Comment on: Familial Mediterranean fever caused by homozygous E148Q mutation complicated by Budd-Chiari syndrome and polyarteritis nodosa.

Comment on: Familial Mediterranean fever caused by homozygous E148Q mutation complicated by Budd Chiari syndrome and polyarteritis nodosa SIR, We read with interest the letter by Standing et al. [1] on a case of FMF complicated by PAN and Budd Chiarri syndrome (BCS). This case deserves special interest as the authors claim a pathophysiological association of FMF not only with PAN but also with BCS. The FMF PAN association has already been described in the literature [2]. However, in this letter, Standing et al. [1] claim association of BCS with both the two other entities, namely FMF and PAN. We note that, in this case, the first well-documented medical problem of the patient is BCS. Thrombotic tendency predisposed by the methelenetetrahydrofolate reductase mutation documented might suffice for a BCS occurring; however, the case was only heterozygote and homocystein status is not reported. Furthermore, the case also developed pain of the abdomen, myalgias, anorexia and night sweats. According to Standing et al. [1], these symptoms indicated FMF; a favourable response to colchicine was considered as pointing to FMF diagnosis. They claim that this diagnosis is further supported by E148Q homozygosity of the Mediterranean Fever gene. We note that, given the anti-inflammatory action of colchicine, a favourable non-specific clinical response must be expected on practically every inflammatory condition and not only in auto-inflammatory entities as FMF. Therefore, if other criteria are not met, the favourable response of colchicine per se is not a strongly supported argument. Furthermore, if the MEFV gene is involved in modifying other diseases [3] then a favourable effect of colchicine on them sounds reasonable. As for the role of E148Q homozygocity in causing FMF phenotype, this still remains rather controversial and the results are inconclusive [4]. First, one should take into account that homozygotes for FMF mutations are not all symptomatic and this refers not only to E148Q mutations [5]. Racial parameters and the putative interaction with other genetic elements must be considered before any association. Documentation of the E148Q mutation and distinction from E148V mutation depends on the restriction enzyme applied in testing and the relevant banding pattern that must be taken into account [6]. To the best of our knowledge, coagulation tendency is not an established complication of FMF, although several single cases are reported in the literature [7]. The role of the auto-inflammatory process in coagulation may sound reasonable, but it merits further investigation. Before well-designed clinical studies are conducted, one must be cautious in considering such a coincidence as pointing to underlying association. The main reason for reluctance is that molecular testing for these putative markers is expensive and not always available. Before accepting the rationality of an association of MEFV mutations with other entities such as inflammatory diseases and/or thrombotic tendency, we need further data on relevant populations. It is worth noting that, recently, wide genome association studies (WGAS) conducted on diseases that have been associated with MEFV mutations, such as Behçet’s [8], Crohn’s disease [9] and ulcerative colitis [10], have not included MEFV-associated markers among the genome areas tested. In this context, WGAS studies encompassing MEFV within the areas under investigation must be encouraged.