Non-canonical manifestations of FMF in homozygous M694V MEFV genotype: Insights from a large patient cohort

Semin Arthritis Rheum. 2025 Oct:74:152821. doi: 10.1016/j.semarthrit.2025.152821. Epub 2025 Aug 29.

Abstract

Objectives: The homozygous M694V genotype is associated with the most severe form of familial Mediterranean fever (FMF). This study aims to explore whether this genotype is linked not only to classical FMF features, but also to additional, non-canonical manifestations.

Methods: A hypothesis-generating study was conducted using an automated algorithm to extract data from structured medical records of patients followed at the FMF clinic of Sheba Medical Center between 2010 and 2020. Patients homozygous for the M694V genotype (study group) were compared with those having other genotypes (control group).

Results: Of 3866 patients, 517 (13.4 %) were homozygous for the M694V mutation, while 3349 (86.6 %) had other genotypes. Homozygous M694V patients required higher colchicine doses and exhibited higher rates of inflammatory markers, colchicine treatment failure, Behcet's disease (BD), ankylosing spondylitis (AS), and chronic renal failure (CRF, in all p < 0.01). New findings included higher rates of deep vein thrombosis (p = 0.03), liver dysfunction (p = 0.02), abnormal liver enzymes (p < 0.001), and congestive heart failure (CHF, p = 0.01). Consequently, more patients in the study group received biologic agents and had more emergency department visits and higher hospitalization rates (p ≤ 0.001 in both).

Conclusions: This study expands the scope of the homozygous M694V-associated phenotype by identifying new non-canonical features and reinforcing previous knowledge on a larger scale. We hypothesized that heightened systemic inflammation may underlie many of these associations. However, further exploration is needed to determine whether these novel findings are indeed attributed to the higher inflammatory nature of the M694V homozygous genotype, or is mediated by established and novel conditions prevailing in this subset of FMF, such as BD, AS, CHF, CRF, and higher colchicine exposure.

Keywords: Congestive heart failure; Deep vein thrombosis; FMF; Homozygous M694V genotype; Liver dysfunction.

MeSH terms

  • Adult
  • Cohort Studies
  • Colchicine / therapeutic use
  • Familial Mediterranean Fever* / complications
  • Familial Mediterranean Fever* / drug therapy
  • Familial Mediterranean Fever* / genetics
  • Female
  • Genotype
  • Homozygote
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Pyrin* / genetics
  • Young Adult

Substances

  • Pyrin
  • Colchicine
  • MEFV protein, human