Search

Objectives To determine whether RA and interstitial lung disease (ILD) severity measures are associated with survival in patients with RA-ILD. Methods We studied US veterans with RA-ILD participating in a multicentre, prospective RA cohort study. RA disease activity (28-joint DAS [DAS28-ESR]) and functional status (multidimensional HAQ [MDHAQ]) were collected longitudinally while pulmonary function tests (forced vital capacity [FVC], diffusing capacity for carbon monoxide) were obtained from medical records. Vital status and cause of death were determined from the National Death Index and administrative data. Predictors of death were assessed using multivariable Cox regression models adjusting for age, sex, smoking status, ILD duration, comorbidity burden and medications. Results We followed 227 RA-ILD participants (93% male and mean age of 69 years) over 1073 person-years. Median survival after RA-ILD diagnosis was 8.5 years. Respiratory diseases (28%) were the leading cause of death, with ILD accounting for 58% of respiratory deaths. Time-varying DAS28-ESR (adjusted hazard ratio [aHR] 1.21; 95% CI: 1.03, 1.41) and MDHAQ (aHR 1.85; 95% CI: 1.29, 2.65) were separately associated with mortality independent of FVC and other confounders. Modelled together, the presence of either uncontrolled disease activity (moderate/high DAS28-ESR) or FVC impairment ( Conclusion Both RA and ILD disease severity measures are independent predictors of survival in RA-ILD. These findings demonstrate the prognostic value of monitoring the systemic features of RA-ILD.

Stimulation of the inflammatory reflex (IR) is a promising strategy to treat systemic inflammatory disorders. However, this strategy is hindered by the cost and side effects of traditional IR activators. Recently, oral intake of sodium bicarbonate (NaHCO3) has been suggested to activate the IR, providing a safe and inexpensive alternative. Critically, the mechanisms whereby NaHCO3 might achieve this effect and more broadly the pathways underlying the IR remain poorly understood. Here, we argue that the recognition of NaHCO3 as a potential IR activator presents exciting clinical and research opportunities. To aid this quest, we provide an integrative review of our current knowledge of the neural and cellular pathways mediating the IR and discuss the status of physiological models of IR activation. From this vantage point, we derive testable hypotheses on potential mechanisms whereby NaHCO3 might stimulate the IR and compare NaHCO3 with classic IR activators. Elucidation of these mechanisms will help determine the therapeutic value of NaHCO3 as an IR activator and provide new insights into the IR circuitry.

Background: Worldwide, there are millions of chronic proton pump inhibitor (PPI) users, often without a compelling indication. Evidence indicates that PPI treatment can increase mortality, in part, due to a higher risk of heart rate–corrected QT interval-related malignant arrhythmias. Drug-induced hypomagnesemia is currently believed to be the only underlying mechanism, and, therefore, serum magnesium monitoring is recommended to minimize arrhythmic risk. However, recent data suggest that PPIs might also directly interfere with cardiac electrophysiology. To test this hypothesis, a translational study was performed using a combination of electrophysiology, molecular dynamics simulations, and population data. Methods: First, the effect of different PPIs on the human ether-a-go-go-related gene potassium channel (hERG) current was evaluated in human embryonic kidney 293 cells expressing hERG. Then, free-energy calculations were performed to investigate the binding of these drugs to hERG. Finally, the impact of PPIs on the risk of heart rate–corrected QT interval prolongation was assessed in a retrospective observational cohort of 3867 US veterans, including 1289 PPI-treated subjects. Results: Clinically relevant concentrations of different PPIs induced a significant inhibition of the hERG current in vitro, pantoprazole and lansoprazole being the most potent compounds. Atomic simulations demonstrated that such a blocking class effect is likely due to direct PPIs binding to hERG channel pore cavity. Accordingly, in a US veterans cohort, PPI treatment was independently associated with an ≈20% to 40% increased risk of heart rate–corrected QT interval prolongation, also regardless of hypomagnesemia. Moreover, a synergistic interaction between PPIs and most of the traditional QT-prolonging risk factors was demonstrated. Conclusions: Altogether, this study provides, for the first time, strong evidence that PPIs can per se promote heart rate–corrected QT interval prolongation, by directly inhibiting hERG function. A careful evaluation of the benefit/risk ratio is recommended whenever PPIs are administered in subjects with other QT-prolonging risk factors, even in the absence of hypomagnesemia.

Background Anti‐Sjögren's syndrome‐related antigen A‐antibodies (anti‐Ro/SSA‐antibodies) are responsible for a novel form of acquired long‐QT syndrome, owing to autoimmune‐mediated inhibition of cardiac human ether‐a‐go‐go‐related gene‐potassium channels. However, current evidence derives only from basic mechanistic studies and relatively small sample‐size clinical investigations. Hence, the aim of our study is to estimate the risk of QTc prolongation associated with the presence of anti‐Ro/SSA‐antibodies in a large population of unselected subjects. Methods and Results This is a retrospective observational cohort study using the Veterans Affairs Informatics and Computing Infrastructure. Participants were veterans who were tested for anti‐Ro/SSA status and had an ECG. Descriptive statistics and univariate and multivariate logistic regression analyses were performed to identify risk factors for heart rate‐corrected QT interval (QTc) prolongation. The study population consisted of 7339 subjects (61.4±12.2 years), 612 of whom were anti‐Ro/SSA‐positive (8.3%). Subjects who were anti‐Ro/SSA‐positive showed an increased prevalence of QTc prolongation, in the presence of other concomitant risk factors (crude odds ratios [OR], 1.67 [1.26–2.21] for QTc >470/480 ms; 2.32 [1.54–3.49] for QTc >490 ms; 2.77 [1.66–4.60] for QTc >500 ms), independent of a connective tissue disease history. Adjustments for age, sex, electrolytes, cardiovascular risk factors/diseases, and medications gradually attenuated QTc prolongation estimates, particularly when QT‐prolonging drugs were added to the model. Nevertheless, stepwise‐fully adjusted OR for the higher cutoffs remained significantly increased in anti‐Ro/SSA‐positive subjects, particularly for QTc >500 ms (2.27 [1.34–3.87]). Conclusions Anti‐Ro/SSA‐antibody positivity was independently associated with an increased risk of marked QTc prolongation in a large cohort of US veterans. Our data suggest that within the general population individuals who are anti‐Ro/SSA‐positive may represent a subgroup of patients particularly predisposed to ventricular arrhythmias/sudden cardiac death.

Background Patients with gout have arterial dysfunction and systemic inflammation, even during intercritical episodes, which may be markers of future adverse cardiovascular outcomes. We conducted a prospective observational study to assess whether initiating guideline-concordant gout therapy with colchicine and a urate-lowering xanthine oxidase inhibitor (XOI) improves arterial function and reduces inflammation. Methods Thirty-eight untreated gout patients meeting American College of Rheumatology (ACR)/European League Against Rheumatism classification criteria for gout and ACR guidelines for initiating urate-lowering therapy (ULT) received colchicine (0.6 mg twice daily, or once daily for tolerance) and an XOI (allopurinol or febuxostat) titrated to ACR guideline-defined serum urate (sU) target. Treatment was begun during intercritical periods. The initiation of colchicine and XOI was staggered to permit assessment of a potential independent effect of colchicine. Brachial artery flow-mediated dilation (FMD) and nitrate-mediated dilation (NMD) assessed endothelium-dependent and endothelium-independent (smooth muscle) arterial responsiveness, respectively. High-sensitivity C-reactive protein (hsCRP), IL-1β, IL-6, myeloperoxidase (MPO) concentrations, and erythrocyte sedimentation rate (ESR) assessed systemic inflammation. Results Four weeks after achieving target sU concentration on colchicine plus an XOI, FMD was significantly improved (58% increase, p = 0.03). hsCRP, ESR, IL-1β, and IL-6 also all significantly improved (30%, 27%, 19.5%, and 18.8% decrease respectively; all p ≤ 0.03). Prior to addition of XOI, treatment with colchicine alone resulted in smaller numerical improvements in FMD, hsCRP, and ESR (20.7%, 8.9%, 13% reductions, respectively; all non-significant), but not IL-1β or IL-6. MPO and NMD did not change with therapy. We observed a moderate inverse correlation between hsCRP concentration and FMD responsiveness (R = − 0.41, p = 0.01). Subgroup analyses demonstrated improvement in FMD after achieving target sU concentration in patients without but not with established cardiovascular risk factors and comorbidities, particularly hypertension and hyperlipidemia. Conclusions Initiating guideline-concordant gout treatment reduces intercritical systemic inflammation and improves endothelial-dependent arterial function, particularly in patients without established cardiovascular comorbidities.

Background The Veterans Affairs (VA) Rheumatoid Arthritis (RA) (VARA) registry is an observational cohort study of US Veterans with RA at 11 VA Medical Centers. VARA investigators capture clinical and laboratory disease activity measures (DAMs) during clinic visits via standardized templates in the electronic health record (EHR). Six clinical (tender/swollen joints, patient/provider global, MD-HAQ, pain) and 2 laboratory (ESR, CRP) DAMs are extracted post-visit using natural language processing (NLP). Objectives This analysis determined the impact of an audit, feedback and data correction system on the quantity and quality of DAMs collected in the VARA registry. Methods After September 2017, VARA site investigators were provided monthly feedback reports of incomplete/missing DAMs for the prior month to allow sites to correct data entry errors. Updated and/or corrected data were entered into the EHR via note addendums and then automatically re-extracted by NLP to complete the capture of DAM data. DAMs from October 1, 2016 to September 30, 2017 (pre-feedback implementation – Pre-IMP) was compared to October 1, 2017 to September 30, 2018 (post-feedback implementation – Post-IMP). Results During the pre-IMP period, there were 2,411 notes with DAMs collected on 1,116 unique patients compared to 2,873 notes on 1,208 unique patients in the post-IMP period - an increase of 92 (8.2%) unique patients and 460 (19.1%) notes. Enrollment in the VARA registry only increased by 121 (6.5%) during post-IMP period. During post-IMP period, there were 541 notes identified with deficiencies in clinical DAMs and monthly audit and feedback reports were provided to VARA sites to allow corrections. Individual site review resulted in 376 additional DAMs in 225 notes, with complete resolution of all error in 137 (25.3%) notes. The quantity of DAMs collected increased from 15,709 to 21,064, a 34.1% increase with the average number of DAMs collected per note rising from 4.9 to 5.6. The quality of data improved as demonstrated by the proportion of notes with all 6 clinical DAMs increasing from 52.5% to 81.1% and other improvements in quality/completeness as noted in table. Conclusion An audit, feedback, and efficient data collection system improved both the quantity and quality of DAMs collected. The improvement in the collection of DAMs in RA patients will further enhance epidemiologic and outcomes studies of RA and provide higher quality longitudinal data to enhance the care of RA patients. References [1] Fed Pract 2015; 32(5):24-29 Acknowledgement Work Support in Part by VA HSR&D and VA Specialty Care Centers of Innovation Disclosure of Interests Grant Cannon Grant/research support from: Amgen Inc., Jorge Rojas: None declared, Neill Bell: None declared, Namrata Singh: None declared, Ted Mikuls: None declared, Liron Caplan: None declared, Gail Kerr: None declared, Joshua Baker: None declared, Angelo Gaffo: None declared, Jennifer Barton: None declared, Deana Lazaro: None declared, J Steuart Richards: None declared, Brian Sauer Grant/research support from: Amgen Inc.

Cytopenias in systemic lupus erythematosus (SLE) require clinical and laboratory workup and bone marrow (BM) examination to determine the cause and for appropriate patient management. Common causes include an increase in SLE activity, immune-mediated hemolysis, iron deficiency, antiphospholipid antibody syndrome, infection, or the effect of medications. We retrospectively evaluated the clinical and laboratory findings of patients with SLE and cytopenias who had undergone BM studies to determine the indicators of malignancy. We retrospectively reviewed medical records of patients with SLE who presented with cytopenias for their disease course, medications, laboratory parameters and documented the spectrum of morphological changes in BM including CD34 expression. Twenty patients with SLE had undergone BM biopsy for evaluation of cytopenias. 14/20 (70%) of the patients had reactive BM, and the rest had hematologic malignancies involving the BM. Of these 14 patients, 8 had hypocellular marrow with loss of precursor cells (low CD34), 4 had left shift in myeloid lineage, 3 had serous atrophy, and 1had multilineage dysplasia. The 6 patients with hematologic malignancies included 2 with diffuse large B cell lymphoma, and one each of natural killer/T cell lymphoma, post-transplant lymphoproliferative disorder, Hodgkin lymphoma, and myelodysplastic syndrome evolving to acute myelogenous leukemia. The presence of autoantibodies, SLE activity, and lupus nephritis were comparable in patients with and without neoplasia. However, the duration of the use of multiple immunosuppressants, years since renal transplant (22 vs 10), multiple transplants, and the presence of other autoimmune diseases were greater in those with neoplasia. Two of the 14 patients with non-neoplastic BM and 1 with the neoplastic BM had nonhematological malignancy. Clinical and laboratory findings, the number of transplants, and the use of immunosuppressive agents can guide physicians to identify patients with a higher risk of developing hematologic malignancy. BM findings of cytopenia in SLE are often due to increased disease activity causing global cell death and dysmaturation. SLE patients presenting with cytopenias, with a history of long-term exposure to immunosuppressive drugs, should be regularly screened for hematologic and nonhematologic malignancies.

Objective The Rheumatology Research Foundation's Clinician Scholar Educator (CSE) award is a 3-year career development award supporting medical education research while providing opportunities for mentorship and collaboration. Our objective was to document the individual and institutional impact of the award since its inception, as well as its promise to strengthen the subspecialty of rheumatology. Methods All 60 CSE Award recipients were surveyed periodically. Fifty-six of those 60 awardees (90%) responded to requests for survey information that included post-award activities, promotions, and further funding. Data were also collected from yearly written progress reports for each grant. Results Of the total CSE recipients to date, 48 of 60 (80%) are adult rheumatologists, 11 of 60 (18%) are pediatric rheumatologists, and 1 is an adult and pediatric rheumatologist. Two-thirds of survey respondents spend up to 30% of their total time in educational activities, and one-third spend greater than 30%. Thirty-one of the 60 CSE recipients (52%) have published a total of 86 medical education papers. Twenty-six of 52 (50%) had received an academic promotion following the award. Eleven awardees earned advanced degrees. Conclusion We describe the creation and evolution of a grant program from a medical subspecialty society foundation and the impact on producing education research, individual identity formation, and ongoing support for educators. This community of rheumatology scholar educators now serves as an important resource at the national level for the American College of Rheumatology and its membership. We believe that this grant may serve as a model for other medical societies that want to promote education scholarship and leadership within their specialties.

Objective Increasing evidence indicates systemic inflammation as a new potential cause of acquired long QT syndrome (LQTS), via cytokine-mediated changes in cardiomyocyte ion channels. Torsade de pointes (TdP) is a life-threatening polymorphic ventricular tachycardia occurring in patients with LQTS, usually when multiple QT-prolonging factors are simultaneously present. Since classical risk factors cannot fully explain TdP events in a number of patients, we hypothesised that systemic inflammation may represent a currently overlooked risk factor contributing to TdP development in the general population. Methods Forty consecutive patients who experienced TdP (TdP cohort) were consecutively enrolled and circulating levels of C-reactive protein (CRP) and proinflammatory cytokines (interleukin-6 (IL-6), tumour necrosis factor alpha (TNFα), interleukin-1 (IL-1)) were compared with patients with active rheumatoid arthritis (RA), comorbidity or healthy controls. An additional 46 patients with different inflammatory conditions (acute infections, n=31; immune-mediated diseases, n=12; others, n=3) and elevated CRP (inflammatory cohort) were prospectively enrolled, and corrected QT (QTc) and cytokine levels were measured during active disease and after a CRP decrease of >75% subsequent to therapy. Results In the TdP cohort, 80% of patients showed elevated CRP levels (median: ~3 mg/dL), with a definite inflammatory disease identifiable in 18/40 cases (acute infections, n=12; immune-mediated diseases, n=5; others, n=1). In these subjects, IL-6, but not TNFα and IL-1, was ~15–20 times higher than in controls, and comparable to RA patients. In the inflammatory cohort, where QTc prolongation was common (mean values: 456.6±30.9 ms), CRP reduction was associated with IL-6 level decrease and significant QTc shortening (−22.3 ms). Conclusion The data are first to show that systemic inflammation via elevated IL-6 levels may represent a novel QT-prolonging risk factor contributing to TdP occurrence in the presence of other classical risk factors. If confirmed, this could open new avenues in antiarrhythmic therapy.

Objective To examine the relationship between posttraumatic stress disorder (PTSD) and disease activity in US veterans with rheumatoid arthritis (RA). Methods US veterans with RA were enrolled in a longitudinal observational study and were categorized as having PTSD, other anxiety/depression disorders, or neither of these psychiatric diagnoses using administrative codes. Generalized linear mixed-effects models were used to examine the associations of the diagnostic groups with outcomes measured over a mean followup period of 3.0 years. Results At enrollment, 1,522 patients had a mean age of 63 years, they were primarily men (91%), and a majority (78%) reported white race. A diagnosis of PTSD was observed in 178 patients (11.7%), and other anxiety/depression diagnoses (excluding PTSD) were found in 360 patients (23.7%). The presence of a PTSD diagnosis was independently associated with higher values of self-reported pain, physical impairment, tender joint count, and worse patient global well-being scores compared to patients with no psychiatric diagnosis. There were no significant group differences in swollen joint count, erythrocyte sedimentation rate, or Disease Activity Score in 28 joints. There were no differences between any outcomes comparing those with PTSD and those with other anxiety/depression diagnoses. Conclusion In this RA cohort, the diagnosis of PTSD was associated with worse patient-reported outcomes and tender joint counts, but not with other physician- or laboratory-based measures of disease activity. These results suggest that PTSD, along with other anxiety/depression disorders, may affect RA disease activity assessments that rely on patient-reported outcomes and the resulting treatment decisions.

Mounting evidence indicates that in chronic inflammatory arthritis (CIA), QTc prolongation is frequent and correlates with systemic inflammatory activation. Notably, basic studies demonstrated that inflammatory cytokines induce profound changes in potassium and calcium channels resulting in a prolonging effect on cardiomyocyte action potential duration, thus on the QT interval on the electrocardiogram. Moreover, it has been demonstrated that in rheumatoid arthritis (RA) patients, the risk of sudden cardiac death is significantly increased when compared to non-RA subjects. Conversely, to date no data are available about torsades de pointes (TdP) prevalence in CIA, and the few cases reported considered CIA only an incidental concomitant disease, not contributing factor to TdP development. We report three patients with active CIA developing marked QTc prolongation, in two cases complicated with TdP degenerating to cardiac arrest. In these patients, a blood sample was obtained within 24 h from TdP/marked QTc prolongation occurrence, and levels of IL-6, TNFα, and IL-1 were evaluated. In all three cases, IL-6 was markedly elevated, ~10 to 100 times more than reference values. Moreover, one patient also showed high circulating levels of TNFα and IL-1. In conclusion, active CIA may represent a currently overlooked QT-prolonging risk factor, potentially contributing in the presence of other “classical” risk factors to TdP occurrence. In particular, a relevant role may be played by elevated circulating IL-6 levels via direct electrophysiological effects on the heart. This fact should be carefully kept in mind, particularly when recognizable risk factors are already present and/or the addition of QT-prolonging drugs is required.

Objective Obesity is a prevalent condition and a serious health concern. The relationship between obesity and rheumatoid arthritis (RA) disease activity and severity has not been adequately examined, and there are concerns that periarticular adipose tissue may reduce the utility of the joint examination. Methods We used a cross-sectional study to compare the performance of swollen joint count (SJC) in subjects with RA across body mass index (BMI) strata. Specifically, regression techniques tested for associations of SJC and 7 RA disease activity/severity measures (including high-sensitivity C-reactive protein level, radiographic changes, and Multidimensional Health Assessment Questionnaire scores) within BMI quartiles. We also evaluated the association of BMI with radiographic evidence of RA in multivariate analyses and the association of BMI with SJC. Clinical and laboratory data from 980 Veterans Affairs Rheumatoid Arthritis registry participants were analyzed using linear and logistic regression. Results Associations were evident between SJC and 6 of the 7 examined RA disease activity/severity measures. SJC predicts RA disease activity/severity in more obese subjects at least as well as in subjects with lower BMIs, and there was a trend toward better performance in individuals with higher BMIs. Subjects with higher BMIs were marginally less likely to be characterized by radiographic changes (odds ratio 0.98, P = 0.051). We found no association between BMI and SJC. Conclusion BMI does not obscure the relationship of SJC and objective disease activity measures. There is a borderline association of higher BMI and the likelihood of radiographic changes characteristic of RA after controlling for clinical characteristics.

Objective Pharmacy Benefits Management program data for patients enrolled in the Veterans Affairs Rheumatoid Arthritis (VARA) registry were linked with clinical data to determine bisphosphonate adherence and persistence among US veterans with rheumatoid arthritis (RA) and to determine factors associated with adherence. Methods The primary outcome measures were the duration of bisphosphonate therapy and the medication possession ratio (MPR). Patients with an MPR 32 months (OR 1.63, 95% CI 1.04–2.57). Whites were less likely to have a low MPR compared with nonwhites (OR 0.52, 95% CI 0.30–0.88). Conclusion Nonadherence with bisphosphonates was common in this cohort of RA patients and was associated with nonwhite ethnicity, a longer duration of RA disease, and a greater duration of bisphosphonate therapy.

Objective Traditional means of testing rheumatology fellows do not adequately assess some skills that are required to practice medicine well, such as humanistic qualities, communication skills, or professionalism. Institution of the New York City Rheumatology Objective Structured Clinical Examination (ROSCE) and our sequential 5 years of experience have provided us with a unique opportunity to assess its usefulness and objectivity as a rheumatology assessment tool. Methods Prior to taking the examination, all of the fellows were rated by their program directors. Fellows from the participating institutions then underwent a multistation patient-interactive examination observed and rated by patient actors and faculty raters. Assessments were recorded by all of the participants using separate but overlapping sets of instruments testing the Accreditation Council of Graduate Medical Education (ACGME) core competencies of patient care, interpersonal and communication skills, professionalism, and overall medical knowledge. Results Although the program directors tended to rate their fellows more highly than the ROSCE raters, typically there was agreement between the program directors and the ROSCE faculty in distinguishing between the highest- and lowest- performing fellows. The ROSCE faculty and patient actor assessments of individual trainees were notable for a high degree of concordance, both quantitatively and qualitatively. Conclusion The ROSCE provides a unique opportunity to obtain a patient-centered assessment of fellows' ACGME-mandated competencies that traditional knowledge-based examinations, such as the rheumatology in-service examination, cannot measure. The ability of the ROSCE to provide a well-rounded and objective assessment suggests that it should be considered an important component of the rheumatology training director's toolbox.