Comparative effectiveness of abatacept versus tocilizumab in rheumatoid arthritis patients with prior TNFi exposure in the US Corrona registry

BACKGROUND: We compared the effectiveness of abatacept (ABA) vs tocilizumab (TCA) in tumor necrosis factor inhibitor (TNFi) experienced patients. METHODS: We identified rheumatoid arthritis (RA) patients from a large observational US cohort (1 January 2010-31 May 2014) who had discontinued at least one TNFi and initiated ABA or TCZ in moderate or high disease activity based on the Clinical Disease Activity Index (CDAI) and had no prior exposure to the comparator drug. Using propensity score matching (1:1) stratified by prior TNF use (1 TNFi vs ≥2 TNFis), effectiveness at 6 months after initiation was evaluated. Mean change in CDAI over 6 months following initiation was the primary outcome, with secondary outcomes of achievement of low disease activity/remission (CDAI ≤ 10) and mean change in modified Health Assessment Questionnaire (mHAQ) score. RESULTS: The 264 pairs of propensity score-matched ABA and TCZ initiators were well matched with no substantial differences in the baseline characteristics, defined as standardized differences \u3e0.1 in the stratification. Both treatment groups had similar mean change in CDAI at 6 months (-11.3 in ABA vs -9.9 in TCZ; mean difference -1.27, 95% CI -3.65, 1.11). Similar proportions of both treatment groups achieved low disease activity/remission (adjusted odds ratio for ABA vs TCZ 0.99, 95% CI 0.69, 1.43). Mean change in mHAQ was -0.12 in ABA initiators vs -0.11 in TCZ initiations (mean difference -0.01, 95% CI -0.09, 0.06). CONCLUSIONS: Patients receiving either ABA or TCZ had substantial improvement in clinical disease activity. In this propensity score-matched sample, similar outcomes were observed for both treatment cohorts

The comparative effectiveness of abatacept versus anti-tumour necrosis factor switching for rheumatoid arthritis patients previously treated with an anti-tumour necrosis factor

OBJECTIVE: We compared the effectiveness of abatacept (ABA) versus a subsequent anti-tumour necrosis factor inhibitor (anti-TNF) in rheumatoid arthritis (RA) patients with prior anti-TNF use. METHODS: We identified RA patients from a large observational US cohort (2/1/2000-8/7/2011) who had discontinued at least one anti-TNF and initiated either ABA or a subsequent anti-TNF. Using propensity score (PS) matching (n:1 match), effectiveness was measured at 6 and 12 months after initiation based on mean change in Clinical Disease Activity Index (CDAI), modified American College of Rheumatology (mACR) 20, 50 and 70 responses, modified Health Assessment Questionnaire (mHAQ) and CDAI remission in adjusted regression models. RESULTS: The PS-matched groups included 431 ABA and 746 anti-TNF users at 6 months and 311 ABA and 493 anti-TNF users at 12 months. In adjusted analyses comparing response following treatment with ABA and anti-TNF, the difference in weighted mean change in CDAI (range 6-8) at 6 months (0.46, 95% CI -0.82 to 1.73) and 12 months was similar (-1.64, 95% CI -3.47 to 0.19). The mACR20 responses were similar at 6 (28-32%, p=0.73) and 12 months (35-37%, p=0.48) as were the mACR50 and mACR70 (12 months: 20-22%, p=0.25 and 10-12%, p=0.49, respectively). Meaningful change in mHAQ was similar at 6 and 12 months (30-33%, p=0.41 and 29-30%, p=0.39, respectively) as was CDAI remission rates (9-10%, p=0.42 and 12-13%, p=0.91, respectively). CONCLUSIONS: RA patients with prior anti-TNF exposures had similar outcomes if they switched to a new anti-TNF as compared with initiation of ABA

Launching PCORnet, a national patient-centered clinical research network

The Patient-Centered Outcomes Research Institute (PCORI) has launched PCORnet, a major initiative to support an effective, sustainable national research infrastructure that will advance the use of electronic health data in comparative effectiveness research (CER) and other types of research. In December 2013, PCORI's board of governors funded 11 clinical data research networks (CDRNs) and 18 patient-powered research networks (PPRNs) for a period of 18 months. CDRNs are based on the electronic health records and other electronic sources of very large populations receiving healthcare within integrated or networked delivery systems. PPRNs are built primarily by communities of motivated patients, forming partnerships with researchers. These patients intend to participate in clinical research, by generating questions, sharing data, volunteering for interventional trials, and interpreting and disseminating results. Rapidly building a new national resource to facilitate a large-scale, patient-centered CER is associated with a number of technical, regulatory, and organizational challenges, which are described here

Epidemiology, genetics, and subtyping of preserved ratio impaired spirometry (PRISm) in COPDGene.

BackgroundPreserved Ratio Impaired Spirometry (PRISm), defined as a reduced FEV1 in the setting of a preserved FEV1/FVC ratio, is highly prevalent and is associated with increased respiratory symptoms, systemic inflammation, and mortality. Studies investigating quantitative chest tomographic features, genetic associations, and subtypes in PRISm subjects have not been reported.MethodsData from current and former smokers enrolled in COPDGene (n = 10,192), an observational, cross-sectional study which recruited subjects aged 45-80 with ≥10 pack years of smoking, were analyzed. To identify epidemiological and radiographic predictors of PRISm, we performed univariate and multivariate analyses comparing PRISm subjects both to control subjects with normal spirometry and to subjects with COPD. To investigate common genetic predictors of PRISm, we performed a genome-wide association study (GWAS). To explore potential subgroups within PRISm, we performed unsupervised k-means clustering.ResultsThe prevalence of PRISm in COPDGene is 12.3%. Increased dyspnea, reduced 6-minute walk distance, increased percent emphysema and decreased total lung capacity, as well as increased segmental bronchial wall area percentage were significant predictors (p-value <0.05) of PRISm status when compared to control subjects in multivariate models. Although no common genetic variants were identified on GWAS testing, a significant association with Klinefelter's syndrome (47XXY) was observed (p-value < 0.001). Subgroups identified through k-means clustering include a putative "COPD-subtype", "Restrictive-subtype", and a highly symptomatic "Metabolic-subtype".ConclusionsPRISm subjects are clinically and genetically heterogeneous. Future investigations into the pathophysiological mechanisms behind and potential treatment options for subgroups within PRISm are warranted.Trial registrationClinicaltrials.gov Identifier: NCT000608764

Immunosuppressive treatment and the risk of diabetes in rheumatoid arthritis

OBJECTIVE: Inflammation and anti-inflammatory treatments might influence the risk of diabetes. The objective of this study was to assess factors associated with incident diabetes in rheumatoid arthritis (RA). METHODS: The study population consisted of RA patients from a multi-center cohort study, Corrona. To assess risk associated with disease modifying antirheumatic drug (DMARD) exposure, we assessed five mutually exclusive DMARD groups. Additionally, we assessed the risk associated with body mass index (BMI, \u3c 25, 25-30, \u3e 30 kg/m2) and glucocorticoid usage. Incident cases of diabetes were confirmed through adjudication, and Cox regression models were fit to estimate the risk of incident diabetes. RESULTS: We identified 21,775 DMARD treatment regimens, the mean (SD) age at the index visit was 58 (13) years, disease duration 10 (10) years, and 30% used oral glucocorticoids at the time. Eighty-four incident cases of diabetes were confirmed within the treatment exposure periods. The hazard ratio (HR, 95% confidence interval) for diabetes was significantly reduced in patients receiving TNF inhibitors, HR 0.35 (0.13, 0.91), compared to patients treated with non-biologic DMARDs other than hydroxychloroquine and methotrexate. Hydroxychloroquine, methotrexate and use of other biologic DMARDs had a numerically reduced risk compared to the same group. Patients prescribed \u3e /=7.5 mg of glucocorticoids had a HR of 2.33 (1.68, 3.22) of incident diabetes compared with patients not prescribed oral glucocorticoids. RA patients with a BMI \u3e 30 had a HR of 6.27 (2.97, 13.25) compared to patients with BMI \u3c /=25. CONCLUSION: DMARDs, glucocorticoids and obesity influenced the risk of incident diabetes in a large cohort of RA patients. Monitoring for the occurrence of diabetes should be part of routine RA management with a focus on specific subgroups

Evanescent Black Holes

A renormalizable theory of quantum gravity coupled to a dilaton and conformal matter in two space-time dimensions is analyzed. The theory is shown to be exactly solvable classically. Included among the exact classical solutions are configurations describing the formation of a black hole by collapsing matter. The problem of Hawking radiation and backreaction of the metric is analyzed to leading order in a $1/N$ expansion, where $N$ is the number of matter fields. The results suggest that the collapsing matter radiates away all of its energy before an event horizon has a chance to form, and black holes thereby disappear from the quantum mechanical spectrum. It is argued that the matter asymptotically approaches a zero-energy ``bound state'' which can carry global quantum numbers and that a unitary $S$-matrix including such states should exist.Comment: 14 page

Identifying factors associated with concordance with the American College of Rheumatology rheumatoid arthritis treatment recommendations

BACKGROUND: Factors associated with care concordant with the American College of Rheumatology (ACR) recommendations for the use of disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (RA) are unknown. METHODS: We identified a national cohort of biologic-naive patients with RA with visits between December 2008 and February 2013. Treatment acceleration (initiation or dose escalation of biologic and nonbiologic DMARDs) in response to moderate to high disease activity (using the Clinical Disease Activity Index) was assessed. The population was divided into two subcohorts: (1) methotrexate (MTX)-only users and (2) multiple nonbiologic DMARD users. In both subcohorts, we compared the characteristics of patients who received care consistent with the ACR recommendations (e.g., prescriptions for treatment acceleration) and their providers with the characteristics of those who did not at the conclusion of one visit and over two visits, using logistic regression and adjusting for clustering of patients by rheumatologist. RESULTS: Our study included 741 MTX monotherapy and 995 multiple nonbiologic DMARD users cared for by 139 providers. Only 36.2 % of MTX monotherapy users and 39.6 % of multiple nonbiologic DMARD users received care consistent with the recommendations after one visit, which increased over two visits to 78.3 % and 76.2 %, respectively (25-30 % achieved low disease activity by the second visit without DMARD acceleration). Increasing time since the ACR publication on RA treatment recommendations was not associated with improved adherence. CONCLUSIONS: Allowing two encounters for treatment acceleration was associated with an increase in care concordant with the recommendations; however, time since publication was not

Predicting risk for radiographic damage in rheumatoid arthritis:comparative analysis of the multi-biomarker disease activity score and conventional measures of disease activity in multiple studies

Pathophysiology and treatment of rheumatic disease

Acute exacerbations of chronic obstructive pulmonary disease are associated with decreased CD4+ & CD8+ T cells and increased growth & differentiation factor-15 (GDF-15) in peripheral blood

Abstract Background Although T cells, especially CD8+, have been implicated in chronic obstructive pulmonary disease (COPD) pathogenesis, their role during acute exacerbations (AE-COPD) is uncertain. Methods We recruited subjects with COPD and a history of previous AE-COPD and studied them quarterly to collect blood and spontaneously expectorated sputum while stable. During exacerbations (defined by a change in symptoms plus physician diagnosis and altered medications), we collected blood and sputum before administering antibiotics or steroids. We used flow cytometry to identify leukocytes in peripheral blood, plus Luminex® analysis or ELISA to determine levels of inflammatory biomarkers in serum and sputum supernatants. Results Of 33 enrolled subjects, 13 participated in multiple stable visits and had ≥1 AE-COPD visit, yielding 18 events with paired data. Flow cytometric analyses of peripheral blood demonstrated decreased CD4+ and CD8+ T cells during AE-COPD (both absolute and as a percentage of all leukocytes) and significantly increased granulocytes, all of which correlated significantly with serum C-reactive protein (CRP) concentrations. No change was observed in other leukocyte populations during AE-COPD, although the percentage of BDCA-1+ dendritic cells expressing the activation markers CD40 and CD86 increased. During AE-COPD, sICAM-1, sVCAM-1, IL-10, IL-15 and GDF-15 increased in serum, while in sputum supernatants, CRP and TIMP-2 increased and TIMP-1 decreased. Conclusions The decrease in CD4+ and CD8+ T cells (but not other lymphocyte subsets) in peripheral blood during AE-COPD may indicate T cell extravasation into inflammatory sites or organized lymphoid tissues. GDF-15, a sensitive marker of cardiopulmonary stress that in other settings independently predicts reduced long-term survival, is acutely increased in AE-COPD. These results extend the concept that AE-COPD are systemic inflammatory events to which adaptive immune mechanisms contribute. Trial registration NCT00281216 , ClinicalTrials.gov.http://deepblue.lib.umich.edu/bitstream/2027.42/112169/1/12931_2015_Article_251.pd