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1.
Clin Exp Rheumatol ; 37(1): 127-132, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30148437

RESUMO

OBJECTIVES: To explore antinuclear autoantibody (ANA) and anti-double-stranded DNA (anti-dsDNA) autoantibody development during abatacept and tumour necrosis factor inhibitor (TNFi) treatment, and effects of switching from TNFi to abatacept in ANA/anti-dsDNA autoantibody-positive patients. METHODS: This was a post hoc analysis of biologic-naïve patients with active RA in ATTEST and AMPLE. In AMPLE, patients received subcutaneous abatacept or adalimumab (2 years). In ATTEST, patients received intravenous abatacept or infliximab (1 year), or placebo (6 months) then abatacept (6 months); at 1 year, all patients could receive abatacept (open-label long-term extension). Serum ANA/anti-dsDNA autoantibody levels were measured at baseline, Month 6 (ATTEST only), Years 1 and 2. RESULTS: At baseline, 25.7 and 0.9% (AMPLE), and 21.6 and 8.4% of patients (ATTEST) were ANA/anti-dsDNA autoantibody positive, respectively. More baseline ANA/anti-dsDNA autoantibody-negative patients became positive during TNFi than abatacept treatment. In ATTEST (TNFi group), 48.5% (48/99; ANA) and 48.3% (57/118; anti-dsDNA) of patients seroconverted to positive status by Year 1, falling to 22.4% (22/98 ANA) and 13.3% (15/113; anti-dsDNA) by Year 2 after switching to abatacept. Of ANA/anti-dsDNA autoantibody-positive patients at Year 1, 41.9% and 68.9%, were negative at Year 2. CONCLUSIONS: ANA/anti-dsDNA seroconversion was more frequent with TNFi than abatacept therapy; TNFi-associated seroconversion decreased after switching from TNFi to abatacept.


Assuntos
Abatacepte/uso terapêutico , Antirreumáticos , Artrite Reumatoide , DNA/análise , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Humanos , Infliximab , Metotrexato/uso terapêutico , Falha de Tratamento
2.
Arthritis Res Ther ; 20(1): 269, 2018 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-30522501

RESUMO

BACKGROUND: To explore the effect of abatacept treatment on patient-reported outcomes (PROs) in psoriatic arthritis (PsA). METHODS: Patients with PsA were randomised (1:1) to subcutaneous abatacept 125 mg weekly/placebo for 24 weeks with early escape (EE) to open-label abatacept (week 16). Adjusted mean changes from baseline to weeks 16 (all patients) and 24 (non-EE responders) in Health Assessment Questionnaire-Disability Index (HAQ-DI), Short Form-36 (SF-36; physical and mental component summary and domains), Dermatology Life Quality Index and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) were evaluated. Subpopulations were analysed by baseline C-reactive protein (CRP) level (> vs ≤ upper limit of normal [ULN]) and prior tumour necrosis factor inhibitor (TNFi) exposure. Proportions of patients reporting improvements ≥ minimal clinically important differences (MCIDs) and ≥ normative values (NVs) in HAQ-DI, SF-36 and FACIT-F (week 16 before EE) were analysed. RESULTS: In total population, numerically higher improvements in most PROs were reported with abatacept (n = 213) versus placebo (n = 211) at both time points (P > 0.05). Higher proportions of abatacept versus placebo patients reported PRO improvements ≥ MCID and ≥ NV at week 16. At week 16, all PRO improvements were numerically greater (P > 0.05) in patients with baseline CRP > ULN versus CRP ≤ ULN (all significant [95% confidence interval] for abatacept vs placebo); improvements in SF-36 component summaries and FACIT-F were greater in TNFi-naïve versus TNFi-exposed patients (abatacept > placebo). Week 24 subgroup data were difficult to interpret due to low patient numbers. CONCLUSIONS: Abatacept treatment improved PROs in patients with PsA versus placebo, with better results in elevated baseline CRP and TNFi-naïve subpopulations. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT01860976 (funded by Bristol-Myers Squibb); date of registration: 23 May 2013.


Assuntos
Abatacepte/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Metotrexato/uso terapêutico , Medidas de Resultados Relatados pelo Paciente , Adulto , Antirreumáticos/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Índice de Gravidade de Doença , Resultado do Tratamento
3.
Arthritis Rheumatol ; 70(8): 1331-1342, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29534336

RESUMO

OBJECTIVE: To develop an objective, readily measurable pharmacodynamic biomarker of glucocorticoid (GC) activity. METHODS: Genes modulated by prednisolone were identified from in vitro studies using peripheral blood mononuclear cells from normal healthy volunteers. Using the criteria of a >2-fold change relative to vehicle controls and an adjusted P value cutoff of less than 0.05, 64 up-regulated and 18 down-regulated genes were identified. A composite score of the up-regulated genes was generated using a single-sample gene set enrichment analysis algorithm. RESULTS: GC gene signature expression was significantly elevated in peripheral blood leukocytes from normal healthy volunteers following oral administration of prednisolone. Expression of the signature increased in a dose-dependent manner, peaked at 4 hours postadministration, and returned to baseline levels by 48 hours after dosing. Lower expression was detected in normal healthy volunteers who received a partial GC receptor agonist, which is consistent with the reduced transactivation potential of this compound. In cohorts of patients with systemic lupus erythematosus and patients with rheumatoid arthritis, expression of the GC signature was negatively correlated with the percentages of peripheral blood lymphocytes and positively correlated with peripheral blood neutrophil counts, which is consistent with the known biology of the GC receptor. Expression of the signature largely agreed with reported GC use in these populations, although there was significant interpatient variability within the dose cohorts. CONCLUSION: The GC gene signature identified in this study represents a pharmacodynamic marker of GC exposure.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Glucocorticoides/administração & dosagem , Leucócitos Mononucleares/efeitos dos fármacos , Prednisolona/administração & dosagem , Administração Oral , Artrite Reumatoide/sangue , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Biomarcadores/sangue , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Feminino , Voluntários Saudáveis , Humanos , Contagem de Leucócitos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/genética , Masculino , Testes Farmacogenômicos , Regulação para Cima/efeitos dos fármacos
4.
Ann Rheum Dis ; 76(9): 1550-1558, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28473423

RESUMO

OBJECTIVES: To assess the efficacy and safety of abatacept, a selective T-cell costimulation modulator, in a phase III study in psoriatic arthritis (PsA). METHODS: This study randomised patients (1:1) with active PsA (~60% with prior exposure to a tumour necrosis factor inhibitor) to blinded weekly subcutaneous abatacept 125 mg (n=213) or placebo (n=211) for 24 weeks, followed by open-label subcutaneous abatacept. Patients without ≥20% improvement in joint counts at week 16 were switched to open-label abatacept. The primary end point was the proportion of patients with ≥20% improvement in the American College of Rheumatology (ACR20) criteria at week 24. RESULTS: Abatacept significantly increased ACR20 response versus placebo at week 24 (39.4% vs 22.3%; p<0.001). Although abatacept numerically increased Health Assessment Questionnaire-Disability Index response rates (reduction from baseline ≥0.35) at week 24, this was not statistically significant (31.0% vs 23.7%; p=0.097). The benefits of abatacept were seen in ACR20 responses regardless of tumour necrosis factor inhibitor exposure and in other musculoskeletal manifestations, but significance could not be attributed due to ranking below Health Assessment Questionnaire-Disability Index response in hierarchical testing. However, the benefit on psoriasis lesions was modest. Efficacy was maintained or improved up to week 52. Abatacept was well tolerated with no new safety signals. CONCLUSIONS: Abatacept treatment of PsA in this phase III study achieved its primary end point, ACR20 response, showed beneficial trends overall in musculoskeletal manifestations and was well tolerated. There was only a modest impact on psoriasis lesions. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number, NCT01860976 (funded by Bristol-Myers Squibb).


Assuntos
Abatacepte/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Adulto , Artrite Psoriásica/fisiopatologia , Método Duplo-Cego , Feminino , Humanos , Hospedeiro Imunocomprometido , Masculino , Pessoa de Meia-Idade , Pneumonia por Pneumocystis/etiologia , Pneumonia por Pneumocystis/imunologia , Qualidade de Vida , Resultado do Tratamento
5.
Ann Rheum Dis ; 75(4): 709-14, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26359449

RESUMO

OBJECTIVES: To examine whether baseline anti-cyclic citrullinated peptide-2 (CCP2) antibody status and concentration correlated with clinical outcomes in patients treated with abatacept or adalimumab on background methotrexate (MTX) in the 2-year AMPLE (Abatacept versus adaliMumab comParison in bioLogic-naïvE rheumatoid arthritis subjects with background MTX) study. METHODS: In this exploratory analysis, anti-CCP2 antibody concentration was measured at baseline, and antibody-positive patients were divided into equal quartiles, Q1-Q4, representing increasing antibody concentrations. Clinical outcomes analysed by baseline anti-CCP2 status and quartile included change from baseline in disease activity and disability and remission rates. RESULTS: Baseline characteristics were generally comparable across quartiles and treatment groups. In both treatment groups, anti-CCP2 antibody-negative patients responded less well than antibody-positive patients. At year 2, improvements in disease activity and disability and remission rates were similar across Q1-Q3, but were numerically higher in Q4 in the abatacept group; in contrast, treatment effects were similar across all quartiles in the adalimumab group. CONCLUSIONS: In AMPLE, baseline anti-CCP2 positivity was associated with a better response for abatacept and adalimumab. Patients with the highest baseline anti-CCP2 antibody concentrations had better clinical response with abatacept than patients with lower concentrations, an association that was not observed with adalimumab. TRIAL REGISTRATION NUMBER: NCT00929864.


Assuntos
Abatacepte/uso terapêutico , Adalimumab/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Autoanticorpos/imunologia , Peptídeos Cíclicos/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/imunologia , Quimioterapia Combinada , Feminino , Humanos , Imunoglobulina G/imunologia , Injeções Subcutâneas , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Prognóstico , Método Simples-Cego , Resultado do Tratamento , Adulto Jovem
6.
Arthritis Rheum ; 63(9): 2630-40, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21560115

RESUMO

OBJECTIVE: Susceptibility to inflammatory arthritis is determined by a complex set of environmental and genetic factors, but only a portion of the genetic effect can be explained. Conventional genome-wide screens of arthritis models using crosses between inbred mice have been hampered by the low resolution of results and by the restricted range of natural genetic variation sampled. The aim of this study was to address these limitations by performing a genome-wide screen for determinants of arthritis severity using a genetically heterogeneous cohort of mice. METHODS: Heterogeneous stock (HS) mice derive from 8 founder inbred strains by serial intercrossing (n>60), resulting in fine-grained genetic variation. With a cohort of 570 HS mice, we performed a genome-wide screen for determinants of arthritis severity in the K/BxN serum-transfer model. RESULTS: We mapped regions on chromosomes 1, 2, 4, 6, 7, and 15 that contain quantitative trait loci influencing arthritis severity at a resolution of a few megabases. In several instances, these regions proved to contain 2 quantitative trait loci: the region on chromosome 2 included the C5 fraction of complement known to be required for K/BxN serum-transfer arthritis but also contained a second adjacent quantitative trait locus, for which an intriguing candidate is Ptgs1 (Cox1). Interesting candidates on chromosome 4 included the Padi family, encoding the peptidyl arginine deiminases responsible for citrulline protein modification; suggestively, Padi2 and Padi4 RNA expression was correlated with arthritis severity in HS mice. CONCLUSION: These results provide a broad overview of the genetic variation that controls the severity of K/BxN serum-transfer arthritis and suggest intriguing candidate genes for further study.


Assuntos
Artrite Experimental/genética , Artrite Reumatoide/genética , Predisposição Genética para Doença , Animais , Mapeamento Cromossômico , Cruzamentos Genéticos , Variação Genética , Genoma , Estudo de Associação Genômica Ampla , Camundongos , Locos de Características Quantitativas , Índice de Gravidade de Doença
7.
PLoS Biol ; 8(12): e1000561, 2010 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-21179499

RESUMO

Neurogenesis continues through the adult life of mice in the subgranular zone of the dentate gyrus in the hippocampus, but its function remains unclear. Measuring cellular proliferation in the hippocampus of 719 outbred heterogeneous stock mice revealed a highly significant correlation with the proportions of CD8+ versus CD4+ T lymphocyte subsets. This correlation reflected shared genetic loci, with the exception of the H-2Ea locus that had a dominant influence on T cell subsets but no impact on neurogenesis. Analysis of knockouts and repopulation of TCRα-deficient mice by subsets of T cells confirmed the influence of T cells on adult neurogenesis, indicating that CD4+ T cells or subpopulations thereof mediate the effect. Our results reveal an organismal impact, broader than hitherto suspected, of the natural genetic variation that controls T cell development and homeostasis.


Assuntos
Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , Proliferação de Células , Hipocampo/citologia , Neurogênese , Animais , Animais não Endogâmicos , Relação CD4-CD8 , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Variação Genética , Hipocampo/imunologia , Antígeno Ki-67/genética , Antígeno Ki-67/imunologia , Camundongos , Camundongos Endogâmicos , Mutação , Locos de Características Quantitativas , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia
8.
Arthritis Rheum ; 58(7): 1947-57, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18576312

RESUMO

OBJECTIVE: It has been suggested that polymorphisms in IL1 are correlated with severe and/or erosive rheumatoid arthritis (RA), but the implicated alleles have differed among studies. The aim of this study was to perform a broad and well-powered search for association between allelic polymorphism in IL1A and IL1B and the susceptibility to or severity of RA. METHODS: Key coding and regulatory regions in IL1A and IL1B were sequenced in 24 patients with RA, revealing 4 novel single-nucleotide polymorphisms (SNPs) in IL1B. These and a comprehensive set of 24 SNPs tagging most of the underlying genetic diversity were genotyped in 3 independent RA case-control sample sets and 1 longitudinal RA cohort, totaling 3,561 patients and 3,062 control subjects. RESULTS: No fully significant associations were observed. Analysis of the discovery case-control sample sets indicated a potential association of IL1B promoter region SNPs with susceptibility to RA (for RA3/A, odds ratio [OR] 1.27, P = 0.0021) or with the incidence of radiographic erosions (for RA4/C, OR 1.56, P = 0.036), but these findings were not replicated in independent case-control samples. No association with rheumatoid factor, anti-cyclic citrullinated peptide, or the Disease Activity Score in 28 joints was found. None of the associations previously observed in other studies were replicated here. CONCLUSION: In spite of a broad and highly powered study, we observed no robust, reproducible association between IL1A/B variants and the susceptibility to or severity of RA in white individuals of European descent. Our results provide evidence that, in the majority of cases, polymorphism in IL1A and IL1B is not a major contributor to genetic susceptibility to RA.


Assuntos
Artrite Reumatoide/genética , Interleucina-1alfa/genética , Interleucina-1beta/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença
9.
Proc Natl Acad Sci U S A ; 104(7): 2325-30, 2007 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-17277081

RESUMO

Mast cells are immune sentinels that participate in the defense against bacteria and parasites. Resident within the joint, mast cells become activated in human rheumatoid arthritis and are implicated in the pathogenesis of experimental murine synovitis. However, their arthritogenic role remains undefined. Using a model of autoantibody-induced arthritis, we show that mast cells contribute to the initiation of inflammation within the joint by elaboration of IL-1. Mast cells become activated to produce this cytokine via the IgG immune complex receptor FcgammaRIII. Interestingly, mast cells become dispensable for the perpetuation of arthritis after delivery of IL-1, highlighting the contribution of this lineage to arthritis induction. These findings illuminate a mechanism by which mast cells can participate in the pathogenesis of autoimmune inflammatory arthritis and provide insights of potential relevance to human rheumatoid arthritis.


Assuntos
Artrite/etiologia , Autoanticorpos , Interleucina-1/biossíntese , Mastócitos/patologia , Receptores de IgG/metabolismo , Animais , Artrite/imunologia , Artrite/patologia , Modelos Animais de Doenças , Inflamação/etiologia , Inflamação/patologia , Mastócitos/metabolismo , Camundongos , Camundongos Knockout
10.
J Rheumatol ; 33(4): 659-64, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16482646

RESUMO

OBJECTIVE: To assess the safety and efficacy of etanercept 50 mg administered twice weekly versus 25 mg administered twice weekly as monotherapy in patients with tumor necrosis factor-alpha (TNF-alpha) blocker-naäve active rheumatoid arthritis (RA). METHODS: Seventy-seven patients with RA were randomized in an unequal allocation (2:1) in a blinded fashion to receive either 50 mg (51 patients) or 25 mg (26 patients) of etanercept twice a week for 24 weeks. RESULTS: The primary outcome measure, the ACR-N AUC at 24 weeks, showed no difference between the 2 dose groups. In addition, there was no difference in ACR 20, 50, and 70 responses or in EULAR response criteria by Week 24. There were no statistically significant differences between the 2 groups in the proportion of patients with any non-infectious adverse event. The proportion of patients with upper respiratory tract infections was significantly higher in patients receiving 50 mg etanercept compared with those receiving 25 mg (26% vs 4%, p = 0.027). CONCLUSION: Etanercept as a monotherapy at 50 mg twice weekly does not provide increased efficacy when compared to the standard dose of 25 mg twice weekly in TNF-alpha blocker-naäve patients.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Imunoglobulina G/uso terapêutico , Receptores do Fator de Necrose Tumoral/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Antirreumáticos/efeitos adversos , Artrite Reumatoide/complicações , Artrite Reumatoide/fisiopatologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Etanercepte , Feminino , Nível de Saúde , Humanos , Imunoglobulina G/efeitos adversos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Índice de Gravidade de Doença , Resultado do Tratamento
11.
Proc Natl Acad Sci U S A ; 102(35): 12489-94, 2005 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-16113081

RESUMO

In humans and in animal models, susceptibility to arthritis is under complex genetic control, reflecting influences on the immunological processes that initiate autoimmunity and on subsequent inflammatory mechanisms in the joints. The effector phases are conveniently modeled by the K/BxN serum transfer system, a robust model well suited for genetic analysis where arthritis is initiated by pathogenic Ig. Here, we mapped the genetic loci distinguishing the high-responder BALB/c vs. low-responder SJL strains. After computational modeling of potential breeding schemes, we adapted a stepwise selective breeding strategy, with a whole-genome scan performed on a limited number of animals. Several genomic regions proved significantly associated with high sensitivity to arthritis. One of these regions, on distal chr2, was centered on the interleukin 1 gene family. Quantitation of transcripts of the Il1a and Il1b candidate genes revealed a 10-fold greater induction of Il1b mRNA in BALB/c than in SJL splenocytes after injection of LPS, whereas Il1a showed much less difference. The differential activity of the Il1b gene was associated with a particular sequence haplotype of noncoding polymorphisms. The BALB/c haplotype was found in 75% of wild-derived strains but was rare among conventional inbred strains (4/33 tested, one of which is DBA/1, the prototype arthritis-susceptible strain) and was associated with vigorous Il1b responses in a panel of inbred strains. Inbred strains carrying this allele were far more responsive to serum-transferred arthritis, confirming its broad importance in controlling arthritis severity.


Assuntos
Artrite Experimental/genética , Artrite Experimental/imunologia , Interleucina-1/genética , Animais , Mapeamento Cromossômico , Simulação por Computador , Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Modelos Genéticos , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Especificidade da Espécie
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