusion
Although response to colchicine is one of the distinctive features of FMF, its narrow therapeutic window may limit its efficacy at the highest tolerable doses in a group of patients with a more severe disease course. IL-1 appears as the most reasonable target in these patients based on the findings showing the MEFV variations cause increased inflammasome activation, and reports showing the efficacy and safety of available anti-IL-1 agents need to be confirmed in randomized clinical trials
Disclosure
Dr. Gül received royalties for invited lectures and advisory board meetings and clinical trial support from Novartis.
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