Increased prevalence of M694V in patients with ankylosing spondylitis: Additional evidence for a link with familial mediterranean fever

Abstract

Objective. To assess whether there is a statistically significant difference in the frequency of common MEFV allele variants in patients with ankylosing spondylitis (AS) as compared with control patients with rheumatoid arthritis (RA) and with healthy control subjects.Methods. Sixty-two patients with AS, 50 healthy control subjects, and 46 patients with RA were assessed for the presence of MEFV variants. Exon 10 was analyzed by direct sequencing. E148Q was analyzed by restriction endonuclease enzyme digestion (REED) or by direct sequencing when REED analysis failed.Results. The allele frequency of all MEFV variants in the AS group was significantly higher than that in the pooled control group of healthy subjects plus RA patients (15.3% versus 6.8%; P ‫؍‬ 0.021). M694V was the only variant that was significantly more common in the AS group than in the combined or individual control groups (P ‫؍‬ 0.026 for AS patients versus healthy controls, P ‫؍‬ 0.046 for AS patients versus RA patient controls, and P ‫؍‬ 0.008 for AS patients versus healthy and RA patient control groups). The carriage rate of M694V was also significantly higher in the AS patient group than in the combined control group (odds ratio 7.0, P ‫؍‬ 0.014). Neither M694V nor any other MEFV variant showed a correlation with most of the diseaserelated measures examined.Conclusion. We found an increased frequency of MEFV variants in AS patients as compared with healthy controls and with RA patient controls. This was primarily due to the presence of M694V. The roles of other exon 10 variants, as well as the relationship between the variant status and the severity and clinical course of the disease, need to be explored in further studies that include sufficiently large sample sizes.Familial Mediterranean fever (FMF) is an autoinflammatory disease that occurs predominantly in Jewish, Armenian, Turkish, and Middle Eastern Arab populations. It is characterized by recurrent attacks of fever and serositis. The disease is caused by MEFV, which encodes an immunoregulatory protein called pyrin, or marenostrin, and is inherited in an autosomal-recessive manner (1,2).We previously identified 3 patients with ankylosing spondylitis (AS) carrying 2 MEFV variants, 2 of whom were homozygous for M694V (3). None of the patients had any current or previous symptoms suggestive of FMF, and all were HLA-B27 negative. These cases are of particular interest in light of recent reports indicating an increased frequency of sacroiliitis or spondylarthritis in patients with FMF (4,5).

MEFV mutation frequency and effect on disease severity in ankylosing spondylitis

“…MEFV mutation frequency was found to be increased as compared to controls in 2 of 3 previous studies (9-11). However, in all studies, M684V mutation was the most common mutation detected in AS patients and the frequency of M694V mutation was increased in AS patients as compared to controls (9)(10)(11)17). In this regard, our results are consistent with the previous results.…”

“…We did not find any clinical and laboratory difference between MEFV mutation carriers and noncarriers in AS patients. The frequency of MEFV mutation carriers was reported between 22% and 30% in AS patients (9)(10)(11)16). MEFV mutation frequency was found to be increased as compared to controls in 2 of 3 previous studies (9-11).…”

“…In one study, authors reported higher BASDAI/BASFI scores and more hip involvement in MEFV mutation carrier AS patients (11). In other studies, authors either did not assess the clinical significance of MEFV mutations or found no clinical difference between MEFV mutation carrier and noncarrier AS patients (9,10). Response to nonsteroidal antiinflammatory drugs was found to be similar among MEFV mutation carrier and noncarrier AS patients (16).…”

“…The impact of MEFV mutations on the clinical course of chronic inflammatory diseases other than FMF, such as Crohn's disease, childhood arthritis, and rheumatoid arthritis, has been shown (5)(6)(7)(8). The presence of MEFV mutations in AS patients was investigated in previous studies but their association with clinical features of AS is controversial (9)(10)(11). The aim of this study is to define the frequency of MEFV mutations and describe different clinical aspects of MEFV mutation carrier and noncarrier AS patients.…”

Decreased MEFV gene expression in rheumatoid arthritis patients

“…Pyrin/marenostrin (P/M) is primarily expressed in neutrophils, eosinophils, cytokine-activated monocytes, dendritic cells, and synovial fibroblasts (Kireçtepe et al, 2011a). Pyrin is involved in a complex interaction with the pyrin-domain protein superfamily and lipopolysaccharides via the Tolllike receptor family and procaspase 1 activation that controls inflammation through leukocyte apoptosis (Akkoc et al, 2010). To date, approximately 80 disease-associated mutations have been identified in MEFV and registered in the autoinflammatory mutation database Infevers (http://fmf.igh.cnrs.fr/infevers/) (Milhavet et al, 2008).…”