FMF Is Associated With a Wide Spectrum of MHC Class I- and Allied SpA Disorders but Not With Classical MHC Class II-Associated Autoimmune Disease: Insights From a Large Cohort Study

Abstract

Objectives: To test the hypothesis that familial Mediterranean fever (FMF)-associated autoinflammation may exaggerate the tendency toward adaptive immunopathology or spondyloarthritis (SpA)-associated disorders including major histocompatibility complex (MHC) class I associated disorders but not classical MHC class II-associated disorders that exhibit transplacental autoimmunity including myasthenia gravis and pemphigus.Methods: Seven thousand seven hundred forty-seven FMF patients and 10,080 age- and sex-matched controls in the Clalit Health Services medical database were identified and compared in terms of prevalence of SpA-associated disorders. We also evaluated four classical and strong MHC class II-associated disorders, namely, pemphigus vulgaris, myasthenia gravis, sarcoidosis, and pernicious anemia, to ascertain whether such associations with SpA-spectrum disease were specific or merely reflected the non-specific consequences of innate immune system activation on driving divergent types of immunity. The diagnosis of FMF was based on the medical records and not genetically proven.Results: FMF showed a strong association with MHC class I-related diseases: odds ratio (OR) of 28.58 [95% confidence interval (95% CI), 6.93–117.87; p < 0.0001] for Behçet's disease, OR of 10.33 (95% CI, 4.09–26.09; p < 0.0001) for ankylosing spondylitis, and OR of 1.67 (95% CI, 1.19–2.33; p = 0.0029) for psoriasis. For weakly MHC class I-linked diseases, an OR of 3.76 (95% CI, 2.48–5.69; p < 0.0001) for Crohn's disease and OR of 2.64 (95% CI, 1.52–4.56; p = 0.0005) for ulcerative colitis were found. No association was found between FMF and the four MHC class II-associated autoimmune disorders.Conclusion: FMF patients are associated with increased risk of SpA-related disease diagnosis including MHC-I-opathies but not MHC-II-associated autoimmune diseases, suggesting that tissue-specific dysregulation of innate immunity share between FMF and SpA spectrum disorders may drive adaptive immune MHC class I-associated conditions.

MEFV Mutations in IBD Patients: A Systematic Review and Meta- analysis

“…Worth mentioning, among IBD subtypes, IC patients performed the closely association with MEFV mutations. It could be argued that some IBD patients are in fact FMF patients with some colonic inflammation at a moment of disease evolution; this might be supported by the overlap observed between FMF and UC (0.6%), as well as FMF and CD (1.2%) [46]. However, whether these cases represent real IBD or merely FMF-associated intestinal mucosal inflammation, or a distinct MEFV gene-related enterocolitis mimicking IBD is unclear [25].…”

Relationship Between Familial Mediterranean Fever and Other Rheumatic Diseases: Coincidence or Coexistence?

“…Therefore, candidate gene and genome-wide association studies suggest that in addition to the IL-17 pathway associated with IL-23R, there is also an increased risk of AS in association with the IL-1 cytokine pathway. 11,13 SpA associated endoplasmic reticulum-associated aminopeptidase 1 plays a role in the modulation of IL-1, IL-6, and TNF. 14,15 There is some evidence that M694V variation may be more common in FMF patients with sacroiliitis.…”

Ocular inflammatory diseases in children with familial Mediterranean fever: a true association or a coincidence?

“…Familial Mediterranean fever is typically described as an autoin ammatory disease that can involve joints, skin, muscles, and kidneys; however, it is a predisposing factor for a variety of different in ammatory diseases involving other organs and systems [17]. Ocular in ammation is an uncommon entity reported in FMF [18].…”