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ObjectiveExamination and conventional radiography of joints are unable to precisely evaluate and measure disease activity in rheumatoid arthritis (RA). We quantified joint inflammation using18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) in people with RA to determine if PET-derived uptake variables were correlated with RA disease activity measures.MethodsWe cross-sectionally studied 34 patients with RA in a substudy of the Rheumatoid Arthritis Study of the Myocardium (RHYTHM). All patients underwent18F-FDG-PET scanning with CT for attenuation correction and anatomic co-registration. Linear regression was used to model the associations of disease activity scores with articular FDG uptake, calculated as standardized uptake values (SUVs). Weighted joint volume SUVs (wjSUV) representing 25%, 50%, 75%, and maximum (100%) uptake (wj25SUV, wj50SUV, wj75SUV, and wjMaxSUV, respectively) were calculated as global variables of the total volume of joint inflammation in each patient.ResultsCalculated wj25SUV (Spearman ρ = 0.39,P= 0.04), wj50SUV (ρ = 0.39,P= 0.04), and wj75SUV (ρ = 0.37,P= 0.045) measures were significantly correlated with the number of swollen joints. Similar significant correlations were found for the Simplified Disease Activity Index but not Clinical Disease Activity or Disease Activity Score in 28 joints. No associations were found between articular FDG uptake and nonarticular RA-related variables (ie, disease duration, seropositivity, or RA treatments).ConclusionArticular FDG uptake in patients with RA was significantly correlated with the number of swollen joints but not with biochemical measures of inflammation.

Lumbar spinal stenosis (LSS) is a common reason for spine surgery in which ligamentum flavum is resected. Transthyretin (TTR) amyloid is an often unrecognized and potentially modifiable mechanism for LSS that can also cause TTR cardiac amyloidosis. Accordingly, older adult patients undergoing lumbar spine (LS) surgery were evaluated for amyloid and if present, the precursor protein, as well as comprehensive characterization of the clinical phenotype.A prospective, cohort study in 2 academic medical centers enrolled 47 subjects (age 69 ± 7 years, 53% male) undergoing clinically indicated LS decompression. The presence of amyloid was evaluated by Congo Red staining and in those with amyloid, precursor protein was determined by laser capture microdissection coupled to mass spectrometry (LCM-MS). The phenotype was assessed by disease-specific questionnaires (Swiss Spinal Stenosis Questionnaire and Kansas City Cardiomyopathy Questionnaire) and the 36-question short-form health survey, as well as biochemical measures (TTR, retinol-binding protein, and TTR stability). Cardiac testing included technetium-99m-pyrophosphate scintigraphy, electrocardiograms, echocardiograms, and cardiac biomarkers as well as measures of functional capacity.Amyloid was detected in 16 samples (34% of participants) and was more common in those aged ≥ 75 years of age (66.7%) compared with those75 years (22.3%, p 0.05). LCM-MS demonstrated TTR as the precursor protein in 62.5% of participants with amyloid while 37.5% had an indeterminant type of amyloid. Demographic, clinical, quality-of-life measures, electrocardiographic, echocardiographic, and biochemical measures did not differ between those with and without amyloid. Among those with TTR amyloid (n = 10), one subject had cardiac involvement by scintigraphy.Amyloid is detected in more than a third of older adults undergoing LSS. Amyloid is more common with advancing age and is particularly common in those75 years old. No demographic, clinical, biochemical, or cardiac parameter distinguished those with and without amyloid. In more than half of subjects with LS amyloid, the precursor protein was TTR indicating the importance of pathological assessment.

Objective To assess predictors of subclinical RA-associated interstitial lung disease (RA-ILD) using quantitative lung densitometry (qLD). Methods RA patients underwent multi-detector row CT scanning at baseline and after an average of 39 months. Scans were analysed with qLD for the percentage of lung parenchyma with high attenuation areas (%HAA: the percentage of voxels of –600 to –250 Hounsfield units). Additionally, a pulmonary radiologist calculated an expert radiologist scoring (ERS) for RA-ILD features. Generalized linear models were used to identify indicators of baseline %HAA and predictors of %HAA change. Results Baseline %HAA was assessed in 193 RA patients and 106 had repeat qLD assessment. %HAA was correlated with ERS (Spearman’s rho = 0.261; P 10% of lung parenchyma with high attenuation) included female sex, higher pack-years of smoking, higher BMI and anti-CCP ≥200 units, collectively contributing an area under the receiver operator curve of 0.88 (95% CI 0.81, 0.95). Predictors of %HAA increase, occurring in 49% with repeat qLD, included higher baseline %HAA, presence of mucin 5B (MUC5B) minor allele and absence of HLA-DRB1 shared epitope (area under the receiver operator curve = 0.69; 95% CI 0.58, 0.79). The association of the MUC5B minor allele with %HAA change was higher among men and those with higher cumulative smoking. Within the group with increased %HAA, anti-CCP level was significantly associated with a greater increase in %HAA. Conclusions %HAA, assessed with qLD, was linked to several known risk factors for RA-ILD and may represent a more quantitative method to identify RA-ILD and track progression than expert radiologist interpretation.

Objective We determined the prevalence of sarcopenic obesity in patients with RA using multiple methods and assessed associations with physical functioning. Methods This study evaluated data from three RA cohorts. Whole-body dual-energy absorptiometry (DXA) measures of appendicular lean mass index (ALMI, kg/m2) and fat mass index (FMI) were converted to age, sex and race-specific Z-Scores and categorized using a recently validated method and compared it to a widely-used existing method. The prevalence of body composition abnormalities in RA was compared with two reference populations. In the RA cohorts, associations between body composition and change in the HAQ and the Short Physical Performance Battery (SPPB) in follow-up were assessed using linear and logistic regression, adjusting for age, sex, race and study. Results The prevalence of low lean mass and sarcopenic obesity was higher in patients with RA (14.2; 12.6%, respectively) compared with the reference population cohorts (7–10%; 4–4.5%, respectively, all P Conclusion RA patients had higher rates of low lean mass and sarcopenic obesity than the general population. The recently validated methods characterized body composition changes differently from traditional methods and were more strongly associated with physical function.

ObjectiveRecent large-scale randomised trials demonstrate that immunomodulators reduce cardiovascular (CV) events among the general population. However, it is uncertain whether these effects apply to rheumatoid arthritis (RA) and if certain treatment strategies in RA reduce CV risk to a greater extent.MethodsPatients with active RA despite use of methotrexate were randomly assigned to addition of a tumour necrosis factor (TNF) inhibitor (TNFi) or addition of sulfasalazine and hydroxychloroquine (triple therapy) for 24 weeks. Baseline and follow-up18F-fluorodeoxyglucose-positron emission tomography/CT scans were assessed for change in arterial inflammation, an index of CV risk, measured as an arterial target-to-background ratio (TBR) in the carotid arteries and aorta.Results115 patients completed the protocol. The two treatment groups were well balanced with a median age of 58 years, 71% women, 57% seropositive and a baseline disease activity score in 28 joints of 4.8 (IQR 4.0, 5.6). Baseline TBR was similar across the two groups. Significant TBR reductions were observed in both groups—ΔTNFi: −0.24 (SD=0.51), Δtriple therapy: −0.19 (SD=0.51)—without difference between groups (difference in Δs: −0.02, 95% CI −0.19 to 0.15, p=0.79). While disease activity was significantly reduced across both treatment groups, there was no association with change in TBR (β=0.04, 95% CI −0.03 to 0.10).ConclusionWe found that addition of either a TNFi or triple therapy resulted in clinically important improvements in vascular inflammation. However, the addition of a TNFi did not reduce arterial inflammation more than triple therapy.Trial registration numberNCT02374021.

Background Obesity is associated with restrictive ventilatory defects and a faster rate of decline in FVC. This association is not exclusively mediated by mechanical factors and may reflect direct pulmonary injury by adipose-derived mediators. Research Question Is adipose tissue involved in the pathogenesis of interstitial lung disease (ILD)? Study Design and Methods We evaluated the association of CT measures of pericardial, abdominal visceral, and abdominal subcutaneous adipose tissue with high-attenuation areas (HAAs) and interstitial lung abnormalities (ILAs) in a large multicenter cohort study of community-dwelling adults, using multivariable-adjusted models. We secondarily evaluated the association of adipose depot size with FVC and biomarkers of obesity and inflammation. Results In fully adjusted models, every doubling in pericardial adipose tissue volume was associated with a 63.4-unit increase in HAA (95% CI, 55.5-71.3), 20% increased odds of ILA (95% CI, –2% to 50%), and a 5.5% decrease in percent predicted FVC (95% CI, –6.8% to –4.3%). IL-6 levels accounted for 8% of the association between pericardial adipose tissue and HAA. Every doubling in visceral adipose tissue area was associated with a 41.5-unit increase in HAA (95% CI, 28.3-54.7), 30% increased odds of ILA (95% CI, –10% to 80%), and a 5.4% decrease in percent predicted FVC (95% CI, –6.6% to –4.3%). IL-6 and leptin accounted for 17% and 18%, respectively, of the association between visceral adipose tissue and HAA. Interpretation Greater amounts of pericardial and abdominal visceral adipose tissue were associated with CT measures of early lung injury and lower FVC in a cohort of community-dwelling adults. Adipose tissue may represent a modifiable risk factor for ILD.

Introduction Global prevalence estimates for chronic kidney disease (CKD) in rheumatoid arthritis (RA) vary. This study assessed real-world prevalence estimates of renal impairment, based on estimated glomerular filtration rate (eGFR), among commercially insured patients with RA in the United States (US). Methods In this retrospective cohort study, we used administrative claims data from the HealthCore Integrated Research Database (HIRD®) between January 2013 and December 2018. Adult patients with ≥ 2 claims for RA and ≥ 2 serum creatinine (SCr) measurements ≥ 90 days apart on or after the index date were included. eGFR was calculated per the Modification of Diet in Renal Disease equation. Prevalence of eGFR-based renal impairment was estimated for the overall RA population and for two subgroups: patients on advanced therapies (biologic disease-modifying antirheumatic drugs/tofacitinib) and patients stratified based on health plan types. Results Among 128,062 patients with ≥ 2 RA claims, 42,173 had qualifying SCr measurements, 16,197 were on advanced RA therapies, and 4911 had Medicare Advantage or Supplemental plus Part D coverage. For the overall population and the subgroup on advanced therapies, mild renal impairment was observed in 52% and 51%, moderate renal impairment in 9% and 7%, and severe renal impairment in 0.5% and 0.3% of patients, respectively. Moderate and severe renal impairment was more prevalent in the Medicare Advantage/Supplemental plus Part D population compared to the commercial coverage population. Conclusions Approximately 7–10% of commercially insured adult patients in the US with RA had moderate or severe renal impairment. Assessment of renal function is an important consideration for safe treatment.

Individuals with rheumatoid arthritis (RA) are at increased risk for atherosclerotic cardiovascular disease (ASCVD) events relative to the general population, potentially mediated by atherosclerotic plaques that are more inflamed and rupture prone. We sought to address whether RA immunomodulators reduce vascular inflammation, thereby reducing ASCVD risk, and whether such reduction depends on the type of immunomodulator. The TARGET (Treatments Against RA and Effect on 18-Fluorodeoxyglucose [18 F-FDG] Positron Emission Tomography [PET]/Computed Tomography [CT]) trial (NCT02374021) will enroll 150 patients with RA with active disease and an inadequate response to methotrexate. Participants will be randomized to add either a tumor necrosis factor (TNF) inhibitor (etanercept or adalimumab) or sulfasalazine and hydroxychloroquine to their background methotrexate. Participants will undergo full-body 18 F-FDG-labelled PET scanning at baseline and after 6 months. Efficacy and safety evaluations will occur every 6 weeks, with therapy modified in a treat-to-target approach. The primary outcome is the comparison of change in arterial inflammation in the wall of the aorta and carotid arteries between the randomized treatment groups, specifically, the change in the mean of the maximum target-to-background ratio of arterial 18 F-FDG uptake in the most diseased segment of either the aorta and carotid arteries. A secondary analysis will compare the effects of achieving low disease activity or remission with those of moderate to high disease activity on vascular inflammation. The TARGET trial will test, for the first time, whether RA treatments reduce arterial inflammation and whether such reduction differs according to treatment strategy with either TNF inhibitors or a combination of nonbiologic disease-modifying antirheumatic drugs.

Examination and conventional radiography of joints are unable to precisely evaluate and measure disease activity in rheumatoid arthritis (RA). We quantified joint inflammation usingWe cross-sectionally studied 34 patients with RA in a substudy of the Rheumatoid Arthritis Study of the Myocardium (RHYTHM). All patients underwentCalculated wj25SUV (Spearman ρ = 0.39,Articular FDG uptake in patients with RA was significantly correlated with the number of swollen joints but not with biochemical measures of inflammation.

Since the first outbreak of Coronavirus Disease-2019 (COVID-19) in January 2020, the medical community has been pursuing effective countermeasures. Early in the pandemic, several small clinical and in vitro studies from France and China reported on the efficacy of chloroquine (CQ) and hydroxychloroquine (HCQ) against SARS-CoV-2 infections, which generated global attention towards these decades-old antimalarials (AM) and heralded numerous studies investigating their role in treating COVID-19. Despite several observational studies early in the pandemic affirming their beneficial role in treating COVID-19, 12 clinical studies reported no mortality benefits for CQ/HCQ in COVID-19 patients. The excitement over CQ/HCQ was ultimately quenched after three large randomized clinical trials, the COALITION-I trial in Brazil, the RECOVERY trial in the United Kingdom (UK), and the SOLIDARITY trial from World Health Organization (WHO) consistently reported no beneficial effects for CQ/HCQ in hospitalized COVID-19 patients. While initial studies suggested that CQ/HCQ might have a role in treating the early phases of infection, the results from three rigorously designed studies investigating their role in non-hospitalized COVID-19 patients were equivocal and inconsistent. Here we review the major social events related to the therapeutic use of CQ/HCQ in COVID-19, and the data from selected clinical studies evaluating their efficacy in hospitalized and non-hospitalized COVID-19 patients along with the major safety concerns.

To develop updated American College of Rheumatology/American Association of Hip and Knee Surgeons guidelines for the perioperative management of disease-modifying medications for patients with rheumatic diseases, specifically those with inflammatory arthritis (IA) and those with systemic lupus erythematosus (SLE), undergoing elective total hip arthroplasty (THA) or elective total knee arthroplasty (TKA).We convened a panel of rheumatologists, orthopedic surgeons, and infectious disease specialists, updated the systematic literature review, and included currently available medications for the clinically relevant population, intervention, comparator, and outcomes (PICO) questions. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology to rate the quality of evidence and the strength of recommendations using a group consensus process.This guideline updates the 2017 recommendations for perioperative use of disease-modifying antirheumatic therapy, including traditional disease-modifying antirheumatic drugs, biologic agents, targeted synthetic small-molecule drugs, and glucocorticoids used for adults with rheumatic diseases, specifically for the treatment of patients with IA, including rheumatoid arthritis and spondyloarthritis, those with juvenile idiopathic arthritis, or those with SLE who are undergoing elective THA or TKA. It updates recommendations regarding when to continue, when to withhold, and when to restart these medications and the optimal perioperative dosing of glucocorticoids.This updated guideline includes recently introduced immunosuppressive medications to help decision-making by clinicians and patients regarding perioperative disease-modifying medication management for patients with IA and SLE at the time of elective THA or TKA.

We read with great interest the paper by Putman et al.(1). The publication reviews data from 45 studies evaluating hydroxychloroquine (HCQ), chloroquine (CQ), anakinra and anti-IL-6 therapies in COVID-19. Except anakinra, none of the other therapies decreased the risk of death in hospitalized COVID-19 patients. We would like to discuss the evidence evaluating the role of HCQ in the prophylaxis of SARS-CoV-2 infections. The in-vitro antiviral effect of antimalarials suggested a role in preventing disease progression(2).

Objective To examine the impact of autoimmune disease on the composite outcome of intensive care unit admission, intubation, or death, from COVID-19 in hospitalized patients. Methods Retrospective cohort study of 186 patients hospitalized with COVID-19 between March 1st–April 15th, 2020 at New York-Presbyterian Hospital/Columbia University Irving Medical Center. The cohort included 62 patients with autoimmune disease and 124 age- and sex- matched controls. The primary outcome was a composite of intensive care unit admission, intubation, and death, with secondary outcome assessing time to in-hospital death. Baseline demographics, comorbidities, medications, vital signs, and laboratory values were collected. Conditional logistic regression and Cox proportional hazards regression were used to assess the association between autoimmune disease and clinical outcomes. Results Patients with autoimmune disease were more likely to have at least one comorbidity (25.8% vs. 12.9%, p=0.03), take chronic immunosuppressive medications (66.1% vs. 4.0%, p Conclusion Among patients hospitalized with COVID-19, individuals with autoimmune disease did not have an increased risk of a composite outcome of intensive care unit admission, intubation, or death. Kaplan-Meier curve examining death, stratified by the presence or absence of autoimmune disease in all 186 patients, with 16 patients censored as of 4/29/2020

OBJECTIVE Citrullinated proteins are hallmark targets of autoantibodies in rheumatoid arthritis (RA). Our study was undertaken to determine the effect of autocitrullination on the recognition of peptidylarginine deiminases (PADs) 2 and 4 by autoantibodies in RA. METHODS Autocitrullination sites in PAD2 and PAD4 were determined by mass spectrometry and literature review. Antibodies against native and autocitrullinated PADs in 184 patients with RA were detected by enzyme-linked immunosorbent assay. Linear regression analysis, outlier calculations, and competition assays were performed to evaluate antibody reactivity to native and citrullinated PADs. RESULTS Autocitrullination of PAD2 and PAD4 was detected in 16 (48%) of 33 arginine residues and 7 (26%) of 27 arginine residues, respectively. Despite robust autocitrullination, autoantibodies bound similarly to native and citrullinated PAD2 or PAD4 (ρ = 0.927 and ρ = 0.903, respectively; each P < 0.0001). Although subsets of anti-PAD-positive sera were identified as exhibiting preferential recognition of native or citrullinated PAD2 (40.5% or 4.8%, respectively) or PAD4 (11.7% or 10.4%, respectively), competition assays confirmed that the majority of anti-PAD reactivity was attributed to a pool of autoantibodies that bound irrespective of citrullination status. CONCLUSION Autocitrullination does not affect autoantibody reactivity to PADs in the majority of patients with RA, demonstrating that anti-PAD antibodies are distinct from anti-citrullinated protein antibodies in their dependence on citrullination for binding.

Peptidylarginine deiminases (PADs) have an important role in the pathogenesis of rheumatoid arthritis (RA) owing to their ability to generate citrullinated proteins - the hallmark autoantigens of RA. Of the five PAD enzyme isoforms, PAD2 and PAD4 are the most strongly implicated in RA at both genetic and cellular levels, and PAD inhibitors have shown therapeutic efficacy in mouse models of inflammatory arthritis. PAD2 and PAD4 are additionally targeted by autoantibodies in distinct clinical subsets of patients with RA, suggesting anti-PAD antibodies as possible biomarkers for RA diagnosis and prognosis. This Review weighs the evidence that supports a pathogenic role for PAD enzymes in RA as both promoters and targets of the autoimmune response, as well as discussing the mechanistic and therapeutic implications of these findings in the wider context of RA pathogenesis. Understanding the origin and consequences of dysregulated PAD enzyme activity and immune responses against PAD enzymes will be important to fully comprehend the pathogenic mechanisms involved in this disease and for the development of novel strategies to treat and prevent RA.

Background Adipokines have inflammatory and fibrotic properties that may be critical in interstitial lung disease (ILD). We examined associations of serum adipokine levels with CT imaging-based measures of subclinical ILD and lung function among community-dwelling adults. Methods A subset of the original Multi-Ethnic Study of Atherosclerosis cohort (n = 1,968) had adiponectin, leptin, and resistin measured during follow-up visits (2002-2005). We used regression models to examine associations of adiponectin, leptin, and resistin levels with (1) high-attenuation areas (HAAs) from CT scans (2004-2005, n = 1,144), (2) interstitial lung abnormalities (ILAs) from CT scans (2010-2012, n = 872), and (3) FVC from spirometry (2004-2006, n = 1,446). We used –(1/HAA2), which we denoted with H, to model HAA as our outcome to meet model assumptions. Results Higher adiponectin was associated with lower HAA on CT imaging among adults with a BMI ≥ 25 kg/m2 (P for BMI interaction = .07). Leptin was more strongly associated with ILA among never smokers compared with ever smokers (P for smoking interaction = .004). For every 1-SD increment of log-transformed leptin, the percent predicted FVC was 3.8% lower (95% CI, −5.0 to −2.5). Higher serum resistin levels were associated with greater HAA on CT in a fully adjusted model. For every 1-SD increment of log-transformed resistin there was an increase in H of 14.8 (95% CI, 3.4-26.3). Conclusions Higher adiponectin levels were associated with lower HAA on CT imaging among adults with a higher BMI. Higher leptin and resistin levels were associated with lower FVC and greater HAA, respectively.

ObjectivesEvaluate risk of major adverse cardiovascular events (MACE) with tofacitinib versus tumour necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis (RA) with or without a history of atherosclerotic cardiovascular disease (ASCVD) in ORAL Surveillance.MethodsPatients with RA aged ≥50 years with ≥1 additional CV risk factor received tofacitinib 5 mg or 10 mg two times per day or TNFi. Hazard rations (HRs) were evaluated for the overall population and by history of ASCVD (exploratory analysis).ResultsRisk of MACE, myocardial infarction and sudden cardiac death were increased with tofacitinib versus TNFi in ORAL Surveillance. In patients with history of ASCVD (14.7%; 640/4362), MACE incidence was higher with tofacitinib 5 mg two times per day (8.3%; 17/204) and 10 mg two times per day (7.7%; 17/222) versus TNFi (4.2%; 9/214). HR (combined tofacitinib doses vs TNFi) was 1.98 (95% confidence interval (CI) 0.95 to 4.14; interaction p values: 0.196 (for HR)/0.059 (for incidence rate difference)). In patients without history of ASCVD, MACE HRs for tofacitinib 5 mg two times per day (2.4%; 30/1251) and 10 mg two times per day (2.8%; 34/1234) versus TNFi (2.3%; 28/1237) were, respectively, 1.03 (0.62 to 1.73) and 1.25 (0.76 to 2.07).ConclusionsThis post hoc analysis observed higher MACE risk with tofacitinib versus TNFi in patients with RA and history of ASCVD. Among patients without history of ASCVD, all with prevalent CV risk factors, MACE risk did not appear different with tofacitinib 5 mg two times per day versus TNFi. Due to the exploratory nature of this analysis and low statistical power, we cannot exclude differential MACE risk for tofacitinib 5 mg two times per day versus TNFi among patients without history of ASCVD, but any absolute risk excess is likely low.Trial registration numberNCT02092467.

We determined associations between adipokines and abnormal body composition in patients with rheumatoid arthritis (RA).Combining data from three RA cohorts, whole-body dual-energy absorptiometry measures of appendicular lean mass and fat mass indices were converted to age-, sex-, and race- and ethnicity-specific Z scores. Lean mass relative to fat mass was determined based on prior methods. Independent associations between body composition profiles and circulating levels of adiponectin, leptin, and fibroblast growth factor (FGF)-21 were assessed using linear and logistic regression models adjusting for demographic characteristics and study cohort. We also determined the improvement in the area under the curve (AUC) for prediction of low lean mass when adipokines were added to predictive models that included clinical factors such as demographic characteristics, study, and body mass index (BMI).Among 419 participants, older age was associated with higher levels of all adipokines, whereas higher C-reactive protein level was associated with lower adiponectin levels and higher FGF-21 levels. Greater fat mass was strongly associated with lower adiponectin levels and higher leptin and FGF-21 levels. Higher levels of adiponectin, leptin, and FGF-21 were independently associated with low lean mass. The addition of adiponectin and leptin levels to regression models improved prediction of low lean mass when combined with demographic characteristics, study, and BMI (AUC 0.75 vs. 0.66).Adipokines are associated with both excess adiposity and low lean mass in patients with RA. Improvements in the prediction of body composition abnormalities suggest that laboratory screening could help identify patients with altered body composition who may be at greater risk of adverse outcomes.

Background Hydroxychloroquine (HCQ) is a cornerstone therapy for systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). However, reports of its use and subsequent fatal arrhythmias in patients with coronavirus disease 19 (COVID-19) have raised concern regarding its cardiovascular (CV) safety. Therefore, we examined the relationship between HCQ use and corrected QT (QTc) length in SLE and RA patients without clinical CV disease (CVD). Methods SLE patients from the Columbia University Lupus Cohort registry (n = 352) and two RA cohorts (n = 178; ESCAPE-RA and RHYTHM-RA) with electrocardiograms (ECGs) collected as part of study data were analyzed. RA cohort participants were recruited from tertiary referral centers with additional referrals from community rheumatologists, while SLE subjects originated from the Columbia University Lupus Cohort. All patients met American College of Rheumatology (ACR) classification criteria for SLE or RA and lacked known CVD. The exposure of interest was HCQ use and main outcome measure was QTc length [continuous or categorical (≥ 440 ms and ≥ 500 ms)]. Results Of the combined SLE and RA cohorts (n = 530), 70% were HCQ users and 44% had a QTc ≥ 440 ms. The adjusted mean QTc length was comparable between HCQ users vs non-users (438 ms vs 437 ms). In multivariable logistic models, HCQ use was not a significant predictor of a QTc ≥ 440 ms for the entire cohort (OR 0.77; 95% CI 0.48–1.23; p = 0.27). Importantly, a QTc ≥ 500 ms was inversely associated with HCQ use and not associated with arrhythmias or deaths. A significant interaction was found between HCQ use and use of anti-psychotics. Ultimately, the use of HCQ combined with any QTc prolonging medication as a group was associated with a QTc length (434 ms; 95% CI 430, 439) which was comparable to that of use of HCQ alone (433 ms; 95% CI 429-437). Conclusion In a combined cohort of SLE and RA patients without clinical CVD, adjusted QTc length was comparable between HCQ and non-HCQ users, supporting its CV safety in patients with rheumatic diseases.

Background:Upadacitinib (UPA) is an oral Janus kinase inhibitor approved for rheumatoid arthritis (RA). The safety and efficacy of UPA has been evaluated across a spectrum of patients (pts) with RA in the phase 3 SELECT clinical program.1,2Objectives:To describe long-term laboratory profiles (cutoff date: June 30, 2020) associated with exposure to UPA, adalimumab (ADA), and methotrexate (MTX) in pts with RA treated in the SELECT trials.Methods:Data were analyzed from 6 randomized controlled UPA RA trials.1,2 The proportions of pts experiencing potentially clinically significant laboratory changes at a single time point were summarized for the following groups: pooled UPA 15 mg once daily (QD; UPA15; 6 trials), pooled UPA 30 mg QD (UPA30; 4 trials), ADA 40 mg every other week (EOW; 1 trial), and MTX monotherapy (1 trial). Pts received UPA with/without background conventional synthetic disease-modifying antirheumatic drugs. Treatment-emergent adverse events are reported as exposure-adjusted event rates (events/100 pt-years [E/100 PY]). Toxicity was graded per OMERACT criteria, or NCI CTCAE for creatine phosphokinase (CPK) and creatinine.Results:4413 pts received ≥1 dose of UPA (UPA15, n=3209; UPA30, n=1204). Exposures were comparable between treatment groups (Table). Proportions of pts with Grade (Gr) 3 and 4 decreases in hemoglobin were highest with UPA30 and MTX (Table). Rates of anemia, as reported by the investigator, were comparable between UPA15, ADA, and MTX groups (Figure); the frequency of UPA-treated pts who discontinued due to anemia was low in all arms. Gr 3 and 4 decreases in neutrophils and lymphocytes with UPA were dose-dependent and higher vs ADA or MTX. Discontinuations due to neutropenia and lymphopenia were rare (Table 1.Pts with potentially clinically significant laboratory changesVariable, n (%)MTX monotherapy (n=314; 637.4 PY)ADA 40 mg EOW (n=579; 1051.8 PY)UPA 15 mg QD (n=3209; 7023.8 PY)UPA 30 mg QD (n=1204; 3091.6 PY)Mean (SD) exposure, weeks106 (67)95 (70)114 (64)134 (66)Median (range) exposure, weeks144 (1, 221)118 (2, 231)136 (0, 232)160 (0, 231)Hemoglobin, g/LGr 3 (70–28a (9.0)24b (4.2)254d (7.9)169f (14.2)Gr 4 (16a (5.1)16b (2.8)101d (3.2)78f (6.5)Neutrophils, 109/LGr 3 (0.5–3a (1.0)3b (0.5)40d (1.2)37g (3.1)Gr 4 (1a (0.3)1b (0.2)10d (0.3)5g (0.4)Lymphocytes, 109/LGr 3 (0.5–74a (23.7)53b (9.2)802d (25.1)423g (35.5)Gr 4 (5a (1.6)3b (0.5)75d (2.3)47g (3.9)ALT, U/LGr 3 (3.0–8.0 × ULN)26a (8.3)13c (2.3)152e (4.8)71h (5.9)Gr 4 (>8.0 × ULN)5a (1.6)4c (0.7)26e (0.8)10h (0.8)AST, U/LGr 3 (3.0–8.0 × ULN)15a (4.8)9c (1.6)101e (3.2)36h (3.0)Gr 4 (>8.0 × ULN)1a (0.3)5c (0.9)18e (0.6)8h (0.7)CPK, U/LGr 3 (>5.0–10.0 × ULN)2a (0.6)3c (0.5)65e (2.0)36i (3.0)Gr 4 (>10.0 × ULN)0a (0)3c (0.5)27e (0.8)15i (1.3)Creatinine, μmol/LGr 3 (>3.0–6.0 × ULN)0a (0)1c (0.2)3e (2j (0.2)Gr 4 (>6.0 × ULN)0a (0)4c (0.7)8e (0.3)1j (an=312. bn=576. cn=577. dn=3201. en=3199. fn=1193. gn=1192. hn=1195. in=1196. jn=1197ULN, upper limit of normalConclusion:This long-term analysis of UPA-treated pts with RA showed dose-dependent relationships for several laboratory abnormalities. Incidences of these with UPA15 were typically higher than with ADA but similar to MTX, except for increased CPK elevations. Treatment discontinuations due to laboratory abnormalities were infrequent and similar across all treatment groups.References:[1]Tanaka Y. Mod Rheumatol 2020;30:779–87; 2. Rubbert-Roth A, et al. N Engl J Med 2020;383:1511–21.Acknowledgements:AbbVie funded this study; contributed to its design; participated in data collection, analysis, and interpretation of the data; and participated in the writing, review, and approval of the abstract. No honoraria or payments were made for authorship. Medical writing support was provided by Russell Craddock, PhD, of 2 the Nth (Cheshire, UK), and was funded by AbbVie.Disclosure of Interests:Christina Charles-Schoeman Consultant of: AbbVie, Gilead, Pfizer, and Sanofi/Regeneron, Grant/research support from: AbbVie, Bristol-Myers Squibb, and Pfizer, Jon T Giles Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, Gilead, Pfizer, and UCB, Grant/research support from: Pfizer, Nancy Lane Consultant of: Amgen, Mallinckrodt, Pfizer, and Roche, Ernest Choy Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Chugai, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, Regeneron, Roche, Sanofi, and UCB, Consultant of: AbbVie, Amgen, Biocon, Biogen, Chugai, Eli Lilly, Gilead, Janssen, Merck Serono, Novartis, Pfizer, Regeneron, Roche, R-Pharm, and Sanofi, Grant/research support from: Bio-Cancer, Biogen, Novartis, Pfizer, Roche, Sanofi, and UCB, Daniel Furst Speakers bureau: AbbVie, Continuing Medical Education, and Novartis, Consultant of: Actelion, Amgen, Bristol-Myers Squibb, Corbus, Galapagos, Novartis, and Pfizer, Grant/research support from: Actelion, Amgen, Bristol-Myers Squibb, Corbus, Galapagos, GSK, NIH, Novartis, Pfizer, Roche/Genentech, and Sanofi, Jiří Vencovský Speakers bureau: AbbVie, Biogen, MSD, Pfizer, Roche, Sanofi, and UCB, Consultant of: AbbVie, Boehringer Ingelheim, Eli Lilly, Gilead, and Octapharma, Anthony G Wilson: None declared, Gerd Rüdiger Burmester Speakers bureau: AbbVie, Eli Lilly, Gilead, Janssen, MSD, Pfizer, Roche, and UCB, Consultant of: AbbVie, Eli Lilly, Gilead, Janssen, MSD, Pfizer, Roche, and UCB, Tim Shaw Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Yanna Song Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Heidi Camp Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Nasser Khan Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Jillian Yee Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Samuel Anyanwu Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Iain McInnes Consultant of: AbbVie, Celgene, Janssen, Novartis, and UCB, Grant/research support from: Celgene, Janssen, Novartis, Pfizer, Roche, and UCB

Background:Upadacitinib (UPA) is an oral Janus kinase (JAK) inhibitor engineered to have greater selectivity for JAK1 vs JAK2, JAK3, and tyrosine kinase 2, and is approved for the treatment of RA. Across 2 double-blind, placebo (PBO)-controlled Phase 3 studies of UPA in patients with RA, after an initial increase through Week 8, lipid levels remained stable up to Week 24.1,2 Previous studies of JAK or IL-6 receptor inhibitors have reported a negative correlation between changes in lipid levels and RA disease activity.3,4Objectives:To determine the relationship between changes in lipid levels and disease activity outcomes in patients with RA treated with UPA.Methods:Patients with RA and an inadequate response to conventional synthetic/biologic DMARDs (cs/bDMARD-IR) from SELECT-NEXT/SELECT-BEYOND, respectively, were randomized to receive UPA 15 mg once daily (QD), UPA 30 mg QD, or PBO for 12 weeks followed by an extension of up to 5 years; patients randomized to PBO switched to UPA 15 or 30 mg after 12 weeks. Spearman correlations of maximum changes from baseline (BL) through Week 12 in fasting-state lipid levels (low- and high-density lipoprotein cholesterol [LDL-C; HDL-C], and total cholesterol [TC]) with clinical disease activity outcomes measured by change from BL in Clinical Disease Activity Index (CDAI), DAS of 28 joints using CRP (DAS28[CRP]), tender/swollen joint count in 28 joints (TJC28/SJC28), and pain by visual analog scale (VAS) at Weeks 12 and 24, were determined. Spearman correlations of maximum changes from BL in lipid levels and CRP through Week 12 were also determined.Results:Available fasting samples from 1,160 pooled patients (UPA 15 mg, n=386; UPA 30 mg, n=384; PBO, n=390) were included. Modest, but statistically significant, negative correlations were observed between maximum changes from BL in TC through Week 12 and change from BL in CDAI, DAS28(CRP), SJC28, and pain (VAS) at Week 12 with UPA 15 or 30 mg (Figure 1); similar trends were observed at Week 24. Significant correlations between changes in LDL-C and HDL-C and disease activity outcomes were also observed, but were not consistent across UPA doses and time points. No significant correlations were noted between changes in lipid levels and disease activity outcomes in the PBO group. Statistically significant weak negative relationships were observed between maximum changes from BL in lipid levels and CRP levels through Week 12 with UPA 15 mg (HDL-C and TC) or UPA 30 mg (LDL-C and TC) (Table 1).Conclusion:In this large pooled data set of patients receiving UPA, increases in lipid levels showed modest, but statistically significant, correlations with improvement in clinical disease activity outcomes in patients with cs/bDMARD-IR RA. These results add to evidence suggesting a relationship between systemic inflammation and lipid metabolism in patients with RA, which is modifiable with effective interventions, and reinforce the importance of monitoring for hyperlipidemia in these patients.References:[1]Burmester GR, et al. Lancet 2018;391:2503–12.[2]Genovese MC, et al. Lancet 2018;391:2513–24.[3]Kremer JM, et al. Arthritis Rheumatol 2017;69:943–52.[4]Cacciapaglia F, et al. Mediators Inflamm 2018;2018:2453265.Table 1.Spearman correlation of maximum changes from BL in lipid levels through Week 12 with maximum change from BL in CRP through Week 12UPA 15 mg QDUPA 30 mg QDPBOLDL-C-0.099 (n=303)-0.174** (n=302)-0.053 (n=303)HDL-C-0.184** (n=305)-0.087 (n=304)-0.024 (n=303)TC-0.189*** (n=305)-0.236*** (n=304)-0.056 (n=303)**pHDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoproteincholesterol; PBO, placebo; QD, once daily; TC, total cholesterol; UPA, upadacitinibAcknowledgements:AbbVie funded this study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship. Medical writing assistance was provided by Frances Smith, PhD, of 2 the Nth, which was funded by AbbVie.Disclosure of Interests:Christina Charles-Schoeman Consultant of: AbbVie, Gilead, Pfizer, and Regeneron-Sanofi., Grant/research support from: AbbVie, Bristol-Myers Squibb, and Pfizer, Jon T Giles Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, and Gilead, Grant/research support from: Pfizer, Nancy Lane Speakers bureau: Amgen and Mallinckrodt, Consultant of: Amgen, Mallinckrodt, Pfizer, and Roche, Ernest Choy Speakers bureau: AbbVie, Amgen, AstraZeneca, Bio-Cancer, Biogen, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Chugai Pharma, Eli Lilly, Ferring Pharmaceuticals, GlaxoSmithKline, Hospira, Janssen, Merck Sharp & Dohme, Napp, Novimmune, Novartis, ObsEva, Pfizer, Regeneron, Roche, R-Pharm, Sanofi, SynAct Pharma, Synovate, Tonix, and UCB, Grant/research support from: AbbVie, Amgen, AstraZeneca, Bio-Cancer, Biogen, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Chugai Pharma, Eli Lilly, Ferring Pharmaceuticals, GlaxoSmithKline, Hospira, Janssen, Merck Sharp & Dohme, Napp, Novimmune, Novartis, ObsEva, Pfizer, Regeneron, Roche, R-Pharm, Sanofi, SynAct Pharma, Synovate, Tonix, and UCB, Heidi Camp Shareholder of: AbbVie, Employee of: AbbVie, Yanna Song Shareholder of: AbbVie, Employee of: AbbVie, Samuel Anyanwu Shareholder of: AbbVie, Employee of: AbbVie, Iain McInnes Consultant of: AbbVie, Celgene, Janssen, Novartis, and UCB, Grant/research support from: Celgene, Janssen, Novartis, Pfizer Inc., Roche, and UCB

OBJECTIVE Rheumatoid arthritis (RA) patients with the lowest circulating low-density lipoprotein (LDL) concentrations are at heightened risk of cardiovascular events. However, the atherosclerosis burden within this subgroup is unknown. METHODS RA patients pooled from 4 cohort studies of cardiovascular disease (CVD; n = 546) were compared with non-RA controls from the Multi-Ethnic Study of Atherosclerosis (n = 5,279). Those taking lipid-lowering medications were excluded. Differences in cardiac computed tomography-derived Agatston coronary artery calcium (CAC) scores between the RA and control groups were compared across strata of LDL concentration. RESULTS Among those with low LDL concentrations ( 4-fold higher for RA patients than for controls (18.6 versus 4.6 Agatston units, respectively; P < 0.001), a difference significantly greater than that in any other LDL concentration stratum except LDL concentration ≥160 mg/dl. Similarly, 32% of the RA patients with low LDL concentration had a CAC score of ≥100 Agatston units compared with only 7% of controls in the same LDL concentration stratum (odds ratio 5.97; P < 0.001), a difference significantly greater than that in all of the other LDL concentration strata. Low LDL concentration was most strongly associated with higher CAC score among RA patients who were white, had ever smoked, or were not obese. Other than a higher frequency of current smokers, RA patients with low LDL concentrations did not have more CVD risk factors or higher measures of RA disease activity or severity than RA patients with higher LDL concentrations. CONCLUSION RA patients with low LDL concentration may represent a group for whom heightened screening and prevention of atherosclerotic CVD is appropriate.

Objectives Hydroxychloroquine (HCQ) is a key therapy in systemic lupus erythematosus (SLE). Medication non-adherence is reported in up to 80% of lupus patients and results in increased morbidity, mortality, and health care utilization. HCQ levels are a sensitive and reliable method to assess medication adherence. Our study evaluated the role of HCQ level measurement in routine clinical care and its association with disease activity in a predominantly Hispanic population. Methods SLE patients from the Columbia University Lupus cohort treated with HCQ for ≥ 6 months and reporting medication adherence were included. HCQ levels were measured by whole blood high performance liquid chromatography. Non-adherence was defined as an HCQ level Results One hundred and eight patients were enrolled; the median age was 38 years, 91% were female, and 63% were Hispanic. The median SLEDAI-2K was 4.3 (0–20). Forty-one percent of patients had an HCQ level Conclusion HCQ levels

PURPOSE: Aromatase inhibitors (AIs) are associated with musculoskeletal symptoms and risk of developing carpal tunnel syndrome (CTS), which can impair quality of life and prompt treatment discontinuation. The incidence of CTS and clinical utility of diagnostic tests such as 2-point discrimination (2-PD) have not been prospectively examined among women receiving AIs. METHODS: Postmenopausal women with stage 0-III hormone receptor-positive breast cancer who were enrolled in a randomized clinical trial investigating adjuvant AIs (Exemestane and Letrozole Pharmacogenetics, ELPh) underwent prospective evaluation of 2-PD with the Disc-criminator™ (sliding aesthesiometer) and completed a CTS questionnaire at baseline, 3, 6, and 12 months, following initiation of AI. Changes in mean 2-PD were analyzed with multivariable mixed effects modelling. A p value < 0.05 was considered statistically significant. RESULTS: Of 100 women who underwent baseline 2-PD testing, CTS was identified by questionnaire in 11% at baseline prior to AI initiation. Prevalence of CTS at any time in the first year was 26%. A significant increase in worst 2-PD score was observed from baseline to 3 months (3.7 mm to 3.9 mm, respectively, p = 0.03) when adjusted for age, prior chemotherapy, randomized treatment assignment, and diabetes. There were no significant differences in treatment discontinuation due to CTS between the arms. CONCLUSION: For women receiving adjuvant AI, 2-PD scores were significantly worse at 3 months compared to baseline. Studies are required to assess whether change in 2-PD is an adequate objective assessment for CTS with AI therapy. Early diagnosis of CTS may expedite management, improve AI adherence, and enhance breast cancer outcomes.

While it is established that psychosocial stress increases the risk of developing diabetes mellitus (DM), two key knowledge gaps remain: 1) the neurobiological mechanisms that are involved in mediating that risk, and 2) the role, if any, that adiposity plays in that mechanism. We tested the hypotheses that: 1) metabolic activity in the amygdala (AmygA), a key center involved in the neurobiological response to stress, associates with subsequent DM risk, and 2) this association is independent of adiposity. AmygA and adipose tissue volumes were measured, and serial blood assessments for DM were obtained in 232 subjects who underwent combined 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) imaging. Higher baseline AmygA predicted subsequent, new-onset DM, independently of adiposity and other DM risk factors. Furthermore, higher adiposity only increased DM risk in the presence of higher AmygA. In a separate cross-sectional cohort, higher AmygA associated with higher insulin resistance. Accordingly, the current study shows, for the first time, that activity in a stress-responsive neural region predicts the onset of DM. Further, we observed that this neurobiological activity acts independently of, but also synergistically with adiposity to increase DM risk. These findings suggest novel therapeutic targets to help manage and possibly prevent DM.

While the five current FDA-approved classes of targeted disease modifying anti-rheumatic drugs (DMARDs) have comparable efficacy in rheumatoid arthritis (RA), the response of an individual patient to each targeted DMARD can vary widely even among drugs within the same class. Thus far, there is no biomarker or assay in routine clinical practice for predicting a patient's response in a drug-specific or even class-specific manner (1).

Obesity is associated with restrictive ventilatory defects and a faster rate of decline in FVC. This association is not exclusively mediated by mechanical factors and may reflect direct pulmonary injury by adipose-derived mediators.Is adipose tissue involved in the pathogenesis of interstitial lung disease (ILD)?We evaluated the association of CT measures of pericardial, abdominal visceral, and abdominal subcutaneous adipose tissue with high-attenuation areas (HAAs) and interstitial lung abnormalities (ILAs) in a large multicenter cohort study of community-dwelling adults, using multivariable-adjusted models. We secondarily evaluated the association of adipose depot size with FVC and biomarkers of obesity and inflammation.In fully adjusted models, every doubling in pericardial adipose tissue volume was associated with a 63.4-unit increase in HAA (95% CI, 55.5-71.3), 20% increased odds of ILA (95% CI, -2% to 50%), and a 5.5% decrease in percent predicted FVC (95% CI, -6.8% to -4.3%). IL-6 levels accounted for 8% of the association between pericardial adipose tissue and HAA. Every doubling in visceral adipose tissue area was associated with a 41.5-unit increase in HAA (95% CI, 28.3-54.7), 30% increased odds of ILA (95% CI, -10% to 80%), and a 5.4% decrease in percent predicted FVC (95% CI, -6.6% to -4.3%). IL-6 and leptin accounted for 17% and 18%, respectively, of the association between visceral adipose tissue and HAA.Greater amounts of pericardial and abdominal visceral adipose tissue were associated with CT measures of early lung injury and lower FVC in a cohort of community-dwelling adults. Adipose tissue may represent a modifiable risk factor for ILD.

ObjectiveTo characterise changes in selected haematological parameters following once-daily oral baricitinib dosing.MethodsData were pooled from eight randomised clinical trials (four phase 3, three phase 2, one phase 1b) and one long-term extension. Changes in haematological parameters were evaluated up to 128 weeks (N=2387); overall safety of baricitinib was assessed up to 6 years (N=3492).ResultsMean absolute neutrophil counts decreased (−1.36×109/L) within 1 month, followed by stabilisation within the normal reference range through week 128. The incidence of serious infections was not elevated in patients with neutropenia during the 24-week placebo-controlled period. Mean lymphocyte counts increased (+0.30×109/L) within 1 month, then decreased to baseline (weeks 12–24). Mean platelet counts increased at week 2 (+51×109/L), then decreased towards baseline. Overall, mean haemoglobin concentrations decreased (−0.12 mmol/L), then returned to baseline; however, reduced baseline haemoglobin concentrations observed in the highest baseline high-sensitivity C reactive protein quartile increased over time. Permanent drug discontinuation occurred due to laboratory abnormalities related to neutrophil count in 8 (0.2%), lymphocyte counts in 6 (0.2%), platelet counts in 8 (0.2%), and haemoglobin levels in 16 (0.5%) of all baricitinib-treated patients (N=3492 with 7993 total person-years of exposure).ConclusionsModerate decreases in neutrophils were seen during baricitinib treatment; however, serious infection was uncommon in patients with neutropenia. Transient increases were observed in lymphocytes and platelets, which returned to baseline over time. Changes in haemoglobin concentration were generally small. Haematological abnormalities seldom led to drug discontinuation.

Objective: Both periodontal disease and cardiovascular disease (CVD) are overrepresented in rheumatoid arthritis (RA). This study was undertaken to investigate the contribution of periodontal pathogens to CVD in RA. Methods: RA patients underwent assessments of coronary artery calcification (CAC), carotid intima-media thickness and plaque, and ankle–brachial index via computed tomography, ultrasound, and Doppler ultrasound, respectively. Sera were assayed for antibodies targeting Porphyromonas gingivalis (Pg), Aggregatibacter actinomycetemcomitans serotype B (Aa), and Aa-derived leukotoxin A (LtxA). Associations of antibodies against these periodontal pathogens with measures of atherosclerosis were explored using generalized linear models. Results: Among 197 RA patients, anti-Pg was detected in 72 patients (37%), anti-Aa in 41 patients (21%), and anti-LtxA in 84 patients (43%). Adjusting for relevant confounders and reported tooth loss, the mean CAC score was 90% higher in those with anti-Aa and/or anti-LtxA compared with those without either antibody (19 units versus 10 units; P = 0.033). The adjusted odds of CAC ≥100 units were 2.23-fold higher in those with anti-Aa and/or anti-LtxA compared with those without either antibody (P = 0.040). Anti-Aa and/or anti-LtxA seropositivity was significantly associated with all other assessed measures of atherosclerosis except carotid plaque. Anti-Pg was not associated with any measure of atherosclerosis. Higher swollen joint count was associated with CAC exclusively in the group with anti-Aa and/or anti-LtxA. Conclusion: Immunoreactivity against Aa and/or its major virulence factor LtxA was associated with atherosclerosis in multiple vascular beds of RA patients and amplified the effect of swollen joints on coronary atherosclerosis, suggesting a role for treatment/prevention of periodontal disease in the prevention of CVD in RA.

Objective Metabolic syndrome (MetS) is a cluster of concurrent risk factors for cardiovascular disease and type 2 diabetes. This post hoc analysis explored key efficacy and safety endpoints in patients with psoriatic arthritis (PsA) and MetS treated with tofacitinib. Methods Tofacitinib 5 and 10 mg twice daily and placebo data were pooled from two Phase 3 studies (OPAL Broaden [12 months; ClinicalTrials.gov identifier NCT01877668]; OPAL Beyond [6 months; ClinicalTrials.gov identifier NCT01882439]); patients received one background conventional synthetic disease-modifying antirheumatic drug. Patients were stratified by baseline presence/absence of MetS. Efficacy and safety were reported to month 3 (tofacitinib and placebo) and 6 (tofacitinib only). Efficacy outcomes included: American College of Rheumatology (ACR)20/50/70, Health Assessment Questionnaire-Disability Index (HAQ-DI) response, Psoriasis Area Severity Index (PASI)75 response, and enthesitis/dactylitis resolution rates; and changes from baseline (Δ) in C-reactive protein, HAQ-DI, Patient's/Physician's Global Assessment of Arthritis, and patient-reported outcomes. Safety outcomes included treatment-emergent all-causality adverse events (AEs), Δ in lipid/hepatic values, and liver parameter increases. Results Of 710 patients, 41.4% (n = 294) had baseline MetS. All efficacy outcomes improved with both tofacitinib doses versus placebo, to month 3; tofacitinib efficacy was consistent to month 6, regardless of MetS status. MetS did not appear to affect the incidence of AEs or Δ in lipid/hepatic values with tofacitinib up to month 3 or 6. Arterial thromboembolism and myocardial infarction (adjudicated major adverse cardiovascular events) were each reported once in tofacitinib-treated patients with MetS. Conclusion Regardless of baseline MetS status, tofacitinib showed greater efficacy versus placebo in patients with active PsA. The tofacitinib safety profile appeared similar in patients with versus without MetS.

Background: Estimated glomerular filtration rate (eGFR) based on serum creatinine (sCr) improves early after left ventricular assist device (LVAD) implantation but subsequently declines. Although sCr is a commonly accepted clinical standard, cystatin C (CysC) has shown superiority in assessment of renal function in disease states characterized by muscle wasting. Among patients with an LVAD, we aimed to (1) longitudinally compare CysC-eGFR and sCr-eGFR, (2) assess their predictive value for early postoperative outcomes, and (3) investigate mechanisms which might explain potential discrepancies. Methods: A prospective cohort (n=116) with CysC and sCr concurrently measured at serial time points, and a retrospective cohort (n=91) with chest computed tomography performed within 40 days post-LVAD were studied. In the prospective cohort, the primary end point was a composite of in-hospital mortality, renal replacement therapy, or severe right ventricular failure. In the retrospective cohort, muscle mass was estimated using pectoralis muscle area indexed to body surface area (pectoralis muscle index). Results: In the prospective cohort, sCr-eGFR significantly improved early post-LVAD and subsequently declined, whereas CysC-eGFR remained stable. CysC-eGFR but not sCr-eGFR predicted the primary end point: odds ratio per 5 mL/(min·1.73 m 2 ) decrease 1.16 (1.02–1.31) versus 0.99 (0.94–1.05). In retrospective cohort, for every 5 days post-LVAD, a 6% decrease in pectoralis muscle index was observed (95% CI, 2%–9%, P =0.003). After adjusting for time on LVAD, for every 1 cm 2 /m 2 decrease in pectoralis muscle index, there was a 4% decrease in 30-day post-LVAD sCr (95% CI, 1%–6%, P =0.004). Conclusions: Initial improvement in sCr-eGFR is likely due to muscle wasting following LVAD surgery. CysC may improve assessment of renal function and prediction of early postoperative outcomes in patients with an LVAD.

Rudolph Virchow (1821-1902) recognized inflammation in histological preparations of coronary arteries and proposed that inflammation plays a causal role in atherosclerosis. Despite this seminal observation, the main focus of research and drug development programs has been cholesterol alone, and inflammation received less attention over time. However, during the past several decades extensive observations supported the importance of inflammation in the development and destabilization of atherosclerosis. Studies in patients affected by rheumatological diseases suggested an interaction between chronic inflammation and atherosclerotic cardiovascular disease. Randomized clinical studies with lipid lowering agents suggested that part of the beneficial effect may have been related to reduction in inflammation. More recently, a few studies were designed to directly address the role of anti-inflammatory treatments in reducing risk of atherosclerotic heart disease beyond traditional risk factors. In this article, we review the pathophysiologic contribution of inflammation to atherosclerosis, biomarkers of inflammation and the evidence collected in observational studies regarding the role of chronic inflammation in the development of atherosclerotic heart disease. Finally, we discuss the most recent randomized clinical trials of anti-inflammatory agents directed at stemming atherosclerotic cardiovascular disease.

Objective.Individuals with rheumatoid arthritis (RA) are at a heightened risk of sudden cardiac death, an outcome increased in those with prolongation of the corrected electrocardiographic QT interval (QTc). We compared QTc between patients with RA and demographically matched controls and studied the change in QTc after treatment with the interleukin 6 inhibitor tocilizumab (TCZ).Methods.Standard 12-lead electrocardiograms were obtained and QTc was measured in patients with RA at baseline and after 24 weeks of TCZ treatment, then compared with non-RA controls who were frequency-matched on age and sex. Indicators of the baseline QTc and predictors of change in QTc were studied using multivariable linear regression.Results.A total of 94 RA and 42 non-RA controls were studied. The average baseline QTc was 10 ms longer in the RA group vs controls (422 vs 412 ms, respectively; p < 0.001) and decreased to an average of 406 ms with treatment (p < 0.001). Baseline QTc was significantly and independently higher among those with anticyclic citrullinated peptide antibodies seropositivity, higher swollen joint counts, and higher levels of C-reactive protein (CRP) and matrix metalloproteinase 3. Each log unit decrease in CRP with treatment was associated with an average reduction in QTc of 2.9 ms (p = 0.002) after adjusting for age and baseline QTc. Clinical response measures were not associated with the change in QTc.Conclusion.The marked normalization of QTc observed with TCZ treatment, and its close parallel with CRP reduction, support the premise that systemic inflammation contributes to cardiac repolarization abnormalities in RA that may be amenable to treatment.

To assess whether more frequent fish consumption is associated with lower rheumatoid arthritis (RA) disease activity scores among participants in an RA cohort.We conducted a cross-sectional analysis using baseline data from participants in the Evaluation of Subclinical Cardiovascular Disease and Predictors of Events in Rheumatoid Arthritis cohort study. Frequency of fish consumption was assessed by a baseline food frequency questionnaire assessing usual diet in the past year. Multivariable, total energy-adjusted linear regression models provided effect estimates and 95% confidence intervals (95% CIs) for frequency of fish consumption (i.e., never to1 time/month, 1 time/month to1 time/week, 1 time/week, and ≥2 times/week) on baseline Disease Activity Score in 28 joints (DAS28) using the C-reactive protein (CRP) level. We also estimated the difference in DAS28-CRP associated with increasing fish consumption by 1 serving per week.Among 176 participants, the median DAS28-CRP score was 3.5 (interquartile range 2.9-4.3). In an adjusted linear regression model, subjects consuming fish ≥2 times/week had a significantly lower DAS28-CRP compared with subjects who ate fish never to1 time/month (difference -0.49 [95% CI -0.97, -0.02]). For each additional serving of fish per week, DAS28-CRP was significantly reduced by 0.18 (95% CI -0.35, -0.004).Our findings suggest that higher intake of fish may be associated with lower disease activity in RA patients.

Objective Adipose tissue macrophages (ATMs) are a potent source of inflammatory cytokines, with profound effects on adipose tissue function, yet their potential role in rheumatoid arthritis (RA) pathobiology is largely unstudied. Methods Periumbilical subcutaneous adipose tissue was obtained from 36 RA patients and 22 non-RA controls frequency matched on demographics and body mass index. Samples were stained for the macrophage marker CD68, and the average proportions of ATMs, crown-like structures (periadipocyte aggregates of 3 or more ATMs), and fibrosis were compared between groups. Results The adjusted proportion of ATMs among all nucleated cells was 76% higher in RA than in non-RA samples (37.7 versus 21.3%, respectively; P < 0.001), and the adjusted average number of crown-like structures was more than 1.5-fold higher in the RA group than in controls (0.58 versus 0.23 crown-like structure/high-power field, respectively; P = 0.001). ATMs were significantly more abundant in early RA and in those with anti–cyclic citrullinated peptide seropositivity. Users of methotrexate, leflunomide, and tumor necrosis factor inhibitors had a significantly lower proportion of ATMs compared with nonusers. Crown-like structures were significantly higher in patients with rheumatoid factor seropositivity and in those with C-reactive protein levels ≥10 mg/liter, and significantly lower among those treated with statins. Linear ATMs were significantly associated with whole-body insulin resistance, but not with serum lipids. Conclusions ATMs and crown-like structures were more abundant in RA patients and were associated with systemic inflammation, autoimmunity, and whole-body insulin resistance, suggesting possible contributions to the RA disease process. Lower levels of ATMs and crown-like structures associated with specific RA treatments suggest that adipose tissue inflammation may be ameliorated by immunomodulation.