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OBJECTIVES: To determine whether RA and interstitial lung disease (ILD) severity measures are associated with survival in patients with RA-ILD. METHODS: We studied US veterans with RA-ILD participating in a multicentre, prospective RA cohort study. RA disease activity (28-joint DAS [DAS28-ESR]) and functional status (multidimensional HAQ [MDHAQ]) were collected longitudinally while pulmonary function tests (forced vital capacity [FVC], diffusing capacity for carbon monoxide) were obtained from medical records. Vital status and cause of death were determined from the National Death Index and administrative data. Predictors of death were assessed using multivariable Cox regression models adjusting for age, sex, smoking status, ILD duration, comorbidity burden and medications. RESULTS: We followed 227 RA-ILD participants (93% male and mean age of 69 years) over 1073 person-years. Median survival after RA-ILD diagnosis was 8.5 years. Respiratory diseases (28%) were the leading cause of death, with ILD accounting for 58% of respiratory deaths. Time-varying DAS28-ESR (adjusted hazard ratio [aHR] 1.21; 95% CI: 1.03, 1.41) and MDHAQ (aHR 1.85; 95% CI: 1.29, 2.65) were separately associated with mortality independent of FVC and other confounders. Modelled together, the presence of either uncontrolled disease activity (moderate/high DAS28-ESR) or FVC impairment (<80% predicted) was significantly associated with mortality risk. Those with a combination of moderate/high disease activity and FVC <80% predicted had the highest risk of death (aHR 4.43; 95% CI: 1.70, 11.55). CONCLUSION: Both RA and ILD disease severity measures are independent predictors of survival in RA-ILD. These findings demonstrate the prognostic value of monitoring the systemic features of RA-ILD.
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Artrite Reumatoide , Doenças Pulmonares Intersticiais , Veteranos , Humanos , Masculino , Idoso , Feminino , Estudos de Coortes , Estudos Prospectivos , Artrite Reumatoide/tratamento farmacológico , Índice de Gravidade de DoençaRESUMO
OBJECTIVES: We aimed to assess whether serum cytokine/chemokine concentrations predict incident cancer in RA patients. METHODS: Data from cancer-free enrollees in the Veterans Affairs Rheumatoid Arthritis (VARA) Registry were linked to a national VA oncology database and the National Death Index (NDI) to identify incident cancers. Seventeen serum cytokines/chemokines were measured from enrollment serum and an overall weighted cytokine/chemokine score (CK score) was calculated. Associations of cytokines/chemokines with all-site, lung, and lymphoproliferative cancers were assessed in Cox regression models accounting for relevant covariates including age, sex, RA disease activity, and smoking. RESULTS: In 1216 patients, 146 incident cancers (42 lung and 23 lymphoproliferative cancers) occurred over 10,072 patient-years of follow-up with a median time of 4.6 years from enrollment (cytokine/chemokine measurement) to cancer incidence. In fully adjusted models, CK score was associated with a higher risk of all-site (aHR 1.32, 95% CI 1.01-1.71, p < 0.001), lung (aHR 1.81, 1.40-2.34, p = 0.001), and lung/lymphoproliferative (aHR 1.54 [1.35-1.75], p < 0.001) cancer. The highest quartile of CK score was associated with a higher risk of all-site (aHR 1.91, 0.96-3.81, p = 0.07; p-trend = 0.005), lung (aHR 8.18, 1.63-41.23, p = 0.01; p-trend < 0.001), and lung/lymphoproliferative (aHR 4.56 [1.84-11.31], p = 0.001; p-trend < 0.001) cancer. Thirteen of 17 individual analytes were associated with incident cancer risk. CONCLUSION: Elevated cytokine/chemokine concentrations are predictive of future cancer in RA patients, particularly lung and lymphoproliferative cancers. These results suggest that the measurement of circulating cytokines/chemokines could be informative in cancer risk stratification and could provide insight into future cancer prevention strategies in RA, and possibly individuals without RA.
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Artrite Reumatoide/complicações , Citocinas/sangue , Neoplasias/epidemiologia , Idoso , Antirreumáticos/uso terapêutico , Artrite Reumatoide/sangue , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Citocinas/imunologia , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neoplasias/imunologia , Neoplasias/prevenção & controle , Estudos Prospectivos , Sistema de Registros/estatística & dados numéricos , Medição de Risco/métodos , Fatores de Risco , Estados Unidos/epidemiologia , United States Department of Veterans Affairs/estatística & dados numéricos , Veteranos/estatística & dados numéricosRESUMO
OBJECTIVE: Interstitial lung disease (ILD) is a frequent complication of rheumatoid arthritis (RA), occurring in up to 40% of patients during the course of their disease. Early diagnosis is critical, particularly given the shared clinicoepidemiologic features between advanced rheumatoid arthritis-associated ILD (RA-ILD) and idiopathic pulmonary fibrosis (IPF). This study was undertaken to define the molecular basis of this overlap through comparative profiling of serum proteins in RA-ILD and IPF. METHODS: Multiplex enzyme-linked immunosorbent assays (ELISAs) were used to profile 45 protein biomarkers encompassing cytokines/chemokines, growth factors, and matrix metalloproteinases (MMPs) in sera obtained from RA patients with ILD and those without, individuals with IPF, and healthy controls. Levels of selected serum proteins were compared between patient subgroups using adjusted linear regression, principal component analysis (PCA), and least absolute shrinkage and selection operator (LASSO) modeling. RESULTS: Multiplex ELISA-based assessment of sera from 2 independent cohorts (Veterans Affairs [VA] and Non-VA) revealed a number of non-overlapping biomarkers distinguishing RA-ILD from RA without ILD (RA-no ILD) in adjusted regression models. Parallel analysis of sera from IPF patients also yielded a discriminatory panel of protein markers in models adjusted for age/sex/smoking, which showed differential overlap with profiles linked to RA-ILD in the VA cohort versus the Non-VA cohort. PCA revealed several distinct functional groups of RA-ILD-associated markers that, in the VA cohort, encompassed proinflammatory cytokines/chemokines as well as 2 different subsets of MMPs. Finally, LASSO regression modeling in the Non-VA and VA cohorts revealed distinct biomarker combinations capable of discriminating RA-ILD from RA-no ILD. CONCLUSION: Comparative serum protein biomarker profiling represents a viable method for distinguishing RA-ILD from RA-no ILD and identifying population-specific mediators shared with IPF.
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Artrite Reumatoide/sangue , Proteínas Sanguíneas/análise , Fibrose Pulmonar Idiopática/sangue , Doenças Pulmonares Intersticiais/sangue , Adulto , Idoso , Artrite Reumatoide/complicações , Biomarcadores/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Doenças Pulmonares Intersticiais/etiologia , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Análise de RegressãoRESUMO
OBJECTIVE: To examine associations of body mass index (BMI) and weight loss with cause-specific mortality in rheumatoid arthritis (RA). METHODS: A cohort of US veterans with RA was followed until death or through 2013. BMI was categorized as underweight, normal, overweight, and obese. Weight loss was calculated as the 1) annualized rate of change over the preceding 13 months, and 2) cumulative percent. Vital status and cause of death were obtained from the National Death Index. Multivariable competing-risks regression models were utilized to assess the time-varying associations of BMI and weight loss with cause-specific mortality. RESULTS: Among 1,600 participants and 5,789 patient-years of followup, 303 deaths occurred (95 cardiovascular, 74 cancer, and 46 respiratory). The highest weight-loss rate and weight-loss percent were associated with a higher risk of cardiovascular mortality (rate: subdistribution hazard ratio [sHR] 2.27 [95% confidence interval (95% CI) 1.61-3.19]; percent: sHR 2.31 [95% CI 1.06-5.01]) and cancer mortality (rate: sHR 2.36 [95% CI 1.11-5.01]; percent: sHR 1.90 [95% CI 1.00-3.62]). Overweight BMI was protective of cardiovascular mortality (sHR 0.59 [95% CI 0.38-0.91]), while underweight BMI was associated with a near 3-fold increased risk of respiratory mortality (sHR 2.93 [95% CI 1.28-6.67]). Incorporation of time-varying BMI and weight loss in the same models did not substantially alter individual associations for cardiovascular and cancer mortality, but an association between weight-loss percentage and respiratory mortality was attenuated after BMI adjustment. CONCLUSION: Both BMI and weight loss are predictors of cause-specific mortality in RA. Weight loss is a strong predictor of cardiovascular and cancer mortality, while underweight BMI is a stronger predictor of respiratory mortality.
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Artrite Reumatoide/mortalidade , Artrite Reumatoide/fisiopatologia , Índice de Massa Corporal , Obesidade/mortalidade , Obesidade/fisiopatologia , Saúde dos Veteranos , Redução de Peso , Idoso , Artrite Reumatoide/diagnóstico , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/fisiopatologia , Causas de Morte , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/mortalidade , Neoplasias/fisiopatologia , Obesidade/diagnóstico , Sistema de Registros , Doenças Respiratórias/mortalidade , Doenças Respiratórias/fisiopatologia , Medição de Risco , Fatores de Risco , Fatores de Tempo , Estados Unidos/epidemiologiaRESUMO
Anti-nuclear antibodies (ANAs) may be induced in patients with rheumatoid arthritis (RA) receiving anti-tumor necrosis factor (TNF) therapy with TNF inhibitors (TNFi), etanercept, infliximab or adalimumab. In the present study, 11 patients who were TNFi drug naive were started on TNFi at a time of high disease activity. Of these, all cases were positive for rheumatoid factor and 9 cases tested were positive for anti-citrullinated peptide (anti-CCP) antibodies prior to TNFi treatment. Peripheral blood mononuclear cells (PBMCs) and serum were collected from all patients before and after TNFi therapy. Serum was assayed for ANAs over time. Total cellular RNA was extracted from PBMCs and assessed using Illumina arrays. Gene expression profiles were examined for alterations in key effector pathways. After 3 or more months on TNFi, 6 patients converted to ANA-positivity. Analysis of transcripts from patients with RA who converted to ANA-positivity after 3 months on TNFi identified complex gene expression profiles that reflected a reduction in cell adhesion, cell stress and lipid metabolism transcripts. In summary, unique transcriptional profiles in PBMCs from patients with RA were observed after TNFi therapy. This pilot study suggests that transcriptional profiling is a precise method of measuring the impact of TNFi therapies and reveals novel pathways that likely influence the immune response.
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This review summarizes traditional and emerging therapies for SLE. Evidence suggests that the heterogeneity of SLE is a crucial aspect contributing to the failure of large clinical trials for new targeted therapies. A clearer understanding of the mechanisms driving disease pathogenesis combined with recent advances in medical science are predicted to enable accelerated progress towards improved SLE diagnosis and personalized approaches to treatment.
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Antirreumáticos/uso terapêutico , Glucocorticoides/uso terapêutico , Imunossupressores/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Azatioprina/uso terapêutico , Ciclofosfamida/uso terapêutico , Descoberta de Drogas , Humanos , Hidroxicloroquina/uso terapêutico , Fatores Imunológicos/uso terapêutico , Interleucina-2/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Metotrexato/uso terapêutico , Terapia de Alvo Molecular , Ácido Micofenólico/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Rituximab , Ustekinumab/uso terapêutico , Vitamina D/uso terapêuticoRESUMO
OBJECTIVE: To assess the 2-year efficacy and safety of the interleukin-17A inhibitor, secukinumab, in active psoriatic arthritis (PsA). METHODS: In the FUTURE-1 study, 606 patients with active PsA were randomized to secukinumab 10 mg/kg intravenously at baseline, and at weeks 2 and 4, followed by 150 mg or 75 mg subcutaneously (SC) every 4 weeks from week 8, or matching placebo. Patients receiving placebo were re-randomized to secukinumab 150 mg or 75 mg SC from week 16 or week 24, depending upon clinical response. Treatment continued to week 104. Exploratory analysis of all primary and secondary end points, on an intent-to-treat basis, continued to week 104. RESULTS: A total of 476 patients (78.5%) completed 104 weeks of treatment. Secukinumab showed sustained efficacy across multiple domains of PsA through week 104, including signs and symptoms, disease activity, quality of life, physical function, skin symptoms, dactylitis, and enthesitis. American College of Rheumatology criteria for 20% improvement response rates were 66.8% with secukinumab 150 mg and 58.6% with secukinumab 75 mg at week 104; Psoriasis Area and Severity Index criteria for 75% improvement response rates were 74.6% and 63.0%, respectively (multiple imputed data). At week 104, 84.3% of patients in the secukinumab 150 mg group and 83.8% in the secukinumab 75 mg group showed no radiographic disease progression (observed data). No new or unexpected safety signals were reported during 2 years of treatment. Immunogenicity to secukinumab was low. CONCLUSION: Secukinumab provided sustained improvements in PsA at 2 years, with very little radiographic progression. Treatment was well tolerated over the long term.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Artrite Psoriásica/tratamento farmacológico , Fatores Imunológicos/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Artrite Psoriásica/diagnóstico , Artrite Psoriásica/imunologia , Método Duplo-Cego , Esquema de Medicação , Humanos , Fatores Imunológicos/efeitos adversos , Indução de Remissão , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVES: Cigarette smoking is a major risk factor for RA and has been associated with increased disease severity and lower rates of disease remission. We hypothesized that inflammation and disease activity would be associated with smoking status and this would be related to levels of ACPA. METHODS: RA patients from the Veterans Affairs RA registry were studied (n = 1466): 76.9% anti-CCP2 positive, 89% male, median age 63 years (interquartile range 57-72), median disease duration 8.45 years (interquartile range 2.8-18). Baseline serum samples were evaluated for levels of anti-CCP2, RF, 19 distinct ACPAs and 17 cytokines. Smoking status at baseline was recorded as current, former or never. The association of smoking status with cytokines, autoantibodies and disease activity (DAS28) was evaluated. RESULTS: Among anti-CCP-positive RA patients, RA-associated cytokines (false-discovery rates q < 0.1%) and DAS28 (P < 0.01) were higher in current smokers compared with former or never smokers. DAS28 and cytokine levels were similar between former and never smokers. In contrast, ACPA concentrations were higher among both current and former smokers compared with never smokers, and levels of ACPA were not associated with DAS28 or cytokine levels. CONCLUSION: Among anti-CCP2-positive RA patients, current smoking status is associated with elevations in pro-inflammatory cytokines and increased RA disease activity. Similar levels of inflammation and disease activity among former and never smokers suggests that the detrimental effects of smoking could be ameliorated through tobacco cessation. The effect of tobacco cessation on RA disease activity should be evaluated prospectively.
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Artrite Reumatoide/etiologia , Fumar/efeitos adversos , Idoso , Artrite Reumatoide/imunologia , Autoantígenos/metabolismo , Biomarcadores/metabolismo , Estudos Transversais , Citocinas/metabolismo , Feminino , Humanos , Inflamação/metabolismo , Inflamação/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fumar/imunologia , Estados Unidos , VeteranosRESUMO
OBJECTIVE: To examine the potential of circulating cytokines and chemokines as biomarkers of cancer mortality risk in patients with rheumatoid arthritis (RA). METHODS: Male participants in the Veterans Affairs RA registry were followed up from the time of enrollment until death or December 2013. Cytokines and chemokines were measured in banked serum obtained at the time of enrollment, using a bead-based multiplex assay, and a previously developed cytokine score was calculated. Vital status and cause of death were determined through the National Death Index. Associations of cytokines with cancer mortality were examined using multivariable competing-risks regression. RESULTS: Among 1,190 men with RA, 60 cancer deaths (30 of which were attributable to lung cancer) occurred over 5,307 patient-years of follow-up. The patients had a mean age of 64.5 years, had established disease (median duration 8.7 years), were seropositive for rheumatoid factor (81%) or anti-cyclic citrullinated peptide antibody (77%), and frequently had a history of smoking (82% current or former). Seven of 17 analytes examined were individually associated with cancer mortality. The cytokine score was associated with overall cancer (subhazard ratio [SHR] 1.42, 95% confidence interval [95% CI] 1.08-1.85) and lung cancer (SHR 1.86, 95% CI 1.57-2.19) mortality in multivariable analyses. Those in the highest quartile of cytokine scores had a >2-fold increased risk of overall cancer mortality (P = 0.039) and a 6-fold increased risk of lung cancer mortality (P = 0.028) relative to the lowest quartile. A synergistic interaction between current smoking and high cytokine score was observed. CONCLUSION: Serum cytokines and chemokines are associated with cancer and lung cancer mortality in men with RA, independent of multiple factors including age, smoking status, and prevalent cancer.
Assuntos
Artrite Reumatoide/imunologia , Citocinas/imunologia , Neoplasias/imunologia , Sistema de Registros , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/epidemiologia , Índice de Massa Corporal , Proteína C-Reativa/imunologia , Quimiocinas/imunologia , Humanos , Leucemia/imunologia , Leucemia/mortalidade , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Linfoma/imunologia , Linfoma/mortalidade , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neoplasias/mortalidade , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/mortalidade , Peptídeos Cíclicos/imunologia , Modelos de Riscos Proporcionais , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/mortalidade , Nódulo Reumático/epidemiologia , Nódulo Reumático/imunologia , Fator Reumatoide/imunologia , Fatores de Risco , Fumar/epidemiologia , Magreza/epidemiologia , Estados Unidos/epidemiologia , United States Department of Veterans AffairsRESUMO
OBJECTIVE: There has been limited investigation into cause-specific mortality and the associated risk factors in men with rheumatoid arthritis (RA). We investigated all-cause and cause-specific mortality in men with RA, examining determinants of survival. METHODS: Men from a longitudinal RA registry were followed from enrollment until death or through 2013. Vital status and cause of death were determined using the National Death Index. Crude mortality rates and standardized mortality ratios (SMRs) were calculated for all-cause, cardiovascular disease (CVD), cancer, and respiratory mortality. Associations with all-cause and cause-specific mortality were examined using multivariable Cox proportional hazards and competing-risks regression. RESULTS: There were 1,652 men with RA and 332 deaths. The leading causes of death were CVD (31.6%; SMR 1.77 [95% confidence interval (95% CI) 1.46-2.14]), cancer (22.9%; SMR 1.50 [95% CI 1.20-1.89]), and respiratory disease (15.1%; SMR 2.90 [95% CI 2.20-3.83]). Factors associated with all-cause mortality included older age, white race, smoking, low body weight, comorbidity, disease activity, and prednisone use. Rheumatoid factor concentration and nodules were associated with CVD mortality. There were no associations of methotrexate or biologic agent use with all-cause or cause-specific mortality. CONCLUSION: Men in this RA cohort experienced increased all-cause and cause-specific mortality, with a 3-fold risk of respiratory-related deaths compared to age-matched men in the general population. Further studies are needed in order to examine whether interventions targeting potentially modifiable correlates of mortality might lead to improved long-term survival in men with RA.
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Artrite Reumatoide/mortalidade , Saúde dos Veteranos , Idoso , Idoso de 80 Anos ou mais , Antirreumáticos/uso terapêutico , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Doenças Cardiovasculares/mortalidade , Causas de Morte , Comorbidade , Humanos , Estilo de Vida , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neoplasias/mortalidade , Prognóstico , Modelos de Riscos Proporcionais , Sistema de Registros , Doenças Respiratórias/mortalidade , Medição de Risco , Fatores de Risco , Fatores Sexuais , Fatores de Tempo , Estados Unidos/epidemiologiaRESUMO
OBJECTIVE: To examine whether vascular calcifications on hand films in RA might aid in determining mortality risk. METHODS: Hand radiographs from 906 RA patients were scored as positive or negative for vascular calcifications. Patient characteristics associated with vascular calcifications were assessed using multivariable logistic regression, and associations with mortality were examined using Cox proportional hazards regression. Cytokines and multiplex ACPA were measured in both groups. RESULTS: A total of 99 patients (11%) demonstrated radiographic vascular calcifications. Factors independently associated with vascular calcifications included diabetes [odds ratio (OR) 2.85; 95% CI 1.43, 5.66], cardiovascular disease at enrolment (OR 2.48; 95% CI 1.01, 6.09), prednisone use (OR 1.90; 95% CI 1.25, 2.91), current smoking (OR 0.06; 95% CI 0.01, 0.23) and former smoking (OR 0.36; 95% CI 0.27, 0.48) vs never smoking. In cytokine and ACPA subtype analysis, IL-4 and anti-citrullinated apolipoprotein E were significantly increased in patients with vascular calcifications in fully adjusted multivariable models. After multivariable adjustment, vascular calcifications were associated with an increase in all-cause mortality (hazard ratio 1.41; 95% CI 1.12, 1.78; P = 0.004). CONCLUSION: Vascular calcifications on hand radiographs were independently associated with increased all-cause mortality in RA. Mechanisms underpinning the associations of IL-4 and select ACPA with vascular calcifications and their utility as biomarkers predictive of cardiovascular disease risk in RA merit further study.
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Artrite Reumatoide/diagnóstico por imagem , Autoanticorpos/sangue , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/mortalidade , Mãos/diagnóstico por imagem , Calcificação Vascular/complicações , Calcificação Vascular/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Apolipoproteínas E/sangue , Artrite Reumatoide/sangue , Artrite Reumatoide/imunologia , Biomarcadores/sangue , Feminino , Mãos/irrigação sanguínea , Humanos , Interleucina-4/sangue , Modelos Logísticos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Peptídeos Cíclicos/imunologia , Radiografia , Fatores de Risco , Taxa de SobrevidaRESUMO
BACKGROUND: This study examines: 1) alveolar bone loss (ABL), a hallmark of periodontitis, in anti-citrullinated protein antibody (ACPA)-positive rheumatoid arthritis (RA) patients versus control patients with osteoarthritis (OA); and 2) the association of ABL with RA disease activity and ACPA concentrations, including multiple antigen-specific ACPA. METHODS: This multicenter case-control study includes 617 patients diagnosed with RA (n = 287) or OA (n = 330). Panoramic radiographs were taken; patients were categorized into low, moderate, or high tertiles based on mean percentage ABL. Serum ACPA was measured using second-generation anticyclic citrullinated peptide enzyme-linked immunosorbent assay and a multiplex platform to assess distinct antigen-specific ACPA. A generalized linear mixed model for binary data was used to compare stratified ABL in RA versus OA patients. Associations of moderate and high ABL (versus low) with RA disease activity and severity measures were examined using multivariate regression. Antigen-specific ACPA responses were compared among ABL tertiles using significance analysis of microarrays. RESULTS: ACPA-positive patients with RA had a significantly higher mean percentage of sites with ABL >20% compared with patients with OA (P = 0.03). After multivariate adjustment, greater ABL was significantly associated with higher serum ACPA concentration (P = 0.004), 28-joint Disease Activity Score (P = 0.023), health assessment questionnaire disability (P = 0.05), tender joint count (P = 0.02) and joint space narrowing scores (P = 0.05) among patients with RA. ACPAs targeting citrullinated vimentin and histone were significantly higher in moderate and high ABL groups versus low, regardless of smoking status (q <0.1%). CONCLUSIONS: Greater ABL was associated with higher ACPA, consistent with findings at articular sites. ACPA targeting could provide novel insight into important linkages between RA and periodontitis.
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Perda do Osso Alveolar/imunologia , Artrite Reumatoide/sangue , Autoanticorpos/sangue , Peptídeos Cíclicos/sangue , Idoso , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/imunologia , Autoantígenos/sangue , Proteína C-Reativa/análise , Estudos de Casos e Controles , Progressão da Doença , Feminino , Cadeias HLA-DRB1/sangue , Articulação da Mão/diagnóstico por imagem , Histonas/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite/sangue , Osteoartrite/diagnóstico por imagem , Osteoartrite/imunologia , Peptídeos Cíclicos/imunologia , Radiografia , Fator Reumatoide/sangue , Fumar/imunologia , Vimentina/sangue , Articulação do Punho/diagnóstico por imagemRESUMO
It is accepted that the optimal management of spondyloarthritis requires a combination of non-pharmacological and pharmacological interventions. Non-pharmacologic therapy in spondyloarthritis has generally focused on the exercise regimens whose purpose is to maintain mobility and strength, relieve symptoms, prevent or decrease spinal deformity, contribute to long-term cardiopulmonary health, and improve overall function and quality of life. Exercise programs such as home exercise, group exercise, inpatient programs, and spa exercise have all been the subject of multiple reports that are reviewed here. Studies reviewed support the use of exercise, spa therapy, manual therapy, and electrotherapeutic modalities. Additional topics that are finding relevance in spondyloarthritis are the behavioral interventions that maximize knowledge, motivation for compliance, and healthy lifestyle choices including smoking cessation, weight management, diet, and probiotics. However, the quality and generalizability of the studies are limited.
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Terapia Comportamental , Terapia por Estimulação Elétrica , Modalidades de Fisioterapia , Espondilartrite/terapia , Humanos , Estilo de Vida , Qualidade de VidaRESUMO
OBJECTIVE: The co-occurrence of rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) positivity in rheumatoid arthritis (RA) is well described. However, the mechanisms underlying the potential interaction between these 2 distinct autoantibodies have not been well defined. The aim of this study was to evaluate the epidemiologic and molecular interaction of ACPAs and RF and its association with both disease activity and measures of RA-associated inflammation. METHODS: In a cohort of 1,488 US veterans with RA, measures of disease activity and serum levels of cytokines and multiplex ACPAs were compared between the following groups of patients: double-negative (anti-cyclic citrullinated peptide [anti-CCP]-/RF-), anti-CCP+/RF-, anti-CCP-/RF+, or double-positive (anti-CCP+/RF+). Additional studies were performed using an in vitro immune complex (IC) stimulation assay in which macrophages were incubated with ACPA ICs in the presence or absence of monoclonal IgM-RF, and tumor necrosis factor α production measured as a readout of macrophage activation. RESULTS: Compared with the double-negative subgroup (as well as each single-positive subgroup), the double-positive subgroup exhibited higher disease activity as well as higher levels of C-reactive protein and inflammatory cytokines (all P < 0.001). In vitro stimulation of macrophages by ACPA ICs increased cytokine production, and the addition of monoclonal IgM-RF significantly increased macrophage tumor necrosis factor α production (P = 0.003 versus ACPA ICs alone). CONCLUSION: The combined presence of ACPAs and IgM-RF mediates increased proinflammatory cytokine production in vitro and is associated with increased systemic inflammation and disease activity in RA. Our data suggest that IgM-RF enhances the capacity of ACPA ICs to stimulate macrophage cytokine production, thereby providing a mechanistic link by which RF enhances the pathogenicity of ACPA ICs in RA.
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Artrite Reumatoide/imunologia , Autoanticorpos/sangue , Inflamação/imunologia , Peptídeos Cíclicos/imunologia , Fator Reumatoide/sangue , Idoso , Complexo Antígeno-Anticorpo/imunologia , Artrite Reumatoide/sangue , Autoanticorpos/imunologia , Proteína C-Reativa/imunologia , Feminino , Humanos , Inflamação/sangue , Mediadores da Inflamação/imunologia , Masculino , Pessoa de Meia-Idade , Fator Reumatoide/imunologiaRESUMO
OBJECTIVE: RA patients have an increased risk of cardiovascular (CV) disease, although the mechanisms are unclear. As RA and CV disease may be associated through lipid profiles, we examined whether single nucleotide polymorphisms (SNPs) associated with RA susceptibility were associated with low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglyceride (TG) levels in RA subjects. METHODS: Patients (n = 763) enrolled in the Veterans Affairs RA registry who were not on hydroxymethylglutaryl-CoA reductase inhibitor were genotyped for human leukocyte antigen shared epitope (HLA-DRB1-SE) and SNPs in the following genes: CTLA-4 (cytotoxic T-lymphocyte antigen 4), IL-10, PTPN22 (protein tyrosine phosphatase, non-receptor type 22), REL (c-Rel), STAT4 (signal transducer and activator of transcription protein), TNF- and TRAF1 (TNF receptor-associated factor 1). Other covariates included patient characteristics (age, gender, race, smoking status, education, BMI, modified CharlsonDeyo comorbidity index), CV characteristics (hypertension, diabetes, alcohol abuse), pharmacologic exposures (MTX, anti-TNF, glucocorticoids) and RA severity/activity markers (RA disease duration, mean DAS, CRP, RF positivity, anti-CCP positivity). Multivariate linear regression was performed to determine the factors associated with LDL, HDL and TG levels. RESULTS: The REL SNP rs9309331 homozygous minor allele was associated with higher LDL levels. Caucasian race and increasing BMI were associated with lower HDL. Factors associated with higher TG were diabetes, Caucasian race and higher BMI. CONCLUSION: The REL SNP rs9309331 was associated with LDL levels in our study. This association is a possible explanation of the increased risk of RA patients for CV disease and requires further inquiry.
Assuntos
Artrite Reumatoide/sangue , Artrite Reumatoide/genética , Lipídeos/sangue , Artrite Reumatoide/complicações , Biomarcadores/sangue , Índice de Massa Corporal , Estudos Transversais , Dislipidemias/sangue , Dislipidemias/etiologia , Dislipidemias/genética , Feminino , Genes rel , Predisposição Genética para Doença , Humanos , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Sistema de Registros , Índice de Gravidade de Doença , Triglicerídeos/sangueRESUMO
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is characterized by defective immune tolerance combined with immune cell hyperactivity resulting in the production of pathogenic autoantibodies. Previous gene expression studies employing whole blood or peripheral blood mononuclear cells (PBMC) have demonstrated that a majority of patients with active disease have increased expression of type I interferon (IFN) inducible transcripts known as the IFN signature. The goal of the current study was to assess the gene expression profiles of isolated leukocyte subsets obtained from SLE patients. Subsets including CD19(+) B lymphocytes, CD3(+)CD4(+) T lymphocytes and CD33(+) myeloid cells were simultaneously sorted from PBMC. The SLE transcriptomes were assessed for differentially expressed genes as compared to healthy controls. SLE CD33(+) myeloid cells exhibited the greatest number of differentially expressed genes at 208 transcripts, SLE B cells expressed 174 transcripts and SLE CD3(+)CD4(+) T cells expressed 92 transcripts. Only 4.4% (21) of the 474 total transcripts, many associated with the IFN signature, were shared by all three subsets. Transcriptional profiles translated into increased protein expression for CD38, CD63, CD107a and CD169. Moreover, these studies demonstrated that both SLE lymphoid and myeloid subsets expressed elevated transcripts for cytosolic RNA and DNA sensors and downstream effectors mediating IFN and cytokine production. Prolonged upregulation of nucleic acid sensing pathways could modulate immune effector functions and initiate or contribute to the systemic inflammation observed in SLE.
Assuntos
Linfócitos B/metabolismo , Interferons/genética , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/genética , Células Mieloides/metabolismo , Subpopulações de Linfócitos T/metabolismo , Transcriptoma/genética , Adulto , Linfócitos B/patologia , DNA/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Interferons/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Pessoa de Meia-Idade , Células Mieloides/patologia , Análise de Sequência com Séries de Oligonucleotídeos , RNA/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes , Subpopulações de Linfócitos T/patologia , Regulação para Cima/genética , Adulto JovemRESUMO
OBJECTIVE: C677T and A1298C polymorphisms in the enzyme methylenetetrahydrofolate reductase (MTHFR) have been associated with increased cardiovascular (CV) events in non-rheumatoid arthritis (RA) populations. We investigated potential associations of MTHFR polymorphisms and use of methotrexate (MTX) with time-to-CV event in data from the Veterans Affairs Rheumatoid Arthritis (VARA) registry. METHODS: VARA participants were genotyped for MTHFR polymorphisms. Variables included demographic information, baseline comorbidities, RA duration, autoantibody status, and disease activity. Patients' comorbidities and outcome variables were defined using International Classification of Diseases-9 and Current Procedural Terminology codes. The combined CV event outcome included myocardial infarction (MI), percutaneous coronary intervention, coronary artery bypass graft surgery, and stroke. Cox proportional hazards regression was used to model the time-to-CV event. RESULTS: Data were available for 1047 subjects. Post-enrollment CV events occurred in 97 patients (9.26%). Although there was a trend toward reduced risk of CV events, MTHFR polymorphisms were not significantly associated with time-to-CV event. Time-to-CV event was associated with prior stroke (HR 2.01, 95% CI 1.03-3.90), prior MI (HR 1.70, 95% CI 1.06-2.71), hyperlipidemia (HR 1.57, 95% CI 1.01-2.43), and increased modified Charlson-Deyo index (HR 1.23, 95% CI 1.13-1.34). MTX use (HR 0.66, 95% CI 0.44-0.99) and increasing education (HR 0.87, 95% CI 0.80-0.95) were associated with a lower risk for CV events. CONCLUSION: Although MTHFR polymorphisms were previously associated with CV events in non-RA populations, we found only a trend toward decreased association with CV events in RA. Traditional risk factors conferred substantial CV risk, while MTX use and increasing years of education were protective.
Assuntos
Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Doenças Cardiovasculares/etiologia , Metotrexato/efeitos adversos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antirreumáticos/uso terapêutico , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/genética , Feminino , Genótipo , Humanos , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Sistema de Registros , Fatores de Risco , Índice de Gravidade de Doença , VeteranosRESUMO
OBJECTIVE: To assess the accuracy of International Classification of Diseases, Ninth Revision, and Current Procedural Terminology codes for identifying cardiovascular (CV) events (myocardial infarction [MI], stroke, coronary artery bypass graft [CABG], and percutaneous coronary intervention [PCI]) in enrollees of the Veterans Affairs Rheumatoid Arthritis (VARA) registry. DESIGN: We performed a validation study from VARA enrollment until 6/1/2010 to compare the accuracy of CV events in those with and without CV-event coding in inpatient and outpatient records to evaluate for CV events +/- 3 months of the coding. The positive predictive value (PPV) was calculated, and codes with a PPV ≥50% were included in a composite coding algorithm. RESULTS: We evaluated 107 individuals for 21 CV-event codes and 60 individuals without CV-event coding. The PPV varied between 0-100%. Composite coding algorithms' PPV ranged from 70-100%. CONCLUSIONS: Validation of these algorithms allows for identification of acute CV events with known accuracy. The sensitivity and PPV of coding algorithms for CABG and PCI exceed that of stroke and MI.
RESUMO
OBJECTIVE: Obesity is a prevalent condition and a serious health concern. The relationship between obesity and rheumatoid arthritis (RA) disease activity and severity has not been adequately examined, and there are concerns that periarticular adipose tissue may reduce the utility of the joint examination. METHODS: We used a cross-sectional study to compare the performance of swollen joint count (SJC) in subjects with RA across body mass index (BMI) strata. Specifically, regression techniques tested for associations of SJC and 7 RA disease activity/severity measures (including high-sensitivity C-reactive protein level, radiographic changes, and Multidimensional Health Assessment Questionnaire scores) within BMI quartiles. We also evaluated the association of BMI with radiographic evidence of RA in multivariate analyses and the association of BMI with SJC. Clinical and laboratory data from 980 Veterans Affairs Rheumatoid Arthritis registry participants were analyzed using linear and logistic regression. RESULTS: Associations were evident between SJC and 6 of the 7 examined RA disease activity/severity measures. SJC predicts RA disease activity/severity in more obese subjects at least as well as in subjects with lower BMIs, and there was a trend toward better performance in individuals with higher BMIs. Subjects with higher BMIs were marginally less likely to be characterized by radiographic changes (odds ratio 0.98, P = 0.051). We found no association between BMI and SJC. CONCLUSION: BMI does not obscure the relationship of SJC and objective disease activity measures. There is a borderline association of higher BMI and the likelihood of radiographic changes characteristic of RA after controlling for clinical characteristics.
Assuntos
Artrite Reumatoide/patologia , Índice de Massa Corporal , Articulações/patologia , Obesidade/complicações , Índice de Gravidade de Doença , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/classificação , Artrite Reumatoide/complicações , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/classificação , Obesidade/fisiopatologia , Sistema de Registros , Sensibilidade e EspecificidadeRESUMO
OBJECTIVE: Pharmacy Benefits Management program data for patients enrolled in the Veterans Affairs Rheumatoid Arthritis (VARA) registry were linked with clinical data to determine bisphosphonate adherence and persistence among US veterans with rheumatoid arthritis (RA) and to determine factors associated with adherence. METHODS: The primary outcome measures were the duration of bisphosphonate therapy and the medication possession ratio (MPR). Patients with an MPR <0.80 were classified as nonadherent. Potential covariates considered in the analysis included patient demographics, RA disease activity and severity parameters, and factors associated with osteoporosis risk. Associations of patient factors with duration of therapy and adherence were examined using multivariable regression modeling. RESULTS: Bisphosphonates were prescribed to 573 (41.5%) of 1,382 VARA subjects. The mean ± SD duration of therapy for bisphosphonates was 39.2 ± 31.4 months. A longer duration of therapy correlated with older age, more years of education, and dual x-ray absorptiometry testing. The mean ± SD MPR of VARA subjects for bisphosphonate therapy was 0.69 ± 0.28; 302 (52.7%) were nonadherent. In multivariate analyses, nonadherence with bisphosphonate therapy was associated with a longer duration of RA disease (odds ratio [OR] 1.02, 95% confidence interval [95% CI] 1.00-1.04) and duration of bisphosphonate therapy >32 months (OR 1.63, 95% CI 1.04-2.57). Whites were less likely to have a low MPR compared with nonwhites (OR 0.52, 95% CI 0.30-0.88). CONCLUSION: Nonadherence with bisphosphonates was common in this cohort of RA patients and was associated with nonwhite ethnicity, a longer duration of RA disease, and a greater duration of bisphosphonate therapy.