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1.
Artigo em Inglês | MEDLINE | ID: mdl-31840168

RESUMO

OBJECTIVES: CYC remains an important treatment option for Behçet's syndrome (BS) patients with life-threatening manifestations. However, adverse events may occur with CYC and this has led to increased use of biologic agents in other vasculitides. We investigated short and long term adverse events associated with CYC use in BS patients. METHODS: We conducted a retrospective chart review of all BS patients treated with CYC between 1972 and 2006. Patients were called in and a standard form was used for collecting demographic characteristics, indication for CYC, its cumulative dose and short term adverse events, defined as those causing discontinuation of CYC, hospitalization and/or death, long term adverse events, including infertility and malignancy, and outcome. RESULTS: Of 5790 BS patients, 198 (3.4%) had used at least one dose of CYC. Main indications were vascular or neurological involvement. After a median follow-up of 17 years, 52 (26%) patients had died, 113 (57%) could be contacted, and 33 (17%) were lost to follow-up. Vascular involvement was the leading cause of death (n = 27). Seventeen (9%) patients experienced short term adverse events with haemorrhagic cystitis being the most common. After a median follow-up of 25 years (interquartile range: 15-26 years), 17 malignancies occurred in 15 (8%) patients. Infertility was experienced by 26 (30%) patients. CONCLUSION: Long term adverse events such as malignancy and infertility were major problems in our BS patients treated with CYC. These results underline the need for safer treatment modalities that are at least as effective as CYC.

2.
Clin Exp Rheumatol ; 37 Suppl 121(6): 111-115, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31856937

RESUMO

OBJECTIVES: The efficacy and safety of biosimilar infliximab (bio-IFX) was shown in randomised controlled trials and it was approved for all indications of the reference product in several countries. However, a previous case series of 3 patients with Behçet's syndrome (BS) reported disappointing results. We aimed to share our experience with bio-IFX treatment in different types of organ involvement in patients with BS. METHODS: We reviewed the charts of all BS patients who were prescribed reference infliximab (ref-IFX) or bio-IFX in our BS clinic. Among the 181 BS patients who were prescribed IFX since 2003, 6 (3%) were prescribed bio-IFX due to refractory disease despite conventional immunosuppressives. RESULTS: A total of 6 patients (mean age: 32.1±6.2, mean disease duration: 5.3±1.8 years, 5 men and 1 woman) received bio-IFX for uveitis, nervous system, vascular and joint involvement. Four of the 6 patients obtained remission and stayed in remission during the 16±6.5 months they used bio-IFX. Among the 4 patients who obtained remission, 2 were switched to ref-IFX due to unavailability of bio-IFX infusion set and did not experience adverse events or loss of efficacy. However, relapses occurred during tapering. The other 2 patients are still in remission with bio- IFX. Among the remaining 2 patients, one had to be switched to ref-IFX after the first infusion, due to a change in the reimbursement policy and the other was non-responsive. CONCLUSIONS: Our limited experience showed that bio-IFX may be a safe and effective alternative for patients with BS, refractory to conventional immunosuppressives.


Assuntos
Síndrome de Behçet , Medicamentos Biossimilares , Infliximab/uso terapêutico , Adulto , Síndrome de Behçet/tratamento farmacológico , Medicamentos Biossimilares/uso terapêutico , Feminino , Humanos , Masculino , Resultado do Tratamento , Uveíte/tratamento farmacológico
3.
Clin Exp Rheumatol ; 37 Suppl 121(6): 125-131, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31856938

RESUMO

OBJECTIVES: Systemic therapy aimed at suppressing the diffuse inflammation in the vessel wall is the major treatment modality for venous thrombosis in Behçet's syndrome (BS). Endovascular and/or surgical interventions are also used. We here report five patients who were referred to our clinic after having such interventions and also present a literature review to assess the outcome of invasive procedures for venous thrombosis in BS. METHODS: Our patients were presented and a literature search for endovascular and/or surgical interventions in Pub-Med was performed. Recanalisation, reocclusion or other complications were assessed as outcomes. RESULTS: Five BS patients with lower extremity thrombosis were referred to our clinic with post thrombotic syndrome due to incomplete recanalisation or infectious complication after endovascular interventions. Twenty-one articles reporting on 36 patients were found suitable for review. There were totally 21 lower extremity venous intervention cases, 14 of which had failure such as complication, reocclusion or incomplete recanalisation. Reocclusions occurred in 10 patients and reinterventions to 8 of them could restore flow only in 4 cases. Ileal infarct and vena cava wall-duodenal perforation were major complications. Invasive procedures of 8 abdominal thrombosis cases resulted with death due to ileus in one patient, and reocclusion in another. Seven of the 12 upper extremity/superior vena cava thrombosis cases resulted with reocclusions. CONCLUSIONS: Endovascular and surgical interventions seemed to be unsuccessful because of recurrent infectious and vascular complications in 22 (53.6%) of 41 patients with venous thrombosis. The indication of these procedures is controversial. Their economic burden on the healthcare system must be considered.


Assuntos
Síndrome de Behçet , Trombose Venosa , Síndrome de Behçet/complicações , Terapia Combinada , Humanos , Terapia Trombolítica , Trombose , Resultado do Tratamento , Trombose Venosa/tratamento farmacológico , Trombose Venosa/etiologia , Trombose Venosa/cirurgia
4.
Clin Exp Rheumatol ; 37 Suppl 121(6): 3-17, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31856939

RESUMO

Several epidemiologic studies report on the prevalence of Behçet's syndrome (BS) and demographic and clinical findings in patients from different countries and ethnicities. Although these studies point out geographic differences in disease course, methodologic differences make it difficult to compare the results of these studies. Recent data suggest that neutrophil extracellular trap levels are elevated in patients with BS, and that it may be a potential therapeutic target for the reduction or prevention of BS-associated thrombotic risk. Details on the mode of functioning of ERAP have been delineated and further epigenetic data reported. Wall thickness of lower extremity veins is increased among BS patients without any apparent clinical involvement. Magnetic resonance (MR) venography and Doppler ultrasonography (USG) were comparable in the diagnosis of chronic deep vein thrombosis, while MR venography is more effective in detecting collateral formations. Results were also collected on some dietary and non-dietary factors in triggering oral ulcers, while smoking seems to have a protective role. With regards to the therapy, it has been demonstrated that endovascular interventions carry the risk of inducing pathergy phenomenon. Apremilast has been convincingly shown to be useful for oral ulcers of BS and classical immunosuppressives are effective as first line therapy in more than half of patients with uveitis. While infliximab and adalimumab seem to be equally effective in the treatment of refractory uveitis of BS, the combination of adalimumab and immunosuppressives appears to be superior to immunosuppressives alone for venous thrombosis of the extremities. In addition, tocilizumab might be an alternative to anti-TNF agents for patients with arterial involvement refractory to immunosuppressives. On the other hand, the place of IL-17 inhibition in the treatment of BS still remains questionable.


Assuntos
Síndrome de Behçet , Imunossupressores/uso terapêutico , Adalimumab , Síndrome de Behçet/complicações , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/tratamento farmacológico , Predisposição Genética para Doença , Humanos , Úlceras Orais/etiologia , Prevalência , Fator de Necrose Tumoral alfa/uso terapêutico , Uveíte/etiologia , Trombose Venosa/etiologia
5.
Clin Exp Rheumatol ; 36(6 Suppl 115): 13-27, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30582516

RESUMO

New epidemiologic studies from Poland, Jordan, Algeria, Taiwan and Korea highlight the geographic differences in incidence, prevalence and clinical features of Behçet's syndrome (BS). A study from Austria comparing clinical manifestations of their BS patients with different countries of origin suggest that environmental factors may be important in the disease phenotype of BS. New genetic association studies dealing with the innate and acquired aspects of BS prevailed during 2017 and novel susceptibility and regulatory factors were described. Common denominators among various disease processes were again highlighted and epigenetic factors were emphasised. "Bagel sign" pattern, a central lesion with hypo-intense core and hyper-intense rim was defined in the spinal MRIs of the patients with neuro-BS especially during the acute attacks of myelopathy. This distinctive pattern suggests venous thrombosis and surrounding oedema in the spinal cord. Pseudotumour cerebri may present with similar clinical presentation to that observed in cerebral venous sinus thrombosis, responds well to immunosuppressive treatment, and could be associated with venous thrombotic relapses. Menstruation and certain food appear to exacerbate skin and mucosa lesions in BS. The EULAR recommendations for the treatment of BS have been updated with 5 new overarching principles and one additional recommendation for surgical management of vascular complications. Infliximab initiated earlier in the course of uveitis yields a better visual outcome. Tapering or stopping of anti-TNF agents seem to be possible when remission has been achieved. Adalimumab appears to be more effective for venous thrombosis than classical immunosuppressives. Oral anticoagulants might not be crucial for cerebral or peripheral venous thrombosis. Transcatheter embolisation of pulmonary aneurysms may be life-saving by providing immediate control of haemoptysis. The results of surgery for pulmonary artery involvement appear to be satisfactory.


Assuntos
Síndrome de Behçet , Animais , Síndrome de Behçet/diagnóstico por imagem , Síndrome de Behçet/tratamento farmacológico , Síndrome de Behçet/epidemiologia , Síndrome de Behçet/imunologia , Progressão da Doença , Predisposição Genética para Doença , Humanos , Imunossupressores/uso terapêutico , Fenótipo , Fatores de Risco , Resultado do Tratamento
6.
Rheumatol Int ; 38(4): 607-622, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29322343

RESUMO

Rituximab (RTX) is becoming a standard treatment for patients with anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) but heterogeneity exists regarding its use. We present our uncontrolled experience with RTX in patients with refractory AAV and also the results of a systematic review of non-randomized studies on RTX in AAV patients. We retrospectively reviewed the records of AAV patients treated with RTX following an inadequate response to immunosuppressives between 2011 and 2015. The systematic review covered all English articles listed in PubMed until June 2017. There were 25 AAV patients (21 GPA, four unclassified) treated with RTX (median 2, IQR 1-3 courses; median follow-up 24, IQR 17-50 months). The kidney and the lung were the most commonly affected organs, observed in 14 and 16 patients, respectively. Complete remission rate was 72% at month 6 and 88% at month 12. Two patients had died and three serious adverse events occurred. The systematic review included 56 studies on 1422 patients with the majority being on refractory or relapsing disease. There was wide variability regarding disease characteristics, endpoints, concomitant immunosuppressives and RTX schedule. Most studies reported > 80% complete or partial remission rates with the lowest response (37.5%) for granulomatous lesions. The relapse rate was 30%. Infections and infusion reactions were the main adverse events. Our experience with RTX in refractory AAV is in line with the literature in terms of efficacy and safety. The systematic review underlines many uncertainties on its optimal use.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Rituximab/uso terapêutico , Adulto , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/sangue , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/mortalidade , Anticorpos Anticitoplasma de Neutrófilos/sangue , Biomarcadores/sangue , Feminino , Humanos , Fatores Imunológicos/efeitos adversos , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Estudos Retrospectivos , Rituximab/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
7.
Clin Exp Rheumatol ; 35 Suppl 108(6): 3-15, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28980900

RESUMO

A meta-analysis showed that methodological differences in prevalence studies such as a sample survey design or census design may be responsible for some of the variance in BS prevalence reported across countries, in addition to a true geographic variation. Efforts towards developing a data driven core set of outcome measures for clinical trials is continuing. Multimodal imaging using color fundus photography, fluorescein angiography, and optical coherence tomography is essential in visualising diagnostic features, detecting structural changes, and monitoring disease activity and response to treatment in Behçet's uveitis. Haemoptysis could also be due to bronchial artery enlargement in BS patients with pulmonary artery involvement and can be effectively treated with embolisation. Recent studies shed light on the link between immune system and thrombosis: fibrin clots seemed to be structurally different and plasmin resistant in BS. Newer genetic associations using immunochip were determined, but HLA-B51 is still the principal genetic link. Various studies on micro-RNA's, important molecules of immune regulation were published and discussed. Anti-TNF agents are still the key biologics for the treatment of various manifestations of BS. Two Phase III trials enrolling a small number of BS patients have shown the efficacy of adalimumab in the treatment of non-infectious, non-anterior uveitis. Interferon-alpha was found to induce long-lasting drug free remissions in a retrospective study. Small observational studies with non-TNF biologics such as ustekinumab, anakinra and canakinumab report beneficial results which await confirmation with further studies.


Assuntos
Síndrome de Behçet , Síndrome de Behçet/diagnóstico por imagem , Síndrome de Behçet/tratamento farmacológico , Síndrome de Behçet/epidemiologia , Síndrome de Behçet/genética , Produtos Biológicos/uso terapêutico , Progressão da Doença , Predisposição Genética para Doença , Humanos , Imunossupressores/uso terapêutico , Imagem Multimodal , Valor Preditivo dos Testes , Prevalência , Fatores de Risco , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores
8.
Clin Exp Rheumatol ; 34(6 Suppl 102): 10-22, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27791958

RESUMO

Several articles highlighting the epidemiology, pathogenesis, clinical features, treatment modalities and disease assessment of Behçet's syndrome (BS) have been published during the last year. Clinical and radiological features of lower extremity deep vein thrombosis due to BS can be quite different than those found in thrombosis due to other causes; additionally, frequency of post-thrombotic syndrome is significantly increased in BS. Some clinical and colonoscopic features are useful in differentiating BS from Crohn's disease. Barkhof criteria may be helpful in differentiating neurologic involvement due to BS from multiple sclerosis. Anatomical localization of papulopustular lesions but not histology has been found to be helpful in differentiating papulopustular lesions of BS from those found in acne vulgaris. Several studies looked at the ovarian reserve with contradicting results. A population-based cohort study found higher risk of hematological malignancies only among female BS patients living in Taiwan. The role of genetic factors and environment is discussed and both autoimmune and autoinflammatory features are underlined in the pathogenesis of BS. New data on the epistatic interactions between ERAP and HLA B51 is available and information on the microbiome have started to appear. New uncontrolled data suggest beneficial effects of anti-TNFs for refractory extra-ocular complications of BS such as pulmonary artery, gastrointestinal and central nervous system involvement. Uncontrolled studies suggest promising results with interleukin-1 inhibition but gevokizumab, a humanised anti IL-1ß antibody, failed to meet the primary endpoint of time to first ocular exacerbation in a phase III trial. The debate on anticoagulation continues with new observational data.


Assuntos
Síndrome de Behçet , Animais , Anticoagulantes/uso terapêutico , Síndrome de Behçet/tratamento farmacológico , Síndrome de Behçet/epidemiologia , Síndrome de Behçet/genética , Síndrome de Behçet/imunologia , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Imunossupressores/uso terapêutico , Mediadores da Inflamação/imunologia , Masculino , Fenótipo , Valor Preditivo dos Testes , Fatores de Risco , Índice de Gravidade de Doença , Resultado do Tratamento
9.
Clin Exp Rheumatol ; 33(6 Suppl 94): S3-14, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26487500

RESUMO

Several studies were published last year which focused on the epidemiology, immunopathogenesis, genetics, clinical manifestations and management of Behçet's syndrome. Recent epidemiologic studies support the earlier contention that the frequency of BS increases from North to South in Europe, BS is rare in Sub-Saharan Africa, it follows a more severe course among young men, especially if the disease onset is at a young age and that in European countries, the frequency is higher among immigrants from BS prevalent countries compared to locals living in the same environment. The relationship between HLA-B51 and Behçet's was re-emphasised and a functional role affecting cellular cytotoxicity was proposed. Innate immunity was explored and TLR7 copy number variations and nucleic acid sensors of varying inflammasome pathways were studied. Vascular relapse risk is decreased when BS patients are treated with immunosuppressives with or without anti-coagulation rather than anti-coagulation alone. Although rare in the Far East, the clinical picture of the vascular involvement was quite similar to the previously published reports. Interestingly a female predominance among those with cerebral vein thrombosis was noted. Venous claudication is a frequent and severe symptom among BS patients with lower extremity DVT. Budd-Chiari syndrome associated with BS is usually associated with IVC thrombosis. Silent cases exist and have a better prognosis. The mortality rate among the patients symptomatic for liver disease remains high. Methotrexate seems to be effective in the treatment of chronic progressive neuro-Behçet's disease. Renal involvement is an uncommon disorder in BS. Suicidal thoughts are increased among BS patients with severe organ involvement. Work-related disability in BS is high and under-appreciated. Apremilast, an inhibitor of phosphodiesterase-4, was effective in a phase 2, double blind, placebo-controlled study. Adalimumab seems to be effective in severe uveitis of BS even after failure of infliximab. New cytokine inhibitors targeting IL-1 and IL-6 appear to be effective especially for uveitis and CNS involvement refractory to anti TNF agents.


Assuntos
Síndrome de Behçet , Fatores Etários , Anticoagulantes/uso terapêutico , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/tratamento farmacológico , Síndrome de Behçet/genética , Síndrome de Behçet/imunologia , Síndrome de Behçet/mortalidade , Feminino , Predisposição Genética para Doença , Humanos , Imunossupressores/uso terapêutico , Masculino , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Fatores de Risco , Índice de Gravidade de Doença , Fatores Sexuais
10.
Arthritis Rheumatol ; 67(5): 1361-8, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25604533

RESUMO

OBJECTIVE: Takayasu arteritis is a rare large vessel vasculitis with incompletely understood etiology. This study was undertaken to perform the first unbiased genome-wide association analysis of Takayasu arteritis. METHODS: Two independent cohorts of patients with Takayasu arteritis from Turkey and North America were included in our study. The Turkish cohort consisted of 559 patients and 489 controls, and the North American cohort consisted of 134 patients and 1,047 controls of European ancestry. Genotyping was performed using the Omni1-Quad and Omni2.5 genotyping arrays. Genotyping data were subjected to rigorous quality control measures and subsequently analyzed to discover genetic susceptibility loci for Takayasu arteritis. RESULTS: We identified genetic susceptibility loci for Takayasu arteritis with a genome-wide level of significance in IL6 (rs2069837) (odds ratio [OR] 2.07, P = 6.70 × 10(-9)), RPS9/LILRB3 (rs11666543) (OR 1.65, P = 2.34 × 10(-8)), and an intergenic locus on chromosome 21q22 (rs2836878) (OR 1.79, P = 3.62 × 10(-10)). The genetic susceptibility locus in RPS9/LILRB3 lies within the leukocyte receptor complex gene cluster on chromosome 19q13.4, and the disease risk variant in this locus correlates with reduced expression of multiple genes including the inhibitory leukocyte immunoglobulin-like receptor gene LILRB3 (P = 2.29 × 10(-8)). In addition, we identified candidate susceptibility genes with suggestive levels of association (P < 1 × 10(-5)) with Takayasu arteritis, including PCSK5, LILRA3, PPM1G/NRBP1, and PTK2B. CONCLUSION: Our findings indicate novel genetic susceptibility loci for Takayasu arteritis and uncover potentially important aspects of the pathophysiology of this form of vasculitis.


Assuntos
Antígenos CD/genética , Cromossomos Humanos Par 21/genética , Grupo com Ancestrais do Continente Europeu/genética , Interleucina-6/genética , Receptores Imunológicos/genética , Proteínas Ribossômicas/genética , Arterite de Takayasu/genética , Estudos de Casos e Controles , Estudos de Coortes , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , América do Norte , Razão de Chances , Turquia
11.
Clin Exp Rheumatol ; 32(4 Suppl 84): S112-22, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25268667

RESUMO

This review focuses on the recent research on the epidemiology, outcome measures, immunopathogenesis, genetics, clinical manifestations and management of Behçet's syndrome (BS). A systematic review of outcomes and outcome measures used in BS points out to a need for reliable and validated outcome measures that would be widely used by researchers. Despite novel methods of analyses and cheaper and more sophisticated technologies are yielding new genetic associations and molecular pathways in BS, HLA-B51 still shows the strongest link. The MHC class I amino acid residues, GIMAP, the neuromodulin pathway, complement component copy variations, microRNA polymorphisms and DNA methylation abnormalities are examples. IL-27, 33 and 37 may also play important roles in the pathogenesis. Clinical studies have shown that the fluorescein angiography scoring system could be a useful tool to discern active inflammation in eye disease from the quiescent phase, the cumulative risk for recurrence of any vascular event was 38% at 5 years in a large vascular cohort and significant correlations between dural sinus thrombosis and pulmonary artery involvement, a retrospective survey of patients with parenchymal NBS revealed a 30% relapse rate and 10% mortality of 10% after a median follow-up of 73 months, and quantitative measurement of the brainstem atrophy using MRI was correlated with clinical symptoms. Studies on the management of BS showed that continuous use of colchicine may not prevent the development of organ involvement at the long-term, remission of uveitis may persist after withdrawal of infliximab, refractory intestinal involvement may respond to infliximab, immunosuppressive treatment is important in reducing complications of endovascular stent grafting for aortic pseudoaneurysm and intravitreal steroid implants or injections may be considered in refractory uveitis.


Assuntos
Síndrome de Behçet/mortalidade , Síndrome de Behçet/terapia , Humanos , Prognóstico , Recidiva , Resultado do Tratamento
12.
Arthritis Rheumatol ; 66(5): 1395-9, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24782196

RESUMO

OBJECTIVE: Detailed information on patient recruitment and study settings is an important component of reports of randomized controlled trials (RCTs). We had the impression that many RCTs published in rheumatology journals lacked this information. This study was undertaken to systemically survey this matter in 6 leading journals. METHODS: A hand search was conducted for RCTs published in 2011 and 2012 in Arthritis & Rheumatism, Annals of the Rheumatic Diseases, Rheumatology (Oxford), Arthritis Care & Research, The Journal of Rheumatology, and Clinical and Experimental Rheumatology. Using the Consolidated Standards of Reporting Trials (CONSORT) guidelines, 2 observers evaluated the articles for the inclusion of patient eligibility criteria, including method of recruitment; study health care settings; geographic location; and, among multicenter studies, a discussion of possible effects of intercenter differences on outcomes. RESULTS: Among 118 articles, an informative account of the method of recruitment was available in 36 (30.5%). Information about the study health care setting was found in 56 (47.5%). Patient socioeconomic profile was available in 11 (9.3%), patient education level in 10 (8.4%), and patient race in 48 (40.7%). Among 76 multicenter studies, the potential effects of possible intercenter differences on outcome were discussed in 13 (17.1%). There were no important differences between the 3 journals that emphasized the use of CONSORT in their author guidelines and the remaining 3 journals. CONCLUSION: Adequate information on patient recruitment, the trial setting, and a discussion of possible multicenter design effects on outcomes are lacking in the majority of RCT reports in rheumatology. This affects the validity of these reports and calls for closer attention of authors, journals, and reviewers.


Assuntos
Publicações Periódicas como Assunto/normas , Editoração/normas , Ensaios Clínicos Controlados Aleatórios como Assunto/normas , Reumatologia , Coleta de Dados , Humanos , Estudos Multicêntricos como Assunto/normas , Seleção de Pacientes , Reprodutibilidade dos Testes , Doenças Reumáticas/terapia
13.
Clin Dermatol ; 32(3): 435-42, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24767193

RESUMO

Behçet's disease usually begins with cutaneous manifestations, such as recurrent aphthous stomatitis, genital ulcers, erythema nodosum-like lesions, papulopustular findings, and pathergy phenomenon. Recurrent aphthous stomatitis is generally the first sign, and other findings may develop in the course of the disease. There is no specific diagnostic available for Behçet's disease. It is most prevalent among patients along the ancient Silk Road. The high frequency of HLA-B51 among a wide range of ethnic populations favors the role of genetic factors. Behçet's disease usually appears in the third to fourth decade of life, and is rarely seen in children and adults over 50 years of age. It affects both genders equally, but the course of the disease is more severe in men. Eye involvement leading to loss of vision, plus vascular, articular, and central nervous system involvement are more commonly observed among men. Behçet's disease is a systemic inflammatory disorder. A complex genetic background, coupled with innate and adaptive immune system activation, causes the diverse clinical manifestations that characterize the clinical picture.


Assuntos
Síndrome de Behçet/complicações , Síndrome de Behçet/patologia , Inflamação/complicações , Artralgia/complicações , Artrite/complicações , Síndrome de Behçet/epidemiologia , Síndrome de Behçet/genética , Doenças do Sistema Nervoso Central/complicações , Humanos
14.
Int Immunol ; 26(2): 71-81, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24135410

RESUMO

Behçet's syndrome (BS) is a systemic inflammatory disorder with unknown etiology. Features of both innate and adaptive immunity have been claimed in the pathogenesis of BS. To test the possible dysregulation of the NLRP3/cryopyrin (Nod-like receptor with a pyrin domain 3) inflammasome, as a result of mutation(s), we performed single-strand conformation polymorphism analyses and/or sequencing of all the coding regions and intron-exon boundaries of NLRP3/cryopyrin and ASC (apoptosis-associated speck-like protein containing CARD) genes from Turkish BS patients and healthy controls. At the same time, we determined pro-inflammatory cytokine secretion profiles of peripheral blood cells in response to LPS treatment using ELISA. BS patients with vascular involvement showed significantly increased levels of TNF-α release at 2-, 4- and 8-h post-treatment and significantly increased IL-1ß levels were detected at 2h (P = 0.005) and 4h (P = 0.025) (n = 10). We identified four mutations in the NLRP3/cryopyrin gene, V200M (n = 3/104) and T195M (n = 1/104), in BS patients but none in control samples. No mutations were detected in the ASC gene. The effect of these NLRP3/cryopyrin mutants on ASC speck assembly and IL-1ß secretion was tested and the V200M mutant was shown to induce IL-1ß secretion. Thus, it is likely that certain mutations in NLRP3/cryopyrin in combination with yet unknown other factors may contribute to the pro-inflammatory cytokine profiles in BS patients.


Assuntos
Síndrome de Behçet/imunologia , Proteínas de Transporte/genética , Mutação/genética , Adulto , Síndrome de Behçet/genética , Proteínas Adaptadoras de Sinalização CARD , Células Cultivadas , Proteínas do Citoesqueleto/genética , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-1beta/metabolismo , Lipopolissacarídeos/imunologia , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR , Polimorfismo Genético , Fator de Necrose Tumoral alfa/metabolismo , Turquia , Adulto Jovem
15.
Clin Exp Rheumatol ; 31(3 Suppl 77): 108-17, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24064024

RESUMO

Recent work on the epidemiology of Behçet's syndrome confirm the previous contention that the prevalence increases from North to South and that the disease follows a more severe course in patients with an early age of onset, also when specifically studied in patients with eye and gastrointestinal involvement. Imputation analyses of genome wide association studies revealed new associations such as ERAP-1, CCR1-CCR3, KLRC4 and STAT4. Further work suggested that the BS associated variant of STAT4 is not related to the previously reported one associated with autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. The prognosis of eye involvement seems to have improved over the last decade with better visual acuity and less frequent severe complications in patients reported in the 2000s compared to the 1990s. Immunosuppresssives and corticosteroids were observed to improve the outcome of cardiac involvement in BS. Recurrence and complications were common in these patients when surgery was performed without immunosuppressives. The cognitive dysfunction in BS patients with neurological involvement seemed to be severely impaired and worse than that of multiple sclerosis patients, suggesting a more severe 'frontal'-executive dysfunction. Gastrointestinal involvement seemed to be brought to a remission in the majority of BS within 5 years, with about one fourth of the patients following a relapsing or chronic disease course. TNF-α inhibitors have become standard treatment for patients resistant to conventional immunosuppressives. Switching to another biologic can be effective when the first or even the second biologic agent fails or is stopped due to adverse events.


Assuntos
Síndrome de Behçet , Animais , Síndrome de Behçet/tratamento farmacológico , Síndrome de Behçet/epidemiologia , Síndrome de Behçet/genética , Síndrome de Behçet/imunologia , Predisposição Genética para Doença , Humanos , Imunossupressores/uso terapêutico , Fenótipo , Prognóstico , Fatores de Risco
16.
Am J Hum Genet ; 93(2): 298-305, 2013 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-23830517

RESUMO

Takayasu arteritis is a rare inflammatory disease of large arteries. The etiology of Takayasu arteritis remains poorly understood, but genetic contribution to the disease pathogenesis is supported by the genetic association with HLA-B*52. We genotyped ~200,000 genetic variants in two ethnically divergent Takayasu arteritis cohorts from Turkey and North America by using a custom-designed genotyping platform (Immunochip). Additional genetic variants and the classical HLA alleles were imputed and analyzed. We identified and confirmed two independent susceptibility loci within the HLA region (r(2) < 0.2): HLA-B/MICA (rs12524487, OR = 3.29, p = 5.57 × 10(-16)) and HLA-DQB1/HLA-DRB1 (rs113452171, OR = 2.34, p = 3.74 × 10(-9); and rs189754752, OR = 2.47, p = 4.22 × 10(-9)). In addition, we identified and confirmed a genetic association between Takayasu arteritis and the FCGR2A/FCGR3A locus on chromosome 1 (rs10919543, OR = 1.81, p = 5.89 × 10(-12)). The risk allele in this locus results in increased mRNA expression of FCGR2A. We also established the genetic association between IL12B and Takayasu arteritis (rs56167332, OR = 1.54, p = 2.18 × 10(-8)).


Assuntos
Loci Gênicos , Predisposição Genética para Doença , Arterite de Takayasu/genética , Feminino , Técnicas de Genotipagem , Antígenos HLA-B/genética , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Subunidade p40 da Interleucina-12/genética , Masculino , Mutação , América do Norte/epidemiologia , Receptores de IgG/genética , Risco , Arterite de Takayasu/etnologia , Turquia/epidemiologia
17.
Clin Exp Rheumatol ; 30(1 Suppl 70): S104-6, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22410354

RESUMO

Immunosuppressives are frequently stopped in patients with granulomatosis with polyangiitis (GPA) (Wegener's granulomatosis) who develop end-stage renal disease. This is done because of the high frequency of infections reported among dialysis patients under immunosuppressives and the former impression that GPA patients no longer experience relapses after the development of end-stage renal disease. We present here a 22-year-old male patient with GPA who had gastrointestinal, genitourinary and respiratory system involvement. The patient died because of a gastrointestinal disease activation that occurred after immunosuppressives were stopped at the initiation of dialysis. The decision to stop immunosuppressives while starting dialysis should be made on an individual basis in patients with GPA, and the risks and benefits should be carefully evaluated.


Assuntos
Granulomatose com Poliangiite/tratamento farmacológico , Imunossupressores/administração & dosagem , Falência Renal Crônica/terapia , Diálise Renal , Colonoscopia , Esquema de Medicação , Quimioterapia Combinada , Evolução Fatal , Hemorragia Gastrointestinal/etiologia , Granulomatose com Poliangiite/complicações , Humanos , Imunossupressores/efeitos adversos , Falência Renal Crônica/etiologia , Masculino , Recidiva , Medição de Risco , Fatores de Risco , Resultado do Tratamento , Adulto Jovem
18.
Arthritis Res Ther ; 14(1): R27, 2012 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-22309845

RESUMO

INTRODUCTION: HLA-B*51 and HLA-B*52 are two close human leukocyte antigen (HLA) allele groups with minor amino acid differences. However, they are associated with two different vasculitides (HLA-B*51 in Behçet's disease and HLA-B*52 in Takayasu's arteritis (TAK)) and with major clinical and immunological differences. In this study, we aimed to screen a large cohort of TAK patients from Turkey for the presence of HLA-B*51 and HLA-B*52 as susceptibility and severity factors. METHODS: TAK patients (n = 330) followed at a total of 15 centers were included in the study. The mean age of the patients was 37.8 years, and 86% were women. DNA samples from the patients and healthy controls (HC; n = 210) were isolated, and the presence of HLA-B*51 or HLA-B*52 was screened for by using PCR with sequence-specific primers. RESULTS: We found a significant association of HLA-B*52 with TAK (20.9% vs HC = 6.7%, P = 0.000, OR = 3.7, 95% CI = 2.02 to 6.77). The distribution of HLA-B*51 did not differ between TAK patients and HCs (22.7% vs 24.8%, OR = 0.9, 95% CI = 0.60 to 1.34). The presence of HLA-B*52 decreased in late-onset patients (> 40 years of age; 12.0%, P = 0.024, OR = 0.43, 95% CI = 0.20 to 0.91). Patients with angiographic type I disease with limited aortic involvement also had a lower presence of HLA-B*52 compared to those with all other disease subtypes (13.1% vs 26%, P = 0.005, OR = 0.43, 95% CI = 0.23 to 0.78). CONCLUSIONS: In this study, the previously reported association of TAK with HLA-B*52 in other populations was confirmed in patients from Turkey. The functional relevance of HLA-B*52 in TAK pathogenesis needs to be explored further.


Assuntos
Predisposição Genética para Doença/genética , Antígeno HLA-B51/genética , Antígeno HLA-B52/genética , Arterite de Takayasu/genética , Adulto , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Turquia
19.
Clin Exp Rheumatol ; 30(1 Suppl 70): S11-4, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22274654

RESUMO

OBJECTIVES: Takayasu's arteritis (TA) is a chronic arterial inflammation of unknown etiology involving mainly the aorta and its major branches. Based on the associations of programmed death-1 (PD-1) protein encoding gene (PDCD1) with connective tissue diseases and vasculitides, PDCD1 polymorphisms are studied for susceptibility to TA in this study. METHODS: The study group is made up of TA patients (n=229) fulfilling the 1990 ACR classification criteria and compared to 193 healthy controls (HC). PD-1.3, PD-1.5 and PD-1.6 single nucleotide polymorphisms of PDCD1 gene are genotyped by polymerase chain reaction and restriction analysis (PCR-RFLP). RESULTS: The distribution of PD-1.5 polymorphism in TA patients and HC revealed a similar presence of TT genotype in patients and controls (13.3% vs. 11.4%). PD-1.3 and PD-1.6 were less polymorphic and did not differ between the groups. Rare AA genotype of PD-1.3 (1.4% vs. 1.0%) and AG genotype of PD-1.6 was again similarly (22.4% vs. 19.2%) present in TA and HC. CONCLUSIONS: PD-1.3, 1.5 and 1.6 polymorphisms of PDCD1 gene, which were shown to be associated with various autoimmune disorders and vasculitides, are not associated with a susceptibility to TA in Turkish population.


Assuntos
Polimorfismo de Nucleotídeo Único , Receptor de Morte Celular Programada 1/genética , Arterite de Takayasu/genética , Adulto , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Masculino , Fenótipo , Reação em Cadeia da Polimerase , Medição de Risco , Fatores de Risco , Arterite de Takayasu/epidemiologia , Turquia/epidemiologia
20.
Clin Exp Rheumatol ; 28(4 Suppl 60): S62-6, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20868573

RESUMO

OBJECTIVES: Case reports on monozygotic (MZ) twins with Behçet's syndrome (BS) have been few and we are not aware of formal twin studies. We sought the frequency of MZ and dizygotic (DZ) twin births in BS and compared it to a healthy population sample from the same geography. We also looked for the concordance rate among the MZ and DZ twins. METHODS: 1705 (1039M/666F) patients attending a dedicated BS outpatient clinic and 7761 (3848M/3913F) medical school students were asked about having a MZ or DZ twin sibling. MZ and DZ twins thus identified among both patients and controls were individually seen at the clinic. In addition, HLA, DNA microsatellite markers and blood groups were typed to further confirm twin- ship. All twins were contacted 8 years later for new emergence of disease. RESULTS: There were 14 (0.82%) patients with BS and 120 (1.55%) controls who had a twin sibling (p=0.022). Of these, 8 (0.47%) patients with BS and 92 (1.19%) controls had a DZ twin sibling (p=0.009). MZ twin frequency was similar between BS patients (6/1705; 0.35%) and control population (28/7761; 0.36%). The pairwise concordance rate for BS was 2/6 (95% CI: -0.21-0.88) for MZ and 1/8 (95% CI: -0.17-0.42) for DZ twins (p=0.538). Genetic effects accounted for 41% of the phenotypic variance for BS among twins. After 8 years of follow-up, 4 of 6 MZ and 6 of 7 DZ twin pairs were still discordant. CONCLUSIONS: The frequency of MZ twin births in BS is not different than that in the general population while the DZ twins were seen less frequently among the BS patients. The concordances for BS were higher in MZ compared with DZ twins, suggesting genetic predisposition. On the other hand, the persistence of discordance after 8 years of follow up among the remaining MZ twins demands further research to understand non- genetic factors in causation of BS.


Assuntos
Síndrome de Behçet/epidemiologia , Doenças em Gêmeos/epidemiologia , Gêmeos Dizigóticos , Gêmeos Monozigóticos , Adulto , Síndrome de Behçet/genética , Estudos de Casos e Controles , Doenças em Gêmeos/genética , Feminino , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Turquia , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética
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