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Objective Patients with rheumatoid arthritis (RA) are 1.5 times more likely to develop cardiovascular disease (CVD) attributed to chronic inflammation. A decrease in inflammation in patients with RA is associated with increased low-density lipoprotein (LDL) cholesterol. This study was undertaken to prospectively evaluate the changes in lipid levels among RA patients experiencing changes in inflammation and determine the association with concomitant temporal patterns in markers of myocardial injury. Methods A total of 196 patients were evaluated in a longitudinal RA cohort, with blood samples and high-sensitivity C-reactive protein (hsCRP) levels measured annually. Patients were stratified based on whether they experienced either a significant increase in inflammation (an increase in hsCRP of ≥10 mg/liter between any 2 time points 1 year apart; designated the increased inflammation cohort [n = 103]) or decrease in inflammation (a decrease in hsCRP of ≥10 mg/liter between any 2 time points 1 year apart; designated the decreased inflammation cohort [n = 93]). Routine and advanced lipids, markers of inflammation (interleukin-6, hsCRP, soluble tumor necrosis factor receptor II), and markers of subclinical myocardial injury (high-sensitivity cardiac troponin T [hs-cTnT], N-terminal pro-brain natriuretic peptide) were measured. Results Among the patients in the increased inflammation cohort, the mean age was 59 years, 81% were women, and the mean RA disease duration was 17.9 years. The average increase in hsCRP levels was 36 mg/liter, and this increase was associated with significant reductions in LDL cholesterol, triglycerides, total cholesterol, apolipoprotein (Apo B), and Apo A-I levels. In the increased inflammation cohort at baseline, 45.6% of patients (47 of 103) had detectable circulating hs-cTnT, which further increased during inflammation (P = 0.02). In the decreased inflammation cohort, hs-cTnT levels remained stable despite a reduction in inflammation over follow-up. In both cohorts, hs-cTnT levels were associated with the overall estimated risk of CVD. Conclusion Among RA patients who experienced an increase in inflammation, a significant decrease in routinely measured lipids, including LDL cholesterol, and an increase in markers of subclinical myocardial injury were observed. These findings highlight the divergence in biomarkers of CVD risk and suggest a role in future studies examining the benefit of including hs-cTnT for CVD risk stratification in RA.

BackgroundHemodynamic stress, conditioned by the morphology of the surrounding vasculature, plays an important role in aneurysm formation. Our goal was to identify image-based location-specific parameters that are associated with posterior communicating artery (PCoA) aneurysms.MethodsThree-dimensional morphological parameters obtained from CT angiography or digital subtraction angiography from 187 patients with unilateral PCoA aneurysms, diagnosed at the Brigham and Women’s Hospital and Massachusetts General Hospital between 1990 and 2016, were evaluated. In order to control for genetic and clinical risk factors, we chose the contralateral unaffected PCoA as a control group. We examined diameters and angles of the surrounding parent and daughter vessels. Univariable and multivariable statistical analyses were performed to determine statistical significance. Sensitivity analyses with small aneurysms (≤5 mm) only and an unmatched analysis of 432 PCoA aneurysms and 197 control patients without PCoA aneurysms were also performed.ResultsIn a multivariable conditional logistic regression model we showed that smaller diameter size ratio (OR 1.45×10−5, 95% CI 1.12×10−7 to 1.88×10−3) and larger daughter-daughter angle (OR 1.04, 95% CI 1.02 to 1.07) were significantly associated with PCoA aneurysm presence after correcting for other variables. In subgroup analyses of small aneurysms (≤5 mm) and in an unmatched analysis the significance and direction of these results were preserved.ConclusionsLarger daughter-daughter angles and smaller diameter size ratio are significantly associated with the presence of PCoA aneurysms. These simple parameters can be utilized to guide the risk assessment for the formation of PCoA aneurysms in high risk patients.

Objective We aimed to determine the real-world prevalence and investigate risk factors for rheumatoid arthritis (RA)-related lung disease on chest computed tomography (CT) imaging. We also investigated the impact of RA-related lung disease on mortality. Methods We studied chest CT imaging abnormalities among RA patients. We determined the presence and type of abnormalities using the chest CT imaging radiologic report. RA-related lung disease was defined as interstitial lung disease (ILD), bronchiectasis, or pleural disease. We examined whether demographics and RA characteristics were associated with RA-related lung disease using logistic regression. RA-related lung disease and mortality was described using survival curves and Cox regression. Results We analyzed 190 patients who had chest CT imaging performed for clinical indications. Mean age was 64.2 years (SD 11.8), 80.0% were female, and 75.3% were seropositive. RA-related lung disease was detected in 54 patients (28.4%); 30 (15.8%) had ILD, 27 (14.2%) had bronchiectasis, and 18 (9.5%) had pleural disease. RA-related lung disease was reported in both seropositive and seronegative RA (28.7% vs. 27.7%, p = 1.00). Male sex (OR 2.62, 95%CI 1.17–5.88) and current methotrexate use (OR 2.73, 95%CI 1.27–5.61 vs. not current) were associated with RA-related lung disease. Twenty-four (44.4%) patients with RA-related lung disease died during mean 7.0 years of follow-up. RA-related lung disease had HR of 5.35 (95%CI 0.72–39.9) for mortality compared to normal chest CT. Conclusions In this real-world study, RA-related lung disease was commonly detected on chest CT imaging regardless of RA serostatus. RA-related lung disease had high mortality, emphasizing the importance in close monitoring of these patients.

OBJECTIVE Seropositivity for anti-citrullinated protein antibody (ACPA)/rheumatoid factor (RF) in rheumatoid arthritis (RA) is associated with increased overall mortality; however, the association between antibody titers and mortality is not well established. Investigating relationships between antibody titers and mortality may clarify their role in RA pathogenesis. This study was undertaken to evaluate the association of antibody titers with mortality and its modification by disease-modifying antirheumatic drugs (DMARDs). METHODS Eligible patients with established RA were identified through administrative claims data linked to laboratory results (2005-2016). Patients were categorized by positivity status for ACPA, RF, or both. Patients were further divided into groups by autoantibody titers. DMARD-exposed patients were categorized into biologic DMARD (bDMARD) and conventional DMARD (cDMARD) subcohorts. Crude mortality rates/1,000 patient-years and Kaplan-Meier curves were compared between antibody categories. Adjusted Cox proportional hazards regression and sensitivity (propensity-matched patients) analyses were conducted. RESULTS Overall, 53,849 and 79,926 patients had evaluable ACPA and RF status, respectively. For both autoantibodies, mortality rates were significantly higher in seropositive versus seronegative patients (risk increase of 48.0% and 44.0% in ACPA- and RF-positive patients, respectively; P < 0.001 each). Mortality rates were greatest in patients with higher versus lower autoantibody titers (ACPA hazard ratio [HR] 1.60 [95% confidence interval (95% CI]) 1.45-1.76]; RF HR 1.78 [95% CI 1.66-1.91]). In cDMARD-exposed patients, HRs were higher in seropositive versus seronegative cohorts; in bDMARD-exposed patients, there was no difference in mortality by serostatus. CONCLUSION Elevated ACPA/RF titers were independently associated with increased mortality among patients with RA and persisted in patients treated with cDMARDs but not with bDMARDs.

We present a cohort of patients with anterior communicating artery (ACoA) aneurysms to investigate morphological characteristics and clinical factors associated with rupture of the aneurysms. 505 patients with ACoA aneurysms were identified at the Brigham and Women’s Hospital and Massachusetts General Hospital between 1990 and 2016, with available CT angiography (CTA). Three-dimensional (3D) reconstructions were performed to evaluate aneurysmal morphologic features, including location, projection, irregularity, the presence of daughter dome, height, height/width ratio, and relationships between surrounding vessels. Patient risk factors assessed included patient age, sex, tobacco use, alcohol use, and family history of aneurysms and aneurysmal subarachnoid hemorrhage. Logistic regression was used to build a predictive ACoA score for rupture. Morphologic features associated with ruptured ACoA aneurysms were the presence of a daughter dome (OR 21.4, 95% CI 10.6–43.1), smaller neck diameter (OR 0.55, 95% CI 0.42–0.71), larger aspect ratio (OR 3.57, 95% CI 2.05–6.24), larger flow angle (OR 1.03, 95% CI 1.02–1.05), and smaller ipsilateral A2-ACoA angle (OR 0.98, 95% CI 0.97–1.00). Tobacco use was predominantly associated with morphological factors intrinsic to the aneurysm that were associated with rupture while younger age was also associated with morphologic features extrinsic to the aneurysm that were associated with rupture. The ACoA score had good predictive capacity for rupture with AUC = 0.92 using the 0.632 bootstrap cross-validation for correction of overfitting bias. Ruptured ACoA aneurysms were associated with morphological features that are simple to assess using a simple scoring system. Tobacco use and younger age were predominantly associated with intrinsic and extrinsic morphological features characteristic of rupture, respectively.

Morphological factors of intracranial aneurysms and the surrounding vasculature could affect aneurysm rupture risk in a location specific manner. Our goal was to identify image-based morphological parameters that correlated with ruptured basilar tip aneurysms. Three-dimensional morphological parameters obtained from CT-angiography (CTA) or digital subtraction angiography (DSA) from 200 patients with basilar tip aneurysms diagnosed at the Brigham and Women’s Hospital and Massachusetts General Hospital between 1990 and 2016 were evaluated. We examined aneurysm wall irregularity, the presence of daughter domes, hypoplastic, aplastic or fetal PCoAs, vertebral dominance, maximum height, perpendicular height, width, neck diameter, aspect and size ratio, height/width ratio, and diameters and angles of surrounding parent and daughter vessels. Univariable and multivariable statistical analyses were performed to determine statistical significance. In multivariable analysis, presence of a daughter dome, aspect ratio, and larger flow angle were significantly associated with rupture status. We also introduced two new variables, diameter size ratio and parent-daughter angle ratio, which were both significantly inversely associated with ruptured basilar tip aneurysms. Notably, multivariable analyses also showed that larger diameter size ratio was associated with higher Hunt-Hess score while smaller flow angle was associated with higher Fisher grade. These easily measurable parameters, including a new parameter that is unlikely to be affected by the formation of the aneurysm, could aid in screening strategies in high-risk patients with basilar tip aneurysms. One should note, however, that the changes in parameters related to aneurysm morphology may be secondary to aneurysm rupture rather than causal.

Objective Previous attempts to estimate rheumatoid arthritis (RA) disease activity using claims data only did not yield high performance. We aimed to assess whether supplementing claims data with readily available electronic medical record (EMR) data might result in improvement. Methods We used a subset of the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS) that had linked Medicare claims. The disease activity score in 28 joints with C-reactive protein (DAS28-CRP) was considered the gold standard of measure. Variables in the linked Medicare claims, as well as EMR recorded in the preceding one-year period were used as potential explanatory variables. We constructed three models: "Claims-Only," "Claims + Medications," and "Claims + Medications + Labs (laboratory data from EMR). We selected variables via adaptive LASSO. Model performance was measured with adjusted R2 for continuous DAS28-CRP and C-statistics for binary category classification (high/moderate vs low disease activity/remission). Results We identified 300 patients with laboratory data and linked Medicare claims. The mean age was 68 years and 80% were female. The mean (SD) DAS28-CRP was 3.6 (1.6) and 51% had high or moderate DAS28-CRP. For the continuous estimation, the adjusted R2 was 0.02 for Claims-Only, 0.09 for Claims + Medications, and 0.18 for Claims + Medications + Labs. The C-statistics for discriminating the binary categories were 0.61 for Claims-Only, 0.68 for Claims + Medications, and 0.76 for Claims + Medications + Labs. Conclusion Adding EMR-derived variables to claims-derived variables resulted in modest improvement. Even with EMR variables, we were unable to estimate continuous DAS28-CRP satisfactorily. However, in claims-EMR models, we were able to discriminate between binary categories of disease activity with reasonable accuracy.

Author(s): Shadick, Nancy A; Katz, Patricia; Iannaccone, Christine I; Maica, Gabriela; Coblyn, Jonathan; Weinblatt, Michael E; Cui, Jing | Abstract: ObjectiveLifestyle factors, such as inactivity and obesity, contribute to cognitive decline in the general population, but little is known about how these factors may affect individuals with a chronic inflammatory condition such as rheumatoid arthritis (RA). We studied the clinical and functional risk factors related to a worsening of perceived cognitive function in patients with RA.MethodsWe collected clinical and functional questionnaire data over 10 years in a prospective RA cohort including yearly self-reported memory, concentration, and word-finding difficulties graded from "never" to "often." Generalized estimating equation models examined the role of exercise (defined as those meeting the Department of Health and Human Services physical activity guidelines of 75 minutes of vigorous or 150 minutes of moderate aerobic activity per week), body mass index (BMI), sleep, depression (Mental Health Index-Depression), Disease Activity Score (DAS)28-c-reactive protein (CRP)3 score, disease-modifying antirheumatic drug, and corticosteroid use from the previous year as predictors of cognitive complaints that progressed to "often" compared with the previous year (the first year (T i ) progressed to "often" 1 year later (T i+1)).ResultsOf 1219 RA subjects, 127 (10.4%) described either poor memory, concentration, or word-finding difficulties as affecting them "often" at study entry. RA patients (n = 1092, mean age = 56.5 years, 82% female, 58% college educated) were less likely to report word-finding difficulties, poor memory, and concentration as "often" if they were physically active (p = 0.0001, P = 0.01, P l 0.0001, respectively). Female RA patients developed more concentration complaints compared with males (P = 0.03); patients taking an anti-tumor necrosis factor therapy were less likely to complain of poor memory (P = 0.01). Sleep, BMI, fatigue, depression, DAS28-CRP3, methotrexate, and corticosteroid use were not independently associated with a worsening of any cognitive complaints.ConclusionRA patients who are physically active are less likely to report cognitive difficulties. Our study suggests potential modifiable risk factors for the prevention of cognitive dysfunction in RA.

Objective To investigate the incidence and predictors of dyspnea on exertion among subjects with rheumatoid arthritis (RA). Methods We investigated dyspnea on exertion using a prospective cohort, the Brigham RA Sequential Study (BRASS). Clinically significant dyspnea on exertion was defined as a score of ≥ 3 (unable to ambulate without breathlessness or worse) on the validated Medical Research Council (MRC) scale (range 0‐5). We analyzed subjects with MRC score < 3 at BRASS baseline and at ≥ 1 year of follow‐up. The MRC scale was administered annually. We determined the incidence rate (IR) of dyspnea on exertion. We used Cox regression to estimate the hazard ration (HR) for dyspnea on exertion occurring one year after potential predictors were assessed. Results We analyzed 829 subjects with RA and no clinically significant dyspnea on exertion during a mean follow‐up period of 3.0 years (SD 1.9). At baseline, mean age was 55.7 years (SD 13.6), 82.4% of subjects were female, and median RA duration was 8 years. During follow‐up, 112 subjects (13.5%) developed incident dyspnea on exertion during 2476 person‐years of follow‐up (incidence rate 45.2 per 1000 person‐years). Independent predictors of incident dyspnea on exertion were older age (HR 1.03 per year, 95% CI, 1.01‐1.04), female sex (HR 2.22, 95% CI, 1.14‐4.29), mild dyspnea (HR 2.62, 95% CI, 1.60‐4.28), and worsened Multi‐Dimensional Health Assessment Questionnaire score (HR 2.36 per unit, 95% CI, 1.54‐3.60). Methotrexate use, RA disease activity, and seropositivity were not associated with incident dyspnea on exertion after accounting for other dyspnea risk factors. Conclusion Dyspnea on exertion occurred commonly in patients with RA. Older women with impaired physical function were especially vulnerable to developing dyspnea on exertion.

Objective To develop and evaluate an adjusted score for the multi-biomarker disease activity (MBDA) test to account for the effects of age, sex and adiposity in patients with RA. Methods Two models were developed to adjust MBDA score for age, sex and adiposity, using either serum leptin concentration or BMI as proxies for adiposity. Two cohorts were studied. A cohort of 325 781 RA patients who had undergone commercial MBDA testing and had data for age, sex and serum leptin concentration was used for both models. A cohort of 1411 patients from five studies/registries with BMI data was used only for the BMI-adjusted MBDA score. Univariate and multivariate linear regression analyses evaluated the adjusted MBDA scores and conventional clinical measures as predictors of radiographic progression, assessed in terms of modified total Sharp score (ΔmTSS). Results Two models were developed, based on findings that MBDA score was higher in females than males and increased with age, leptin concentration and BMI. In pairwise regression analyses, the leptin-adjusted (P = 0.00066) and BMI-adjusted (P = 0.0027) MBDA scores were significant independent predictors of ΔmTSS after adjusting for DAS28-CRP, whereas DAS28-CRP was not, after adjusting for leptin-adjusted (P = 0.74) or BMI-adjusted (P = 0.87) MBDA score. Moreover, the leptin-adjusted MBDA score was a significant predictor of ΔmTSS after adjusting for the BMI-adjusted MBDA score (P = 0.025) or the original MBDA score (0.027), whereas the opposite was not true. Conclusion Leptin-adjusted MBDA score significantly adds information to DAS28-CRP and the original MBDA score in predicting radiographic progression. It may offer improved clinical utility for personalized management of RA.

Objectives We performed a systematic review and meta-analysis for the prevalence and risk factors of rheumatoid arthritis-related bronchiectasis (RA-BR). Methods We queried PubMed and EMBASE databases to identify published literature related to prevalence and risk factors for RA-BR among patients with RA. Data extraction included study design, country, year, method of RA-BR detection, RA characteristics, numerator of RA-BR cases and denominator of patients with RA, and associations with RA-BR presence. We performed a meta-analysis using random or fixed effects models to estimate the prevalence of RA-BR among RA. Results Out of a total of 253 studies, we identified 41 total studies that reported on prevalence (n = 34), risk factors (n = 5), or both (n = 2). The included studies had heterogeneous methods to identify RA-BR. Among the 36 studies reporting prevalence, 608 RA-BR cases were identified from a total of 8569 patients with RA. In the meta-analysis, the pooled overall prevalence of RA-BR among RA was 18.7% (95%CI 13.7–24.3%) using random effects and 3.8% (95%CI 3.3–4.2%) using fixed effects. Among studies that used high-resolution chest computed tomography (HRCT) imaging, the prevalence of RA-BR was 22.6% (95%CI 16.8–29.0%) using random effects. When only considering retrospective studies (n = 12), the pooled prevalence of RA-BR among RA was 15.5% (95%CI 7.5–25.5%); among prospective studies (n = 24), the pooled prevalence was 20.7% (95% CI 14.7–27.4%). Risk factors for RA-BR included older age, longer RA duration, genetics (CFTR and HLA), and undetectable circulating mannose binding lectin (MBL) as a biomarker. Conclusion In this systematic review and meta-analysis, the prevalence of RA-BR was nearly 20% among studies with HRCT imaging, suggesting that bronchiectasis may be a common extra-articular feature of RA. Relatively few factors have been associated with RA-BR. Future studies should standardize methods to identify RA-BR cases and investigate the natural history and clinical course given the relatively high prevalence among RA.

Drs. Pincus, Bergman, and Yazici have raised some concerns about our published article comparing the Clinical Disease Activity Index (CDAI) with simultaneous measures of the Routine Assessment of Patient Index Data 3 (RAPID3).1 We believe our publication has clearly established that the validated CDAI scores provide a fundamentally different evaluation of disease status compared with the RAPID3.

Idiopathic multicentric Castleman disease (iMCD) is a poorly understood hematologic disorder involving cytokine-induced polyclonal lymphoproliferation, systemic inflammation, and potentially fatal multiorgan failure. Although the etiology of iMCD is unknown, interleukin-6 (IL-6) is an established disease driver in approximately one-third of patients. Anti–IL-6 therapy, siltuximab, is the only US Food and Drug Administration–approved treatment. Few options exist for siltuximab nonresponders, and no validated tests are available to predict likelihood of response. We procured and analyzed the largest-to-date cohort of iMCD samples, which enabled classification of iMCD into disease categories, discovery of siltuximab response biomarkers, and identification of therapeutic targets for siltuximab nonresponders. Proteomic quantification of 1178 analytes was performed on serum of 88 iMCD patients, 60 patients with clinico-pathologically overlapping diseases (human herpesvirus-8–associated MCD, N = 20; Hodgkin lymphoma, N = 20; rheumatoid arthritis, N = 20), and 42 healthy controls. Unsupervised clustering revealed iMCD patients have heterogeneous serum proteomes that did not cluster with clinico-pathologically overlapping diseases. Clustering of iMCD patients identified a novel subgroup with superior response to siltuximab, which was validated using a 7-analyte panel (apolipoprotein E, amphiregulin, serum amyloid P-component, inactivated complement C3b, immunoglobulin E, IL-6, erythropoietin) in an independent cohort. Enrichment analyses and immunohistochemistry identified Janus kinase (JAK)/signal transducer and activator of transcription 3 signaling as a candidate therapeutic target that could potentially be targeted with JAK inhibitors in siltuximab nonresponders. Our discoveries demonstrate the potential for accelerating discoveries for rare diseases through multistakeholder collaboration.

Background The multi-biomarker disease activity (MBDA) test measures 12 serum protein biomarkers to quantify disease activity in RA patients. A newer version of the MBDA score, adjusted for age, sex, and adiposity, has been validated in two cohorts (OPERA and BRASS) for predicting risk for radiographic progression. We now extend these findings with additional cohorts to further validate the adjusted MBDA score as a predictor of radiographic progression risk and compare its performance with that of other risk factors. Methods Four cohorts were analyzed: the BRASS and Leiden registries and the OPERA and SWEFOT studies (total N = 953). Treatments included conventional DMARDs and anti-TNFs. Associations of radiographic progression (ΔTSS) per year with the adjusted MBDA score, seropositivity, and clinical measures were evaluated using linear and logistic regression. The adjusted MBDA score was (1) validated in Leiden and SWEFOT, (2) compared with other measures in all four cohorts, and (3) used to generate curves for predicting risk of radiographic progression. Results Univariable and bivariable analyses validated the adjusted MBDA score and found it to be the strongest, independent predicator of radiographic progression (ΔTSS > 5) compared with seropositivity (rheumatoid factor and/or anti-CCP), baseline TSS, DAS28-CRP, CRP SJC, or CDAI. Neither DAS28-CRP, CDAI, SJC, nor CRP added significant information to the adjusted MBDA score as a predictor, and the frequency of radiographic progression agreed with the adjusted MBDA score when it was discordant with these measures. The rate of progression (ΔTSS > 5) increased from Conclusion The adjusted MBDA score was validated as an RA disease activity measure that is prognostic for radiographic progression. The adjusted MBDA score was a stronger predictor of radiographic progression than conventional risk factors, including seropositivity, and its prognostic ability was not significantly improved by the addition of DAS28-CRP, CRP, SJC, or CDAI.

Rheumatoid arthritis (RA) is a systemic and incurable autoimmune disease characterized by chronic inflammation in synovial lining of joints. To identify the signaling pathways involved in RA, its disease activity, and treatment response, we adapted a systems immunology approach to simultaneously quantify 42 signaling nodes in 21 immune cell subsets (e.g., IFNα→p-STAT5 in B cells) in peripheral blood mononuclear cells (PBMC) from 194 patients with longstanding RA (including 98 patients before and after treatment), and 41 healthy controls (HC). We found multiple differences between patients with RA compared to HC, predominantly in cytokine-induced Jak/STAT signaling in many immune cell subsets, suggesting pathways that may be associated with susceptibility to RA. We also found that high RA disease activity, compared to low disease activity, was associated with decreased (e.g., IFNα→p-STAT5, IL-10→p-STAT1) or increased (e.g., IL-6→STAT3) response to stimuli in multiple cell subsets. Finally, we compared signaling in patients with established, refractory RA before and six months after initiation of methotrexate (MTX) or TNF inhibitors (TNFi). We noted significant changes from pre-treatment to post-treatment in IFNα→p-STAT5 signaling and IL-10→p-STAT1 signaling in multiple cell subsets; these changes brought the aberrant RA signaling profiles toward those of HC. This large, comprehensive functional signaling pathway study provides novel insights into the pathogenesis of RA and shows the potential of quantification of cytokine-induced signaling as a biomarker of disease activity or treatment response.

ObjectiveTo determine the association between novel lifestyle factors on risk of rheumatoid arthritis (RA)-associated interstitial lung disease (ILD), define the threshold at which smoking increases RA-ILD risk, and calculate the degree to which known lifestyle and clinical factors predict RA-ILD.MethodsThis nested case-control study matched incident RA-ILD cases to RA non-ILD controls on age, sex, RA duration, rheumatoid factor, and time from exposure assessment to RA-ILD. Exposures included education, BMI, smoking, anticyclic citrullinated peptide antibodies, race, joint erosions, rheumatoid nodules, C-reactive protein (CRP), disease activity score, functional status, disease-modifying antirheumatic drug use, and glucocorticoid use. OR for each exposure on risk of RA-ILD were obtained from logistic regression models. Area under the curve (AUC) was calculated based on all lifestyle and clinical exposures.ResultsWe identified 84 incident RA-ILD cases and 233 matched controls. After adjustment, obesity, high-positive CRP (≥ 10 mg/L), and poor functional status (multidimensional Health Assessment Questionnaire [MDHAQ] ≥ 1) were associated with increased risk of RA-ILD (OR 2.42, 95% CI 1.11–5.24 vs normal BMI; OR 2.61, 95% CI 1.21–5.64 vs CRP < 3 mg/L; OR 3.10, 95% CI 1.32–7.26 vs MDHAQ < 0.2). Smoking 30 pack-years or more was strongly associated with risk of RA-ILD compared to never smokers (OR 6.06, 95% CI 2.72–13.5). Together, lifestyle and clinical risk factors for RA-ILD had an AUC of 0.79 (95% CI 0.73–0.85).ConclusionObesity, CRP, functional status, and extensive smoking may be novel risk factors for RA-ILD that may be useful for RA-ILD risk assessment and prevention. The overall ability to predict RA-ILD remains modest.

Hemodynamic stress is thought to play an important role in the formation of intracranial aneurysms, which is conditioned by the geometry of the surrounding vasculature. Our goal was to identify image-based morphological parameters that were associated with basilar artery tip aneurysms (BTA) in a location-specific manner. Three-dimensional morphological parameters obtained from CT-angiography (CTA) or digital subtraction angiography (DSA) from 207 patients with BTAs and a control group of 106 patients with aneurysms elsewhere to control for non-morphological factors, who were diagnosed at the Brigham and Women’s Hospital and Massachusetts General Hospital between 1990 and 2016, were evaluated. We examined the presence of hypoplastic, aplastic or fetal PCoAs, vertebral dominance, and diameters and angles of surrounding parent and daughter vessels. Univariable and multivariable statistical analyses were performed to determine statistical significance. Sensitivity analyses with small (≤ 3 mm) aneurysms only and with angles excluded, were also performed. In multivariable analysis, daughter–daughter angle was directly, and parent artery diameter and diameter size ratio were inversely associated with BTAs. These results remained significant in the subgroup analysis of small aneurysms (width ≤ 3 mm) and when angles were excluded. These easily measurable and robust parameters that are unlikely to be affected by aneurysm formation could aid in risk stratification for the formation of BTAs in high-risk patients.

Risk of intracranial aneurysm rupture could be affected by geometric features of intracranial aneurysms and the surrounding vasculature in a location specific manner. Our goal is to investigate the morphological characteristics associated with ruptured posterior communicating artery (PCoA) aneurysms, as well as patient factors associated with the morphological parameters. Three-dimensional morphological parameters in 409 patients with 432 PCoA aneurysms diagnosed at the Brigham and Women’s Hospital and Massachusetts General Hospital between 1990 and 2016 who had available CT angiography (CTA) or digital subtraction angiography (DSA) were evaluated. Morphological parameters examined included aneurysm wall irregularity, presence of a daughter dome, presence of hypoplastic or aplastic A1 arteries and hypoplastic or fetal PCoA, perpendicular height, width, neck diameter, aspect and size ratio, height/width ratio, and diameters and angles of surrounding parent and daughter vessels. Univariable and multivariable statistical analyses were performed to determine the association of morphological parameters with rupture of PCoA aneurysms. Additional analyses were performed to determine the association of patient factors with the morphological parameters. Irregular, multilobed PCoA aneurysms with larger height/width ratios and larger flow angles were associated with ruptured PCoA aneurysms, whereas perpendicular height was inversely associated with rupture in a multivariable model. Older age was associated with lower aspect ratio, with a trend towards lower height/width ratio and smaller flow angle, features that are associated with a lower rupture risk. Morphological parameters are easy to assess and could help in risk stratification in patients with unruptured PCoA aneurysms. PCoA aneurysms diagnosed at older age have morphological features associated with lower risk.

Objectives: Describe the development and feasibility of a telephone peer support program that provides education, emotional support, and enhances coping skills among rheumatoid arthritis (RA) patients. Methods: In an academic arthritis center, peer coaches received 5 training modules: 1) definition and expectations of peer coaching, 2) structure/management of phone calls, 3) confidentiality, 4) psychological techniques for encounters, 5) referral guidelines and resources. Follow-up, acceptability and comparison with patients receiving standard care included mean adjusted change differences at 6 months in fatigue, pain, self-efficacy, functional status (SF-12), flare frequency and medication adherence (ASK-20). Results: Eighteen peer coaches were assigned on average, 1.7 (SD, 1.4) patients. They spoke 8.4 (SD, 7.2) times; 21 of 29 patients completed the program. The most common topics requested were how to manage flares, 10(48%), medical aspects of RA, 10(48%) and understanding how to live with RA, 9(43%). After 6 months, non-significant improvements occurred in study outcomes (largest changes SF-12 PCS (mean adjusted change (SE) intervention v. standard care, 4.7(2.6) v. 0.5(2.0)) and how RA impacts one’s life (1.8(6.4) v. −4.9(5.8)). Participants reported many benefits from peer support. They felt less alone, 13(62%), more part of a sharing community, 12(57%) and had a better understanding of RA, 9(43%). They felt calmer, 9(43%), less sad,5(24%) and that they had more support from family and friends, 5(24%). Conclusions: An RA telephone peer support program is feasible and acceptable to patients. While the study was underpowered to detect statistical improvements, patients reported benefits suggesting the need for randomized evaluation.

OBJECTIVE Current validated cardiovascular (CV) risk estimates were developed in populations with relatively stable levels of inflammation, whereas patients with rheumatoid arthritis (RA) routinely experience significant changes in inflammation. This study was undertaken to test whether changes in inflammation affect estimated CV risk as measured using validated population-based risk calculators. METHODS Participants in a prospective RA cohort who experienced a decrease or an increase of ≥10 mg/liter in the C-reactive protein (CRP) level at 2 consecutive time points 1 year apart (CRP decrease group and CRP increase group, respectively) were included in this study. We estimated 10-year CV risk using the following calculators: Framingham Risk Score, 2013 American College of Cardiology/American Heart Association Atherosclerotic Cardiovascular Disease Risk Score, Reynolds Risk Score (RRS), and QRISK2. Of these calculators, only the RRS includes a variable addressing the CRP level. Paired t-tests were performed to compare risk scores at baseline and 1-year follow-up. We calculated the correlations between the changes in risk scores and changes in pro-B-type natriuretic peptide (pro BNP), a surrogate marker of CV risk. RESULTS One hundred eighty RA patients were included in the study (mean age 57.8 years, 84% female, 80% seropositive). Of the calculators studied, only the RRS was sensitive to changes in inflammation; an increase in inflammation was associated with increased estimated CV risk (P < 0.0001), and only the RRS was correlated with changes in proBNP (r = 0.17, P = 0.03). CONCLUSION Our data showed no significant change in CV risk estimated using validated general population CV risk calculators except for the RRS. These findings suggest that CV risk may be modulated by changes in inflammation in RA, which is not typically considered when using existing CV risk calculators.

Background and Purpose— Both low serum calcium and magnesium levels have been associated with the extent of bleeding in patients with intracerebral hemorrhage, suggesting hypocalcemia- and hypomagnesemia-induced coagulopathy as a possible underlying mechanism. We hypothesized that serum albumin-corrected total calcium and magnesium levels are associated with ruptured intracranial aneurysms. Methods— The medical records of 4701 patients, including 1201 prospective patients, diagnosed at the Brigham and Women’s Hospital and Massachusetts General Hospital between 1990 and 2016 were reviewed and analyzed. One thousand two hundred seventy-five patients had available serum calcium, magnesium, and albumin values within 1 day of diagnosis. Individuals were divided into cases with ruptured aneurysms and controls with unruptured aneurysms. Univariable and multivariable logistic regression analyses were performed to determine the association between serum albumin-corrected total calcium and magnesium levels and ruptured aneurysms. Results— In multivariable analysis, both albumin-corrected calcium (odds ratio, 0.33; 95% confidence interval, 0.27–0.40) and magnesium (odds ratio, 0.40; 95% confidence interval, 0.28–0.55) were significantly and inversely associated with ruptured intracranial aneurysms. Conclusions— In this large case–control study, hypocalcemia and hypomagnesemia at diagnosis were significantly associated with ruptured aneurysms. Impaired hemostasis caused by hypocalcemia and hypomagnesemia may explain this association.

Introduction To assess the relationship between low bone mineral density (BMD), anti-cyclic citrullinated peptide-2 (anti-CCP2) antibodies, and disease activity in patients with established rheumatoid arthritis (RA). Methods Patients enrolled in a single-center, observational cohort registry of patients with RA. Eligible patients had known BMD, as measured by digital X-ray radiogrammetry (DXR–BMD), and anti-CCP2 antibody measurements at the same time point or within 6 months. Anti-CCP2–immunoglobulin (Ig)G-positive (+) patients (≥ 20 U/mL) were distributed into three equal groups (Gp1–3), representing increasing anti-CCP2 antibody concentrations. Associations between BMD and anti-CCP2 antibody status and titer were explored in multivariate regression analyses controlling for covariates (including age, duration of RA, use of steroids, use of osteoporosis medication). Association between disease activity (DAS28 [CRP] Results A total of 149 patients (all women) were included (47 anti-CCP2 antibody negative [−], 102 anti-CCP2+ [34\titer group]). Mean disease duration was greater in the three anti-CCP2+ groups vs. the anti-CCP2− group. DXR–BMD was lower in the anti-CCP2+ vs. the anti-CCP2− groups (Gp1–3 vs. anti-CCP2−: P P P = 0.0181). Conclusion Among patients with established RA, data suggest that anti-CCP2+ patients, particularly those with high anti-CCP2 antibody titers, have lower hand BMD, and patients with lower hand BMD are less likely to have low disease activity. Funding Bristol-Myers Squibb. Trial Registration Clinicaltrials.gov identifier, NCT01793103.

Background and Purpose— Previous studies have suggested a protective effect of diabetes mellitus on aneurysmal subarachnoid hemorrhage risk. However, reports are inconsistent, and objective measures of hyperglycemia in these studies are lacking. Our aim was to investigate the association between aneurysmal subarachnoid hemorrhage and antihyperglycemic agent use and glycated hemoglobin levels. Methods— The medical records of 4701 patients with 6411 intracranial aneurysms, including 1201 prospective patients, diagnosed at the Massachusetts General Hospital and Brigham and Women’s Hospital between 1990 and 2016 were reviewed and analyzed. Patients were separated into ruptured and nonruptured groups. Univariate and multivariate logistic regression analyses were performed to determine the association between aneurysmal subarachnoid hemorrhage and antihyperglycemic agents and glycated hemoglobin levels. Propensity score weighting was used to account for selection bias. Results— In both unweighted and weighted multivariate analysis, antihyperglycemic agent use was inversely and significantly associated with ruptured aneurysms (unweighted odds ratio, 0.58; 95% confidence interval, 0.39–0.87; weighted odds ratio, 0.57; 95% confidence interval, 0.34–0.96). In contrast, glycated hemoglobin levels were not significantly associated with rupture status. Conclusions— Antihyperglycemic agent use rather than hyperglycemia is associated with decreased risk of aneurysmal subarachnoid hemorrhage, suggesting a possible protective effect of glucose-lowering agents in the pathogenesis of aneurysm rupture.

Background and Purpose— Growing evidence from experimental animal models and clinical studies suggests the protective effect of statin use against rupture of intracranial aneurysms; however, results from large studies detailing the relationship between intracranial aneurysm rupture and total cholesterol, HDL (high-density lipoprotein), LDL (low-density lipoprotein), and lipid-lowering agent use are lacking. Methods— The medical records of 4701 patients with 6411 intracranial aneurysms diagnosed at the Massachusetts General Hospital and the Brigham and Women’s Hospital between 1990 and 2016 were reviewed and analyzed. Patients were separated into ruptured and nonruptured groups. Univariable and multivariable logistic regression analyses were performed to determine the effects of lipids (total cholesterol, LDL, and HDL) and lipid-lowering medications on intracranial aneurysm rupture risk. Propensity score weighting was used to account for differences in baseline characteristics of the cohorts. Results— Lipid-lowering agent use was significantly inversely associated with rupture status (odds ratio, 0.58; 95% confidence interval, 0.47–0.71). In a subgroup analysis of complete cases that includes both lipid-lowering agent use and lipid values, higher HDL levels (odds ratio, 0.95; 95% confidence interval, 0.93–0.98) and lipid-lowering agent use (odds ratio, 0.41; 95% confidence interval, 0.23–0.73) were both significantly and inversely associated with rupture status, whereas total cholesterol and LDL levels were not significant. A monotonic exposure–response curve between HDL levels and risk of aneurysmal rupture was obtained. Conclusions— Higher HDL values and the use of lipid-lowering agents are significantly inversely associated with ruptured intracranial aneurysms.

While cocaine use is thought to be associated with aneurysmal rupture, it is not known whether heroin use increases the risk of rupture in patients with non-mycotic saccular aneurysms. Our goal was to investigate the association between heroin and cocaine use and the rupture of saccular non-mycotic aneurysms. The medical records of 4701 patients with 6411 intracranial aneurysms, including 1201 prospective patients, diagnosed at the Brigham and Women’s Hospital and Massachusetts General Hospital between 1990 and 2016 were reviewed and analyzed. Patients were separated into ruptured and non-ruptured groups. Univariable and multivariable logistic regression analyses were performed to determine the association between heroin, cocaine, and methadone use and the presence of ruptured intracranial aneurysms. In multivariable analysis, current heroin use was significantly associated with rupture status (OR 3.23, 95% CI 1.33–7.83) whereas former heroin use (with and without methadone replacement therapy), and current and former cocaine use were not significantly associated with intracranial aneurysm rupture. In the present study, heroin rather than cocaine use is significantly associated with intracranial aneurysm rupture in patients with non-mycotic saccular cerebral aneurysms, emphasizing the possible role of heroin in the pathophysiology of aneurysm rupture and the importance of heroin cessation in patients harboring unruptured intracranial aneurysms.

ObjectiveTo determine the association between ruptured saccular aneurysms and aspirin use/aspirin dose.MethodsFour thousand seven hundred one patients who were diagnosed at the Massachusetts General Hospital and Brigham and Women's Hospital between 1990 and 2016 with 6,411 unruptured and ruptured saccular intracranial aneurysms were evaluated. Univariable and multivariable logistic regression analyses were performed to determine the association between aneurysmal subarachnoid hemorrhage and aspirin use, including aspirin dose. Inverse probability weighting using propensity scores was used to adjust for potential differences in baseline characteristics between cases and controls. Additional analyses were performed to examine the association of aspirin use and rerupture before treatment.ResultsIn multivariate analysis with propensity score weighting, aspirin use (odds ratio [OR] 0.60, 95% confidence interval [CI] 0.45–0.80) was significantly associated with decreased risk of ruptured intracranial aneurysms. There was a significant inverse dose-response relationship between aspirin dose and aneurysmal subarachnoid hemorrhage (OR 0.65, 95% CI 0.53–0.81). In contrast, there was a significant association between aspirin use and increased risk of rerupture before treatment (OR 8.15, 95% CI 2.22–30.0).ConclusionsIn this large case-control study, aspirin therapy at diagnosis was associated with a significantly decreased risk of subarachnoid hemorrhage, with an inverse dose-response relationship among aspirin users. However, once rupture has occurred, aspirin is associated with an increased risk of rerupture before treatment.

Alcohol consumption may be a modifiable risk factor for rupture of intracranial aneurysms. Our aim is to evaluate the association between ruptured aneurysms and alcohol consumption, intensity, and cessation. The medical records of 4701 patients with 6411 radiographically confirmed intracranial aneurysms diagnosed at the Brigham and Women's Hospital and Massachusetts General Hospital between 1990 and 2016 were reviewed. Individuals were divided into cases with ruptured aneurysms and controls with unruptured aneurysms. Univariable and multivariable logistic regression analyses were performed to determine the association between alcohol consumption and rupture of intracranial aneurysms. In multivariable analysis, current alcohol use (OR 1.36, 95% CI 1.17-1.58) was associated with rupture status compared with never drinkers, whereas former alcohol use was not significant (OR 1.23, 95% CI 0.92-1.63). In addition, the number of alcoholic beverages per day among current alcohol users (OR 1.13, 95% CI 1.04-1.23) was significantly associated with rupture status, whereas alcohol use intensity was not significant among former users (OR 1.02, 95% CI 0.94-1.11). Current alcohol use and intensity are significantly associated with intracranial aneurysm rupture. However, this increased risk does not persist in former alcohol users, emphasizing the potential importance of alcohol cessation in patients harboring unruptured aneurysms.

Objective Patients with rheumatoid arthritis (RA) often ask whether specific foods, popularized as inflammatory or antiinflammatory, can improve or worsen their RA. Patients with RA took a survey on diet and RA symptoms, and the survey data were collected and analyzed. Methods A dietary survey was mailed to 300 subjects in a single-center RA registry at a large academic center. Subjects were asked about their consumption of 20 foods and whether these foods make their RA symptoms better, worse, or unchanged. Semiannual registry data include demographics, medications, comorbidities, and disease activity scores. Fisher's exact test and Wilcoxon's rank sum tests evaluated associations between subject characteristics from the most recent registry assessment and changes in RA symptoms from specific foods. Results Of the 217 subjects (72% response rate), 83% were female; the median RA duration was 17 years (interquartile range 9–27 years), and 58% were taking a biologic disease-modifying antirheumatic drug. Twenty-four percent of subjects reported that foods affect their RA symptoms, with 15% reporting improvement and 19% reporting worsening. Blueberries and spinach were the foods most often reported to improve RA symptoms, while soda with sugar and desserts were those most often reported to worsen RA symptoms. Younger age and noting that sleep, warm room temperature, and vitamin/mineral supplements improve RA were each associated with reporting that foods affect RA symptoms. Medication use, sex, body mass index, smoking, disease duration, disease activity scores, and self-reported RA flares were not associated with reporting that foods affect RA. Conclusion Nearly one-quarter of RA subjects with longstanding disease reported that diet had an effect on their RA symptoms.

Objective Previous cross-sectional studies have shown that rheumatoid arthritis (RA) patients with fibromyalgia (FM) have higher disease activity, greater medical costs, and worse quality of life compared to RA patients without FM. We determined the impact of FM on 2-year changes in the functional status of RA patients in a prospective study. Methods Subjects included participants in the Brigham Rheumatoid Arthritis Sequential Study who were enrolled in a substudy of the effects of pain in RA. Subjects completed questionnaires, including the Multi-Dimensional Health Assessment Questionnaire (MDHAQ) and Polysymptomatic Distress (PSD) scale, semiannually, and underwent physical examination and laboratory tests yearly. Results Of the 156 included RA subjects, 16.7% had FM, while 83.3% did not. In a multivariable linear regression model adjusted for age, sex, race, baseline MDHAQ score, disease duration, rheumatoid factor/cyclic citrullinated peptide antibody seropositivity, disease activity, and psychological distress, RA patients with FM had a 0.14 greater 2-year increase in MDHAQ score than RA patients without FM (P = 0.021). In secondary analyses examining the association between continuous PSD scale score and change in MDHAQ, higher PSD scale scores were significantly associated with greater 2-year increases in MDHAQ score (β coefficient 0.013, P = 0.011). Conclusion Both the presence of FM and increasing number of FM symptoms predicted worsening of functional status among individuals with RA. Among individuals with RA and FM, the magnitude of the difference in changes in MDHAQ was 4- to 7-fold higher than typical changes in MDHAQ score among individuals with established RA.

Objective: To characterize physical activity (PA) participation (meeting ≥150-minutes of moderate intensity or 75-minutes of vigorous (MVPA/week)), examine associations between disease activity and MVPA and identify MVPA correlates in adults with rheumatoid arthritis (RA) over 3 years. Methods: This study included 573 RA patients (94% Caucasian, 83% female, mean age 61 years, mean RA duration 19.5 years) with ≥1 annual registry visit and who completed the PA questionnaire. Baseline and annual measures included: demographics/medical history, self-efficacy for disease management, quality of life, patient/physician global assessment, physical function, and self-reported PA. A logistic repeated measures model using the Generalized Estimation Equation examined the relationship between disease activity and MVPA. Results: Average disease activity (DAS28-CRP3) was 3.1 (SD, 1.4), 36% were physically inactive and 29% met MVPA recommendations. There was a negative borderline association with disease activity (OR=0.89; 95%CI 0.79–1.00). Correlates of meeting MVPA recommendations, adjusting for disease activity, were being Caucasian (OR=2.95; 95%CI 1.29–6.75), older age (age >69 OR=0.58; 95%CI 0.36–0.92) poor mental health (OR=0.63; 95%CI 0.41–0.95), poor physical function (OR=0.59; 95%CI 0.34–1.01), overweight/obese (body mass index >25–30 OR=0.69; 95%CI 0.50–0.95; >30–39.9 OR=0.60; 95%CI 0.41–0.88; ≤40 OR=0.24; 95%CI 0.08–0.74) and patient global assessment (≥10-20) OR=0.57; 95%CI 0.39–0.83). Conclusions: A small proportion met MVPA recommendations despite well-controlled disease. Disease activity was negatively associated with PA over time. PA correlates were linked to lifestyle, mental health and patient perceptions of disease, suggesting PA interventions that address patient perspectives may facilitate RA management. This article is protected by copyright. All rights reserved.

Background The collection of routine clinical data in the setting of research registries can serve an important role in understanding real world care. However, relatively little is known about the patient experience in registries, motivating us to survey patients enrolled in two chronic disease registries. Methods We conducted similar surveys in two disease-based registries based at one academic medical center in the US. One group of patients with rheumatoid arthritis (RA) had been enrolled in a registry, and we focused on retention factors. In a second group of patients with inflammatory bowel disease (IBD) recently enrolled or considering enrollment, we examined factors that would influence their enrollment and willingness to answer frequent questionnaires and give biospecimens. The surveys were analyzed using descriptive statistics and the two cohorts were compared using nonparametric and chi-square tests. Results We received 150 (50%) completed surveys from RA and 169 (63%) from IBD patients. Mean age of subjects was 62 years in RA and 43 in IBD with more women respondents with RA (83%) than IBD (62%). The two groups described very similar factors as the top three motivations for participation: desire to help others, desire to improve care of own disease, and ease of volunteering. Preferred methods of surveying included mail, e-mail, but telephone was not favored; age was an important correlate of this preference. Respondents preferred surveys either every 1–3 months (28.7% RA and 55.0% IBD) or every 4–6 months (50.7% RA and 29.0% IBD). They differed in the preference for payment for answering surveys with 68.0% with RA answering that no payment was necessary but only 36.1% with IBD felt similarly. Conclusions Patients engaged in clinical registries demonstrate a high level of commitment to improve care and many report a willingness to answer questions relatively frequently. Electronic supplementary material The online version of this article (doi:10.1186/s12874-017-0343-3) contains supplementary material, which is available to authorized users.

Objective To quantify differences and determine the factors contributing to the difference in patient global assessment of rheumatoid arthritis (RA) disease activity (PtGA) between RA patients with multiple morbidities (RA-MM) and those with RA only. Methods We compared the PtGA between RA-MM patients and those with RA only, followed up in a longitudinal cohort (n = 1,040). In analyses performed on RA-MM patients (n = 575) and those with RA only (matched for swollen joint count, tender joint count, evaluator global assessment, and disease duration), the mean difference in PtGA (ΔPtGA) between the 2 groups was assessed. The contribution of patient characteristics to the explained variation of ΔPtGA in the matched cohort was calculated as semipartial R2 and summarized as the percentage of the total R2 in linear regression models. Results RA-MM patients reported higher (or worse) PtGA, with an increased PtGA associated with more morbidities (P for linear trend

Objective:To use natural language processing (NLP) in conjunction with the electronic medical record (EMR) to accurately identify patients with cerebral aneurysms and their matched controls.Methods:ICD-9 and Current Procedural Terminology codes were used to obtain an initial data mart of potential aneurysm patients from the EMR. NLP was then used to train a classification algorithm with .632 bootstrap cross-validation used for correction of overfitting bias. The classification rule was then applied to the full data mart. Additional validation was performed on 300 patients classified as having aneurysms. Controls were obtained by matching age, sex, race, and healthcare use.Results:We identified 55,675 patients of 4.2 million patients with ICD-9 and Current Procedural Terminology codes consistent with cerebral aneurysms. Of those, 16,823 patients had the term aneurysm occur near relevant anatomic terms. After training, a final algorithm consisting of 8 coded and 14 NLP variables was selected, yielding an overall area under the receiver-operating characteristic curve of 0.95. After the final algorithm was applied, 5,589 patients were classified as having aneurysms, and 54,952 controls were matched to those patients. The positive predictive value based on a validation cohort of 300 patients was 0.86.Conclusions:We harnessed the power of the EMR by applying NLP to obtain a large cohort of patients with intracranial aneurysms and their matched controls. Such algorithms can be generalized to other diseases for epidemiologic and genetic studies.

Background\ud Previous studies of radiological damage in rheumatoid arthritis (RA) have used candidate-gene approaches, or evaluated single genome-wide association studies (GWAS). We undertook the first meta-analysis of GWAS of RA radiological damage to: (1) identify novel genetic loci for this trait; and (2) test previously validated variants.\ud \ud Methods\ud Seven GWAS (2,775 RA cases, of a range of ancestries) were combined in a meta-analysis. Radiological damage was assessed using modified Larsen scores, Sharp van Der Heijde scores, and erosive status. Single nucleotide polymophsim (SNP) associations with radiological damage were tested at a single time-point using regression models. Primary analyses included age and disease duration as covariates. Secondary analyses also included rheumatoid factor (RF). Meta-analyses were undertaken in trans-ethnic and European-only cases.\ud \ud Results\ud In the trans-ethnic primary meta-analysis, one SNP (rs112112734) in close proximity to HLA-DRB1, and strong linkage disequilibrium with the shared-epitope, attained genome-wide significance (P = 4.2x10-8). In the secondary analysis (adjusting for RF) the association was less significant (P = 1.7x10-6). In both trans-ethnic primary and secondary meta-analyses 14 regions contained SNPs with associations reaching P

Rheumatoid arthritis (RA), a chronic autoimmune disease characterized by circulating autoantibodies, involves many cytokine-mediated signaling pathways in multiple immune cell subsets. Most studies of immune cells in RA have limitations, such as analysis of a small number of cell subsets or pathways, and limited longitudinal data on patient phenotypes. In this study, we used an innovative systems immunology approach to simultaneously quantify up to 882 signaling nodes (Jak/STAT signaling readouts modulated by cytokines and other stimuli) in 21 immune cell subsets. We studied 194 RA patients and 41 controls, including 146 well-characterized RA patients prior to, and 6 months after, initiation of methotrexate or biologic agents from the Treatment Efficacy and Toxicity in RA Database and Repository (TETRAD). There was strikingly attenuated signaling capacity in RA patients in IFNα stimulation followed by measurement of phosphorylated STAT1 [IFNα→p-STAT1] in six immune cell subsets. Multiple nodes showed negative association with disease activity, including IFNα→STAT5 signaling in naive and memory B cells. In contrast, IL-6-induced STAT1 and STAT3 activation in central memory CD4-negative T cells showed a positive association with disease activity. Multiple nodes were associated with treatment response, including IFNα→STAT1 in monocytes and IL-6→STAT3 in CD4+ naive T cells. Decision tree analysis identified a model combining these two nodes as a high-performing classifier of treatment response to TNF inhibitors. Our study provides novel information on RA disease mechanisms and serves as a framework for the discovery and validation of biomarkers of treatment response in RA.

Background Introduction of multiple biologic DMARDs, targeted synthetic DMARDs and biosimilars has led to a paradigm shift in the management of patients (pts) with RA. There are, however, limited head-to-head studies comparing these agents to guide evidence-based treatment decisions. Abatacept versus adaliMumab comParison in bioLogic-naivE RA subjects with background MTX (AMPLE) was the first head-to-head randomised controlled trial to evaluate the efficacy of abatacept (ABA) and adalimumab. However, there are limited data replicating AMPLE findings in real-world settings. Objectives To compare effectiveness of ABA versus TNF inhibitors (TNFis) in pts with RA by line of therapy (LOT) and by LOT stratified by anti-citrullinated protein antibody (ACPA) status using data from real-world clinical practice. Methods Data from two independent RA registries comprising pts treated by physicians in routine care were used for the analysis. An RA disease-specific registry provided data on pts treated with TNFis; the other was a product-specific RA registry and provided data on pts treated with ABA.1,2 The disease-specific registry was a US-based single-centre registry; the product-specific registry was a multi-centre, 12-country registry excluding the US. Frequency matching on age (in years [yrs]; ±4 yrs’ window), RA disease duration (in yrs; ±4 yrs) and baseline CDAI category (remission [≤2.8], low activity [≤10], medium activity [≤22], high activity [>22]) between TNFi and ABA pts was done for biologic-naive and -experienced pts. Descriptive statistics were used to summarise baseline demographics, disease activity measures and serostatus for both treatment groups by LOT. Disease activity in the follow-up period was measured at the 12-month mark (±6 months). Change in disease activity after 12 months was evaluated for TNFi and ABA pts by LOT, and statistical comparison using Kruskal–Wallis test was performed. The analysis was repeated for pts stratified by ACPA status. Results Data for 105 first-line and 91 second- or further-line (subsequent-line) matched pairs of TNFi and ABA pts were included in the analysis (68 first-line and 60 subsequent-line matched pairs of TNFi and ABA pts, respectively, in ACPA+ cohort; 31 first-line and 21 subsequent-line matched pairs of TNFi and ABA pts, respectively, in ACPA– cohort; Table 1). In the biologic-experienced pts, ABA (vs TNFi) had a higher reduction in CDAI score (10.2 vs 5.2, p=0.035; Table 2). In the biologic-experienced ACPA+ pts, ABA (vs TNFi) had higher reduction in disease activity (CDAI: 13.3 vs 6.2, p=0.023; Table 2; SDAI: 13.9 vs 7.0, p=0.046). No difference in disease activity was observed between the two groups among the ACPA– pts. Conclusion Real-world RA registry data further confirm findings from the AMPLE study that the overall efficacy of ABA is similar to TNFi agents in biologic-naive pts with RA. Efficacy of ABA (vs TNFis) in biologic-experienced pts is greater, and greater reductions in joint disease activity in ACPA+ ABA (vs TNFis) pts were observed. References [1] Brigham and Women’s Hospital. BRASS. https://www.brassstudy.org/. Accessed September 12, 2018. [2] Alten R, et al. RMD Open2017;3:e000538. Disclosure of Interests Evo Alemao Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Sean Connolly Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Yedid Elbez Employee of: Employee of Excelya which received funding from Bristol-Myers Squibb as contract research organization., Aarti Rao Consultant for: Bristol-Myers Squibb, Yogesh Saini Consultant for: Bristol-Myers Squibb, Christine Iannaccone: None declared, Michael E. Weinblatt Shareholder of: Stock option: CanFite, Lycera, Scipher, Inmedix, Grant/research support from: Crescendo Bioscience, Bristol Myers Squibb, Sanofi, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, CanFite, Corrona, Crescendo, GlaxoSmithKline, Gilead, Horizon, Lilly, Lycera, Merck, Novartis, Pfizer, Roche, Samsung, Scipher, Set Point, Nancy Shadick Grant/research support from: Bristol-Myers Squibb, Sanofi/Regeneron, Crescendo Biosciences, Mallinckrodt, Amgen, Consultant for: Consulting work for Bristol-Myers Squibb for under $10,000.

Background RA-associated interstitial lung disease (RA-ILD) is an extra-articular manifestation of RA and is one of the leading causes of death in patients (pts) with RA.1 Previous studies have indicated that clinical factors such as age, sex, smoking and autoantibody positivity are strongly associated with RA-ILD.2 There is also evidence of active RA being related to increased risk for clinically apparent ILD.3 However, there are limited data on how pts with RA-ILD are managed for their joint conditions and joint outcomes. Objectives To evaluate RA treatment patterns in pts with subclinical and clinical RA-ILD compared with pts with RA without ILD, and to assess joint disease activity at baseline and change in disease activity by treatment in all cohorts. Methods Data from adult pts with RA enrolled in a longitudinal sequential RA registry were analysed. Pts in the registry were evaluated annually by a rheumatologist for disease activity and treatment, and semi-annually on multiple clinical patient-reported outcomes (PROs) and resource utilisation parameters. Pts with chest computed tomography (CT) scans performed to evaluate clinical indications for ILD and with blood samples were included in this analysis. Pts with chest CT scans that were indeterminate for ILD were excluded from the study. Pts were then divided into two mutually exclusive groups: non-ILD RA pts and RA-ILD pts. RA-ILD pts were further divided into subclinical and clinically evident ILD. Date of chest CT scan was considered the index date. The two cohorts were compared using descriptive statistics to summarise baseline differences in demographics, disease activity measures, serostatus and treatments. Kruskal–Wallis test for continuous variables and chi-square test for categorical variables were performed, with two-sided significance level of 0.05. Multivariable linear regression was used to evaluate change from baseline to 12 months in joint disease activity for pts with available data at baseline and follow-up. Results 75 pts with chest CT scans were included in the analysis. Of these, 38.7% (n=29) were non-ILD RA and 61.3% (n=46) had some manifestation of RA-ILD. Of the RA-ILD cohort, 63.0% (n=29) and 37.0% (n=17) were classified as subclinical and clinically evident RA-ILD, respectively. At the time of chest CT scan, RA-ILD (vs non-ILD RA) pts were older with longer disease duration, a greater proportion were male and had higher anti-citrullinated protein antibody and RF titres (Table 1). In terms of RA treatments, a significantly greater proportion of RA-ILD (vs non-ILD RA) pts were on corticosteroids (CS; 47.8% vs 20.7%) and a significantly greater proportion of clinically evident RA-ILD (vs non-ILD RA) were on non-TNF inhibitor (TNFi) biologics. RA-ILD (vs non-ILD RA) pts had numerically higher joint disease activity and modified HAQ score at baseline (Table 1). However, the change in joint disease activity and PROs in RA-ILD pts was numerically greater vs non-ILD RA pts. In a multivariable analysis, RA-ILD status did not impact change in joint disease activity, but baseline joint disease activity was significantly associated with reduction in joint disease activity at 12 months (Table 2). Conclusion RA-ILD pts compared with non-ILD RA pts in clinical practice are more likely to be managed with CS therapy and non-TNFi bDMARDs. The improvement in joint disease activity was similar between RA-ILD and non-ILD RA pts. The analysis was limited by small sample size; further studies with larger pt numbers are required to confirm the findings. References [1] Doyle JT, et al. Am J Respir Crit Care Med2015;191:1403–12. [2] Sparks JA, et al. Arthritis Care Res (Hoboken)2016;68:753–62. [3] Sparks JA, et al. Arthritis Rheumatol2018; 70(suppl 10):abstract 884. Disclosure of Interests Evo Alemao Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Tracy Doyle Grant/research support from: Receive research support from Bristol-Myers Squibb and I’m involved in a clinical trial funded by Genentech., Jeffrey Sparks Grant/research support from: Bristol-Myers Squibb, Amgen, Consultant for: Optum, Aarti Rao Consultant for: Bristol-Myers Squibb, Yogesh Saini Consultant for: Bristol-Myers Squibb, Christine Iannaccone: None declared, Michael E. Weinblatt Shareholder of: Stock option: CanFite, Lycera, Scipher, Inmedix, Grant/research support from: Crescendo Bioscience, Bristol Myers Squibb, Sanofi, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, CanFite, Corrona, Crescendo, GlaxoSmithKline, Gilead, Horizon, Lilly, Lycera, Merck, Novartis, Pfizer, Roche, Samsung, Scipher, Set Point, Nancy Shadick Grant/research support from: Bristol-Myers Squibb, Sanofi/Regeneron, Crescendo Biosciences, Mallinckrodt, Amgen, Consultant for: Consulting work for Bristol-Myers Squibb for under $10,000.

Objective.Describe strategies used to manage rheumatoid arthritis (RA) flares that contribute to a successful postflare outcome.Methods.Data were collected from the BRASS registry, including clinical and patient-reported outcomes, and a survey with a Likert scale assessing postflare symptoms (better, unchanged, or worse). A logistic regression analysis adjusting for age, sex, flare number in the past 6 months, flare pain severity, home management, clinical consultation, and medication change was performed to evaluate factors influencing flare outcome.Results.Of 503 participants, 185 reported at least 1 flare that had resolved in the past 6 months, with median (interquartile range) 28-joint count Disease Activity Score based on C-reactive protein 3 score 2.1 (1.7–2.8). Compared with RA symptoms before the flare, 22 (12%) patients felt worse, 125 (68%) were unchanged, and 38 (20%) felt better. To manage flares, 72% of patients used home-based remedies, 23% sought clinical consultation, and 56% made medication change. Of 103 patients who changed medication, 70% did so without seeking clinical advice. Making a medication change (OR 3.48, 95% CI 1.68–7.21) and having lower flare pain (OR 0.83, 95% CI 0.71–0.97) were associated with better flare outcome.Conclusion.Flares occur frequently even in patients with low disease activity. Independent of home-based or clinically guided care, making a medication change and having less severe pain during a flare were associated with better flare outcomes. Of interest, the decision to change medications was frequently made without clinical advice. Future studies might address how best to intervene when patients experience flares and whether patient-initiated medication changes have adverse outcomes.

Background: Data-driven principal component (PC) and cluster analysis has the potential to identify previously unknown patient subgroups within a rheumatoid arthritis (RA) registry to establish prognosis, predict disease trajectory, and help inform treatment. Objectives: The Brigham and Women’s Rheumatoid Arthritis Sequential Study (BRASS), established in 2003, is a single-center, prospective observational registry cohort providing a comprehensive set of clinical disease activity measures in >1400 patients with RA. Our objective was to use PC and cluster analysis of baseline demographic, socio-economic, health and disease characteristics in BRASS to identify and characterize distinct patient clusters in RA. Methods: Patient variables recorded at entry into BRASS were refined and combined using PC analysis to reduce dimensionality and collinearity. The number of PCs was established by eigenvalue >1, cumulative variance, and interpretability. Patients were clustered using a k-means approach with non-hierarchical, exclusive, and complete clustering, with minimum cluster size 5% of population, and maximum 19 clusters. The final number of clusters was determined according to the cubic clustering criterion and pseudo F. Results: Analysis of baseline data from 1443 patients identified 41 PCs that capture the fundamental characteristics involved in RA. Cluster analysis distinguished 5 patient clusters. Each cluster reflected a different profile of PCs, and can be described based on overall health, RA disease activity and duration (Table). Key differentiators between clusters include comorbidity PCs (metabolic comorbidities predominate in cluster 1, neurologic in cluster 4, and orthopedic in cluster 5) and patient characteristics/social PCs (greatest number of doctor visits and family history of MI in cluster 3, greatest BMI in cluster 1, highest income in cluster 2, lowest income in cluster 5, and least emotional support in cluster 1). Conclusion: Data-driven cluster analysis of RA patient characteristics at entry into the BRASS registry identified five distinct patient phenotypes, providing a convenient method to potentially derive novel insights into the multifactorial drivers, commonly co-occurring health conditions, and manifestations of RA. Investigation of longitudinal outcomes in these different clusters in the BRASS registry and validation in an independent dataset is ongoing. Acknowledgement: Study funding and medical writing support (Matt Lewis, Adelphi) provided by Sanofi and Regeneron Pharmaceuticals, Inc. Disclosure of Interests: Jeffrey R. Curtis Grant/research support from: Abbvie, Amgen, BMS, Corrona, Janssen, Lilly, Myriad, Pfizer, Roche/Genentech, UCB, Crescendo Bioscience Inc., Consultant for: Abbvie, Amgen, BMS, Corrona, Janssen, Lilly, Myriad, Pfizer, Roche/Genentech, UCB, Crescendo Bioscience Inc., Michael E. Weinblatt Shareholder of: Stock option: CanFite, Lycera, Scipher, Inmedix, Grant/research support from: Crescendo Bioscience, Bristol Myers Squibb, Sanofi, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, CanFite, Corrona, Crescendo, GlaxoSmithKline, Gilead, Horizon, Lilly, Lycera, Merck, Novartis, Pfizer, Roche, Samsung, Scipher, Set Point, Kenneth Saag Grant/research support from: Amgen, Ironwood/AstraZeneca, Horizon, SOBI, Takeda, Consultant for: Abbvie, Amgen, Ironwood/AstraZeneca, Bayer, Gilead, Horizon, Kowa, Radius, Roche/Genentech, SOBI, Takeda, Teijin, Vivian Bykerk Grant/research support from: Mallinckrodt, BMS, Crescendo Biosciences, Sanofi/Regeneron., Consultant for: Amgen, Pfizer, UCB, Scipher, Sanofi/Genzyme/Regeneron, Christina Charles-Schoeman Grant/research support from: Bristol-Myers Squibb, AbbVie, and Pfizer, Consultant for: Regeneron-Sanofi, Pfizer, and Gilead, Stefano Fiore Shareholder of: Sanofi, Employee of: Sanofi, Gregory St. John Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, Toshio Kimura Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., Shen Zheng Consultant for: Sanofi, Clifton Bingham Grant/research support from: BMS, Consultant for: AbbVie, BMS, Eli Lilly, Genentech/Roche, Janssen, Pfizer, Sanofi/Regeneron, Grace Wright Consultant for: Abbvie, Amgen, BMS, Exagen, LILLY, Myriad Autoimmune, NOVARTIS, Pfizer, Sanofi Genzyme Regeneron, UCB, Speakers bureau: Abbvie, Amgen, BMS, Exagen, LILLY, Myriad Autoimmune, NOVARTIS, Sanofi Genzyme Regeneron, UCB, Martin Bergman Shareholder of: Johnson and Johnson (parent company of Janssen), Consultant for: AbbVie, Amgen, BMS, Celgene, Genentech/Roche, Janssen, Merck, Novartis, Pfizer, and Sanofi/Regeneron, Speakers bureau: AbbVie, Amgen, BMS, Celgene, Genentech/Roche, Janssen, Merck, Novartis, Pfizer, and Sanofi/Regeneron, Kamala Nola Shareholder of: Gilead, Johnson & Johnson, Proctor & Gamble, Consultant for: Yes – Gilead, Sanofi Genzyme, Regeneron, Speakers bureau: Coherus, Daniel E. Furst Grant/research support from: AbbVie, Actelion, Amgen, BMS Corbus, NIH, Novartis, Pfizer, Roche/Genentech, Consultant for: AbbVie, Actelion, Amgen, BMS, Cytori, Novartis, Pfizer, Roche/Genentech, Speakers bureau: CMC Connect (McCann Health Company), Nancy Shadick Grant/research support from: Mallinckrodt, BMS, Crescendo Biosciences, Sanofi/Regeneron.

We investigated whether rheumatoid arthritis (RA)-related autoantibodies were associated with abnormalities on pulmonary function tests (PFTs).We studied RA serostatus and PFT abnormalities within a RA registry. RA serostatus was assessed by research assays for cyclic citrullinated peptide (CCP) and rheumatoid factor (RF). Outcomes were abnormalities on clinically indicated PFTs, including restriction, obstruction, and diffusion abnormality. Logistic regression was used to obtain ORs and 95% CIs for the PFT abnormalities by RA serologic phenotypes independent of lifestyle and RA characteristics.Among 1272 analyzed subjects, mean age was 56.3 years (SD 14.1), 82.2% were female, and 69.5% were seropositive. There were 100 subjects with abnormal PFTs. Compared with seronegativity, seropositivity was associated with increased odds of any PFT abnormality (multivariable OR 2.29, 95% CI 1.30-4.03). When analyzing type of PFT abnormality, seropositivity was also associated with restriction, obstruction, and diffusion abnormalities; multivariable ORs were 2.48 (95% CI 1.26-4.87), 3.12 (95% CI 1.28-7.61), and 2.30 (95% CI 1.09-4.83), respectively. When analyzing by CCP and RF status, the associations were stronger for RF+ than for CCP+ (any PFT abnormality OR 1.99, 95% CI 1.21-3.27 for RF+ vs. RF-; OR 1.67, 95% CI 1.03-2.69 for CCP+ vs. CCP-) with a dose effect of higher RF titer increasing odds for each PFT abnormality (p for trend 0.05).Seropositive RA patients had two-fold increased risk for abnormalities on PFTs performed for clinical indications compared with seronegative RA. Patients with seropositive RA, particularly those with high-titer RF positivity, may be more likely to have obstructive and restrictive abnormalities, independent of smoking.Key points• Due to the known excess pulmonary morbidity/mortality in RA, we studied the relationship of rheumatoid arthritis (RA)-related autoantibodies with pulmonary function test (PFT) abnormalities using a large RA registry.• We evaluated whether presence and levels of cyclic citrullinated peptide (CCP) and rheumatoid factor (RF) were associated with restriction, obstruction, and diffusion abnormalities on PFTs among 1272 subjects with RA.• Seropositivity was associated with two-fold increased risk for any PFT abnormality, independent of confounders including smoking. Higher titers of RF conferred greatest risk for all PFT outcomes: obstruction, restriction, and diffusion abnormality.• These results provide evidence that patients with RA should be closely monitored for pulmonary involvement, particularly those with high-titer RF seropositivity.

Iron and its derivatives play a significant role in various physiological and biochemical pathways, and are influenced by a wide variety of inflammatory, infectious, and immunological disorders. We hypothesized that iron and its related factors play a role in intracranial aneurysm pathophysiology and investigated if serum iron values are associated with ruptured intracranial aneurysms. 4,701 patients with 6,411 intracranial aneurysms, including 1201 prospective patients, who were diagnosed at the Massachusetts General Hospital and Brigham and Women’s Hospital between 1990 and 2016 were evaluated. A total of 366 patients with available serum iron, ferritin and total iron binding capacity (TIBC) values were ultimately included in the analysis. 89% of included patients had anemia. Patients were categorized into ruptured and non-ruptured groups. Univariable and multivariable logistic regression analyses were performed to determine the association between ruptured aneurysms and iron, ferritin, and TIBC. TIBC values (10−3 g/L) within 1 year of diagnosis (OR 0.41, 95% CI 0.28–0.59) and between 1 and 3 years from diagnosis (OR 0.52, 95% CI 0.29–0.93) were significantly and inversely associated with intracranial aneurysm rupture. In contrast, serum iron and ferritin were not significant. In this case-control study, low TIBC was significantly associated with ruptured aneurysms, both in the short- and long term. However, this association may not apply to the general population as there may be a selection bias as iron studies were done in a subset of patients only.

Biologics effectively manage symptoms and disease activity in rheumatoid arthritis (RA), but their long-term effects remain unclear.Longitudinal data were examined from the Brigham and Women's Rheumatoid Arthritis Sequential Study (BRASS) registry. Linear regression modeled the effect of biologic exposure on changes in disease activity (Disease Activity Score-28 with C-reactive protein [DAS28-CRP]), functional status (modified Health Assessment Questionnaire [mHAQ]), and RA severity (Routine Assessment of Patient Index Data [RAPID3]). Biologic exposure was the ratio of time on a biologic relative to time participating in the BRASS cohort.The analysis included 1395 RA patients, 82.3% female, with 6783 unique study visits from 2003 to 2015. At the patient's first visit, mean (SD) age was 56.3 (14.2) years and mean (SD) duration of RA was 12.7 (11.9) years. Average follow-up duration was 5.59 years (range, 1-13). Over time, DAS28-CRP, mHAQ, and RAPID3 scores decreased as the biologic exposure ratio increased. In repeated measures regression models, increased biologic exposure was significantly associated with decreased DAS28-CRP score (β = - 0.647; P 0.001), decreased mHAQ score (β = - 0.096; P 0.001), and decreased RAPID3 score (β = - 0.724; P 0.001) during follow-up. Methotrexate use at baseline predicted decreased DAS28-CRP, mHAQ, and RAPID3 scores during follow-up. Biologic use at baseline predicted increased DAS28-CRP or mHAQ during follow-up.Increased biologic exposure is associated with decreased disease activity, function impairment, and RA severity. Future studies should examine whether earlier initiation of biologics improves patient outcomes in RA.ClinicalTrials.gov , NCT01793103 Key Points • Biologics effectively manage symptoms and disease activity in rheumatoid arthritis (RA), but their long-term effects remain unclear. • In this analysis of longitudinal annual population samples of 1395 RA patients in the Brigham and Women's Rheumatoid Arthritis Sequential Study (BRASS) registry, disease activity, function, and severity scores improved as time on biologic therapy increased. • In repeated measures regression models, time on biologic therapy was a significant predictor of improved outcomes for disease activity, function, and RA severity. • Further studies should examine whether earlier initiation of biologics limits the long-term effect of inflammation on RA outcomes.

Anticitrullinated protein antibody (ACPA) concentration, beyond ACPA positivity, is indicative of more aggressive radiographic progression in patients with rheumatoid arthritis (RA). However, there is limited information on the association of changes in ACPA with resource use measures and/or disease activity measures. We evaluate associations between changes in levels of ACPA and outcomes, including durable medical equipment (DME) use, hospitalizations, and disease activity, in patients with established RA.Patients from the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study who had ACPA measurements at baseline and month 12 were included. Changes in ACPA levels from baseline to month 12 were categorized as a decrease (-10%), no change (-10% to +10%), or increase (+10%). DME use and hospitalizations were assessed twice yearly using patient questionnaires; disease activity was assessed annually. Binary multivariate logistic regression was used to analyze the association between changes in ACPA levels and DME use and hospitalizations; linear regression was used to assess the association with disease activity.Of 840 patients included in the analysis, 291 (34.6%), 266 (31.7%), and 283 (33.7%) had a decrease, no change, or increase in ACPA levels, respectively. A decrease in ACPA levels was associated with a reduction in DME use (adjusted odds ratio [aOR] = 0.64; 95% CI, 0.44-0.93; P = 0.02) and hospitalizations (aOR = 0.62; 95% CI, 0.41-0.95; P = 0.03) versus no change or increase. Adjusted mean changes in disease activity score in 28 joints (C-reactive protein), total and swollen joint counts, and pain scores were significantly greater in patients with decreased ACPA levels versus those with no change or increase (P 0.05).Among patients with RA, reductions in ACPA levels of10% were associated with reductions in DME use, hospitalizations, and disease activity. ClinicalTrials.gov identifier: NCT01793103.

[This corrects the article DOI: 10.1371/journal.pone.0214981.].

Objective To evaluate rheumatoid arthritis (RA) disease activity and risk of RA-associated interstitial lung disease (RA-ILD). Methods We investigated disease activity and risk of RA-ILD using the Brigham RA Sequential Study (BRASS, 2003-2016). All patients were diagnosed as having RA according to accepted criteria. Disease Activity Scores in 28 joints (DAS28) and covariate data were measured prospectively at annual study visits. Diagnosis of RA-ILD was determined by review of images from clinically indicated chest computed tomography scans. We analyzed patients without RA-ILD at baseline. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for RA-ILD, using annually updated DAS28 data, with adjustment for known RA-ILD risk factors (age, sex, smoking status, RA duration, and serologic status). We performed alternative analyses that did not censor at the time of missing DAS28 data and included adjustment for use of methotrexate, use of glucocorticoids, presence of bone erosions, and presence of rheumatoid nodules. Results Among 1,419 participants, the mean ± SD age was 55.8 ± 14.2 years, and 68.6% were seropositive for either cyclic citrullinated peptide or rheumatoid factor. We identified 85 incident cases of RA-ILD during a mean ± SD follow-up duration of 8.9 ± 4.2 years per patient. The moderate/high disease activity group had a multivariable HR of 2.22 (95% CI 1.28-3.82) for RA-ILD compared to the remission/low disease activity group. Risk of RA-ILD increased across disease activity categories: multivariable HR 1.00 (reference) for remission, 1.41 (95% CI 0.61-3.28) for low disease activity, 2.08 (95% CI 1.06-4.05) for moderate disease activity, and 3.48 (95% CI 1.64-7.38) for high disease activity (P for trend = 0.001). For each unit increase in the DAS28, the risk of RA-ILD increased by 35% (95% CI 14-60%). Results were similar in analyses that included follow-up for missing DAS28 data and with adjustment for use of methotrexate, use of glucocorticoids, presence of bone erosions, or presence of rheumatoid nodules. Conclusion Active articular RA was associated with an increased risk of developing RA-ILD. These results suggest that decreasing systemic inflammation may alter the natural history of RA-ILD development.

Objective Patient registries have contributed substantially to progress in clinical research in rheumatic diseases. However, not much is known about how to optimize the patient experience in such registries. We assessed patient views, motivations, and potential barriers towards participation in registry research to better understand how registries can be improved to maximize patient engagement. Methods Focus groups were held with 23 patients (mean ± SD age 59 ± 13 years) from the Boston area and led by a bilingual moderator trained in focus group methodology, using a semistructured moderator guide. Three separate focus groups were conducted to thematic saturation: patients with rheumatoid arthritis (RA) who had registry experience, patients with any chronic illness, and Spanish-speaking patients with RA or osteoarthritis. Patients in the latter 2 groups had no prior registry experience. Focus groups were audiotaped and transcribed. Four researchers independently analyzed transcripts using open data coding to identify themes. A normative group process was used to consolidate and refine themes. Results Seven major themes were identified, including personalization/convenience of data collection, trust and confidentiality, camaraderie, learning about yourself and your disease, altruism, material motivators, and capturing mental health and other elements of the lived experience. We observed distinct differences in the discussion content of the Spanish-speaking patients compared to the English-speaking patients. Conclusion This study identified patient attitudes towards registry research among those with and without prior experience in a registry. The results provide insight into strategies for registry design to maximize patient engagement, which can lead to more robust registry data.

Objective To evaluate associations between achieving guideline‐recommended targets of disease activity, defined by the Disease Activity Score in 28 joints using C‐reactive protein level (DAS28‐CRP)

Purpose This study examined the accuracy of claims-based algorithms to identify smoking against self-reported smoking data. Methods Medicare patients enrolled in the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study were identified. For each patient, self-reported smoking status was extracted from Women's Hospital Rheumatoid Arthritis Sequential Study and the date of this measurement was defined as the index-date. Two algorithms identified smoking in Medicare claims: (i) only using diagnoses and procedure codes and (ii) using anti-smoking prescriptions in addition to diagnoses and procedure codes. Both algorithms were implemented: first, only using 365-days pre-index claims and then using all available pre-index claims. Considering self-reported smoking status as the gold standard, we calculated specificity, sensitivity, positive predictive value, negative predictive value (NPV), and area under the curve (AUC). Results A total of 128 patients were included in this study, of which 48% reported smoking. The algorithm only using diagnosis and procedure codes had the lowest sensitivity (9.8%, 95%CI 2.4%–17.3%), NPV (54.9%, 95%CI 46.1%–63.9%), and AUC (0.55, 95%CI 0.51–0.59) when applied in the period of 365 days pre-index. Incorporating pharmacy claims and using all available pre-index information improved the sensitivity (27.9%, 95%CI 16.6%–39.1%), NPV (60.4%, 95%CI 51.3%–69.5%), and AUC (0.64, 95%CI 0.58–0.70). The specificity and positive predictive value was 100% for all the algorithms tested. Conclusion Claims-based algorithms can identify smokers with limited sensitivity but very high specificity. In the absence of other reliable means, use of a claims-based algorithm to identify smoking could be cautiously considered in observational studies. Copyright © 2016 John Wiley & Sons, Ltd.