RESUMO
Programmed cell death protein 1 (PD-1)-expressing T cells are expanded in individuals with established rheumatoid arthritis (RA). However, little is known about their functional role in the pathogenesis of early RA. To address this, we investigated the transcriptomic profiles of circulating CD4+ and CD8+ PD-1+ lymphocytes from patients with early RA (n = 5) using fluorescence activated cell sorting in conjunction with total RNA sequencing. Additionally, we assessed for alterations in CD4+PD-1+ gene signatures in previously published synovial tissue (ST) biopsy data (n = 19) (GSE89408, GSE97165) before and after six-months of triple disease modifying anti-rheumatic drug (tDMARD) treatment. Comparisons of gene signatures between CD4+PD-1+ vs. PD-1- cells identified significant upregulation of genes including CXCL13 and MAF, and in pathways including Th1 and Th2, cross talk between dendritic cells and NK cells, B cell development and antigen presentation. Gene signatures from early RA ST before and after six-month tDMARD treatment revealed downregulation of the CD4+PD-1+ signatures following treatment, identifying a mechanism through which tDMARDs exert their effect by influencing T cell populations. Furthermore, we identify factors associated with B cell help that are enhanced in the ST compared with PBMCs, highlighting their importance in driving synovial inflammation.
Assuntos
Antirreumáticos , Artrite Reumatoide , Humanos , Linfócitos T CD4-Positivos , Transcriptoma , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico , Antirreumáticos/metabolismo , ApoptoseRESUMO
OBJECTIVES: Programmed cell death protein 1 (PD-1)-expressing T cells are implicated in the pathogenesis of autoimmune inflammatory diseases such as rheumatoid arthritis. A subset of CXCR5- T cells, termed T peripheral helper (Tph) cells, which drive B cell differentiation, have been identified in ectopic lymphoid structures in established rheumatoid arthritis synovial tissue. Here, we aimed to characterise these in treatment-naïve, early rheumatoid arthritis to determine whether these cells accumulate prior to fully established disease. METHODS: Fresh dissociated tissue and peripheral blood mononuclear cell (PBMC) suspensions were stained with Zombie UV, followed by anti-CD45RO, PD-1, CD3, ICOS, CD8, CD4, CD20, CXCR5, TIGIT and CD38 antibodies prior to analysis. For histology, rheumatoid arthritis synovial sections were prepared for Opal multispectral immunofluorescence with anti-CD45RO, CD20, PD-1 and CXCR5 antibodies. Images were acquired on the Perkin Elmer Vectra V.3.0 imaging system and analysed using InForm Advanced Image Analysis software. RESULTS: Flow cytometry revealed T cell infiltration in the rheumatoid arthritis synovium with differential expression of PD-1, CD45RO, ICOS, TIGIT and CD38. We observed a higher frequency of PD1hiCXCR5- Tph in rheumatoid arthritis synovial tissue and PBMCs versus controls, and no significant difference in T follicular helper cell frequency. Microscopy identified a 10-fold increase of Tph cells in early rheumatoid arthritis synovial follicular and diffuse regions, and identified Tph adjacent to germinal centre B cells. CONCLUSIONS: These data demonstrate that PD-1hi Tph cells are present in early rheumatoid arthritis, but not osteoarthritis synovium, and therefore may provide a target for treatment of patients with early rheumatoid arthritis.
Assuntos
Artrite Reumatoide , Osteoartrite , Humanos , Receptor de Morte Celular Programada 1/metabolismo , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Auxiliares-Indutores/patologia , Membrana Sinovial/metabolismo , Receptores CXCR5/metabolismo , Osteoartrite/patologiaRESUMO
BACKGROUND: Immune checkpoint inhibitors (ICIs) are associated with rheumatic and musculoskeletal immune-related adverse events (irAEs) in 5%-20% of patients. Currently, patients refractory to corticosteroids and conventional disease-modifying antirheumatic drugs (cDMARD) are treated with biological DMARDs (bDMARDs) targeting tumor necrosis factor α (TNFα) and interleukin-6, although without a clear biological rationale. Synovial tissue (ST) biopsy presents a valuable opportunity to investigate irAE pathogenesis and appropriately stratify bDMARD use in refractory irAE patients. CASE PRESENTATION: We provide the first report of comparative, parallel ST and synovial fluid (SF) analyses of severe, cDMARD-refractory, seronegative polyarthritis, classified as a grade 3 irAE occurring in response to nivolumab treatment for metastatic squamous cell lung cancer, in comparison with ST and SF from patients with untreated rheumatoid arthritis (RA). We investigated immunohistochemical labeling of ST cytokine expression as a biological rationale for selecting therapy. Flow cytometric analysis of lymphocytes from ST, SF and blood collected before and after synovial biopsy-guided therapy, in comparison with RA, were evaluated for insights into the immunopathogenesis of irAE. Immunolabeling of ST demonstrated an excess of TNFα cytokine expression. Subsequent treatment with infliximab resulted in resolution of inflammatory symptoms and a significant reduction in C reactive protein levels. Flow cytometric analysis of synovial infiltrates indicated absence of programmed cell death protein-1 (PD-1) receptor positivity despite cessation of nivolumab approximately 200 days prior to the analyzes. CONCLUSIONS: A deeper understanding of the immunopathogenetic basis of immune activation in irAEs is required in order to select therapy that is likely to be the most effective. This is the first report investigating parallel blood, ST and SF in ICI-induced severe rheumatic irAE. Use of a bDMARD directed by the dominant inflammatory cytokine achieved resolution of synovitis while maintaining cancer remission.
Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Infliximab/uso terapêutico , Nivolumabe/efeitos adversos , Sinovite/tratamento farmacológico , Linfócitos T/imunologia , Carcinoma de Células Escamosas , Fármacos Gastrointestinais/uso terapêutico , Humanos , Neoplasias Pulmonares , Masculino , Pessoa de Meia-Idade , Prognóstico , Sinovite/induzido quimicamente , Sinovite/imunologia , Linfócitos T/efeitos dos fármacosRESUMO
BACKGROUND: Plasmablasts and plasma cells play a key role in many autoimmune diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). This study was undertaken to evaluate the potential of targeting CD38 as a plasma cell/plasmablast depletion mechanism by daratumumab in the treatment of patients with RA and SLE. METHODS: RNA-sequencing analysis of synovial biopsies from various stages of RA disease progression, flow cytometry analysis of peripheral blood mononuclear cells (PBMC) from patients with RA or SLE and healthy donors, immunohistochemistry assessment (IHC) of synovial biopsies from patients with early RA, and ex vivo immune cell depletion assays using daratumumab (an anti-CD38 monoclonal antibody) were used to assess CD38 as a therapeutic target. RESULTS: We demonstrated that the plasma cell/plasmablast-related genes CD38, XBP1, IRF4, PRDM1, IGJ and TNFSF13B are significantly up-regulated in synovial biopsies from patients with arthralgia, undifferentiated arthritis (UA), early RA and established RA as compared to healthy controls and control patients with osteoarthritis. In addition, the highest CD38 expression was observed on plasma cells and plasmablasts compared to natural killer (NK) cells, classical dendritic cells (DCs), plasmacytoid DCs (pDCs) and T cells, in blood from healthy controls and patients with SLE and RA. Furthermore, IHC showed CD38 staining in the same region as CD3 and CD138 staining in synovial tissue biopsies from patients with early RA. Most importantly, our data show for the first time that daratumumab effectively depletes plasma cells/plasmablasts in PBMC from patients with SLE and RA in a dose-dependent manner ex vivo. CONCLUSION: These results indicate that CD38 may be a potential target for RA disease interception and daratumumab should be evaluated clinically for the treatment of both RA and SLE.
Assuntos
ADP-Ribosil Ciclase 1/antagonistas & inibidores , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Plasmócitos/metabolismo , ADP-Ribosil Ciclase 1/genética , ADP-Ribosil Ciclase 1/metabolismo , Adulto , Idoso , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Células Cultivadas , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Leucócitos Mononucleares/metabolismo , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/metabolismo , Masculino , Pessoa de Meia-Idade , Membrana Sinovial/metabolismo , Membrana Sinovial/patologiaRESUMO
Immune checkpoint blockade with therapeutic anti-cytotoxic T lymphocyte-associated antigen (CTLA)-4 (Ipilimumab) and anti-programmed death (PD)-1 (Nivolumab and Pembrolizumab) antibodies alone or in combination has shown remarkable efficacy in multiple cancer types, concomitant with immune-related adverse events, including arthralgia and inflammatory arthritis (IA) in some patients. Herein, using Nivolumab (anti-PD-1 antagonist)-responsive genes along with transcriptomics of synovial tissue from multiple stages of rheumatoid arthritis (RA) disease progression, we have interrogated the activity status of PD-1 pathway during RA development. We demonstrate that the expression of PD-1 was increased in early and established RA synovial tissue compared to normal and OA synovium, whereas that of its ligands, programmed death ligand-1 (PD-L1) and PD-L2, was increased at all the stages of RA disease progression, namely arthralgia, IA/undifferentiated arthritis, early RA and established RA. Further, we show that RA patients expressed PD-1 on a majority of synovial tissue infiltrating CD4+ and CD8+ T cells. Moreover, enrichment of Nivolumab gene signature was observed in IA and RA, indicating that the PD-1 pathway was downregulated during RA disease progression. Furthermore, serum soluble (s) PD-1 levels were increased in autoantibody positive early RA patients. Interestingly, most of the early RA synovium tissue sections showed negative PD-L1 staining by immunohistochemistry. Therefore, downregulation in PD-1 inhibitory signaling in RA could be attributed to increased serum sPD-1 and decreased synovial tissue PD-L1 levels. Taken together, these data suggest that agonistic PD1 antibody-based therapeutics may show efficacy in RA treatment and interception.
Assuntos
Artrite Reumatoide/patologia , Regulação para Baixo , Receptor de Morte Celular Programada 1/metabolismo , Membrana Sinovial/patologia , Progressão da Doença , Feminino , Humanos , Masculino , Membrana Sinovial/metabolismoRESUMO
BACKGROUND AND AIMS: The effects of low dose prednisolone on circulating markers of endothelial function, the arginine metabolites asymmetric dimethyl arginine (ADMA), mono methyl arginine (MMA), and homoarginine, are uncertain. We assessed whether patients with rheumatoid arthritis have perturbations in arginine metabolite concentrations that are reversed by low dose prednisolone. METHODS: Eighteen rheumatoid arthritis patients who had not taken prednisolone for >6 months (non-glucocorticoid (GC) users), 18 rheumatoid arthritis patients taking continuous oral prednisolone (6.5 ± 1.8 mg/day) for >6 months (GC users) and 20 healthy controls were studied. Fasting plasma concentrations of ADMA, MMA, and homoarginine were measured by ultra-performance liquid-chromatography. Baseline data from non-GC users were compared with healthy controls to assess the effect of rheumatoid arthritis. The change in arginine metabolites in non-GC users after 7 days of prednisolone (6 mg/day) was used to assess the acute effects of prednisolone. Baseline data from non-GC users were compared with GC users to assess the chronic effects of prednisolone. RESULTS: Non-GC users had higher ADMA (0.59 ± 0.03 vs. 0.47 ± 0.01 µM, p = 0.004) and MMA concentrations (0.10 ± 0.01 vs. 0.05 ± 0.00 µM, p < 0.001) than controls. The only change with acute prednisolone was a reduction in homoarginine (1.23 ± 0.06 vs. 1.08 ± 0.06 µM, p = 0.04) versus baseline. GC users had lower concentrations of ADMA (0.51 ± 0.02 vs. 0.59 ± 0.03 µM, p = 0.03) than non-GC users. CONCLUSIONS: Rheumatoid arthritis patients have higher concentrations of ADMA and MMA, inhibitors of endothelial function. Chronic, but not acute, prednisolone therapy is associated with a lower ADMA concentration, suggesting a salutary effect of long-term glucocorticoid treatment on endothelial function.
Assuntos
Arginina/sangue , Artrite Reumatoide/tratamento farmacológico , Glucocorticoides/administração & dosagem , Metabolômica/métodos , Prednisolona/administração & dosagem , Administração Oral , Idoso , Arginina/análogos & derivados , Artrite Reumatoide/sangue , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/fisiopatologia , Biomarcadores/sangue , Estudos de Casos e Controles , Cromatografia Líquida , Esquema de Medicação , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Feminino , Homoarginina/sangue , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVES: This study sought to investigate the genome-wide transcriptional effects of a combination of disease modifying anti-rheumatic drugs (tDMARD; methotrexate, sulfasalazine and hydroxychloroquine) in synovial tissues obtained from early rheumatoid arthritis (RA) patients. While combination DMARD strategies have been investigated for clinical efficacy, very little data exists on the potential molecular mechanism of action. We hypothesized that tDMARD would impact multiple biological pathways, but the specific pathways were unknown. METHODS: Paired synovial biopsy samples from early RA patients before and after 6 months of tDMARD therapy were collected by arthroscopy (n = 19). These biopsies as well as those from subjects with normal synovium (n = 28) were profiled by total RNA sequencing. RESULTS: Large differences in gene expression between RA and control biopsies (over 5000 genes) were identified. Despite clinical efficacy, the expression of a restricted set of less than 300 genes was reversed after 6 months of treatment. Many genes remained elevated, even in patients who achieved low disease activity. Interestingly, tDMARD downregulated genes included those involved in T cell activation and signaling and plasmablast/plasma cell differentiation and function. CONCLUSIONS: We have identified transcriptomic signatures that characterize synovial tissue from RA patients with early disease. Analysis after 6 months of tDMARD treatment highlight consistent alterations in expression of genes related to T cell activation and plasmablast/plasma cell differentiation. These results provide novel insight into the biology of early RA and the mechanism of tDMARD action and may help identify novel drug targets to improve rates of treatment-induced disease remission.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Membrana Sinovial/efeitos dos fármacos , Linfócitos T/citologia , Adulto , Idoso , Artroscopia , Biópsia , Estudos de Casos e Controles , Diferenciação Celular , Regulação para Baixo , Quimioterapia Combinada , Feminino , Humanos , Hidroxicloroquina/uso terapêutico , Ativação Linfocitária/efeitos dos fármacos , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Plasmócitos/citologia , Análise de Componente Principal , Indução de Remissão , Análise de Sequência de RNA , Sulfassalazina/uso terapêutico , Membrana Sinovial/metabolismo , Linfócitos T/efeitos dos fármacos , TranscriptomaRESUMO
Osteoclast-associated receptor (OSCAR) is a co-stimulatory receptor in osteoclastogenesis. Synovial tissues from active rheumatoid arthritis (RA) patients express higher levels of OSCAR compared with osteoarthritic and normal patients; however, the comparison of OSCAR levels in different regions of active RA synovium has not been reported. The regulation of OSCAR by TNF-α and receptor activator of NF kappa ß ligand (RANKL) in pre-osteoclasts/osteoclasts in vitro is unclear. OSCAR and tartrate-resistant acid phosphatase (TRAP) expression levels did not differ between the cartilage pannus junction (CPJ) and non-CPJ regions in active RA. We demonstrate a similar pattern of OSCAR expression in the CPJ and non-CPJ synovial tissue from patients with active RA. OSCAR was associated with mononuclear cells in both the lining and sub-lining and endothelial cells (von Willebrand factor positive). Pre-osteoclasts (TRAP-positive cells) were present in the lining and sub-lining of both regions. OSCAR messenger RNA (mRNA) expression and release by pre-oscteoclasts/osteoclasts was modulated by RANKL with/without TNF-α in vitro. Osteoclast resorption on dentine slices was significantly greater with TNF-α pre-treatment and RANKL (10 ng/ml) than RANKL 10 or 50 ng/ml alone or RANKL 10 ng/ml with TNF-α given from day 3 post-RANKL. The lower levels of OSCAR mRNA expression corresponded with high osteoclast activity levels.
Assuntos
Artrite Reumatoide/metabolismo , Osteoclastos/metabolismo , Receptores de Superfície Celular/metabolismo , Membrana Sinovial/química , Células Endoteliais/química , Humanos , Leucócitos Mononucleares/química , Ligante RANK/fisiologia , RNA Mensageiro/metabolismo , Receptores de Superfície Celular/genética , Membrana Sinovial/metabolismo , Fosfatase Ácida Resistente a Tartarato/metabolismo , Fator de Necrose Tumoral alfa/fisiologiaRESUMO
The inflammatory CD40-CD40L pathway is implicated in various autoimmune diseases, but the activity status of this pathway in various stages of rheumatoid arthritis (RA) progression is unknown. In this study, we used gene signatures of CD40L stimulation derived from human immature dendritic cells and naive B cells to assess the expression of CD40-downstream genes in synovial tissues from anti-citrullinated protein Ab-positive arthralgia, undifferentiated arthritis (UA), early RA, and established RA cohorts in comparison with healthy donors. Interestingly, the expression of CD40LG and active full-length CD40 was increased in the disease tissues, whereas that of a dominant-negative CD40 isoform was decreased. Gene set variation analysis revealed that CD40L-responsive genes in immature dendritic cells and naive B cells were significantly enriched in synovial tissues from UA, early RA, and established RA patients. Additionally, CD40L-induced naive B cell genes were also significantly enriched in synovial tissues from arthralgia patients. In our efforts to characterize downstream mediators of CD40L signaling, we have identified GPR120 and KDM6B as novel components of the pathway. In conclusion, our data suggest that therapeutic CD40-CD40L blocking agents may prove efficacious not only in early and established RA, but also in inhibiting the progression of the disease from arthralgia or UA to RA.
Assuntos
Artrite Reumatoide/imunologia , Artrite/imunologia , Ligante de CD40/imunologia , Ligante de CD40/metabolismo , Progressão da Doença , Transdução de Sinais , Adulto , Idoso , Artralgia/imunologia , Artralgia/fisiopatologia , Artrite Reumatoide/fisiopatologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Biópsia , Linfócitos T CD4-Positivos/imunologia , Antígenos CD40/deficiência , Antígenos CD40/genética , Antígenos CD40/imunologia , Antígenos CD40/metabolismo , Ligante de CD40/genética , Ligante de CD40/farmacologia , Células Dendríticas/imunologia , Células Dendríticas/fisiologia , Feminino , Voluntários Saudáveis , Humanos , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Líquido Sinovial/citologia , Líquido Sinovial/imunologia , TranscriptomaRESUMO
OBJECTIVES: Quantification of work disability in patients with early rheumatoid arthritis (RA) receiving conventional DMARDs according to a treat-to-target strategy. METHODS: This is a retrospective cohort analysis of RA patients who received combination conventional DMARDs, escalated to achieve DAS28(ESR) remission and completed an annual work and arthritis questionnaire. Random effect mixed modeling was used to assess associations between average hours worked per week (HWPW), and baseline prognostic factors. HWPW were compared with matched population averages. Cox proportional hazards modeling was employed to evaluate associations between permanent loss of employment and treatment response, disease and demographic factors. RESULTS: Work data from 135 patients working at baseline and 137 working at any point followed for up to 14 years (range 1-14) were available for analysis. The mean age was 45 years, 70% were female, and 70% and 68% were seropositive for rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP), respectively. Men worked more hours than women; there was a highly significant association between working hours lost and increasing age (0.28 hours, P = 0.04) and female gender (11.92 hours, P < 0.001). HWPW were maintained over the study time comparable to the general population (loss of 0.78 vs. 0.24 HWPW). EULAR good responders at 6 months were more likely to be working at 10 years compared to those with moderate/no response. Permanent loss of employment and baseline age were strongly associated for anti-CCP positive participants (P = 0.04). CONCLUSIONS: Treat-to-target combination conventional DMARD therapy maintains work capacity, particularly in good responders, comparable to the general population. Improving treatment response in moderate/no responders early in disease may increase work retention.
Assuntos
Anticorpos Antiproteína Citrulinada/análise , Antirreumáticos/uso terapêutico , Artrite Reumatoide , Recuperação de Função Fisiológica/efeitos dos fármacos , Indução de Remissão/métodos , Avaliação da Capacidade de Trabalho , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/epidemiologia , Austrália/epidemiologia , Estudos de Coortes , Quimioterapia Combinada/métodos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Fatores Sexuais , Inquéritos e QuestionáriosRESUMO
BACKGROUND AND AIMS: Glucocorticoids could impair vascular function directly, or indirectly by reducing insulin sensitivity. The aim of this study was to determine the direct and indirect effects of acute and chronic low dose prednisolone on arterial stiffness and endothelial function. METHODS: Twelve subjects with inflammatory arthritis, who had not taken oral glucocorticoids for ≥6 months, and 12 subjects with inflammatory arthritis, taking chronic (>6 months) low dose (6.3 ± 2.2 mg/day) prednisolone, were studied. Patients not on glucocorticoids underwent measurement of arterial stiffness (pulse wave velocity (PWV)) and endothelial function (reactive hyperaemia index (RHI)) before and after 7-10 days of prednisolone (6 mg/day), to assess the acute effects of prednisolone. Baseline data from patients not on glucocorticoids were compared with patients on long-term prednisolone to assess the chronic effects of prednisolone. Hepatic insulin sensitivity was estimated from percentage suppression of endogenous glucose production and peripheral insulin sensitivity as glucose infusion rate (M/I) during a hyperinsulinaemic-euglycaemic clamp. RESULTS: There were no significant changes in PWV with acute (9.2 ± 0.8 vs. 8.9 ± 0.8 m/sec, p = 0.33) or chronic (8.9 ± 0.8 vs. 9.0 ± 0.7 m/sec, p = 0.69) prednisolone. In multiple regression analysis, PWV was negatively associated with M/I during hyperinsulinemic-euglycemic clamp (p = 0.02), but not with suppression of endogenous glucose production (p = 0.15) or glucocorticoid use (p = 0.70). Chronic (2.4 ± 0.2 vs. 1.9 ± 0.1, p = 0.02), but not acute (1.8 ± 0.2 vs. 1.9 ± 0.1, p = 0.24), prednisolone resulted in a higher RHI. CONCLUSIONS: Arterial stiffness is not affected by low dose prednisolone per se, but is negatively associated with peripheral insulin sensitivity. Patients with rheumatoid arthritis taking long-term prednisolone had better endothelial function.
Assuntos
Artrite Reumatoide/tratamento farmacológico , Endotélio Vascular/efeitos dos fármacos , Glucocorticoides/administração & dosagem , Resistência à Insulina , Prednisolona/administração & dosagem , Rigidez Vascular/efeitos dos fármacos , Administração Oral , Idoso , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/fisiopatologia , Glicemia/metabolismo , Estudos Transversais , Esquema de Medicação , Endotélio Vascular/fisiopatologia , Feminino , Glucocorticoides/efeitos adversos , Técnica Clamp de Glucose , Humanos , Hiperemia/fisiopatologia , Insulina/sangue , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Prednisolona/efeitos adversos , Análise de Onda de Pulso , Fatores de Tempo , Resultado do TratamentoRESUMO
Synovial membrane (SM) pathology has provided valuable insights into our current understanding of immunopathological processes and treatment responses in the inflammatory arthritides. Amongst various methods of synovial biopsy, arthroscopic techniques remain the 'gold standard' owing to better sampling from sites of interest, particularly in patients with partially treated disease and from areas within joints that may be difficult to access using other techniques. Newer sophisticated techniques of SM membrane analyses allow assessment of differentially regulated pathways, the knowledge of which may help elucidate diagnostic and therapeutic targets in an attempt towards developing strategies for personalised medicine in the current era of targeted biologic therapies.
Assuntos
Artroscopia , Doenças Reumáticas/patologia , Reumatologia/métodos , Membrana Sinovial/patologia , Biópsia , Humanos , Valor Preditivo dos Testes , Prognóstico , Doenças Reumáticas/imunologia , Doenças Reumáticas/terapia , Membrana Sinovial/imunologiaRESUMO
OBJECTIVE: Glucocorticoids can cause postprandial hyperglycaemia, but the effects on postprandial energy and fat metabolism are uncertain. We investigated the effects of acute and chronic low-dose prednisolone on fasting and postprandial energy expenditure and substrate metabolism. DESIGN: An open interventional and cross-sectional study was undertaken. PATIENTS AND MEASUREMENTS: Eighteen patients who had not taken oral glucocorticoids for ≥6 months were studied before and after 7 days prednisolone (6 mg/day) to assess the acute effects of prednisolone. Baseline data from patients, not on glucocorticoids, were compared with 18 patients on long-term prednisolone (6·5 ± 1·8 mg/day for >6 months) to assess the chronic effects. Energy expenditure and substrate oxidation were measured using indirect calorimetry before and after a mixed meal. Adipocyte insulin resistance index and insulin-mediated suppression of NEFA were calculated from fasting and postprandial insulin and NEFA concentrations. RESULTS: There were no significant differences in resting energy expenditure or diet-induced thermogenesis with prednisolone. Acute (-2·1 ± 6·2 vs -16·3 ± 4·8 mg/min, P = 0·01) and chronic (-1·4 ± 2·8 vs -16·3 ± 4·8 mg/min, P = 0·01) prednisolone attenuated postprandial suppression of fat oxidation. Chronic (31·6 ± 3·8 vs 17·0 ± 3·3, P = 0·007), but not acute, prednisolone increased adipocyte insulin resistance index. However, insulin-mediated suppression of NEFA was not significantly different after acute or chronic prednisolone. CONCLUSIONS: Prednisolone does not alter energy expenditure. However, even at low doses, prednisolone exerts adverse effects on fat metabolism, which could exacerbate insulin resistance and increase cardiovascular risk. Attenuated postprandial suppression of fat oxidation, but not lipolysis, suggests that prednisolone causes greater insulin resistance in skeletal muscle than in adipocytes.
Assuntos
Artrite Reumatoide/tratamento farmacológico , Metabolismo Energético/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Prednisolona/farmacologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Idoso , Calorimetria Indireta , Ácidos Graxos não Esterificados/análise , Feminino , Humanos , Resistência à Insulina , Lipólise , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Oxirredução , Prednisolona/administração & dosagem , Termogênese/efeitos dos fármacosRESUMO
Giant cell arteritis (GCA) is one of the commonest forms of vasculitis in the elderly, and may result in blindness and stroke. The pathogenesis of GCA is not understood, although environmental, infectious and genetic risk factors are implicated. One gene of interest is PTPN22, encoding lymphoid protein tyrosine phosphatase (Lyp), expressed exclusively in immune cells, which is proposed to be an 'archetypal non-HLA autoimmunity gene'. The minor allele of a functional PTPN22 single nucleotide polymorphism (rs2476601, R620W), which disrupts an interaction motif in the protein, was originally reported to be associated with biopsy-proven GCA in Spanish patients, with supporting data from three replicate Northern European studies. Recently, this observation was extended with additional patients and controls, and studies encompassing European, Scandinavian, UK and American patients. The aim of our study was to determine the association between PTPN22 rs2476601 (R620W) and biopsy-proven GCA in an Australian case cohort.
RESUMO
OBJECTIVE: Gout is associated with dyslipidaemia. Association of the apolipoprotein A1-C3-A4 gene cluster with gout has previously been reported in a small study. To investigate a possible causal role for this locus in gout, we tested the association of genetic variants from APOA1 (rs670) and APOC3 (rs5128) with gout. METHODS: We studied data for 2452 controls and 2690 clinically ascertained gout cases of European and New Zealand Polynesian (Maori and Pacific) ancestry. Data were also used from the publicly available Atherosclerosis Risk in Communities study (n = 5367) and the Framingham Heart Study (n = 2984). Multivariate adjusted logistic and linear regression was used to test the association of single-nucleotide polymorphisms with gout risk, serum urate, triglyceride and high-density lipoprotein cholesterol (HDL-C). RESULTS: In Polynesians, the T-allele of rs670 (APOA1) increased (odds ratio, OR = 1.53, P = 4.9 × 10(-6)) and the G-allele of rs5128 (APOC3) decreased the risk of gout (OR = 0.86, P = 0.026). In Europeans, there was a strong trend to a risk effect of the T-allele for rs670 (OR = 1.11, P = 0.055), with a significant protective effect of the G-allele for rs5128 being observed after adjustment for triglycerides and HDL-C (OR = 0.81, P = 0.039). The effect at rs5128 was specific to males in both Europeans and Polynesians. Association in Polynesians was independent of any effect of rs670 and rs5128 on triglyceride and HDL-C levels. There was no evidence for association of either single-nucleotide polymorphism with serum urate levels (P ⩾ 0.10). CONCLUSION: Our data, replicating a previous study, supports the hypothesis that the apolipoprotein A1-C3-A4 gene cluster plays a causal role in gout.
Assuntos
Apolipoproteína A-I/genética , Gota/genética , Família Multigênica/genética , Adulto , Apolipoproteína C-III/genética , Apolipoproteínas C/genética , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Havaiano Nativo ou Outro Ilhéu do Pacífico/genética , Fatores de Risco , Ácido Úrico/metabolismo , População Branca/genéticaRESUMO
OBJECTIVE: To determine whether foot synovitis is associated with adverse radiographic and functional outcomes after 3 years in an inception rheumatoid arthritis (RA) cohort receiving treat-to-target combination disease-modifying antirheumatic drug therapy. METHODS: Disease activity was assessed in early RA patients (n = 266) using the Disease Activity Score in 28 joints, Clinical Disease Activity Index (CDAI), and Simplified Disease Activity Index (SDAI). Radiographic outcomes were assessed with annual hand and feet radiographs and quality of life with the Short Form 36 (SF-36). The prevalence of remission and foot synovitis was calculated using marginal binomial generalized estimating equations, transition between remission and nonremission states by a multistate Markov model, and changes in radiographic scores by a negative binomial mixed regression log-link model. Population-matched SF-36 data were analyzed by mixed-effects linear regression. RESULTS: Disease activity scores that omit foot joints were modest in their ability to capture foot synovitis. Despite the relative stringency of the SDAI and CDAI for remission, 25-36% of patients in remission had foot synovitis. In patients in remission, foot synovitis predicted transition from remission into relapse by up to 2-fold. The sustainability of remission markedly influenced the progression of erosion scores (P = 0.006). After adjusting for disease activity, foot synovitis was associated with worse SF-36 physical functioning scores (P = 0.025). CONCLUSION: Disease activity measures that omit foot joints capture foot synovitis poorly. When it is used to define remission, foot synovitis is found in a substantial proportion of patients, which predicts relapse and worse physical function. Foot synovitis influences the sustainability of remission, which in turn markedly influences radiographic progression. Regardless of remission status, persistent foot synovitis should prompt therapy escalation in order to improve long-term outcomes.
Assuntos
Artrite Reumatoide/complicações , Progressão da Doença , Articulações do Pé/diagnóstico por imagem , Sinovite/diagnóstico por imagem , Adulto , Idoso , Antirreumáticos/uso terapêutico , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/tratamento farmacológico , Estudos de Coortes , Feminino , Articulações do Pé/fisiopatologia , Mãos/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Qualidade de Vida , Recidiva , Indução de Remissão , Índice de Gravidade de Doença , Sinovite/epidemiologia , Sinovite/etiologia , Resultado do TratamentoRESUMO
OBJECTIVE: Because limited data currently support the clinical utility of peripherally expressed biomarkers in guiding treatment decisions for patients with rheumatoid arthritis, the search has turned to the disease tissue. The strategic aim of the Outcome Measures in Rheumatology (OMERACT) synovitis working group over the years has been to develop novel diagnostic and prognostic synovial biomarkers. A critical step in this process is to refine and validate minimally invasive, technically simple, robust techniques to sample synovial tissue, for use both in clinical trials and routine clinical practice. The objective of the synovitis working group (SWG) at OMERACT 12 (2014) was to examine whether recently developed ultrasound (US)-guided synovial biopsy techniques could be validated according to the OMERACT filter for future clinical use recommendation. METHODS: The SWG examined whether current data reporting US-guided synovial biopsy of both large and small joints addressed the OMERACT filters of truth, discrimination, and feasibility. RESULTS: There are currently limited data examining the performance of US-guided synovial biopsy, mainly from observational studies. Thus, it remains critical to evaluate its performance, within the clinical trials context, against the current gold standard of arthroscopic biopsy, with particular reference to: (1) synovial tissue yield, (2) capacity to determine treatment response as measured by a validated synovial biomarker, and (3) tolerability of the procedure. CONCLUSION: We summarize the discrete work packages agreed to as requirements to validate US-guided synovial biopsy and therefore lead to a global consensus on the use of synovial biopsy for research and clinical practice.
Assuntos
Artrite Reumatoide/patologia , Biópsia Guiada por Imagem/normas , Guias de Prática Clínica como Assunto/normas , Sinovite/patologia , Antirreumáticos/uso terapêutico , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/tratamento farmacológico , Feminino , Humanos , Biópsia Guiada por Imagem/métodos , Masculino , Procedimentos Cirúrgicos Minimamente Invasivos , Segurança do Paciente , Índice de Gravidade de Doença , Membrana Sinovial/patologia , Sinovite/diagnóstico por imagem , Sinovite/tratamento farmacológico , Resultado do Tratamento , Ultrassonografia Doppler/métodos , Ultrassonografia Doppler/normasRESUMO
OBJECTIVE: Postprandial hyperglycaemia is associated with increased arterial stiffness and cardiovascular events. Low-dose prednisolone causes insulin resistance that typically manifests as postprandial hyperglycaemia. We investigated whether prednisolone causes postprandial vascular dysfunction in a cohort of patients with rheumatoid arthritis. DESIGN: An open interventional and cross-sectional study was undertaken. PATIENTS AND MEASUREMENTS: Eighteen subjects with rheumatoid arthritis who had not taken oral glucocorticoids for ≥6 months were studied before and after prednisolone 6 mg/day for 7 days to determine the acute effects of prednisolone. Pre-prednisolone data were compared to 18 subjects with rheumatoid arthritis taking long-term (>6 months) prednisolone (6·5 ± 1·8 mg/day) to assess the chronic effects of prednisolone. Augmentation index (by applanation tonometry) and reactive hyperaemia index (by peripheral artery tonometry) were measured before and after a mixed-meal (10 kcal/kg, 45% carbohydrate, 15% protein, 40% fat). Insulin sensitivity was estimated by the Matsuda index and sympathetic nervous system activity from urinary noradrenaline excretion. RESULTS: Matsuda index was lower after acute (2·0 ± 1·0 vs 3·6 ± 1·1, P = 0·01) and chronic (1·9 ± 1·0 vs 3·6 ± 1·1, P = 0·04) prednisolone. Postprandial augmentation index was lower after acute prednisolone (2551 ± 197 vs 2690 ± 272%*min, P ≤ 0·001), but not chronic prednisolone. There were no significant differences in reactive hyperaemia index with acute or chronic prednisolone. Noradrenaline excretion was lower after acute (54 ± 8 vs 93 ± 23 nmol/6 h, P = 0·02), but not chronic, prednisolone. CONCLUSIONS: Prednisolone-induced insulin resistance is not associated with postprandial vascular dysfunction in patients with rheumatoid arthritis. Reduced sympathetic activity may contribute to the reduction in postprandial arterial stiffness with acute prednisolone.
Assuntos
Artrite Reumatoide/tratamento farmacológico , Glicemia/análise , Resistência à Insulina/fisiologia , Prednisolona/uso terapêutico , Idoso , Artrite Reumatoide/sangue , Artrite Reumatoide/fisiopatologia , Estudos Transversais , Esquema de Medicação , Feminino , Glucocorticoides/administração & dosagem , Glucocorticoides/uso terapêutico , Humanos , Hiperglicemia/sangue , Hiperglicemia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial , Prednisolona/administração & dosagem , Fatores de Tempo , Resultado do Tratamento , Rigidez Vascular/efeitos dos fármacosRESUMO
OBJECTIVE: To investigate the effect of Embelin, an inhibitor of X-Linked Inhibitor of Apoptosis Protein (XIAP), on inflammation and bone erosion in a collagen antibody induced arthritis (CAIA) in mice. METHODS: Four groups of mice (n = 6 per group) were allocated: CAIA untreated mice, CAIA treated with Prednisolone (10 mg/kg/day), CAIA treated with low dose Embelin (30 mg/kg/day), and CAIA treated with high dose Embelin (50 mg/kg/day). Joint inflammation was evaluated using clinical paw score and histological assessments. Bone erosion was assessed using micro-CT, tartrate resistant acid phosphatase (TRAP) staining, and serum carboxy-terminal collagen crosslinks (CTX-1) ELISA. Immunohistochemistry was used to detect XIAP protein. TUNEL was performed to identify apoptotic cells. RESULTS: Low dose, but not high dose Embelin, suppressed inflammation as reflected by lower paw scores (P < 0.05) and lower histological scores for inflammation. Low dose Embelin reduced serum CTX-1 (P < 0.05) and demonstrated lower histological score and TRAP counting, and slightly higher bone volume as compared to CAIA untreated mice. XIAP expression was not reduced but TUNEL positive cells were more abundant in Embelin treated CAIA mice. CONCLUSION: Low dose Embelin suppressed inflammation and serum CTX-1 in CAIA mice, indicating a potential use for Embelin to treat pathological bone loss.