Familial Mediterranean Fever

The aim of this study was to evaluate the clinical manifestations and prevalence of familial Mediterranean fever (FMF) in Japanese patients with unexplained fever and rheumatic manifestations. We enrolled 601 patients with unexplained fever or suspected FMF throughout Japan between 2009 and 2015. Patients were divided into three groups according to Tel Hashomer criteria: sure FMF, probable FMF, and non-FMF patients, including definitive rheumatic diseases. Mutation detection in exons 1, 2, 3, and 10 of the FMF gene MEFV was performed by direct sequencing. A total of 192 patients (31.9 %) were diagnosed with FMF according to FMF diagnostic criteria. These could be divided into sure FMF (56.3 %, n = 108) and probable FMF (43.7 %, n = 84) patients. Fever, abdominal symptoms, and thoracic symptoms were significantly more common in FMF than non-FMF patients. Among FMF patients, 26 (13.5 %) had concomitant rheumatic diseases. Most FMF patients (94.3 %, 181/192) carried at least one MEFV m...

The term autoinflammatory syndromes describes a distinct group of systemic inflammatory diseases apparently different from infectious, autoimmune, allergic and immunodeficient ones. Originally, it was almost synonymous with clinically defined hereditary periodic fever syndromes, including familial Mediterranean fever, hyper immunoglobulin D syndrome with periodic fever and tumor necrosis factor receptor-associated periodic syndrome. Similar but distinct periodic fever syndromes accompanied by urticarial rash, familial cold autoinflammatory syndrome, Muckle-Wells syndrome and chronic infantile neurological cutaneous articular syndrome, have all been reportedly associated with CIAS1 mutations and are collectively called cryopyrin-associated periodic syndromes. Consequently, the concept of autoinflammatory syndromes has been spread to contain other systemic inflammatory diseases: rare hereditary diseases with or without periodic fevers, such as pyogenic sterile arthritis, pyoderma gangrenosum and acne syndrome, Blau syndrome and chronic recurrent multifocal osteomyelitis, and the more common collagen disease-like diseases, such as Behcet's disease, Crohn's disease, sarcoidosis and psoriatic arthritis. These diseases are all caused by or associated with mutations of genes regulating innate immunity and have common clinical features accompanied with activation of neutrophils and/or monocytes/macrophages. In this review, major autoinflammatory syndromes are summarized and the pathophysiology of related skin disorders is discussed in association with dysregulated innate immune signaling.

Dutch type periodic fever (DPF) is an autosomal recessive hereditary fever syndrome. Cases have been reported worldwide, the majority from France and The Netherlands. From infancy the patients suffer fever attacks that recur every 2-8 weeks, often precipitated by immunizations, infections or emotional stress. Fever lasts 2-7 days and can be accompanied by malaise, headache, diarrhea, abdominal pain, vomiting, skin rashes, arthralgia, arthritis, tender lymphadenopathy, hepatosplenomegaly, and oral and genital ulcers. Laboratory evaluation during fever shows granulocytosis and elevated acute phase reactants. DPF is caused by a deficiency of the enzyme mevalonate kinase (MK). Besides DPF, the spectrum of MK deficiency includes a severe phenotype, mevalonic aciduria (MA). MA patients have less residual MK activity, leading to substantially higher urinary mevalonic acid excretion than in DPF. Mevalonic aciduria is characterized by mental retardation and dysmorphic features in addition to...

Serum homocysteine, folic acid, lipoprotein (a) (Lp(a)), fibrinogen, and C-reactive protein (CRP) concentrations and erythrocyte sedimentation rates (ESR) were measured in 52 patients with familial Mediterranean fever (FMF) during attack-free periods and in 30 healthy control subjects. Serum homocysteine levels were significantly higher in the FMF patients (median 17.8 microg/dl; range 5.6-80.8) than in controls (median 11.7; range 5.6-42.2; p = 0.013). Serum homocysteine levels were elevated above the upper reference limit (15 microg/dl) in 56% of the FMF patients compared to 27% of the controls (p = 0.011). Serum Lp(a) levels were significantly higher in the FMF patients (median 39.3 mg/dl; range 6.6-124.5) than in controls (median 27.2; range 11.1-78.1; p = 0.035). Serum Lp(a) levels were elevated above the upper reference limit (30 mg/dl) in 71% of the FMF patients compared to 47% of the controls (p = 0.028). The ESR, fibrinogen, CRP, and folic acid levels were similar in both g...

Familial Mediterranean fever (FMF) is the most frequent hereditary inflammatory disease characterized by self-limited recurrent attacks of fever and serositis. The aim of the current study is to determine the frequency of the mutations in 365 suspected FMF patients and to reveal whether there is a correlation between genotype and phenotype of these patients. All patients were clinically examined according to Tell-Hashomer FMF criteria and were screened genetically in terms of common 12 Mediterranean fever gene (MEFV) mutations. Various point mutations were detected in 270 (74%) patients. The most frequent mutation was M694V (26.85% of the alleles) and was followed by E148Q (15.55%), M680I (G/C) (9.62%) and V726A (7.96%). Patients who bear M694V homozygous mutation had most severe disease phenotype and high risk for amyloidosis (P = 0.04). Our results indicate that Sivas population has a wide range of heterozygous mutated carriers of MEFV gene and there is a high frequency of E148Q allele when compared to the other Mediterranean groups.

... Watermelon stomach and familial Mediterranean fever. Spyros Michopoulos , Panayotis Tsibouris , Maria Sotiropoulou , Kalliopi Petraki , Dimitrios Vassilopoulos & Nick Kralios. Abstract. ... I am a member of the American College of Gastroenterology. ...

This open-label pilot study aimed to investigate the efficacy of canakinumab in colchicine-resistant familial Mediterranean fever (FMF) patients. Patients with one or more attacks in a month in the preceding 3 months despite colchicine were eligible to enter a 30-day run-in period. Patients who had an attack during the first run-in period advanced to a second 30-day period. At the first attack, patients started to receive three canakinumab 150 mg subcutaneous injections at 4-week intervals, and were then followed for an additional 2 months. Primary efficacy outcome measure was the proportion of patients with 50 % or more reduction in attack frequency. Secondary outcome measures included time to next attack following last canakinumab dose and changes in quality of life assessed by SF-36. Thirteen patients were enrolled in the run-in period and 9 advanced to the treatment period. All 9 patients achieved a 50 % or more reduction in attack frequency, and only one patient had an attack d...

To investigate the expression of the familial Mediterranean fever (FMF) gene (MEFV) in human synovial fibroblasts. MEFV messenger RNA in synovial fibroblasts, chondrocytes, and peripheral blood leukocytes (PBLs) was analyzed by semiquantitative and real-time polymerase chain reaction and ribonuclease protection assay. The subcellular localization of pyrin, the MEFV product, was determined in transfected synovial fibroblasts and HeLa cells with plasmids encoding pyrin isoforms. Native pyrin was detected with an antipyrin antibody. MEFV was expressed in synovial fibroblasts, but not in chondrocytes. Four alternatively spliced transcripts were identified: an extension of exon 8 (exon 8ext) resulting in a frameshift that predicts a truncated protein lacking exons 9 and 10, the addition of an exon (exon 4a) predicting a truncated protein at exon 5, the in-frame substitution of exon 2a for exon 2, and the previously described removal of exon 2 (exon 2Delta). Exon 8ext transcripts represented 27% of the total message population in synovial fibroblasts. All other alternatively spliced transcripts were rare. Consensus and alternatively spliced transcripts were induced by lipopolysaccharide in synovial fibroblasts and PBLs. In transfected cells, the proteins encoded by all highly expressed splice forms were cytoplasmic. In contrast, native pyrin was predominantly nuclear in synovial fibroblasts, neutrophils, and dendritic cells, but was cytoplasmic in monocytes. Several MEFV transcripts are expressed and inducible in synovial fibroblasts. A prominent isoform lacks the C-terminal domain that contains the majority of mutations found in patients with FMF. While recombinant forms of all major pyrin isoforms are cytoplasmic, native pyrin is nuclear in several cell types. Thus, mechanisms in addition to splicing patterns must control pyrin's subcellular distribution.