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1.
Clin Exp Rheumatol ; 38 Suppl 127(5): 49-52, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33331265

RESUMO

OBJECTIVES: The modification and pathogenesis of MEFV exon 2 or 3 variants in familial Mediterranean fever (FMF) remains unclear. We compared the clinical and laboratory characteristics between the coexistence and noncoexistence of MEFV exon 2 or 3 variants in patients with FMF that had a heterozygous MEFV exon 10 mutation. METHODS: We excluded patients with FMF that had two MEFV exon 10 mutations in one or more alleles and/or MEFV mutations in exons other than in exons 2, 3, or 10. Finally, we reviewed 131 Japanese patients with FMF that had a heterozygous MEFV exon 10 mutation, and they were divided into the groups with and without MEFV exon 2 or 3 variants of 97 and 34, respectively. RESULTS: All patients with MEFV exon 2 variants had either E148Q and/or L110P variants, none of patients had exon 3 variants. In the univariate analysis, the group with variants had significantly earlier onset, a higher percentage of thoracic pain with febrile attacks, a higher frequency of attack, and a higher IL-18 level at remission compared to the group without variants (all, p<0.05). Importantly, multivariate analyses showed that the coexistence of MEFV exon 2 variants was independently and significantly associated with earlier onset of FMF and thoracic pain (both, p<0.05). CONCLUSIONS: Our results suggested that coexistence of MEFV exon 2 variants have additional effects on manifestations of FMF with MEFV exon 10 mutations. Our findings highlighted the modifications and pathogenesis of such MEFV variants in FMF.


Assuntos
Febre Familiar do Mediterrâneo , Inflamassomos , Éxons , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/genética , Humanos , Japão , Mutação , Pirina/genética
4.
Nihon Shokakibyo Gakkai Zasshi ; 117(11): 978-984, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-33177260

RESUMO

A 69-year-old man had been intermittently experiencing abdominal pain from his 30s and was diagnosed with colonic diverticulitis. He further experienced right lower abdominal pain and received treatment. However, his condition did not improve, and he was referred to the National Defense Medical College Hospital. His abdominal pain episodes continued even after treatment for few weeks;subsequently, familial Mediterranean fever (FMF) was suspected based on the clinical course because of elevated inflammatory responses, although his body temperature was ≤38°C. After administrating colchicine as a diagnostic treatment, the repeated abdominal pain disappeared. Considering the other findings and genetic examination that showed the representative gene mutation of MEFV (M694I), he was diagnosed with FMF. This case indicates that high body temperature, one of the primary diagnostic criteria of FMF, is sometimes not evident in elderly patients, thereby causing potential misdiagnosis in some elderly patients with FMF.


Assuntos
Doença Diverticular do Colo , Febre Familiar do Mediterrâneo , Dor Abdominal/etiologia , Idoso , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre Familiar do Mediterrâneo/genética , Febre , Humanos , Masculino , Mutação , Pirina/genética
5.
Front Immunol ; 11: 574593, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33072117

RESUMO

Familial Mediterranean Fever (FMF) and COVID-19 show a remarkable overlap of clinical symptoms and similar laboratory findings. Both are characterized by fever, abdominal/chest pain, elevation of C-reactive protein, and leukocytosis. In addition, colchicine and IL-1 inhibitors treatments that are effective in controlling inflammation in FMF patients have recently been proposed for off-label use in COVID-19 patients. Thus, FMF may resemble a milder recapitulation of the cytokine storm that is a hallmark of COVID-19 patients progressing to severe disease. We analyzed the sequence of the MEFV-encoded Pyrin protein - whose mutations cause FMF- in mammals, bats and pangolin. Intriguingly, although Pyrin is extremely conserved in species that are considered either a reservoir or intermediate hosts for SARS-CoV-2, some of the most common FMF-causing variants in humans are present as wildtype residues in these species. We propose that in humans, Pyrin may have evolved to fight highly pathogenic infections.


Assuntos
Betacoronavirus , Colchicina/uso terapêutico , Infecções por Coronavirus , Febre Familiar do Mediterrâneo , Mutação , Pandemias , Pneumonia Viral , Pirina , Animais , Betacoronavirus/genética , Betacoronavirus/imunologia , Proteína C-Reativa/genética , Proteína C-Reativa/imunologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/imunologia , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre Familiar do Mediterrâneo/epidemiologia , Febre Familiar do Mediterrâneo/genética , Febre Familiar do Mediterrâneo/imunologia , Humanos , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Pneumonia Viral/genética , Pneumonia Viral/imunologia , Pirina/genética , Pirina/imunologia
8.
Nat Immunol ; 21(8): 857-867, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32601469

RESUMO

Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by homozygous or compound heterozygous gain-of-function mutations in MEFV, which encodes pyrin, an inflammasome protein. Heterozygous carrier frequencies for multiple MEFV mutations are high in several Mediterranean populations, suggesting that they confer selective advantage. Among 2,313 Turkish people, we found extended haplotype homozygosity flanking FMF-associated mutations, indicating evolutionarily recent positive selection of FMF-associated mutations. Two pathogenic pyrin variants independently arose >1,800 years ago. Mutant pyrin interacts less avidly with Yersinia pestis virulence factor YopM than with wild-type human pyrin, thereby attenuating YopM-induced interleukin (IL)-1ß suppression. Relative to healthy controls, leukocytes from patients with FMF harboring homozygous or compound heterozygous mutations and from asymptomatic heterozygous carriers released heightened IL-1ß specifically in response to Y. pestis. Y. pestis-infected MefvM680I/M680I FMF knock-in mice exhibited IL-1-dependent increased survival relative to wild-type knock-in mice. Thus, FMF mutations that were positively selected in Mediterranean populations confer heightened resistance to Y. pestis.


Assuntos
Resistência à Doença/genética , Febre Familiar do Mediterrâneo/genética , Peste , Pirina/genética , Seleção Genética/genética , Animais , Proteínas da Membrana Bacteriana Externa/imunologia , Proteínas da Membrana Bacteriana Externa/metabolismo , Resistência à Doença/imunologia , Haplótipos , Humanos , Inflamassomos/imunologia , Inflamassomos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Peste/imunologia , Peste/metabolismo , Pirina/imunologia , Pirina/metabolismo , Turquia , Fatores de Virulência/imunologia , Fatores de Virulência/metabolismo , Yersinia pestis
9.
Intern Med ; 59(11): 1373-1378, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32475906

RESUMO

Objective Familial Mediterranean Fever (FMF) is the most frequent autoinflammatory syndrome, and its frequency is reported to be increasing in Japan. We studied the clinical features and genetic background of patients with FMF in our hospital. Methods We analyzed the clinical features and genomic variants of MEFV, as well as 10 genes related to other autoinflammatory syndromes, in 22 Japanese patients with FMF. A genetic analysis was performed with a next generation sequencer. Results The patients were classified into the typical FMF (n=16) and atypical FMF (n=6) groups. Fever, abdominal pain, thoracic pain, and arthralgia were observed in 22, 12, 8, and 10 patients, respectively. MEFV variants were found in 19 patients (86.4%). Two cases had no MEFV variants and one case only had a variant in the 3' untranslated region (3'-UTR) of MEFV. Genomic variants were found in genes other than MEFV in 7 patients (31.8%); however, none met the diagnostic criteria for autoinflammatory syndromes with disease-related gene variants, and all were classified as typical FMF. Moreover, none of the 6 patients with atypical FMF had any variants among the 10 disease-related genes. All cases in which the onset occurred before 20 years of age were classified as typical FMF. Conclusion The clinical features of FMF recorded in our hospital coincided with those from the Japanese national epidemiological survey of FMF in Japan. More than 30% of the patients with FMF had non-MEFV genes, related to other autoinflammatory syndromes, thereby suggesting that variants of these genes may act as a disease-modifier in FMF.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Febre Familiar do Mediterrâneo/genética , Febre Familiar do Mediterrâneo/fisiopatologia , Predisposição Genética para Doença , Pirina/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Análise Mutacional de DNA , Testes Diagnósticos de Rotina , Febre Familiar do Mediterrâneo/diagnóstico , Feminino , Humanos , Lactente , Recém-Nascido , Japão , Masculino , Pessoa de Meia-Idade , Adulto Jovem
10.
Ann Rheum Dis ; 79(7): 960-968, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32312770

RESUMO

BACKGROUND AND OBJECTIVE: Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease (AID) worldwide. The disease is caused by mutations in the MEFV gene encoding the inflammasome sensor Pyrin. Clinical diagnosis of FMF is complicated by overlap in symptoms with other diseases, and interpretation of genetic testing is confounded by the lack of a clear genotype-phenotype association for most of the 340 reported MEFV variants. In this study, the authors designed a functional assay and evaluated its potential in supporting FMF diagnosis. METHODS: Peripheral blood mononuclear cells (PBMCs) were obtained from patients with Pyrin-associated autoinflammation with an FMF phenotype (n=43) or with autoinflammatory features not compatible with FMF (n=8), 10 asymptomatic carriers and 48 healthy donors. Sera were obtained from patients with distinct AIDs (n=10), and whole blood from a subset of patients and controls. The clinical, demographic, molecular genetic factors and other characteristics of the patient population were assessed for their impact on the diagnostic test read-out. Interleukin (IL)-1ß and IL-18 levels were measured by Luminex assay. RESULTS: The ex vivo colchicine assay may be performed on whole blood or PBMC. The functional assay robustly segregated patients with FMF from healthy controls and patients with related clinical disorders. The diagnostic test distinguished patients with classical FMF mutations (M694V, M694I, M680I, R761H) from patients with other MEFV mutations and variants (K695R, P369S, R202Q, E148Q) that are considered benign or of uncertain clinical significance. CONCLUSION: The ex vivo colchicine assay may support diagnosis of FMF and functional subtyping of Pyrin-associated autoinflammation.


Assuntos
Febre Familiar do Mediterrâneo/diagnóstico , Imunofenotipagem/métodos , Pirina/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Criança , Pré-Escolar , Colchicina/análise , Febre Familiar do Mediterrâneo/genética , Feminino , Estudos de Associação Genética , Humanos , Leucócitos Mononucleares , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Pirina/genética , Adulto Jovem
11.
Arerugi ; 69(1): 53-58, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32051370

RESUMO

We report an adult case of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome, who had a tonsillectomy at 10 years old and relapsed later. An early 40's-year-old man had been suffering from recurrent fever attack once in 1-2 months during childhood. He was accompanied by fever which was persist for several days, aphthous stomatitis, tongued tonsillitis with moss, pharyngitis, and submandibular lymphadenitis with tenderness. He was not doing well during fare-up. At the time of admission, CRP level was 12.5mg/dl and the remarkably increased expression of CD64 on neutrophils was found. Bacterial infections and collagen diseases were excluded by the several examinations. We suspected PFAPA syndrome, and treated with cimetidine, but cimetidine was not effective. At the time of flare up, administration of prednisolone was remarkably effective. We diagnosed PFAPA syndrome on the basis of clinical courses. Genetic analysis of responsible gene of familial Mediterranean fever, MEFV showed E148Q heterozygous mutation in exon 2.Since an adult case of PFAPA syndrome is likely to be made misunderstanding for infectious recurrent pharyngitis, it is important to note that we should consider PFAPA syndrome as a differential diagnosis when we meet with the adult patient of recurrent fever.


Assuntos
Febre/diagnóstico , Linfadenite/diagnóstico , Faringite/diagnóstico , Pirina/genética , Estomatite Aftosa/diagnóstico , Adulto , Criança , Humanos , Masculino , Recidiva , Síndrome
12.
Mol Biol Rep ; 47(3): 1835-1843, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31989427

RESUMO

Familial Mediterranean fever is an auto inflammatory genetic disease involving especially Turks, Armenians, Arabs and non-Ashkenazi Jews and caused by variants in the MEFV gene. In this study, we aimed to evaluate the distribution and frequency of clinical, MEFV gene variants in FMF patients and the relationship between mutations in different exons and phenotype-genotype and clinical findings. 1028 patients diagnosed as FMF were included. The most common genotypes were M694V / R202Q heterozygous (10.4%), M694V homozygous (7.5%), M694V / E148Q / R202Q heterozygous (4.6%), V726A heterozygous (4.5%), M680I heterozygous (4.2%). c.1611-1 G > C, G152R, S104C, R116S, E336K, R461Q mutations were detected in the literature for the first time in FMF patients. We also divided the patients into 4 groups according to whether the MEFV mutations were exon 10 or non-exon 10. The first group consisted of non-exon 10 homozygous or compound heterozygous (n = 180) patients, Group 2 consisted of exon 10- non-exon 10 compound heterozygous (n = 318) patients, Group 3 consisted of exon 10 homozygous or compound heterozygous (n = 256) patients, while Group 4 consisted of heterozygous (n = 227) patients at any exon. There was no significant difference between the groups in terms of abdominal pain, arthritis, arthralgia, vomiting diarrhea, erysipelas like rash, amyloidosis, renal failure family history. There was no difference in fever between Group 1 (55.6%) and 2 (62.3%); however, these two groups were different from Group 3 (75.8%) and 4 (76.7%). Group 3 (18.8%) had the highest rate of appendectomy. In addition, allele frequencies of all mutations detected in the analyses were compared with allele frequencies of healthy people in the gnomad database. It is useful to analyse all exons in the MEFV gene with the next generation sequence analysis in the detection of FMF disease. S104C, R116S, G152R, E336K, R461Q, L508Q and c.1611-1 G > C mutations are also new variants in literature. c.1611-1 G > C is a possible pathogenic variant.


Assuntos
Febre Familiar do Mediterrâneo/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Mutação , Pirina/genética , Adolescente , Adulto , Éxons , Feminino , Frequência do Gene , Estudos de Associação Genética , Humanos , Masculino , Análise de Sequência de DNA/métodos , Adulto Jovem
13.
Mod Rheumatol ; 30(3): 564-567, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31116049

RESUMO

Objectives: Most patients with familial Mediterranean fever (FMF) have their first attack at age < 20 years. Information about late-onset (age ≥40 years) FMF is limited. We aimed to evaluate the demographic, clinical, and genetic characteristics of late-onset FMF patients in the Japanese population.Methods: We retrospectively analyzed 292 patients with FMF. Patients were divided into three groups according to age of disease onset: Group I, ≤19 years; Group II, 20-39 years; and Group III, ≥40 years.Results: Of 292 patients, 44 (15.1%) experienced their first attack at age ≥40 years. While high fever (97.7%) and arthritis (45.5%) were common symptoms in Group III patients, peritonitis (40.9%) and pleuritis (25.0%) were significantly lower than in other groups. The frequency of patients carrying p.M694I (18.2%), which is the most representative mutation in Japan, was significantly lower in Group III than in Group I. The response to colchicine therapy was good (95.1%) and similar in all groups.Conclusions: In Japan, more patients than expected had late-onset FMF. They had a milder form of disease, with less frequent peritonitis and pleuritis. The response to colchicine treatment was good. Clinicians should consider FMF for patients with unexplained recurrent febrile episodes, regardless of age.


Assuntos
Febre Familiar do Mediterrâneo/epidemiologia , Adolescente , Adulto , Idade de Início , Artrite/epidemiologia , Colchicina/uso terapêutico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre Familiar do Mediterrâneo/genética , Febre Familiar do Mediterrâneo/patologia , Feminino , Febre/epidemiologia , Humanos , Japão/epidemiologia , Masculino , Mutação , Pleurisia/epidemiologia , Pirina/genética
14.
Rheumatology (Oxford) ; 59(3): 554-558, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31384939

RESUMO

OBJECTIVES: Hereditary systemic autoinflammatory diseases are rare genetic disorders, which if untreated, can be complicated by AA amyloidosis leading to renal failure and premature death. Our objective was to find a genetic cause in a British family with a dominantly inherited autoinflammatory disease complicated by AA amyloidosis. METHODS: The index patient and his sister underwent comprehensive clinical and laboratory assessment including the next-generation sequencing panel targeting autoinflammatory genes. Subsequently, other relatives underwent clinical evaluation and genetic testing. Screening of the SAA1 gene was performed in all symptomatic cases. RESULTS: The index case and his sister presented with proteinuria due to AA amyloidosis. They have been suffering from episodes of fever accompanied by severe abdominal and chest pain, arthritis and erythema since childhood. Their father died aged 52 years from complications following a cadaveric renal transplantation. The post-mortem examination demonstrated AA amyloidosis. The index case's grandmother, two paternal cousins and two of their children described similar symptoms. All symptomatic individuals had excellent responses to colchicine. Next-generation sequencing analysis identified a single MEFV p.P373L variant in the index case, his sister and subsequently, in symptomatic family members. Sequencing of the SAA1 gene revealed all cases were heterozygous for the SAA1.1 allele. CONCLUSION: Typically FMF is an autosomal recessive disorder; nonetheless rare cases of dominantly inherited disease have previously been described. Here we report a novel MEFV variant p.P373L, causing dominant FMF complicated by AA amyloidosis in four generations of a British family.


Assuntos
Amiloidose/genética , Febre Familiar do Mediterrâneo/genética , Pirina/genética , Adulto , Amiloidose/tratamento farmacológico , Colchicina/uso terapêutico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Resultado do Tratamento , Moduladores de Tubulina/uso terapêutico
15.
Clin Rheumatol ; 39(2): 585-594, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31401792

RESUMO

An 86-year-old Caucasian man had prior episodes of fever (up to 38 °C), mild abdominal pain, tachycardia, and malaise in the last 3 months, lasting 2-3 days. He never suffered from abdominal or chest pain, rash, or arthralgia. Major causes of fever were excluded (pulmonary, urinary, abdomen, skin infections, neoplasms, and major rheumatologic disorders). The patient was native of Altamura with a family history of familial Mediterranean fever (FMF). The genetic testing confirmed the presence of MEFV gene variants c.442G>C (E148Q) on exon 2 and c.2282G>A (R761H) on exon 10, all in heterozygosity. Mildly elevated serum transaminases suggested an ongoing form of FMF hepatitis on nonalcoholic liver steatosis. The patient started colchicine 1 mg/day that induced symptom control and normalization of inflammatory markers, hyperbilirubinemia, and markers of cholestasis. Symptoms of FMF can appear at any age in life and our patient represents a very late-onset clinical case. The Apulian region has a consistent clustering of MEFV variants and FMF families with affected individuals in multiple consecutive generations. Families show unique clinical features and rare signs of secondary amyloidosis without kidney damage. Genetic and environmental bases of this phenotypic variant are under scrutiny. Colchicine lifetime remains the mainstay of treatment in FMF patients. KEY POINTS: • Familial Mediterranean fever (FMF) is the most frequent hereditary monogenic recurrent fever syndrome, and symptoms can appear at any age in life. • Late-onset FMF approaches 30% in late adulthood, but in general, onset of FMF after the age of 40 (late onset FMF) is rare, usually associated with M694V heterozygosity. • In a local cluster of FMF families (Altamura, Puglia, Southern Italy), we report a very late-onset FMF (variants E148Q, R761H) in an 86-year-old patient with a positive family history of FMF in two generations of descendants. • While lifetime colchicine remains the mainstay of treatment in FMF patients, prospective studies need to identify the characteristics of several phenotypic variants accounting for (very)-late onset FMF.


Assuntos
Febre Familiar do Mediterrâneo/genética , Pirina/genética , Idade de Início , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Linhagem
16.
Scand J Rheumatol ; 49(2): 154-158, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31478409

RESUMO

Objective: Prodrome is defined by manifestations that precede a familial Mediterranean fever (FMF) attack and predict its emergence. We aimed to determine the frequency, characteristics, and clinical determinants of prodrome in patients with FMF.Method: This cross-sectional study was conducted in a tertiary rheumatology clinic. During the clinical interview, all patients completed a standardized questionnaire about the pre-attack period. Prodrome was defined as the presence of any recurrent pre-attack manifestation occurring at least 4 h before an attack. Patients were classified according to whether they had prodrome of any kind of attack.Results: The study enrolled 401 patients aged 37.7 ± 11.0 years (mean ± sd). Male gender, M694V/M694V, homozygous MEFV mutation, peritonitis, pleuritis, and arthritis were more frequent in prodrome-positive patients. Altogether, 141 patients (35.2%) had prodrome. Male gender and ever having attack types of peritonitis or arthritis were independent clinical determinants of prodrome [relative risk (95% confidence interval): 1.72 (1.07-2.76), p = 0.02; 4.27 (1.80-10.1), p = 0.001; 1.77 (1.04-3.04), p = 0.04, respectively]. Age, MEFV mutations, pleuritis, and erysipelas-like erythema were not clinical determinants.Conclusions: All FMF patients, particularly males and patients who had peritonitis or arthritis at any time, should be questioned about prodrome. Prodrome should be analysed in terms of elucidating the pathogenesis of FMF and as an opportunity for a secondary prevention strategy for impending attacks. This study may shed light on prodrome for future cytokine or drug studies with the purpose of developing new cost-effective treatment protocols irrespective of colchicine resistance.


Assuntos
Febre Familiar do Mediterrâneo/complicações , Sintomas Prodrômicos , Adulto , Colchicina/uso terapêutico , Estudos Transversais , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre Familiar do Mediterrâneo/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Pirina/genética
17.
Clin Rheumatol ; 39(1): 255-261, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31502094

RESUMO

INTRODUCTION/OBJECTIVES: Familial Mediterranean fever (FMF) is characterized by recurrent attacks of fever, serositis, and arthritis, but some patients may experience long-term complications of disease such as infertility/subfertility. The published data about FMF-associated infertility is still limited. The aim of this study is to investigate the frequency and to determine potential factors for FMF-associated infertility/subfertility. METHODS: We enrolled 971 adult patients with FMF. We defined infertility as the failure to conceive after 12 months of regular, unprotected intercourse. All patients fulfilled Tel Hashomer criteria. Demographic data, FMF disease characteristics and genotype data (if available), disease complications, laboratory parameters, and treatment features were recorded. RESULTS: There were 582 subjects eligible for the present study (mean age 41.05 ± 10.6 years, 65.8% female). MEFV mutations were available in 482 subjects, and 74.9% of subjects were harboring M694 V mutation (25.1% homozygous for M694 V). Infertility was present in 64 patients (14.6% of females and 4% of males). Multivariate analysis showed female sex [odds ratio (OR), 4.47; 95% confidence interval (CI95%) 1.75-11.42; p = 0.002], FMF disease onset < 20 years [OR, 2.99; (CI95% 1.04-8.61);p = 0.04], disease severity (ISSF) [OR, 4.81; (CI95% 2.28-10.17); p < 0.001], and colchicine nonresponse [OR, 2.80; (CI95% 1.17-6.74) p = 0.021] were the independent predictors of infertility. We also observed reversal of infertility in five patients who were treated with IL-1 ß antagonists. CONCLUSION: Disease severity, FMF disease onset < 20 years, colchicine nonresponse, and female sex were found to be the independent predictors of infertility. The value of effective therapeutic interventions must be determined to treat infertility in these patients.Key Points•The prevalence of infertility increased in female patients with FMF.• Female sex, FMF disease onset < 20 years, disease severity, and colchicine nonresponse were risk factors for FMF-associated infertility.• With effective treatment of FMF, reversal of infertility was observed in five patients.


Assuntos
Febre Familiar do Mediterrâneo/complicações , Infertilidade/etiologia , Adulto , Colchicina/uso terapêutico , Progressão da Doença , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre Familiar do Mediterrâneo/genética , Feminino , Genótipo , Homozigoto , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Mutação , Pirina/genética , Fatores de Risco , Índice de Gravidade de Doença , Turquia/epidemiologia
18.
Rheumatology (Oxford) ; 59(6): 1372-1380, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31598713

RESUMO

OBJECTIVES: FMF is the most common periodic fever syndrome, characterized by recurrent episodes of fever and serosal inflammation accompanied with high acute phase reactants. The analysis of possible comorbidities is important to understand the impact of these conditions on clinical care and whether they share a common aetiological pathway. In this study, we aimed to evaluate the comorbidities associated with FMF patients in a large genetically diagnosed cohort. METHODS: We retrospectively evaluated the medical and genetic records of FMF patients who were followed up by rheumatologists in Hacettepe University for 15 years. The FMF patients who had homozygous or compound heterozygous mutations were included in the study. Comorbidities associated with FMF were divided into three groups: (i) comorbidities directly related to FMF, (ii) comorbidities due to increased innate inflammation, and (iii) comorbidities that were regarded as being incidental. RESULTS: A total of 2000 patients with a diagnosis of FMF were enrolled in the study. Among them 636 were children (31.8%) and M694V was the most common mutation in patients with associated inflammatory conditions. The frequency of AS, Iga Vasculitis (Henoch-Schönlein purpura), juvenile idiopathic arthritis, polyarteritis nodosa, multiple sclerosis and Behçet's disease were increased in patients with FMF when compared with those in the literature. CONCLUSION: This study represents the largest genetically confirmed cohort and compares the frequencies with existing national and international figures for each disease. The increased innate immune system inflammation seen in FMF may be considered as a susceptibility factor since it predisposes to certain inflammatory conditions.


Assuntos
Febre Familiar do Mediterrâneo/epidemiologia , Febre Familiar do Mediterrâneo/genética , Doenças Genéticas Inatas/epidemiologia , Doenças Genéticas Inatas/genética , Pirina/genética , Adolescente , Adulto , Amiloidose/epidemiologia , Amiloidose/genética , Artrite Juvenil/epidemiologia , Artrite Juvenil/genética , Síndrome de Behçet/epidemiologia , Síndrome de Behçet/genética , Criança , Comorbidade , Feminino , Humanos , Masculino , Esclerose Múltipla/epidemiologia , Esclerose Múltipla/genética , Mutação , Poliarterite Nodosa/epidemiologia , Poliarterite Nodosa/genética , Púrpura de Schoenlein-Henoch/epidemiologia , Púrpura de Schoenlein-Henoch/genética , Estudos Retrospectivos , Adulto Jovem
19.
Scand J Rheumatol ; 49(2): 131-136, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31657276

RESUMO

Objective: Osteomyelitis (OM) is an acute or chronic inflammatory process, characterized by severe inflammation and progressive bone destruction. Limited efforts have been made to explore the genetic basis of OM.Method: The genome-wide association study data set of OM was obtained from the UK Biobank. A transcriptome-wide association study (TWAS) of OM was conducted by the FUSION tool using the gene expression reference weights of lymphocytes and blood. The OM-associated genes identified by TWAS were subjected to gene ontology (GO) enrichment analysis to explore OM-related gene sets. The TWAS results of OM were finally compared with a genome-wide mRNA expression profiling of OM to detect common genes and gene sets.Results: TWAS of OM detected 86 genes for lymphocytes and 387 genes for blood. Comparing the genes identified by TWAS and mRNA expression profiling detected eight common genes for OM, including VWF (pTWAS = 0.0030, pmRNA = 3.44 × 10-9), CCDC50 (pTWAS = 0.0130, pmRNA = 0.0003), and TPD52 (pTWAS = 0.0180, pmRNA = 1 × 10-6). GO analysis of the genes identified by TWAS detected multiple OM-associated GO terms, e.g. peroxisomal matrix (pTWAS = 0.0082), extracellular exosome (pTWAS = 0.0248), and monooxygenase activity (pTWAS = 0.0040). Further comparing the GO results of TWAS and mRNA expression profiling detected one common GO term, named extracellular exosome (pTWAS = 0.0248, pmRNA = 0.0027).Conclusion: This integrative study of TWAS and mRNA expression profiling detected multiple candidate genes and GO terms for OM. Our results provide novel clues for understanding the pathogenesis of OM.


Assuntos
Perfilação da Expressão Gênica , Osteomielite/genética , Transcriptoma , Adulto , Idoso , Exossomos , Ontologia Genética , Estudo de Associação Genômica Ampla , Humanos , Pessoa de Meia-Idade , Osteomielite/etiologia , Pirina/genética , RNA Mensageiro/análise
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