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1.
Arthritis Rheumatol ; 71(12): 2081-2089, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31237427

RESUMO

OBJECTIVE: To compare the efficacy of infliximab (IFX) versus adalimumab (ADA) as a first-line biologic drug over 1 year of treatment in a large series of patients with refractory uveitis due to Behçet's disease (BD). METHODS: We conducted an open-label multicenter study of IFX versus ADA for BD-related uveitis refractory to conventional nonbiologic treatment. IFX or ADA was chosen as the first-line biologic agent based on physician and patient agreement. Patients received 3-5 mg/kg intravenous IFX at 0, 2, and 6 weeks and every 4-8 weeks thereafter, or 40 mg subcutaneous ADA every other week without a loading dose. Ocular parameters were compared between the 2 groups. RESULTS: The study included 177 patients (316 affected eyes), of whom 103 received IFX and 74 received ADA. There were no significant baseline differences between treatment groups in main demographic features, previous therapy, or ocular sign severity. After 1 year of therapy, we observed an improvement in all ocular parameters in both groups. However, patients receiving ADA had significantly better outcomes in some parameters, including improvement in anterior chamber inflammation (92.31% versus 78.18% for IFX; P = 0.06), improvement in vitritis (93.33% versus 78.95% for IFX; P = 0.04), and best-corrected visual acuity (mean ± SD 0.81 ± 0.26 versus 0.67 ± 0.34 for IFX; P = 0.001). A nonsignificant difference was seen for macular thickness (mean ± SD 250.62 ± 36.85 for ADA versus 264.89 ± 59.74 for IFX; P = 0.15), and improvement in retinal vasculitis was similar between the 2 groups (95% for ADA versus 97% for IFX; P = 0.28). The drug retention rate was higher in the ADA group (95.24% versus 84.95% for IFX; P = 0.042). CONCLUSION: Although both IFX and ADA are efficacious in refractory BD-related uveitis, ADA appears to be associated with better outcomes than IFX after 1 year of follow-up.

2.
Sci Rep ; 9(1): 2777, 2019 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-30808881

RESUMO

Behçet's disease (BD) is an immune-mediated systemic disorder with a well-established genetic base. In a previous study, using a next generation sequencing approach, we found many rare variants and some functional polymorphisms in genes related to autoinflammatory syndromes (AID): CECR1, MEFV, MVK, NLRP3, NOD2, PSTPIP1 and TNFRSF1A in our BD cohort. Our strategy did not allow us to establish either number of patients with variants, proportion of individuals accumulating them or relationship with other genetic factors. With the goal to answer these questions, the individual samples were sequenced. Additionally, three functional polymorphisms: NLRP3 p.Gln703Lys, NOD2 p.Arg702Trp and p.Val955Ile were genotyped using TaqMan assays. A total of 98 patients (27.6%) carried at least one rare variant and 13 of them (3.7%) accumulated two or three. Functional regression model analysis suggests epistatic interaction between B51 and MEFV (P = 0.003). A suggestive protective association of the minor allele of NOD2 p.Arg702Trp (P = 0.01) was found in both, B51 positive and negative individuals. Therefore, a high percentage of patients with BD have rare variants in AID genes. Our results suggest that the association of MEFV with BD could be modulated by the HLA molecules; whereas the protective effect of NOD2 p.Arg702Trp would be independent of HLA.

3.
Arthritis Rheumatol ; 2018 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-30343531

RESUMO

OBJECTIVE: To investigate the efficacy and safety of ixekizumab in patients with active radiographic axial spondyloarthritis (r-axSpA) and prior inadequate response or intolerance to 1 or 2 TNF inhibitors (TNFi). METHODS: In this randomized, double-blind placebo-controlled, Phase 3 trial, adult patients with inadequate response/intolerance to 1 or 2 TNFi and an established diagnosis of axSpA and fulfilling ASAS criteria for r-axSpA with radiographic sacroiliitis defined per modified NY criteria and ≥1 SpA feature were recruited and randomized 1:1:1 to placebo or 80-mg subcutaneous ixekizumab every 2 (IXEQ2W) or 4 (IXEQ4W) weeks, with a 80-mg or 160-mg starting dose. The primary endpoint was ASAS40 response at Week 16. Secondary outcomes and safety were also assessed. RESULTS: In total, 316 patients were randomized to placebo (N=104), IXEQ2W (N=98), or IXEQ4W (N=114). At Week 16, significantly higher proportions of IXEQ2W (N=30 [30.6%]; p=0.003) or IXEQ4W (N=29 [25.4%]; p=0.017) patients achieved ASAS40 versus placebo (N=13 [12.5%]), with statistically significant differences reported as early as Week 1 with ixekizumab treatment. Statistically significant improvements in disease activity, function, quality of life, and spinal MRI inflammation were observed with 16 weeks of ixekizumab treatment versus placebo. Treatment-emergent adverse events (AE) with ixekizumab treatment were more frequent than with placebo. Serious AEs were similar across treatment arms. One death was reported (IXEQ2W). CONCLUSION: Ixekizumab treatment for 16 weeks in patients with active r-axSpA and previous inadequate response or intolerance to 1 or 2 TNFi yielded rapid and significant improvements in the signs and symptoms of r-axSpA versus placebo. This article is protected by copyright. All rights reserved.

4.
Ophthalmology ; 125(9): 1444-1451, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29602570

RESUMO

PURPOSE: To assess efficacy, safety, and cost-effectiveness of adalimumab (ADA) therapy optimization in a large series of patients with uveitis due to Behçet disease (BD) who achieved remission after the use of this biologic agent. DESIGN: Open-label multicenter study of ADA-treated patients with BD uveitis refractory to conventional immunosuppressants. SUBJECTS: Sixty-five of 74 patients with uveitis due to BD, who achieved remission after a median ADA duration of 6 (range, 3-12) months. ADA was optimized in 23 (35.4%) of them. This biologic agent was maintained at a dose of 40 mg/subcutaneously/2 weeks in the remaining 42 patients. METHODS: After remission, based on a shared decision between the patient and the treating physician, ADA was optimized. When agreement between patient and physician was reached, optimization was performed by prolonging the ADA dosing interval progressively. Comparison between optimized and nonoptimized patients was performed. MAIN OUTCOME MEASURES: Efficacy, safety, and cost-effectiveness in optimized and nonoptimized groups. To determine efficacy, intraocular inflammation (anterior chamber cells, vitritis, and retinal vasculitis), macular thickness, visual acuity, and the sparing effect of glucocorticoids were assessed. RESULTS: No demographic or ocular differences were found at the time of ADA onset between the optimized and the nonoptimized groups. Most ocular outcomes were similar after a mean ± standard deviation follow-up of 34.7±13.3 and 26±21.3 months in the optimized and nonoptimized groups, respectively. However, relevant adverse effects were only seen in the nonoptimized group (lymphoma, pneumonia, severe local reaction at the injection site, and bacteremia by Escherichia coli, 1 each). Moreover, the mean ADA treatment costs were lower in the optimized group than in the nonoptimized group (6101.25 euros/patient/year vs. 12 339.48; P < 0.01). CONCLUSION: ADA optimization in BD uveitis refractory to conventional therapy is effective, safe, and cost-effective.

5.
Rheumatology (Oxford) ; 57(5): 900-908, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29415145

RESUMO

Objective: RA patients who have failed biologic DMARDs (bDMARDs) represent an unmet medical need. We evaluated the effects of baseline characteristics, including prior bDMARD exposure, on baricitinib efficacy and safety. Methods: RA-BEACON patients (previously reported) had moderate to severe RA with insufficient response to one or more TNF inhibitor and were randomized 1:1:1 to once-daily placebo or 2 or 4 mg baricitinib. Prior bDMARD use was allowed. The primary endpoint was a 20% improvement in ACR criteria (ACR20) at week 12 for 4 mg vs placebo. An exploratory, primarily post hoc, subgroup analysis evaluated efficacy at weeks 12 and 24 by ACR20 and Clinical Disease Activity Index (CDAI) ⩽10. An interaction P-value ⩽0.10 was considered significant, with significance at both weeks 12 and 24 given more weight. Results: The odds ratios predominantly favored baricitinib over placebo and were generally similar to those in the overall study (3.4, 2.4 for ACR20 weeks 12 and 24, respectively). Significant quantitative interactions were observed for baricitinib 4 mg vs placebo at weeks 12 and 24: ACR20 by region (larger effect Europe) and CDAI ⩽10 by disease duration (larger effect ⩾10 years). No significant interactions were consistently observed for ACR20 by age; weight; disease duration; seropositivity; corticosteroid use; number of prior bDMARDs, TNF inhibitors or non-TNF inhibitors; or a specific prior TNF inhibitor. Treatment-emergent adverse event rates, including infections, appeared somewhat higher across groups with greater prior bDMARD use. Conclusion: Baricitinib demonstrated a consistent, beneficial treatment effect in bDMARD-refractory patients across subgroups based on baseline characteristics and prior bDMARD use. Trial registration: ClinicalTrials.gov (https://clinicaltrials.gov/), NCT01721044.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Azetidinas/administração & dosagem , Produtos Biológicos/uso terapêutico , Tolerância a Medicamentos , Sulfonamidas/administração & dosagem , Administração Oral , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento
6.
Sci Rep ; 7(1): 8453, 2017 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-28814775

RESUMO

Behçet's disease (BD) is an immune-mediated systemic disorder with a well-established association with HLA class I and other genes. BD has clinical overlap with many autoinflammatory diseases (AIDs). The aim of this study was to investigate the role of rare variants in seven genes involved in AIDs: CECR1, MEFV, MVK, NLRP3, NOD2, PSTPIP1 and TNFRSF1A using a next generation sequencing (NGS) approach in 355 BD patients. To check global association of each gene, 4 tests: SKAT, CollapseBt, C(α) and weighted KBAC were used. Databases: 1000 Genomes Project Phase 3, Infevers, HGMD and ClinVar and algorithms: PolyPhen2 and SIFT were consulted to collect information of the 62 variants found. All the genes resulted associated using SKAT but only 3 (MVK, NOD2 and PSTPIP1) with C(α) and weighted KBAC. When all the genes are considered, 40 variants were associated to AIDs in clinical databases and 25 were predicted as pathogenic at least by one of the algorithms. Including only MVK, NOD2 and PSTPIP1, the associated to AIDs variants found in BD were 20 and the predicted as pathogenic, 12. The maxima contribution corresponds to NOD2. This study supports influence of rare variants in genes involved in AIDs in the pathogenesis of BD.

7.
Ann Rheum Dis ; 76(4): 694-700, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27799159

RESUMO

OBJECTIVES: To assess baricitinib on patient-reported outcomes (PROs) in patients with moderately to severely active rheumatoid arthritis, who had insufficient response or intolerance to ≥1 tumour necrosis factor inhibitors (TNFis) or other biological disease-modifying antirheumatic drugs (bDMARDs). METHODS: In this double-blind phase III study, patients were randomised to once-daily placebo or baricitinib 2 or 4 mg for 24 weeks. PROs included the Short Form-36, EuroQol 5-D, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient's Global Assessment of Disease Activity (PtGA), patient's assessment of pain, duration of morning joint stiffness (MJS) and Work Productivity and Activity Impairment Questionnaire-Rheumatoid Arthritis. Treatment comparisons were performed with logistic regression for categorical measures or analysis of covariance for continuous variables. RESULTS: 527 patients were randomised (placebo, 176; baricitinib 2 mg, 174; baricitinib 4 mg, 177). Both baricitinib-treated groups showed statistically significant improvements versus placebo in most PROs. Improvements were generally more rapid and of greater magnitude for patients receiving baricitinib 4 mg than 2 mg and were maintained to week 24. At week 24, more baricitinib-treated patients versus placebo-treated patients reported normal physical functioning (HAQ-DI <0.5; p≤0.001), reductions in fatigue (FACIT-F ≥3.56; p≤0.05), improvements in PtGA (p≤0.001) and pain (p≤0.001) and reductions in duration of MJS (p<0.01). CONCLUSIONS: Baricitinib improved most PROs through 24 weeks compared with placebo in this study of treatment-refractory patients with previously inadequate responses to bDMARDs, including at least one TNFi. PRO results aligned with clinical efficacy data for baricitinib. TRIAL REGISTRATION NUMBER: NCT01721044; Results.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Azetidinas/uso terapêutico , Medidas de Resultados Relatados pelo Paciente , Inibidores de Proteínas Quinases/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Artrite Reumatoide/complicações , Método Duplo-Cego , Eficiência , Humanos , Medição da Dor , Presenteísmo , Qualidade de Vida , Índice de Gravidade de Doença , Inquéritos e Questionários , Adulto Jovem
8.
PLoS One ; 11(8): e0161305, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27548383

RESUMO

Behcet's disease (BD) is an immuno-mediated vasculitis in which knowledge of its etiology and genetic basis is limited. To improve the current knowledge, a genetic analysis performed with the Immunochip platform was carried out in a population from Spain. A discovery cohort comprising 278 BD cases and 1,517 unaffected controls were genotyped using the Immunochip platform. The validation step was performed on an independent replication cohort composed of 130 BD cases and 600 additional controls. The strongest association signals were observed in the HLA class I region, being HLA-B*51 the highest peak (overall P = 6.82E-32, OR = 3.82). A step-wise conditional logistic regression with classical alleles identified HLA-B*57 and HLA-A*03 as additional independent markers. The amino acid model that best explained the association, includes the position 97 of the HLA-B molecule and the position 66 of the HLA-A. Among the non-HLA loci, the most significant in the discovery analysis were: IL23R (rs10889664: P = 3.81E-12, OR = 2.00), the JRKL/CNTN5 region (rs2848479: P = 5.00E-08, OR = 1.68) and IL12A (rs1874886: P = 6.67E-08, OR = 1.72), which were confirmed in the validation phase (JRKL/CNTN5 rs2848479: P = 3.29E-10, OR = 1.66; IL12A rs1874886: P = 1.62E-08, OR = 1.61). Our results confirm HLA-B*51 as a primary-association marker in predisposition to BD and suggest additional independent signals within the class I region, specifically in the genes HLA-A and HLA-B. Regarding the non-HLA genes, in addition to IL-23R, previously reported in our population; IL12A, described in other populations, was found to be a BD susceptibility factor also in Spaniards; finally, a new associated locus was found in the JRKL/CNTN5 region.


Assuntos
Síndrome de Behçet/genética , Contactinas/genética , Predisposição Genética para Doença , Antígeno HLA-B51/genética , Subunidade p35 da Interleucina-12/genética , Receptores de Interleucina/genética , Alelos , Síndrome de Behçet/imunologia , Síndrome de Behçet/patologia , Estudos de Casos e Controles , Contactinas/imunologia , Frequência do Gene , Loci Gênicos , Antígeno HLA-A3/genética , Antígeno HLA-A3/imunologia , Antígenos HLA-B/genética , Antígenos HLA-B/imunologia , Antígeno HLA-B51/imunologia , Humanos , Imunoensaio , Subunidade p35 da Interleucina-12/imunologia , Modelos Logísticos , Análise em Microsséries , Modelos Moleculares , Receptores de Interleucina/imunologia , Espanha
9.
Clin Exp Rheumatol ; 34(6 Suppl 102): S41-S45, 2016 Sep-Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27050764

RESUMO

OBJECTIVES: The functional variant R620W of the protein tyrosine phosphatase non receptor-22 (PTPN22) gene plays an important role in susceptibility to several immuno-mediated pathologies. Behçet's disease (BD) is a complex disease related to the immune system with a demonstrated genetic base. The HLA class I genes are the most important genetic factors in BD although other genes are also involved in the susceptibility to this disease. The PTPN22 has been proposed as a candidate gene in BD but this association has not been clearly demonstrated yet. The aim of this study was to assess the association of PTPN22 with BD. METHODS: A cohort composed of 404 Spanish BD patients and 1517 unrelated healthy individuals ethnically matched was genotyped in rs2476601 (R620W). Five tag SNPs: rs1217412, rs2476599, rs3789607, rs3765598 and rs1217419 (spanning a 57 Kb region between 3'UTR and 5'UTR) and rs2488457 (located at the promoter region) were also studied in order to perform a screening of the complete gene. Genotyping was performed using TaqMan® assays. The rs2476601 data were included in a meta-analysis together with those published till the date. The rest of SNPs were used in a case-control study. RESULTS: No evidence of the association of rs2476601 with BD in the meta-analysis (P = 0.504 in the model of alleles) was found. In the case-control study, no statistically significant differences were observed when comparing the distribution of variants in patients and controls. CONCLUSIONS: Our results do not support a major role of the PTPN22 gene in BD.


Assuntos
Síndrome de Behçet/genética , Polimorfismo de Nucleotídeo Único , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/enzimologia , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Feminino , Estudos de Associação Genética , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Masculino , Razão de Chances , Fenótipo , Regiões Promotoras Genéticas , Fatores de Risco , Espanha
10.
Clin Exp Rheumatol ; 33(6 Suppl 94): S117-22, 2015 Nov-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26486764

RESUMO

OBJECTIVES: The aim of this study was to investigate the role of the TLR8, a mediator of innate inflammatory response, in susceptibility to two immune-mediated disorders characterised by dysregulation of the immune response, Crohn's and Behçet's diseases (CD and BD). METHODS: A total of 844 CD, 371 BD patients and 1385 controls were genotyped in 8 tag single nucleotide polymorphisms (tSNPs) in the locus TLR8 (chromosome X). All these tSNPs have a minor allele frequency greater than 0.05 in the Caucasian population. RESULTS: The rs2407992 and the rs5744067 were associated with susceptibility to BD and CD, respectively (OR=1.34, 95%CI=1.10-1.62, p=0.0025 and OR=0.82, 95%CI=0.68-0.99, p=0.045, respectively). Although after stratification by gender, statistically significant differences in the distribution of the aforementioned SNPs were only observed in the females groups (BD OR=1.31, 95%CI=1.06-1.64, p=0.012 and CD OR=0.84, 95%CI=0.72-0.98, p=0.044) the trend was similar among males. Since the rs5744067 and rs2407992 are located in the same linkage disequilibrium block, we performed a haplotypic analysis by combination of the tSNPs. One haplotype (H1) was identified as a protective factor in BD (OR=0.75, 95%CI=0.62-0.90, p=0.0027) and another (H2) as a protective factor in CD (OR=0.78, 95%CI=0.64-094, p=0.0102). No statistically significant differences in the mean of the levels of expression attributable to the haplotype variants were found in the in silico analysis performed. CONCLUSIONS: Our results suggest a relationship between the TLR8 and the susceptibility to CD and BD. Nevertheless, these differences could not be imputed to the levels of expression.


Assuntos
Síndrome de Behçet/genética , Doença de Crohn/genética , Haplótipos , Polimorfismo de Nucleotídeo Único , Receptor 8 Toll-Like/genética , Adulto , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/imunologia , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Simulação por Computador , Doença de Crohn/diagnóstico , Doença de Crohn/imunologia , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fenótipo , Fatores de Proteção , Medição de Risco , Fatores de Risco , Fatores Sexuais , Espanha , Receptor 8 Toll-Like/imunologia , Adulto Jovem
11.
Clin Exp Rheumatol ; 33(6 Suppl 94): S96-100, 2015 Nov-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26393284

RESUMO

OBJECTIVES: Behçet's disease (BD) is an immune-mediated and complex disease associated with HLA class I and other genes. The aim of this study was to contribute to a better understanding of the relationship of the 32-bp deletion in the CCR5 gene (CCR5Δ32) and this disease by conducting a case-control study in the Spanish population and also a meta-analysis including all the studies available to date. METHODS: A cohort composed of 348 BD Spanish patients and 477 unrelated healthy and ethnically matched individuals were genotyped in CCR5Δ32 using polymerase chain reaction (PCR) and capillary electrophoresis with fluorescent detection. In the meta-analysis, data from a total of seven populations extracted from four previous studies along with data of the present study were included. RESULTS: Regarding the case-control study, no statistically significant differences were observed when the patient and control groups were compared (allelic model: 0.07 in patients vs. 0.06 in controls, p=0.303). In the meta-analysis, no evidence of association of the CCR5Δ32 polymorphism with BD was observed (pMH=0.091; OR=1.22; 95%CI 0.98 to 1.52 in the allelic model). CONCLUSIONS: The results of this meta-analysis discard a major role of the CCR5Δ32 polymorphism in BD.


Assuntos
Síndrome de Behçet/genética , Receptores CCR5/genética , Adulto , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/epidemiologia , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fenótipo , Medição de Risco , Fatores de Risco , Espanha
12.
Semin Arthritis Rheum ; 45(3): 361-8, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26092330

RESUMO

OBJECTIVES: To assess anti-TNF-α therapy response in uveitis associated with sarcoidosis refractory to conventional immunosuppressive therapy. METHODS: Open-label, multicenter, retrospective study on patients with sarcoid uveitis who underwent anti-TNF-α therapy because of inadequate response to conventional therapy including corticosteroids and at least 1 systemic synthetic immunosuppressive drug. The main outcome measurements were degree of anterior and posterior chamber inflammation, visual acuity, macular thickness, and immunosuppression load. RESULTS: A total of 17 patients (8 men; 29 affected eyes; mean ± standard deviation age 38.4 ± 16.8; range: 13-76 years) were studied. The patients had bilateral hilar lymphadenopathy (58.8%), lung parenchyma involvement (47.1%), peripheral lymph nodes (41.2%), and involvement of other organs (52.9%). Angiotensin-converting enzyme was elevated in 58.8%. The most frequent ocular pattern was bilateral chronic relapsing panuveitis. The first biologic agent used was adalimumab in 10 (58.8%) and infliximab in 7 (41.2%) cases. Infliximab 5mg/kg intravenously every 4-8 weeks and adalimumab 40mg subcutaneously every 2 weeks were the most common administration patterns. In most cases anti-TNF-α therapy was given in combination with immunosuppressive drugs. The mean duration of follow-up was 33.9 ± 17.1 months. Significant improvement was observed following anti-TNF-α therapy. Baseline results versus results at 2 years from the onset of biologic therapy were the following: the median of cells in the ocular anterior chamber (interquartile range-IQR) 0.5 (0-2) versus 0 (0-0) (p = 0.003), vitritis 0 (0-1.25) versus 0 (0-0) (p = 0.008), macular thickness (391.1 ± 58.8 versus 247 ± 40.5µm) (p = 0.028), and visual acuity 0.60 ± 0.33 versus 0.74 ± 0.27; p = 0.009. The median daily (interquartile range) dose of prednisone was also reduced from 10 (0-30)mg at the onset of the anti-TNF-α therapy to 0 (0-0)mg at 2 years (p = 0.02). Significant reduction was also achieved in the immunosuppressive load. CONCLUSION: Anti-TNF-α therapy is effective in sarcoid uveitis patients refractory to conventional immunosuppressive therapy. Infliximab and adalimumab allowed a substantial reduction in prednisone dose despite having failed standard therapy.


Assuntos
Adalimumab/uso terapêutico , Imunossupressores/uso terapêutico , Infliximab/uso terapêutico , Sarcoidose/tratamento farmacológico , Uveíte/tratamento farmacológico , Adolescente , Adulto , Idoso , Ciclosporina/uso terapêutico , Feminino , Humanos , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Retratamento , Estudos Retrospectivos , Sarcoidose/complicações , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Uveíte/complicações , Adulto Jovem
13.
Clin Exp Rheumatol ; 33(6 Suppl 94): S36-9, 2015 Nov-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26005883

RESUMO

OBJECTIVES: Behçet's disease (BD) is an immune-mediated and complex disease which has been associated with HLA class I molecules although other genes such as IL23R and IL10 have also been involved in the susceptibility to BD. Recently, an association of variants of the JAK1 and TNFAIP3 genes with the disease has been reported in the Chinese Han population. The aim of the present work was to asses whether the association described in Asian populations is replicated in Europeans. METHODS: This study includes a total of 1155 Spanish subjects of European origin (372 BD and 783 unrelated healthy individuals). Patients were recruited from different hospitals and controls were collected in the same geographic regions and they matched with patients in age and gender. A total of five SNPs, two in the JAK1 gene: rs2780815 and rs310241 and the other three in the TNFAIP3: rs10499194, rs9494885 and rs610604, were included in this study. The genotyping of these SNPs was performed using a real time PCR system (TaqMan® SNP Genotyping Assays). RESULTS: No statistically significant differences were found when the patient and control groups were compared. The distribution of the risk alleles was similar in patients with and without eye manifestations and in patients with and without HLA-B*51. CONCLUSIONS: The association of variants of the genes JAK1 and the TNFAIP3 with BD which has been described in the Chinese population was not replicated in Europeans.


Assuntos
Síndrome de Behçet/genética , Proteínas de Ligação a DNA/genética , Grupo com Ancestrais do Continente Europeu/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Janus Quinase 1/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único , Adulto , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/enzimologia , Síndrome de Behçet/etnologia , Estudos de Casos e Controles , Feminino , Frequência do Gene , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Fatores de Risco , Espanha/epidemiologia , Proteína 3 Induzida por Fator de Necrose Tumoral alfa
14.
J Rheumatol ; 42(4): 695-701, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25641891

RESUMO

OBJECTIVE: Behçet disease (BD) is a multifactorial disease in which infectious agents have been proposed as triggers in genetically predisposed individuals. The aim of our study was to investigate the role of innate immunity receptors, specifically the nucleic acid sensors, in susceptibility to BD. METHODS: Seventy-four tag single nucleotide polymorphisms (tSNP) selected in 9 candidate genes (DDX58, IFIH1, TLR3, TLR7, TLR8, AIM2, IFI16, ZBP1, and TLR9) were genotyped in 371 patients and 854 controls. Assays of mRNA expression and allele-specific transcript quantification (ASTQ) were performed in 110 and 50 controls, respectively. RESULTS: Patients and controls were genotyped and 2 tSNP (rs6940 in IFI16 and rs855873 in AIM2) were associated with BD. To confirm this association, these tSNP were genotyped in 850 additional controls, and the total cohort was randomly divided into 2 cohorts. The association of these 2 tSNP with the disease remained in both cohorts. One haplotype (rs6940T-rs855873G) was identified as a risk factor (OR 1.41, 95% CI 1.06-1.86, p = 0.015), and another (rs6940A-rs855873A) as a protective factor (OR 0.65, 95% CI 0.47-0.90, p = 0.009). Samples with the risk haplotype had lower IFI16 expression levels than samples with the protective (0.99 ± 0.29 vs 1.23 ± 0.50, p = 0.022). Consistently, in the ASTQ assays performed with the nonsynonymous rs6940 SNP, the risk allele had lower IFI16 expression levels than the protective (p = 0.027). CONCLUSION: Our findings suggest association of IFI16, a cytosolic sensor of dsDNA and mediator of the AIM2 inflammasome-dependent pathway, in susceptibility to BD. Differences genetically determined in the levels of this molecule could be the cause of this association.


Assuntos
Síndrome de Behçet/genética , Predisposição Genética para Doença , Proteínas Nucleares/genética , Fosfoproteínas/genética , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/genética , Adulto , Alelos , Feminino , Genótipo , Haplótipos , Humanos , Inflamassomos/genética , Masculino , Pessoa de Meia-Idade , Adulto Jovem
15.
PLoS One ; 9(7): e102100, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25019531

RESUMO

Behçet's disease (BD) is a multifactorial disorder associated with the HLA region. Recently, the ERAP1 gene has been proposed as a susceptibility locus with a recessive model and with epistatic interaction with HLA-B51. ERAP1 trims peptides in the endoplasmic reticulum to optimize their length for MHC-I binding. Polymorphisms in this gene have been related with the susceptibility to other immune-mediated diseases associated to HLA class I. Our aim was, the replication in the Spanish population of the association described in the Turkish population between ERAP1 (rs17482078) and BD. Additionally, in order to improve the understanding of this association we analyzed four additional SNPs (rs27044, rs10050860, rs30187 and rs2287987) associated with other diseases related to HLA class I and the haplotype blocks in this gene region. According to our results, frequencies of the homozygous genotypes for the minor alleles of all the SNPs were increased among patients and the OR values were higher in the subgroup of patients with the HLA-B risk factors, although differences were not statistically significant. Moreover, the presence of the same mutation in both chromosomes increased the OR values from 4.51 to 10.72 in individuals carrying the HLA-B risk factors. Therefore, although they were not statistically significant, our data were consistent with an association between ERAP1 and BD as well as with an epistatic interaction between ERAP1 and HLA-B in the Spanish population.


Assuntos
Aminopeptidases/metabolismo , Síndrome de Behçet/epidemiologia , Síndrome de Behçet/genética , Epistasia Genética/genética , Antígenos HLA-B/metabolismo , Adulto , Aminopeptidases/genética , Feminino , Frequência do Gene , Antígenos HLA-B/genética , Haplótipos/genética , Humanos , Modelos Logísticos , Masculino , Antígenos de Histocompatibilidade Menor , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética , Espanha/epidemiologia
16.
Rheumatology (Oxford) ; 53(12): 2223-31, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24996907

RESUMO

OBJECTIVE: The aim of this study was to assess the efficacy of anti-TNF-α therapy in refractory uveitis due to Behçet's disease (BD). METHODS: We performed a multicentre study of 124 patients with BD uveitis refractory to conventional treatment including high-dose corticosteroids and at least one standard immunosuppressive agent. Patients were treated for at least 12 months with infliximab (IFX) (3-5 mg/kg at 0, 2 and 6 weeks and then every 4-8 weeks) or adalimumab (ADA) (usually 40 mg every 2 weeks). The main outcome measures were degree of anterior and posterior chamber inflammation, visual acuity, macular thickness and immunosuppression load. RESULTS: Sixty-eight men and 56 women (221 affected eyes) were studied. The mean age was 38.6 years (s.d. 10.4). HLA-B51 was positive in 66.1% of patients and uveitis was bilateral in 78.2%. IFX was the first biologic agent in 77 cases (62%) and ADA was first in 47 (38%). In most cases anti-TNF-α drugs were used in combination with conventional immunosuppressive drugs. At the onset of anti-TNF-α therapy, anterior chamber and vitreous inflammation was observed in 57% and 64.4% of patients, respectively. In both conditions the damage decreased significantly after 1 year. At baseline, 50 patients (80 eyes) had macular thickening [optical coherence tomography (OCT) >250 µm] and 35 (49 eyes) had cystoid macular oedema (OCT>300 µm) that improved from 420 µm (s.d. 119.5) at baseline to 271 µm (s.d. 45.6) at month 12 (P < 0.01). The best-corrected visual acuity and the suppression load also showed significant improvement. After 1 year of follow-up, 67.7% of patients were inactive. Biologic therapy was well tolerated in most cases. CONCLUSION: Anti-TNF-α therapy is effective and relatively safe in refractory BD uveitis.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Síndrome de Behçet/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Uveíte/tratamento farmacológico , Adalimumab , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Síndrome de Behçet/complicações , Produtos Biológicos/efeitos adversos , Produtos Biológicos/uso terapêutico , Criança , Esquema de Medicação , Resistência a Medicamentos , Quimioterapia Combinada , Feminino , Seguimentos , Glucocorticoides/administração & dosagem , Glucocorticoides/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Infliximab , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/uso terapêutico , Resultado do Tratamento , Uveíte/etiologia , Adulto Jovem
18.
Arthritis Res Ther ; 15(5): R145, 2013 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-24286189

RESUMO

INTRODUCTION: According to genome wide association (GWA) studies as well as candidate gene approaches, Behçet's disease (BD) is associated with human leukocyte antigen (HLA)-A and HLA-B gene regions. The HLA-B51 has been consistently associated with the disease, but the role of other HLA class I molecules remains controversial. Recently, variants in non-HLA genes have also been associated with BD. The aims of this study were to further investigate the influence of the HLA region in BD and to explore the relationship with non-HLA genes recently described to be associated in other populations. METHODS: This study included 304 BD patients and 313 ethnically matched controls. HLA-A and HLA-B low resolution typing was carried out by PCR-SSOP Luminex. Eleven tag single nucleotide polymorphisms (SNPs) located outside of the HLA-region, previously described associated with the disease in GWA studies and having a minor allele frequency in Caucasians greater than 0.15 were genotyped using TaqMan assays. Phenotypic and genotypic frequencies were estimated by direct counting and distributions were compared using the χ(2) test. RESULTS: In addition to HLA-B*51, HLA-B*57 was found as a risk factor in BD, whereas, B*35 was found to be protective. Other HLA-A and B specificities were suggestive of association with the disease as risk (A*02 and A*24) or protective factors (A*03 and B*58). Regarding the non-HLA genes, the three SNPs located in IL23R and one of the SNPs in IL10 were found to be significantly associated with susceptibility to BD in our population. CONCLUSION: Different HLA specificities are associated with Behçet's disease in addition to B*51. Other non-HLA genes, such as IL23R and IL-10, play a role in the susceptibility to the disease.


Assuntos
Síndrome de Behçet/genética , Predisposição Genética para Doença/genética , Antígenos HLA/genética , Interleucina-10/genética , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina/genética , Adulto , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla/métodos , Genótipo , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígeno HLA-B35/genética , Antígeno HLA-B51/genética , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Espanha
19.
Reumatol. clín. (Barc.) ; 7(5): 305-313, sept.-oct. 2011. tab, ilus
Artigo em Espanhol | IBECS | ID: ibc-90948

RESUMO

Objetivo: Recoger información sobre cómo se realiza el diagnóstico, la clasificación y el tratamiento de los pacientes osteoporóticos con alto riesgo de fractura en las consultas de Reumatología. Material y métodos: Se realizó una encuesta a reumatólogos españoles que atienden de forma habitual a pacientes con osteoporosis (OP), donde se recogieron datos demográficos, clínicos y sobre los factores de riesgo de OP y de fractura considerados más importantes, así como pruebas diagnósticas y tratamiento según el riesgo de fractura de los pacientes. Resultados: El 99,5% de los reumatólogos encuestados consideraba que existe un grupo de pacientes con OP con alto riesgo de fractura, siendo la fractura previa el factor de riesgo más importante, riesgo que se incrementaba en caso de fracturas múltiples, severas, de cadera, o si se presentaban en pacientes tratados. Le siguieron en orden decreciente el tratamiento con glucocorticoides, la edad avanzada y la densidad mineral ósea (DMO) baja. El número de fracturas vertebrales fue considerado el dato radiológico más importante, seguido de la cronología y la severidad de las fracturas. En pacientes calificados de alto riesgo, la mayoría de los encuestados seleccionó teriparatida como primera opción de tratamiento. Conclusiones: La definición de paciente con OP con alto riesgo de fractura en la práctica diaria no es homogénea, aunque la mayoría de reumatólogos consideró que el factor más importante es tener fractura previa, seguido del tratamiento con glucocorticoides, edad avanzada y DMO baja. El tratamiento osteoformador es el más utilizado en pacientes con OP con alto riesgo de fractura (AU)


Objective: To collect information about diagnosis, classification and treatment of patients at high risk of fracture in the rheumatologist’s practice. Material and Methods: A survey was conducted among Spanish rheumatologists. The survey was aimed at gathering data on the physician’s healthcare activity, the osteoporosis (OP) and fracture risk factors considered as most relevant, the diagnostic used tests and the treatment indication according to the presence of different risk factors. Results: 99.5% of rheumatologists felt that there is a group of patients with OP at high risk of fracture. Previous fracture was considered the most important risk factor, particularly in case of multiple fractures, severe fractures, hip fracture, or that occurred during treatment. Glucocorticoid treatment, older age and low bone mineral density were considered, in this order, other important risk factors. The number of vertebral fractures was considered the most relevant radiological data, followed by the fracture’s chronology and severity. Most of the respondents selected teriparatide as the first treatment option in high-risk patients. Conclusions: The definition of OP patient with high risk of fracture is not uniform in daily practice, although the majority of rheumatologists considered that having a previous fracture is the most important risk factor, followed by glucocorticoid treatment, older age and low BMD. Anabolic treatment was the approach most commonly used in OP patients with high risk of fracture (AU)


Assuntos
Humanos , Masculino , Feminino , Ferimentos e Lesões/epidemiologia , Osteoporose/classificação , Osteoporose/diagnóstico , Osteoporose/terapia , Fatores de Risco , Conhecimentos, Atitudes e Prática em Saúde , Guias de Prática Clínica como Assunto , Glucocorticoides/uso terapêutico , Projetos , Administração da Prática Médica/organização & administração
20.
Reumatol Clin ; 7(5): 305-13, 2011 Sep-Oct.
Artigo em Espanhol | MEDLINE | ID: mdl-21925446

RESUMO

OBJECTIVE: To collect information about diagnosis, classification and treatment of patients at high risk of fracture in the rheumatologist's practice. MATERIAL AND METHODS: A survey was conducted among Spanish rheumatologists. The survey was aimed at gathering data on the physician's healthcare activity, the osteoporosis (OP) and fracture risk factors considered as most relevant, the diagnostic used tests and the treatment indication according to the presence of different risk factors. RESULTS: 99.5% of rheumatologists felt that there is a group of patients with OP at high risk of fracture. Previous fracture was considered the most important risk factor, particularly in case of multiple fractures, severe fractures, hip fracture, or that occurred during treatment. Glucocorticoid treatment, older age and low bone mineral density were considered, in this order, other important risk factors. The number of vertebral fractures was considered the most relevant radiological data, followed by the fracture's chronology and severity. Most of the respondents selected teriparatide as the first treatment option in high-risk patients. CONCLUSIONS: The definition of OP patient with high risk of fracture is not uniform in daily practice, although the majority of rheumatologists considered that having a previous fracture is the most important risk factor, followed by glucocorticoid treatment, older age and low BMD. Anabolic treatment was the approach most commonly used in OP patients with high risk of fracture.


Assuntos
Atitude do Pessoal de Saúde , Conservadores da Densidade Óssea/uso terapêutico , Osteoporose/tratamento farmacológico , Fraturas por Osteoporose/prevenção & controle , Padrões de Prática Médica/estatística & dados numéricos , Pesquisas sobre Serviços de Saúde , Humanos , Osteoporose/complicações , Osteoporose/diagnóstico , Fraturas por Osteoporose/etiologia , Reumatologia , Medição de Risco , Fatores de Risco , Prevenção Secundária , Espanha , Inquéritos e Questionários , Teriparatida/uso terapêutico
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