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1.
Scand J Rheumatol ; 49(5): 361-370, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32468892

RESUMO

Objective: SB4, SB2, and SB5 are biosimilars of etanercept (ETN), infliximab (INF), and adalimumab (ADA), respectively. This pooled analysis evaluated the immunogenicity of these treatments across three phase III randomized controlled trials of patients with rheumatoid arthritis (RA). Methods: Patients had to have at least one anti-drug antibody (ADAb) assessment up to the time of the primary endpoint from each study (week 24 in SB4 and SB5 studies; week 30 in SB2 study). The effect of ADAbs on American College of Rheumatology 20% (ACR20) response and the incidences of injection-site reactions (ISRs)/infusion-related reactions (IRRs) were evaluated. Results: The study included 1709 patients. The cumulative incidences of ADAbs were 30.3% in the all-treatments-combined group, 29.1% in the biosimilars combined group, and 31.5% in the reference products combined group. ACR20 response rates were significantly lower in ADAb-positive patients in the all-treatments-combined [odds ratio (95% confidence interval) 1.77 (1.37, 2.27), p < 0.0001], biosimilars combined [2.24 (1.53, 3.30), p < 0.0001], and reference products combined [1.49 (1.06, 2.09), p = 0.0225] groups. ADAb-positive patients also had a higher likelihood of developing ISRs/IRRs in the all-treatments-combined group [0.56 (0.31, 1.01), p = 0.0550], predominantly due to the results observed with SB2 + INF combined rather than with SB4 + ETN or SB5 + ADA combined. Conclusion: In this pooled analysis, ADAbs were associated with reduced efficacy in patients with RA treated with biosimilars (SB4, SB2, and SB5) or their reference products (ETN, INF, and ADA). ADAbs were associated with an increased incidence of ISRs/IRRs in those treated with SB2 + INF. Clinical trial registration numbers: NCT01936181 (SB2 study), NCT01895309 (SB4 study), and NCT02167139 (SB5 study).


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Medicamentos Biossimilares/uso terapêutico , Etanercepte/uso terapêutico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Adalimumab/efeitos adversos , Adalimumab/uso terapêutico , Adulto , Anticorpos , Antirreumáticos/efeitos adversos , Medicamentos Biossimilares/efeitos adversos , Etanercepte/efeitos adversos , Feminino , Humanos , Infliximab/efeitos adversos , Infliximab/uso terapêutico , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Inibidores do Fator de Necrose Tumoral/efeitos adversos
2.
Ann Rheum Dis ; 76(1): 96-104, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27165179

RESUMO

OBJECTIVES: To assess the efficacy and safety of certolizumab pegol (CZP)+dose-optimised methotrexate (MTX) versus placebo (PBO)+dose-optimised MTX in inducing and sustaining clinical remission in DMARD-naïve patients with moderate-to-severe, active, progressive rheumatoid arthritis (RA), with poor prognostic factors over 52 weeks. METHODS: DMARD-naïve patients with ≤1 year of active RA were randomised (3:1) in a double-blind manner to CZP (400 mg Weeks 0, 2, 4, then 200 mg Q2W to Week 52)+MTX or PBO+MTX (the mean optimised-MTX dose=21 and 22 mg/week, respectively). Sustained remission (sREM) and sustained low disease activity (sLDA; DAS28(ESR)<2.6 and DAS28(ESR)≤3.2, respectively, at both Weeks 40 and 52) were the primary and secondary endpoints. RESULTS: Patients were randomised to CZP+MTX (n=660) and PBO+MTX (n=219). At Week 52, significantly more patients assigned to CZP+MTX compared with PBO+MTX achieved sREM (28.9% vs 15.0%, p<0.001) and sLDA (43.8% vs 28.6%, p<0.001). Inhibition of radiographic progression and improvements in physical functioning were significantly greater for CZP+MTX versus PBO+MTX (van der Heijde modified total Sharp score (mTSS) mean absolute change from baseline (CFB): 0.2 vs 1.8, p<0.001, rate of mTSS non-progressors: 70.3% vs 49.7%, p<0.001; least squares (LS) mean CFB in Health Assessment Questionnaire-Disability Index (HAQ-DI): -1.00 vs -0.82, p<0.001). Incidence of adverse events (AEs) and serious AEs was similar between treatment groups. Infection was the most frequent AE, with higher incidence for CZP+MTX (71.8/100 patient-years (PY)) versus PBO+MTX (52.7/100 PY); the rate of serious infection was similar between CZP+MTX (3.3/100 PY) and PBO+MTX (3.7/100 PY). CONCLUSIONS: CZP+dose-optimised MTX treatment of DMARD-naïve early RA resulted in significantly more patients achieving sREM and sLDA, improved physical function and inhibited structural damage compared with PBO+dose-optimised MTX. TRIAL REGISTRATION NUMBER: NCT01519791.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Certolizumab Pegol/uso terapêutico , Metotrexato/uso terapêutico , Adulto , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Artrite Reumatoide/diagnóstico por imagem , Certolizumab Pegol/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada/efeitos adversos , Feminino , Humanos , Infecções/induzido quimicamente , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Prognóstico , Radiografia , Indução de Remissão
3.
Ann Rheum Dis ; 74(12): 2107-16, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26395500

RESUMO

No consensus has previously been formed regarding the types and presentations of infectious pathogens to be considered as 'opportunistic infections' (OIs) within the setting of biologic therapy. We systematically reviewed published literature reporting OIs in the setting of biologic therapy for inflammatory diseases. The review sought to describe the OI definitions used within these studies and the types of OIs reported. These findings informed a consensus committee (infectious diseases and rheumatology specialists) in deliberations regarding the development of a candidate list of infections that should be considered as OIs in the setting of biologic therapy. We reviewed 368 clinical trials (randomised controlled/long-term extension), 195 observational studies and numerous case reports/series. Only 11 observational studies defined OIs within their methods; no consistent OI definition was identified across studies. Across all study formats, the most numerous OIs reported were granulomatous infections. The consensus group developed a working definition for OIs as 'indicator' infections, defined as specific pathogens or presentations of pathogens that 'indicate' the likelihood of an alteration in host immunity in the setting of biologic therapy. Using this framework, consensus was reached upon a list of OIs and case-definitions for their reporting during clinical trials and other studies. Prior studies of OIs in the setting of biologic therapy have used inconsistent definitions. The consensus committee reached agreement upon an OI definition, developed case definitions for reporting of each pathogen, and recommended these be used in future studies to facilitate comparison of infection risk between biologic therapies.


Assuntos
Terapia Biológica/métodos , Consenso , Imunossupressores/uso terapêutico , Infecções Oportunistas , Vigilância de Produtos Comercializados/métodos , Ensaios Clínicos como Assunto , Saúde Global , Humanos , Morbidade/tendências , Infecções Oportunistas/epidemiologia , Infecções Oportunistas/imunologia , Infecções Oportunistas/terapia , Fatores de Risco
4.
Genes Immun ; 15(2): 107-14, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24385024

RESUMO

The objective of this study was to study genetic factors that influence quantitative anticyclic citrullinated peptide (anti-CCP) antibody levels in RA patients. We carried out a genome-wide association study (GWAS) meta-analysis using 1975 anti-CCP+ RA patients from three large cohorts, the Brigham Rheumatoid Arthritis Sequential Study (BRASS), North American Rheumatoid Arthritis Consortium (NARAC) and the Epidemiological Investigation of RA (EIRA). We also carried out a genome-wide complex trait analysis (GCTA) to estimate the heritability of anti-CCP levels. GWAS-meta-analysis showed that anti-CCP levels were most strongly associated with the human leukocyte antigen (HLA) region with a P-value of 2 × 10(-11) for rs1980493. There were 112 SNPs in this region that exceeded the genome-wide significance threshold of 5 × 10(-8), and all were in linkage disequilibrium (LD) with the HLA- DRB1*03 allele with LD r(2) in the range of 0.25-0.88. Suggestive novel associations outside of the HLA region were also observed for rs8063248 (near the GP2 gene) with a P-value of 3 × 10(-7). None of the known RA risk alleles (∼52 loci) were associated with anti-CCP level. Heritability analysis estimated that 44% of anti-CCP variation was attributable to genetic factors captured by GWAS variants. In summary, anti-CCP level is a heritable trait, and HLA-DR3 and GP2 are associated with lower anti-CCP levels.


Assuntos
Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Autoanticorpos/imunologia , Peptídeos Cíclicos/imunologia , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Proteínas Ligadas por GPI/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Antígeno HLA-DR3/genética , Antígeno HLA-DR3/imunologia , Cadeias HLA-DRB1/genética , Cadeias HLA-DRB1/imunologia , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos
5.
Arthritis Rheum ; 63(8): 2203-8, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21484766

RESUMO

OBJECTIVE: To determine whether certolizumab pegol (CZP) dosage escalation from 200 mg to 400 mg every other week benefits some patients with rheumatoid arthritis (RA). METHODS: In the extension of the Rheumatoid Arthritis Prevention of Structural Damage 1 (RAPID 1) study into an open-label study, all patients received CZP 400 mg every other week in combination with methotrexate (MTX). Before the open-label phase of the study, patients had received CZP 200 mg or 400 mg every other week, or placebo every other week, as add-on therapy to MTX. The open-label study included those who had completed the RAPID 1 study (to week 52) and also those who had been withdrawn from the study (at week 16, due to inadequate response). At 12 weeks and 48 weeks after enrollment in the open-label study, changes in the Disease Activity Score in 28 joints (DAS28) were compared in dose-escalation patients (200 mg increased to 400 mg every other week) versus stable-dosage patients (400 mg every other week), using cumulative probability plots of individual patient-level data. RESULTS: In the group of patients who had completed the RAPID 1 study and had moderate or severe disease activity at entry into the open-label study, and in those who had been withdrawn early from the RAPID 1 study, the median DAS28 improvements 12 weeks after enrollment into the open-label study were similar in the dose-escalation and stable-dose groups. Individual patient-level data revealed no greater likelihood of response in the group of patients who received an increased dosage of CZP versus those in whom a stable dosage was maintained, whether they had completed the RAPID 1 study or had been withdrawn early. CONCLUSION: Although patient heterogeneity in clinical settings is acknowledged, the present results indicate that increasing the dose of CZP from 200 mg to 400 mg offers little additional benefit in RA, even for selected patients.


Assuntos
Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Fragmentos Fab das Imunoglobulinas/administração & dosagem , Polietilenoglicóis/administração & dosagem , Adulto , Anticorpos Monoclonais Humanizados , Antirreumáticos/uso terapêutico , Certolizumab Pegol , Relação Dose-Resposta a Droga , Humanos , Fragmentos Fab das Imunoglobulinas/uso terapêutico , Polietilenoglicóis/uso terapêutico , Resultado do Tratamento
7.
J Exp Med ; 177(6): 1623-31, 1993 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-8496681

RESUMO

Rheumatoid arthritis (RA) represents a heterogenous disease characterized by chronic polyarthritis. Most patients with adult RA inherit HLA-DR4 or -DR1 major histocompatibility complex (MHC) genes. While the molecular basis for this genetic predisposition is unknown, the major function of these MHC-encoded molecules is to present peptides to T lymphocytes. It is hypothesized that an endogenous or environmental antigen initiates a MHC-restricted immune response mediated by T lymphocytes, which is followed by a chronic inflammatory reaction involving many cell types. In chronic RA, previous or ongoing antigenic activation might result in detectable skewing of the peripheral alpha/beta T cell receptor (TCR) repertoire. Here we demonstrate a marked expansion of V alpha 12.1-bearing CD8+ T cells in the peripheral blood (mean, 22%; range, 10-43%) of > 15% of RA patients. A major proportion of these patients shared HLA-DQ2 in addition to the expected high frequency DR1 and DR4 alleles. Detailed molecular analysis in three of the RA patients with elevated V alpha 12.1+ T cells identified repeated TCR alpha chain sequences consistent with clonal V alpha 12.1+,CD8+ T cell expansion. In addition to shared TCR V alpha 12.1 germline gene usage among unrelated subjects, a conserved J alpha motif was also detected. Together, these results suggest an antigen-driven mechanism of T cell expansion in these patients and may offer a new approach in examining specific antigen that stimulate T cells in RA.


Assuntos
Artrite Reumatoide/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/análise , Linfócitos T/fisiologia , Sequência de Aminoácidos , Sequência de Bases , Antígenos CD8/análise , Antígenos HLA-DQ/análise , Humanos , Memória Imunológica , Dados de Sequência Molecular , Oligodesoxirribonucleotídeos , Membrana Sinovial/imunologia , Linfócitos T/imunologia
8.
Clin Exp Rheumatol ; 28(5 Suppl 61): S9-12, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-21044426

RESUMO

The development of methotrexate (MTX) as a therapy for rheumatoid arthritis (RA) evolved initially from positive case reports, uncontrolled case series and then several decades later placebo controlled studies followed by active comparator studies. These studies established MTX as a major therapy for RA. The importance of MTX in the treatment paradigm has only been enhanced over the past decade by the increased efficacy observed when small molecules and biologics are added to MTX. Since the first randomised studies were performed in the 1980s, MTX has now become the most well-studied disease modifying therapy to date and the most popular drug worldwide in the treatment of RA. This chapter will review the history of the development of MTX in RA.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Ensaios Clínicos como Assunto , Medicina Baseada em Evidências , Metotrexato/uso terapêutico , Antirreumáticos/história , Artrite Reumatoide/história , Ensaios Clínicos como Assunto/história , Medicina Baseada em Evidências/história , História do Século XX , Humanos , Metotrexato/história , Resultado do Tratamento
9.
Ann Rheum Dis ; 67(3): 358-63, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17666451

RESUMO

BACKGROUND: HLA-DRB1 shared epitope (HLA-SE), PTPN22 and CTLA4 alleles are associated with cyclic citrullinated peptide (CCP) and rheumatoid arthritis (RA). OBJECTIVE: We examined associations between HLA-SE, PTPN22, CTLA4 genotypes and RA phenotypes in a large cohort to (a) replicate prior associations with CCP status, and (b) determine associations with radiographic erosions and age of diagnosis. METHODS: A total of 689 RA patients from the Brigham RA Sequential Study (BRASS) were genotyped for HLA-SE, PTPN22 (rs2476601) and CTLA4 (rs3087243). Association between genotypes and CCP, rheumatoid factor (RF) erosive phenotypes and age at diagnosis were assessed with multivariable models adjusting for age, sex and disease duration. Novel causal pathway analysis was used to test the hypothesis that genetic risk factors and CCP are in the causal pathway for predicting erosions. RESULTS: In multivariable analysis, presence of any HLA-SE was strongly associated with CCP+ (odds ratio (OR) 3.05, 95% CI 2.18-4.25), and RF+ (OR 2.53, 95% CI 1.83-3.5) phenotypes; presence of any PTPN22 T allele was associated with CCP+ (OR 1.81, 95% CI 1.24-2.66) and RF+ phenotypes (OR 1.84, 95% CI 1.27-2.66). CTLA4 was not associated with CCP or RF phenotypes. While HLA-SE was associated with erosive RA phenotype (OR 1.52, 95% CI 1.01-2.17), this was no longer significant after conditioning on CCP. PTPN22 and CTLA4 were not associated with erosive phenotype. Presence of any HLA-SE was associated with an average 3.6 years earlier diagnosis compared with absence of HLA-SE (41.3 vs 44.9 years, p = 0.002) and PTPN22 was associated with a 4.2 years earlier age of diagnosis (39.5 vs 43.6 years, p = 0.002). CTLA4 genotypes were not associated with age at diagnosis of RA. CONCLUSIONS: In this large clinical cohort, we replicated the association between HLA-SE and PTPN22, but not CTLA4 with CCP+ and RF+ phenotypes. We also found evidence for associations between HLA-SE, and PTPN22 and earlier age at diagnosis. Since HLA-SE is associated with erosive phenotype in unconditional analysis, but is not significant after conditioning on CCP, this suggests that CCP is in the causal pathway for predicting erosive phenotype.


Assuntos
Artrite Reumatoide/genética , Autoanticorpos/sangue , Predisposição Genética para Doença , Adulto , Fatores Etários , Idoso , Antígenos CD/genética , Antígenos de Diferenciação/genética , Artrite Reumatoide/imunologia , Biomarcadores/sangue , Antígeno CTLA-4 , Estudos de Coortes , Feminino , Genótipo , Antígenos HLA-DR/genética , Cadeias HLA-DRB1 , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeos Cíclicos/sangue , Fenótipo , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Fator Reumatoide/sangue
10.
Ann Rheum Dis ; 67(10): 1360-4, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18791055

RESUMO

OBJECTIVE: To make recommendations on how to report disease activity in clinical trials of rheumatoid arthritis (RA) endorsed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). METHODS: The project followed the EULAR standardised operating procedures, which use a three-step approach: (1) expert-based definition of relevant research questions (November 2006); (2) systematic literature search (November 2006 to May 2007); and (3) expert consensus on recommendations based on the literature search results (May 2007). In addition, since this is the first joint EULAR/ACR publication on recommendations, an extra step included a meeting with an ACR panel to approve the recommendations elaborated by the expert group (August 2007). RESULTS: Eleven relevant questions were identified for the literature search. Based on the evidence from the literature the expert panel recommended that each trial should report the following items: (1) disease activity response and disease activity states; (2) appropriate descriptive statistics of the baseline, the endpoints and change of the single variables included in the core set; (3) baseline disease activity levels (in general); (4) the percentage of patients achieving a low disease activity state and remission; (5) time to onset of the primary outcome; (6) sustainability of the primary outcome; (7) fatigue. CONCLUSIONS: These recommendations endorsed by EULAR and ACR will help harmonise the presentations of results from clinical trials. Adherence to these recommendations will provide the readership of clinical trials with more details of important outcomes, while the higher level of homogeneity may facilitate the comparison of outcomes across different trials and pooling of trial results, such as in meta-analyses.


Assuntos
Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Ensaios Clínicos como Assunto/normas , Índice de Gravidade de Doença , Artrite Reumatoide/complicações , Ensaios Clínicos como Assunto/métodos , Medicina Baseada em Evidências/métodos , Fadiga/diagnóstico , Fadiga/etiologia , Humanos , Cooperação Internacional , Indução de Remissão , Projetos de Pesquisa/normas , Sociedades Médicas , Resultado do Tratamento
11.
Rheumatology (Oxford) ; 47(2): 194-9, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18178593

RESUMO

OBJECTIVES: There is a lack of agreement on assessing disease activity in patients with RA and determining when the RA treatment should be changed or continued. A panel of rheumatologists was convened to develop guidelines to assess adequacy of disease control, focusing on the use of disease-modifying anti-rheumatic drugs. METHODS: The Research and Development/University of California in Los Angeles (RAND/UCLA) Appropriateness Method was used to evaluate disease control adequacy. After a literature review, 108 scenarios were developed to simulate situations most likely to be encountered in clinical practice and rated on a 9-point scale by a 10-member expert panel. RESULTS: Final appropriateness rankings for the scenarios were as follows: 37% 'appropriate', 48% 'inappropriate', and 16% 'neutral'. The panelists felt that patients with disease control in the 'appropriate' range have adequate control with their current therapy, whereas those in the 'inappropriate' range should be considered for a change in therapy. Those in 'neutral' areas should have their therapy reviewed carefully. The panelists recommended that the clinically active joint count should be considered the most important decision factor. In patients with no clinically active joints, regardless of other factors no change in therapy was felt to be warranted. Patients with five or more active joints should be considered inadequately treated, and in patients with one to four active joints other variables must be considered in the decision to change therapy. CONCLUSION: These preliminary guidelines will assist the clinician in determining when a patient's clinical situation warrants therapy escalation and when continuing the current regimen would be appropriate.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Anti-Inflamatórios não Esteroides/uso terapêutico , Antirreumáticos/classificação , Antirreumáticos/normas , Ensaios Clínicos como Assunto/normas , Atenção à Saúde , Estudos de Avaliação como Assunto , Medicina Baseada em Evidências , Humanos , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Resultado do Tratamento
12.
J Clin Invest ; 101(4): 746-54, 1998 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-9466968

RESUMO

T cells infiltrating inflammatory sites are usually of the activated/memory type. The precise mechanism for the positioning of these cells within tissues is unclear. Adhesion molecules certainly play a role; however, the intricate control of cell migration appears to be mediated by numerous chemokines and their receptors. Particularly important chemokines for activated/memory T cells are the CXCR3 ligands IP-10 and Mig and the CCR5 ligands RANTES, macrophage inflammatory protein-1alpha, and macrophage inflammatory protein-1beta. We raised anti-CXCR3 mAbs and were able to detect high levels of CXCR3 expression on activated T cells. Surprisingly, a proportion of circulating blood T cells, B cells, and natural killer cells also expressed CXCR3. CCR5 showed a similar expression pattern as CXCR3, but was expressed on fewer circulating T cells. Blood T cells expressing CXCR3 (and CCR5) were mostly CD45RO+, and generally expressed high levels of beta1 integrins. This phenotype resembled that of T cells infiltrating inflammatory lesions. Immunostaining of T cells in rheumatoid arthritis synovial fluid confirmed that virtually all such T cells expressed CXCR3 and approximately 80% expressed CCR5, representing high enrichment over levels of CXCR3+ and CCR5+ T cells in blood, 35 and 15%, respectively. Analysis by immunohistochemistry of various inflamed tissues gave comparable findings in that virtually all T cells within the lesions expressed CXCR3, particularly in perivascular regions, whereas far fewer T cells within normal lymph nodes expressed CXCR3 or CCR5. These results demonstrate that the chemokine receptor CXCR3 and CCR5 are markers for T cells associated with certain inflammatory reactions, particularly TH-1 type reactions. Moreover, CXCR3 and CCR5 appear to identify subsets of T cells in blood with a predilection for homing to these sites.


Assuntos
Quimiocinas CXC , Inflamação/imunologia , Receptores CCR5/imunologia , Receptores de Quimiocinas/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Anticorpos Monoclonais/imunologia , Biomarcadores , Quimiocina CXCL10 , Quimiocinas/imunologia , Quimiotaxia , Humanos , Memória Imunológica/imunologia , Leucócitos/imunologia , Ativação Linfocitária/imunologia , Linfócitos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Receptores CXCR3 , Receptores de Quimiocinas/biossíntese , Líquido Sinovial/citologia , Líquido Sinovial/imunologia , Subpopulações de Linfócitos T/citologia , Células Tumorais Cultivadas
14.
RMD Open ; 1(1): e000044, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26509064

RESUMO

OBJECTIVES: We report the incidence of tuberculosis (TB) across certolizumab pegol (CZP) clinical trials in rheumatoid arthritis (RA), psoriasis, psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA), before and after the introduction of stricter TB screening. METHODS: TB incidence rates (IRs) were assessed and stratified according to screening guidelines used at the time of CZP trials. Before 2007 (original trials), purified protein derivative (PPD) tuberculin skin test positivity varied according to local standards (induration ≥5 up to ≥20 mm). Since 2007, all CZP trial protocols have been amended, including trials spanning (intermediate) and initiated after 2007 (current), mandating that any patient with PPD≥5 mm receives treatment for latent TB infection (LTBI). All cases of suspected TB or PPD≥5 mm, in pooled data from 5402 CZP patients across all CZP trials up to 2012, underwent blinded central review by independent experts. RESULTS: 44 TB cases were confirmed in pooled CZP RA trials (IR 0.47/100PY, patient-years) with no cases in Japanese RA trials (J-RAPID, HIKARI). Single TB cases were confirmed in psoriasis and axSpA trials (RAPID-axSpA), and no cases in the PsA trial (RAPID-PsA). IR of TB was 0.51/100PY across original or intermediate RA trials and 0.18/100PY in current trials. The majority of TB cases in RA occurred in Eastern (IR 1.02/100PY) and Central Europe (IR 0.58/100PY). Of 242/370 PPD≥5 mm patients who received 9 months isoniazid (INH) treatment for latent TB infection (LTBI), none developed TB, versus 7.8% of 128 untreated PPD≥5 mm patients. CONCLUSIONS: Implementation of more stringent LTBI screening, plus treatment for LTBI, reduced the IR of TB, even when INH was administered after starting CZP therapy.

15.
Clin Pharmacol Ther ; 39(4): 420-4, 1986 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-3956057

RESUMO

A 1500 mg dose of salsalate (SSA) was given to five patients undergoing chronic hemodialysis on an interdialytic day and again before dialysis. Compared with control subjects, patients undergoing dialysis had a lower peak plasma SSA level (17 +/- 3 vs. 45 +/- 2 micrograms/ml; P less than 0.01) that occurred slightly later. In contrast, plasma salicylic acid (SA), the active SSA metabolite, had a similar but later peak level that remained substantially higher. Therefore, the AUC for SA was increased by 50% and the SA t1/2 was prolonged in the patients receiving dialysis (8.1 +/- 0.7 vs 3.8 +/- 0.2 hours; P less than 0.01). During a single treatment, dialysis clearance reduced plasma SA levels, removed 18% of total body SA, and returned the SA t1/2 to nearly normal. Because the elimination of SA is impaired in patients undergoing dialysis, the interdialytic SSA dosage should be reduced. Hemodialysis improves SA kinetics and may be followed by a normal SSA replacement dose. However, periodic monitoring of plasma SA levels is recommended when SSA dosing is begun in patients receiving dialysis.


Assuntos
Falência Renal Crônica/metabolismo , Diálise Renal , Salicilatos/metabolismo , Administração Oral , Adulto , Idoso , Creatinina/metabolismo , Feminino , Meia-Vida , Hematócrito , Humanos , Cinética , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Salicilatos/sangue , Ácido Salicílico
16.
Medicine (Baltimore) ; 68(2): 95-106, 1989 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-2921941

RESUMO

Aortitis as a feature of rheumatoid arthritis is considered rare. We have, however, identified 10 patients with aortitis from among 188 consecutive autopsy cases of rheumatoid arthritis. There were 5 men and 5 women with a mean duration of rheumatoid arthritis of 9.6 years. Nine were rheumatoid factor positive and had associated nodules. In addition to standard treatment regimens, 9 patients received corticosteroids. Although involvement of the thoracic aorta was most common, involvement of both the thoracic and abdominal aorta was present in 4 cases. Two patients had aneurysmal dilatation of the thoracic aorta and 1 of the abdominal aorta. Microscopic features of aortitis included necrosis of medial smooth muscle and elastica, with an inflammatory infiltrate comprising primarily lymphocytes and plasma cells. A panmural aortitis was seen in 3 cases. Rheumatoid granulomas were noted in the aortic wall in 5. The diagnosis of aortitis was not made until autopsy in any case. Aortitis was hemodynamically significant in 3 patients. Two had congestive heart failure secondary to thoracic aortitis and aortic valvulitis, and 1 had rupture of an abdominal aortic aneurysm at a site involved by aortitis. Seven patients had rheumatoid vasculitis with a mean of 10 organs involved. Six of these died of complications directly related to vasculitis, including 4 patients with coronary arteritis and associated myocardial infarction. Aortitis can be a feature of severe rheumatoid arthritis and is often associated with rheumatoid vasculitis. Hemodynamic compromise does occur and may be fatal.


Assuntos
Aortite/etiologia , Artrite Reumatoide/complicações , Idoso , Idoso de 80 Anos ou mais , Aorta Abdominal/patologia , Aorta Torácica/patologia , Aortite/patologia , Artrite Reumatoide/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nódulo Reumatoide/patologia , Vasculite/etiologia , Vasculite/patologia
17.
Medicine (Baltimore) ; 73(3): 161-70, 1994 May.
Artigo em Inglês | MEDLINE | ID: mdl-8190039

RESUMO

Bronchiectasis as a feature of rheumatoid arthritis is considered rare and, in most series, has preceded rheumatoid arthritis. We identified 23 patients with rheumatoid arthritis and bronchiectasis at the Brigham and Women's Hospital followed between 1984 and 1991, 18 of whom had arthritis preceding lung disease. The 18 patients with rheumatoid arthritis and subsequent bronchiectasis had a mean age of 63.8 years. Fourteen were women and 4 were men, with a mean arthritis duration of 24.7 years before bronchiectasis developed. Most patients had seropositive and nodular disease. All but 1 had advanced radiographic changes of rheumatoid arthritis, and many had received joint replacement surgery. In addition to standard treatment regimens, 17 patients had received corticosteroids. Productive cough, hemoptysis, and dyspnea were the most common respiratory symptoms and were present for an average of 4.3 years prior to bronchiectasis diagnosis. The most common radiographic abnormalities were bibasilar diffusely increased interstitial markings and focal infiltrates, although nodules, bullae, cysts, and air-fluid levels were found. Common pulmonary-function abnormalities were obstructive and/or restrictive abnormalities. Three patients died of complications relating to bronchiectasis. Five patients with rheumatoid arthritis had antecedent bronchiectasis. Compared with patients with rheumatoid arthritis and subsequent bronchiectasis, those with antecedent lung disease had milder arthritis (stage I or II radiographic changes, p < 0.001), a lower frequency of rheumatoid nodules (p < 0.05) and a lower comorbidity score (5.8 versus 9.4, p < 0.01). They also had received fewer disease-modifying agents for the treatment of their rheumatoid arthritis. Bronchiectasis can be a feature of rheumatoid arthritis and is often found in patients with severe, long-standing nodular disease. Recurrent pulmonary infections and respiratory failure occur and may be fatal.


Assuntos
Artrite Reumatoide/diagnóstico , Bronquiectasia/diagnóstico , Adulto , Idoso , Anti-Inflamatórios/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/epidemiologia , Bronquiectasia/epidemiologia , Bronquiectasia/patologia , Comorbidade , Feminino , Haemophilus influenzae/isolamento & purificação , Humanos , Masculino , Pseudomonas/isolamento & purificação , Testes de Função Respiratória , Estudos Retrospectivos , Fatores de Risco , Escarro/microbiologia , Staphylococcus aureus/isolamento & purificação , Tomografia Computadorizada por Raios X
18.
Arch Neurol ; 46(5): 575-6, 1989 May.
Artigo em Inglês | MEDLINE | ID: mdl-2712755

RESUMO

To date, chronic myopathy has not been reported (to our knowledge) to occur in carnitine palmityltransferase (CPT) deficiency, a disorder of muscle lipid metabolism. We describe two patients with CPT deficiency: a mother, who had a partial CPT deficiency associated with fixed proximal weakness but without rhabdomyolysis, and her son, who had a complete CPT deficiency (95% reduction in enzyme activity) and who suffered from classic attacks of exercise-induced rhabdomyolysis but had normal strength on recovery. Careful examination of family members of patients with complete CPT deficiency is suggested in order to identify clinically affected heterozygotes.


Assuntos
Aciltransferases/deficiência , Carnitina O-Palmitoiltransferase/deficiência , Doenças Musculares/complicações , Adolescente , Doença Crônica , Eletromiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculos/patologia , Doenças Musculares/genética , Doenças Musculares/patologia
19.
Am J Med ; 79(1): 131-4, 1985 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-3893121

RESUMO

This report describes a patient with status asthmaticus and respiratory failure in whom profound hypoxemia developed during mechanical ventilation. During the hypoxemic episode, breath sounds were absent over the left lung, and chest radiography revealed a hyperlucent left hemithorax with tension shift of the mediastinum to the right. The presence of lung markings in the left lung on radiography eliminated the possibility of tension pneumothorax and led to the diagnosis of tension mediastinal shift secondary to a ball valve obstruction by a central mucus plug. Bronchoscopic lung lavage removed the mucus plug, thereby correcting the hypoxemia. Recognition of this previously undescribed acute complication of mechanical ventilation in status asthmaticus is essential so that confusion with tension pneumothorax is avoided and appropriate therapy instituted.


Assuntos
Asma/terapia , Muco , Respiração com Pressão Positiva/efeitos adversos , Atelectasia Pulmonar/etiologia , Estado Asmático/terapia , Adulto , Feminino , Humanos , Atelectasia Pulmonar/diagnóstico por imagem , Radiografia , Estado Asmático/complicações
20.
Pediatrics ; 80(6): 898-903, 1987 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-3317262

RESUMO

An adolescent with anemia and weight loss was found to have bilateral renal cell carcinoma (hypernephroma). Further investigation revealed an underlying tuberous sclerosis that had escaped previous clinical detection. Several reports of this association were subsequently found when the world's literature was reviewed. Physicians treating patients with tuberous sclerosis should be aware of the possible development of these renal malignancies in their patients.


Assuntos
Carcinoma de Células Renais/complicações , Neoplasias Renais/complicações , Esclerose Tuberosa/complicações , Adolescente , Carcinoma de Células Renais/patologia , Feminino , Humanos , Neoplasias Renais/patologia , Esclerose Tuberosa/patologia
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