Familial Mediterranean Fever

Abstract: Background: Familial Mediterranean Fever (FMF) is the most common autoinflammatory disease. Autoinflammatory disorders are characterized by exaggerated immune system responses. Neutrophils and their byproduct, myeloperoxidase, are important components of the innate immune system. In the present study, we searched for myeloperoxidase gene polymorphisms in FMF patients. Methodology/Principal Findings: We evaluated 83 children diagnosed with FMF by their physicians and 93 controls without any family history of FMF. MPO gene polymorphisms were detected using polymerase chain reaction (PCR)-based methods. We genotyped all samples in terms of the -463G/A single-nucleotide polymorphism, the most extensively studied MPO polymorphism. Allelic and genotypic frequencies were calculated, and possible associations with FMF explored. The frequencies of MPO polymorphisms differed significantly between the study and control groups (P = 0.003). The AA and AG gene poly- morphisms were more prevalent in the FMF group than in the controls. The A allele was more prevalent in the FMF group (P = 0.001), and the frequency of the G allele was similar between the two groups (P = 0.128). Conclusion: MPO gene polymorphisms and allelic differences may be important in the pathogenesis of FMF.

Abstract: Familial Mediterranean fever is an autosomal recessive autoinflammatory disorder mainly affecting Mediterranean populations, which is associated with mutations of the MEFV gene that encodes pyrin. Functional studies suggest that pyrin is implicated in the maturation and secretion of interleukin-1 (IL-1). The IL-1 receptor antagonist or anti-IL-1 monoclonal antibody may therefore represent a rational approach for the treatment of the rare patients who are refractory to conventional therapy. We report the case of a young female affected by familial Mediterranean fever who proved to be resistant to colchicine and was successfully treated with canakinumab. Keywords: interleukin-1, colchicine, familial Mediterranean fever, anti-IL-1 treatment, biologic agents

Present study was carried out for the molecular modeling of the pyrin protein. Tertiary structure of pyrin protein was developed by de novo modeling and treading methods. Subsequent evaluation of the developed model was also carried out and found it stereochemical correct. Furthermore, influence of the mutation on the stability of the pyrin tertiary structure and development of Familial Mediterranean Fever was also studied in the present study. Total 66 mutations were localized at B30.2 domain of pyrin protein and this domain is responsible for manifestation of Familial Mediterranean Fever. It was also reported that among 66 localized mutations 24 mutations affects the stability of pyrin structure while 25 mutations have neutral effect on the stability and rest 17 mutations have stabilizing effect on the tertiary structure of pyrin.

Familial Mediterranean fever (FMF) is an auto-inflammatory disease characterized by periodic episodes of fever and recurrent polyserositis. It is caused by a dysfunction of pyrin (or marenostrin) as a result of a mutation within the MEFV gene. It occurs most- ly in individuals of Mediterranean origin; however, it has also been reported in non- Mediterranean populations. In this report, we describe the first case of FMF in a Kore- an child. As eight-year-old boy presented recurrent febrile attacks from an unknown cause, an acute scrotum and renal amyloidosis. He also showed splenomegaly, lymphadenopathy, pleural effusion, ascites and elevated acute phase reactants. After MEFV gene analysis, he was diagnosed as FMF combined with amyloidosis.

ABSTRACT. Objective. The gene causing familial Mediterranean fever (FMF)—an autosomal recessive dis- ease characterized by recurrent short episodes of fever associated most commonly with peritonitis, pleuritis, and arthritis— has recently been found and several mu- tations identified. The most severe complication of the disease is amyloidosis, which can lead to renal failure. The aim of this study was to investigate the role of genetic versus nongenetic factors on the phenotype as well as on the development of amyloidosis in FMF in a large and heterogeneous group of patients.

Introduction: In 5%–10% of patients with familial Mediterranean fever (FMF), colchicine is not effective in preventing inflammatory attacks. Another 5%–10% of patients are intoler- ant to effective doses of colchicine and experience serious side effects. Treatment with anti- interleukin-1 (IL-1) drugs may be an alternative for these patients, although it is not reimbursed for this indication in many countries.

Familial Mediterranean fever (FMF) is an autosomal, re- cessively inherited autoinflammatory disease, associated with the MEditerranean FeVer gene (MEFV) and charac- terized by recurrent episodes of fever and serositis, mostly peritonitis, but also pleuritis, pericarditis and synovitis [1,2]. The MEFV gene product is pyrin, a pro- tein thought to play an important role in the regulation of interleukin 1 β (IL1 β ) and thereby of inflammation [3]. To date, according to Infevers, a database dedicated to auto-inflammatory mutations, more than 100 sequence variations have been identified in the MEFV , mostly due to single nucleotide substitutions [4]. Only a small num- ber of these variants are unambiguously pathogenic and

107. Cohen MM, Levy M, Eliakim M. A cytogenic evaluation of long-term colchicine therapy in the treatment of familial Mediterranean fever (FMF). Am J Med Sci. 1977;274:147–152 108. Akar S, Soyturk M, Onen F, Tunca M. The relations between attacks and menstrual periods and pregnancies of familial Mediterranean fever patients. Rheumatol Int. 2006;26: 676 – 679

To clarify mechanisms responsible for the self-limiting and nonerosive features of autoinflammatory joint disease in familial Mediterranean fever (FMF), we performed a study on synovial tissue obtained surgi- cally from an acutely inflamed hip joint from a boy feared to have septic arthritis but later found to be homozygous for mutation M694I in pyrin/ marenostrin. We defined by immunohistology the infiltrating cells and examined the in situ expression of plausible protagonists in synovitis of FMF: myeloperoxidase, lysozyme, galectin 1, galectin 3, p65 (RelA)/ nuclear factor ␬ B, inducible nitric-oxide synthase, cyclooxygenase 2, and cleaved caspase 3. Neutrophils deficient in myeloperoxidase and lysozyme, macrophages, and mast cells outnumbered T and B lympho- cytes as well as plasma cells. Among cells of adaptive immunity, B lymphocytes were predominant. Galectin 1 was detected in numerous cells of the innate immune system throughout the synovial tissue, whereas expression of galectin 3 was less abundant and scattered. p65 (RelA)/nuclear factor ␬ B and inducible nitric-oxide synthase were both upregulated in most of the infiltrating cells. Cyclooxygenase 2 expres- sion was low, and cleaved caspase 3 was undetectable. We conclude that the exquisitely inflammatory yet nondestructive character of FMF arthritis could correlate with the presence of nonpathogenic neutro- phils lacking effector molecules and the widespread expression of anti-inflammatory galectin 1 in regulatory cells of the innate immune system. Intrinsic apoptosis seemed irrelevant for confining synovial autoinflammation, but regulation through pyroptosis or the adaptive immune system remains possible. Pediatrics 2011;128:e464–e470

Abstract: Familial Mediterranean Fever (FMF) is the most prevalent genetic autoin fl am- matory disorder. In most patients, treatment with colchicine can prevent attacks of fever and in fl ammation. However, 5% – 10% of patients are resistant to colchicine treatment, while a similar percentage cannot tolerate colchicine in doses needed to prevent attacks. For these patients, Canakinumab, a full human antibody against IL-1 β , has been approved recently by the FDA and EMA. In this article, we present a systematic review of the long-term ef fi cacy, safety, and tolerability of Canakinumab in FMF patients who cannot tolerate colchicine or who are resistant to colchicine treatment.

AA: Amyloid A; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; BPM: Beats per minute; ESR: Erythrocyte sedimentation rate; FMF: Familial Mediterranean fever; GGT: Gamma- glutamyltransferase; GI: Gastrointestinal; H. pylori : Helicobacter pylori ; HCV: Hepatitis C virus; IFN: Interferon; IL: Interleukin; LPS: Lipopolysaccharide; NLRP3: NOD-like receptor family, pyrin domain containing 3; SAA: Serum amyloid A; SVR: Sustained virological response; TNF: Tumor necrosis factor; WBC: White blood cells

Familial Mediterranean fever (FMF) is an autosomal reces- sive disease that is prevalent among eastern Mediterranean populations, mainly non-Ashkenazi Jews, Armenians, Turks, and Arabs [1]. Patients experience recurrent, self-limiting inflammatory febrile attacks, as well as ab- dominal, chest, and joint pain. The factors that trigger or terminate these periodic attacks are unknown. Some patients with FMF have chronic immune activation, reflected by subtle clinical signs of inflammation, such as chronic normocytic normochromic anemia, spleno- megaly, decreased bone mineral density, persistent eleva- tion of fibrinogen levels and erythrocyte sedimentation rates (ESRs), and growth retardation [2].

Background and Aims: Familial Mediterranean fever (FMF) is a prototype of autoin- fl ammatory disease and mainly associated with MEFV gene mutations. This single-center study as an experience represents FMF-coexisting disease in the FMF registration database. Methods: Four hundred patients who had FMF based on clinical criteria (Tel-Hashomer) and/or MEFV mutations enrolled the study. Twelve most common MEFV mutations (P369S, F479L, M680I (G/C), M680I (G/A), I692del, M694V, M694I, K695R, V726A, A744S, R761H, E148Q) were analyzed if needed by the reverse hybridization assay. Any co- existed disease had been con fi rmed by a related subspecialist. All data were analyzed by a simple analytical method.

Familial Mediterranean fever (FMF) is a genetic, auto- inflammatory disease, characterized by acute episodes of serosal and cutaneous inflammation, expressed with pain, fever, neutrophilia, and intense acute-phase re- sponse, caused by activation of the innate immune system [1]. The FMF gene, named MEFV, is located on the short arm of chromosome 16 [2, 3]. It encodes a 781 – amino acid protein called pyrin or marenostrin which is expressed mostly in neutrophils and acts in controlling inflammation by deactivating inflammatory peptides [4, 5]. Mutated forms of it may be involved in a series of reactions that ultimately enhance the overexpression of IL-1b and consequent inflammation [1]. FMF has been associated with an increased risk for secondary amyloidosis, mainly affecting the renal and

Familial Mediterranean Fever (FMF) is the most common autoinflammatory disease. A mutation of the MEFV gene on chromosome 16, which codes for protein pyrin, is asso- ciated with the disease pathogenesis. Colchicine, which has been prescribed to treat FMF since 1972, remains the main- stay for treatment although its use has been complicated by resistance and intolerance in a minority of patients. Since FMF patients have high levels of certain cytokines, practi- tioners have found in biologics a solution for colchicine re- sistant and intolerant cases given the success that biologics have shown in other autoimmune and auto-inflammatory diseases. Anti-interleukin 1, anti-interleukin 6, anti-TNF, and Janus Kinase inhibitors drugs, can be beneficial add-on to colchicine in treating FMF manifestations.

Familial Mediterranean Fever (FMF) is an autosomal recessive autoinflammatory disease characterized by recurrent attacks of fever and serositis, prevalent among eastern Mediterranean populations. Life-long, daily colchi- cine treatment prevents the recurrence of inflammatory attacks and also the development of AA amyloidosis, which is the most devastating complication of the disease related with increased mortality [1]. Development of AA amyloidosis in a compliant patient on regular prophylactic dose of colchicine is extremely rare. However poor com- pliance is common and intolerance due to side effects may render the patient from receiving the proper dose that will protect from amyloidosis [2].

Abstract: Familial Mediterranean fever (FMF) is the most frequent monogenic autoinflammatory disease, and it is characterized by recurrent attacks of fever and polyserositis. The disease is associated with mutations in the MEFV gene encoding pyrin, which causes exaggerated inflammatory response through uncontrolled production of interleukin 1. The major long-term complication of FMF is amyloidosis. Colchicine remains the principle therapy, and the aim of treatment is to prevent acute attacks and the consequences of chronic inflammation. With the evolution in the concepts about the etiopathogenesis and genetics of the disease, we have understood that FMF is more complicated than an ordinary autosomal recessive monogenic disorder. Recently, recommendation sets have been generated for interpretation of genetic test- ing and genetic diagnosis of FMF. Here, we have reviewed the current perspectives in FMF in light of recent recommendations.

The relationship between FMF and stroke has not been completely studied and it is limited to a case report in children. Seven cases of stroke were reported in 3,034 patients with FMF in Kalyoncu et al's 9 study. Although these patients also had other risk factors, this indicates a high prevalence compared to the general population rates (0.2% vs 0.005 – 0.015 in adults older than 50 years), whether FMF can be considered as a risk factor for stroke is still to be answered; however, some associated disease with FMF, particularly systemic vasculitis, may involve CNS and pre- sents CNS vascular disorders such as stroke and ischemia. 26 There have been some case reports about the coexis- tence of familial Mediterranean fever and posterior rever- sible leukoencephalopathy (PRES); 9 however there was, not any co-existence of stork and PRES in our study.

The disease has been firstly defined as “unusu- al recurrent peritonitis” by Janeway and Mosenthal in a 16-years-old Jewish girl with recurrent fever, abdominal pain and leukocytosis in 1908 (2). It has been described as “benign recurrent peritonitis” by Siegal in 1945 (3), due to the observation of the same clinical findings in 10 patients. One year after, the first case was published in our country (4). The association of the disease with amyloidosis and familial inheritance has been demonstrated by Mamau and Kattan (5) at the beginning of 1950s. Heller et al. (6) has named the disease as “Familial Mediterranean Fever” in 1958, based on its autosomal recessive inheritance trait, its high prevalence in people of Mediterranean origin and its course with recurrent febrile episodes. An important step was made in its treatment in 1972. In the publications of Ozkan et al. (7) and Goldfinger (8), it was reported that colchicine therapy was efficient for preventing amyloidosis in addition to prevention of attacks. Another important ad- vance was that, in 1997, the gene responsible for FMF was cloned on short arm of the Chromosome 16 concomitantly and independently by international FMF Consortium and French FMF Consortium (9–10).

Objective: The aim of our study was to evaluate the clinical features, to define the frequency of mutation type, to assess genotype-phenotype correlation and the response to colchicine in child- hood-onset Familial Mediterranean fever (FMF) in Lebanon. Methods: The characteristics of 550 children, presenting with FMF symptoms between January 2003 and January 2013 and having a positive Mediterranean fever gene (MEFV gene) mutation, were prospectively investigated. The clinical and genetic characteristics as well as the response to colchicine and its side effects were studied in 321 FMF children. The mutations were correlated with clinical presentation and disease severity. Results: Out of the 321 patients (183 males and 138 females), abdominal pain was the most common presenting feature documented in 84.7%. Mutational analysis detected simple he- terozygotes, compound heterozygotes and homozygotes in 56.4%, 30.9% and 11.2% patients re- spectively. The most frequent mutation was M694V (37.2%), followed by E148Q mutation (27.4%). 71% patients received colchicine therapy; only 33.3% of them showed complete response. Geno- type-phenotype correlation showed that M694V followed by E148Q was associated with moderate to severe disease form (71.6% and 62.7% respectively, P = 0.005). There was no association be- tween mutation type and colchicine response. Conclusion: The most important features were the predominance of the M694V and E148Q. The M694V subgroup, followed by E148Q subgroup had a high disease severity score. Our data indicate an enhanced expression of the disease with E148Q mutation.