Severe disease in patients with rheumatoid arthritis carrying a mutation in the Mediterranean fever gene

Abstract

Background: Pyrin is a newly recognised intracellular regulator of inflammation, and mutations in MEFV, the gene encoding pyrin, are the cause of familial Mediterranean fever. Objective: To determine if known mutations of MEFV are associated with rheumatoid arthritis (RA) morbidity or can modify RA severity. Methods: The frequency of the three most common MEFV mutations: M694V, V726A, and E148Q, was determined in 98 Israeli patients with RA (74 women, 24 men) and compared with that in 100 healthy subjects matched for origin. RA severity was determined using a new clinical score of 126 grades. The median severity score of mutation carrier and non-carrier groups was compared after confounding measures were eliminated by logistic regression. Results: 17/98 (17%) patients with RA (all women) were heterozygous for common MEFV mutations, predominantly E148Q (12 patients), and one patient was homozygous for the V726A mutation. The overall mutation rate was comparable between patients with RA and healthy subjects. Patients carrying a mutation had a higher median severity score than the non-carrier group (42 v 29, p = 0.0005). The logistic regression model assigned a 15-fold odds ratio for severe RA in carriers, after adjusting for sex, presence of rheumatoid factor, age at onset, and disease duration (n = 97, p = 0.01, 95% CI 1.74 to 128). Conclusion: MEFV, and particularly the E148Q mutation, is an independent modifier of the clinical manifestations of RA. This is the second Th1-type autoimmune disease in which MEFV mutations have been shown to aggravate the clinical status.

MEFV mutation frequency and effect on disease severity in ankylosing spondylitis

“…Our results also support the suggested association between M694V mutation and development of AS (17). Musculoskeletal manifestations are common and include peripheral arthritis and sacroiliitis in FMF (8,20). Some authors suggested that FMF may be included in the spectrum of diseases with seronegative spondyloarthropathy (8).…”

“…FMF-AS patients had more peripheral joint involvement, total hip replacement, higher acute phase reactant levels, and proteinuria (23). The presence of MEFV mutations is shown to be associated with disease severity in inflammatory diseases such as Crohn's disease, childhood arthritis, and rheumatoid arthritis (5)(6)(7)(8). However, unexpectedly, we could not demonstrate any clinical or laboratory difference between MEFV mutation carriers and noncarriers in AS patients.…”

“…Some authors suggested that FMF may be included in the spectrum of diseases with seronegative spondyloarthropathy (8). On the other hand, the absence of HLA B27 and lumbar spinal involvement are considered to be characteristics of FMF musculoskeletal manifestations (8,21,22). The frequency of sacroiliitis in FMF patients has been reported to be higher than expected in Turkish patients (20,21).…”

“…Musculoskeletal manifestations are common and include peripheral arthritis and sacroiliitis in FMF (8,20). Some authors suggested that FMF may be included in the spectrum of diseases with seronegative spondyloarthropathy (8). On the other hand, the absence of HLA B27 and lumbar spinal involvement are considered to be characteristics of FMF musculoskeletal manifestations (8,21,22).…”

“…MEFV mutation carriers include about 20%-30% of the population in certain ethnic groups (4). 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).…”