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To investigate previously identified and novel correlates of acute calcium pyrophosphate (CPP) crystal arthritis among well-characterized cases.In this case-control study, we identified cases of acute CPP crystal arthritis using a validated algorithm (positive predictive value 81%) applied in the Partners HealthCare electronic health record (EHR). Cases were matched to general patient controls on the year of first EHR encounter and index date. Prespecified potential correlates included sex, race, and comorbidities and medications previously associated with CPP deposition/acute CPP crystal arthritis in the literature. We estimated odds ratios (ORs) and 95% confidence intervals using conditional logistic regression models adjusted for demographic characteristics, comorbidities, medications prescribed in the past 90 days, health care utilization, and multimorbidity score.We identified 1,697 cases matched to 6,503 controls. Mean ± SD age was 73.7 ± 11.8 years, 56.7% were female, 80.8% were White, and 10.3% were Black. All prespecified covariates were more common in cases than controls. Osteoarthritis (OR 3.08), male sex (OR 1.35), rheumatoid arthritis (OR 2.09), gout (OR 2.83), proton pump inhibitors (OR 1.94), loop diuretics (OR 1.60), and thiazides (OR 1.46) were significantly associated with acute CPP crystal arthritis after full adjustment. Black race was associated with lower odds for acute CPP crystal arthritis compared to White race (OR 0.47).Using a validated algorithm to identify nearly 1,700 patients with acute CPP crystal arthritis, we confirmed important correlates of this acute manifestation of CPP deposition. This is the first study to report higher odds for acute CPP crystal arthritis among males.

To develop a claims-based model to predict persistent high-dose opioid use among patients undergoing total knee replacement (TKR).Using Medicare claims (2010-2014), we identified patients ages ≥65 years who underwent TKR with no history of high-dose opioid use (mean 25 morphine milligram equivalents [MMEs]/day) in the year prior to TKR. We used group-based trajectory modeling to identify distinct opioid use patterns. The primary outcome was persistent high-dose opioid use in the year after TKR. We split the data into training (2010-2013) and test (2014) sets and used logistic regression with least absolute shrinkage and selection operator regularization, utilizing a total of 83 preoperative patient characteristics as candidate predictors. A reduced model with 10 prespecified variables, which included demographic characteristics, opioid use, and medication history was also considered.The final study cohort included 142,089 patients who underwent TKR. The group-based trajectory model identified 4 distinct trajectories of opioid use (group 1: short-term, low-dose; group 2: moderate-duration, low-dose; group 3: moderate-duration, high-dose; and group 4: persistent high-dose). The model predicting persistent high-dose opioid use achieved high discrimination (receiver operating characteristic area under the curve [AUC] 0.85 [95% confidence interval (95% CI) 0.84-0.86]) in the test set. The reduced model with 10 predictors performed equally well (AUC 0.84 [95% CI 0.84-0.85]).In this cohort of older patients, 10.6% became persistent high-dose (mean 22.4 MME/day) opioid users after TKR. Our model with 10 readily available clinical factors may help identify patients at high risk of future adverse outcomes from persistent opioid use after TKR.

Aims : Patients with rheumatoid arthritis (RA) have an increased risk of venous thromboembolism (VTE), likely related to underlying inflammation. We examined VTE risk associated with two commonly used immunomodulators in RA patients, methotrexate and hydroxychloroquine. Methods and Results : Using U.S. Medicare claims data (2008-2017), we identified RA patients (≥65 years) who initiated methotrexate or hydroxychloroquine without prior use of any immunomodulators. The primary outcome was VTE, a composite of pulmonary embolism (PE) or deep vein thrombosis (DVT). Secondary outcomes included PE, DVT, and all-cause mortality. After 1:1 propensity score matching for confounding control, we identified 26,534 pairs of methotrexate and hydroxychloroquine initiators (mean (SD) age 74 (7) years; 79% female). During a total of 56,686 person-years of follow-up, 208 methotrexate and 83 hydroxychloroquine initiators developed VTE. The incidence rate of VTE was higher among methotrexate initiators (6.94/1,000 person-years) than hydroxychloroquine initiators (3.11/1,000 person-years) with a hazard ratio (HR) of 2.26 (95%CI 1.75, 2.91). Methotrexate initiators had a greater risk of PE (HR 3.30, 95%CI 2.28, 4.77) and DVT (HR 1.53, 95%CI 1.07, 2.19) than hydroxychloroquine initiators. All-cause mortality was similar between the two groups (HR 0.91, 95%CI 0.83, 1.00). Conclusion : In this large real-world cohort of older RA patients, treatment with methotrexate was associated with a 2-fold increased risk of VTE relative to hydroxychloroquine, although all-cause mortality was similar. Future experimental studies with non-user control groups are needed to determine the causal relationships between the study drugs and VTE and whether methotrexate elevates or hydroxychloroquine reduces the risk of VTE.

Objective Vaccination against preventable infections is widely recommended for patients with systemic rheumatic disease. The coronavirus disease 2019 (COVID‐19) pandemic has highlighted variability in attitudes toward vaccination, particularly with the use of novel vaccine platforms. We studied attitudes toward vaccination against COVID‐19 and other preventable infections among patients with systemic rheumatic disease and compared these against the general population. Methods We surveyed patients treated at Brigham and Women’s Hospital for systemic rheumatic disease using a secure web‐based survey or paper survey in English or Spanish, from December 2020 to April 2021. We included survey questions used in the nationwide Harris Poll (October 2020 and February 2021), allowing the comparison of responses with those from the general population. Response frequencies were estimated and compared using descriptive statistics. Results Of 243 participants (25% response rate), the mean age was 56 years, 82% were women, and 33% were nonwhite. Rheumatoid arthritis (50%) and systemic lupus erythematosus (28%) were the most common diagnoses. Thirty percent had been hospitalized previously for any infection. Seventy‐six percent worried a lot or somewhat about contracting COVID‐19. Attitudes toward vaccination were very favorable, with 92% having received a flu shot in the past year and 84% desiring a COVID‐19 vaccine as soon as possible compared with 30% to 40% of Harris Poll respondents (P < 0.001). Physician recommendation to receive a vaccine and desire to avoid infection were the most common reasons for desiring vaccinations. Conclusion Vaccine acceptability, including toward COVID‐19 vaccines, was high among this population of patients with systemic rheumatic disease seen at an academic medical center cohort. Physician recommendation is a key factor for vaccine uptake.

PURPOSE Medication side effects are a major concern in aging adults who report using an increasing number of medications. The relationship between accumulating medication use and physical function has not been examined in a longitudinal cohort. METHODS We conducted a longitudinal cohort study using prospectively collected data from the Study of Women's Health Across the Nation (SWAN). Community-dwelling women from five US cities were followed for up to 20 years. The exposure of interest was the number of prescription medications. They were examined as a count variable and then for specific categories of medication. The outcome of interest was physical function measured repeatedly using the short form (SF)-36 physical function (PF) scale. Linear mixed models, using repeated measures of sociodemographics and comorbidities were assessed. RESULTS 1452 participants qualified for the analyses with a median follow-up of 19.2 years. At baseline, the mean age was 46.5 years and 53.5% reported White race. Fully adjusted models demonstrated a reduction in the SF-36 PF of 0.99 for each additional prescription medication used or a 6.14-point reduction for women reporting more than five medications and an 8.92-point reduction among those reporting more than 10 medications. These results were similar across race and ethnicity. Specific medication categories with a significant and largely negative impact (at least a two-point reduction) on physical component score included beta-blockers, analgesics, glucocorticoids, anticonvulsants, anxiolytics, anticoagulants, and anti-depressants. CONCLUSIONS There is a moderate association between increasing medication use and decreasing physical function among women transitioning through the mid-life.

Objective Medication nonadherence is linked to worsened clinical outcomes and increased costs. Existing system-level adherence interventions rely on insurer claims for patient identification and outcome measurement, yet suffer from incomplete capture and lags in data acquisition. Data from pharmacies regarding prescription filling, captured in retail dispensing, may be more efficient. Data sources Pharmacy fill and insurer claims data. Study design We compared adherence measured using pharmacy fill data to adherence using insurer claims data, expressed as proportion of days covered (PDC) over 12 months. Agreement was evaluated using correlation/validation metrics. We also explored the relationship between adherence in both sources and disease control using prediction modeling. Data extraction methods Large pragmatic trial of cardiometabolic disease in an integrated delivery network. Principal findings Among 1113 patients, adherence was higher in pharmacy fill (mean = 50.0%) versus claims data (mean = 47.4%), although they had moderately high correlation (R = 0.57, 95% CI: 0.53-0.61) with most patients (86.9%) being similarly classified as adherent or nonadherent. Sensitivity and specificity of pharmacy fill versus claims data were high (0.89, 95% CI: 0.86-0.91 and 0.80, 95% CI: 0.75-0.85). Pharmacy fill-based PDC predicted better disease control slightly more than claims-based PDC, although the difference was nonsignificant. Conclusions Pharmacy fill data may be an alternative to insurer claims for adherence measurement.

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.

OBJECTIVES: Giant cell arteritis (GCA) can manifest in cranial and/or extracranial arteries. We investigated the distribution of affected arteries on vascular ultrasound (VUS) among patients with new-onset or prior-onset GCA. METHODS: We retrospectively studied patients with either new-onset or prior-onset GCA and an abnormal VUS, 2013–2017. Trained vascular technologists imaged the bilateral temporal arteries and carotid, axillary, and subclavian arteries. Vascular medicine physicians interpreted the images. Vasculitis-related abnormalities in individual vessels and their distribution (temporal artery, large artery, or both) were evaluated. Phi coefficients (φ) and Fisher’s exact test were used to assess correlations among individual abnormal arteries. RESULTS: Among 66 GCA patients, 28.8% had prior-onset GCA (median duration 17.8 months). Acute arteritis on VUS was observed in the majority of patients with both new-onset GCA (72.3%) and prior-onset GCA (68.4%); the remainder had hyperechoic wall thickening without acute arteritis. Involvement of the temporal arteries only (45.5%) or large arteries only (34.8%) was more common than involvement of both (19.7%); this finding was similar in new-onset and prior-onset GCA. There were moderate positive correlations among temporal artery branches (φ=0.51–0.58, p

OBJECTIVE Identifying pseudogout in large data sets is difficult due to its episodic nature and a lack of billing codes specific to this acute subtype of calcium pyrophosphate (CPP) deposition disease. The objective of this study was to evaluate a novel machine learning approach for classifying pseudogout using electronic health record (EHR) data. METHODS We created an EHR data mart of patients with ≥1 relevant billing code or ≥2 natural language processing (NLP) mentions of pseudogout or chondrocalcinosis, 1991-2017. We selected 900 subjects for gold standard chart review for definite pseudogout (synovitis + synovial fluid CPP crystals), probable pseudogout (synovitis + chondrocalcinosis), or not pseudogout. We applied a topic modeling approach to identify definite/probable pseudogout. A combined algorithm included topic modeling plus manually reviewed CPP crystal results. We compared algorithm performance and cohorts identified by billing codes, the presence of CPP crystals, topic modeling, and a combined algorithm. RESULTS Among 900 subjects, 123 (13.7%) had pseudogout by chart review (68 definite, 55 probable). Billing codes had a sensitivity of 65% and a positive predictive value (PPV) of 22% for pseudogout. The presence of CPP crystals had a sensitivity of 29% and a PPV of 92%. Without using CPP crystal results, topic modeling had a sensitivity of 29% and a PPV of 79%. The combined algorithm yielded a sensitivity of 42% and a PPV of 81%. The combined algorithm identified 50% more patients than the presence of CPP crystals; the latter captured a portion of definite pseudogout and missed probable pseudogout. CONCLUSION For pseudogout, an episodic disease with no specific billing code, combining NLP, machine learning methods, and synovial fluid laboratory results yielded an algorithm that significantly boosted the PPV compared to billing codes.

OBJECTIVE Using a quality improvement approach, our objective was to integrate a treat-to-target approach for rheumatoid arthritis (RA) through routine electronic collection of patient-reported disease activity scores and a multidisciplinary learning collaborative for rheumatologists. METHODS RA patients completed a patient-reported outcome measure, the Routine Assessment of Patient Index Data 3 (RAPID3), at check-in. Nine rheumatologists and their patients were allocated to a learning collaborative intervention group focused on a treat-to-target approach and 13 were allocated to a control group. The primary outcome was documentation of a treat-to-target implementation score: disease activity score, disease activity score used in the medication change decision, the presence of a treatment target, and an indication of shared decision-making. A primary analysis of patient visits with medication changes was conducted using an interrupted time-series analysis. RESULTS We studied 554 individual rheumatology patients with 709 patient visits. Treat-to-target implementation scores among intervention rheumatologists (mean ± SD 44.6% ± 1.63%) were 12.4% higher than in the control group (mean ± SD 32.2% ± 1.50%; P < 0.0001). We observed differences in treat-to-target implementation score components, comparing intervention group to control group rheumatologists: disease activity score present, 77.2% versus 68.0% (P = 0.02); disease activity score used in the medication change decision, 45.2% versus 30.0% (P < 0.01); treatment target, 9.0% versus 0.4% (P < 0.01); and shared decision-making, 46.9% versus 30.0% (P < 0.01). Secondary analysis of patient visits with high RAPID3 scores found that medication changes were 54% less likely in the intervention versus control group (odds ratio 0.46 [95% confidence interval 0.27-0.79], P = 0.005). CONCLUSION This nonrandomized, interrupted time-series trial demonstrated a modest but significant impact of a learning collaborative intervention on rheumatologist documentation of a treat-to-target approach in RA.

Purpose of review To review recent literature with relevance to the management of multimorbid patients with gout, i.e., gout medication repurposed for comorbidities and vice versa. Recent findings Adding to the previous success of interleukin-1 inhibition, two trials on low-dose colchicine's role in cardiovascular disease (CVD) demonstrated potential benefits in patients with or without gout. In Colchicine Cardiovascular Outcomes Trial, a composite CVD endpoint was reduced by 23% among patients who had experienced a recent myocardial infarction. In Low-Dose Colchicine 2, the composite CVD endpoint was reduced 31% among those with stable coronary artery disease. Use of urate-lowering therapy (ULT) for renal protection in patients without gout produced null results. Allopurinol did not benefit the glomerular filtration rate in two trials (Controlled trial of slowing of Kidney Disease progression From the Inhibition of Xanthine oxidase and Preventing Early Renal Function Loss) among patients with chronic kidney disease (with or without hyperuricemia, but not gout). SGLT-2 inhibitors, a medication recommended for patients with diabetes and CVD, diabetic kidney disease, or heart failure, demonstrated a protective effect against gout flares in a secondary trial analysis and a large observational study. Summary The role of colchicine may expand beyond gout flare prevention to patients with existing CVD. The renal benefit of ULT among patients with gout remains unclear. SGLT-2 inhibitors may benefit diabetic patients who have gout as a comorbidity.

OBJECTIVE We previously reported that low-dose methotrexate (MTX) was associated with an increased risk of pulmonary adverse events (AEs) in a large randomized, placebo-controlled trial. Herein, we report details on the predictors and severity of pulmonary AEs. METHODS We conducted a prespecified analysis of pulmonary AEs in the Cardiovascular Inflammation Reduction Trial. Adults with known cardiovascular disease and diabetes/metabolic syndrome were randomly allocated to receive low-dose MTX (target dose 15-20 mg/week) or placebo after a 6-8-week open-label run-in phase in which all patients received low-dose MTX. Individuals with systemic inflammatory diseases were excluded. Pulmonary AEs were adjudicated in a blinded manner. We described severe pulmonary AEs and examined associations of baseline characteristics with pulmonary AEs in patients receiving low-dose MTX. RESULTS A total of 2,391 subjects were randomized to receive low-dose MTX and 2,395 to receive placebo. There were 13 severe pulmonary AEs (0.5%) and 7 cases of possible pneumonitis (0.3%) in the low-dose MTX group, compared to 8 (0.3%) and 1 (

Background: Osteoarthritis is a common inflammatory disorder with no disease-modifying therapies. Whether inhibition of interleukin-1β (IL-1β) can reduce the consequences of large joint osteoarthritis is unclear. Objective: To determine whether IL-1β inhibition with canakinumab reduces incident total hip or knee replacement (THR/TKR). Design: Exploratory analysis of a randomized trial. (ClinicalTrials.gov: NCT01327846) Setting: 1091 clinical sites in 39 countries. Participants: 10 061 CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) participants. Intervention: Random allocation to placebo or canakinumab (50, 150, or 300 mg) subcutaneously once every 3 months. Measurements: The primary and secondary outcomes were time to first incident THR/TKR and time to first occurrence of an osteoarthritis-related adverse event (AE). Data were obtained through blinded ascertainment of trial clinical and safety databases. Results: Median follow-up was 3.7 years. For the individual canakinumab dose groups, compared with placebo, hazard ratios (HRs) for incident THR/TKR during follow-up were 0.60 (95% CI, 0.38 to 0.95) for the 50-mg group, 0.53 (CI, 0.33 to 0.84) for the 150-mg group, and 0.60 (CI, 0.38 to 0.93) for the 300-mg group. Thus, in the pooled canakinumab groups, compared with the placebo group, incidence rates for THR/TKR were 0.31 and 0.54 events per 100 person-years (HR, 0.58 [CI, 0.42 to 0.80]; P = 0.001), respectively. The HR for the secondary end point of osteoarthritis-related AEs was 0.73 (CI, 0.61 to 0.87). Similar findings were observed in analyses restricted to participants with a history of osteoarthritis. Limitation: Because the parent trial was not designed to examine the efficacy of IL-1β inhibitors in osteoarthritis, information on structural joint outcomes was not collected. Conclusion: Findings from this exploratory analysis of a randomized controlled trial support further investigation of IL-1β inhibition for treatment of large joint osteoarthritis. Primary Funding Source: Novartis Pharmaceuticals.

BACKGROUND: Less than half of patients with cardiometabolic disease consistently take prescribed medications. While health insurers and some delivery organizations use claims to measure adherence, most clinicians do not have access during routine interactions. Self-reported scales exist, but their practical utility is often limited by length or cost. By contrast, the accuracy of a new 3-item self-reported measure has been demonstrated in individuals with HIV. We evaluated its concordance with claims-based adherence measures in cardiometabolic disease. METHODS: We used data from a recently-completed pragmatic trial of patients with cardiometabolic conditions. After 12 months of follow-up, intervention subjects were mailed a survey with the 3-item measure that queries about medication use in the prior 30 days. Responses were linearly transformed and averaged. Adherence was also measured in claims in Month 12 and Months 1–12 of the trial using proportion of days covered (PDC) metrics. We compared validation metrics for non-adherence for self-report (average

Background Rates of statin use among minority women are unclear. Hypothesis We hypothesized that statin use would vary by race/ethnicity with lower rates among minority women compared with Whites. Methods Data from the study of women's health across the nation, a multiethnic cohort of women collected between 2009 to 2011 were used to examine reported statin use by race/ethnicity and risk profile. Multivariable logistic modeling was performed to estimate the odds ratio (OR) of statin treatment. Results Of the 2399 women included, 234 had a diagnosis of atherosclerotic disease (ASCVD), 254 were diabetic (without ASCVD), 163 had an LDL ≥190 mg/dL, and 151 had a 10 year ASCVD pooled risk score ≥7.5%. Statins were used by 49.6% of women with CVD; 59.8% of women with diabetes without known ASCVD; 42.3% of women with an LDL ≥190 mg/dL; and 19.9% of women with an ASCVD risk ≥7.5%. Rates of statin use were 43.8% for women with ≥ two prior ASCVD events and 69.4% for women with ≥ one prior ASCVD event plus multiple high‐risk conditions. Among women eligible for statins, Black women had a significantly reduced adjusted odds of being on a statin (OR 0.53, 95% confidence interval [CI] 0.36‐0.78) compared with White women. Conclusions In this cohort of multiethnic women, rates of statin use among women who would benefit were low, with Black women having lower odds of statin use than White women.

Purpose Sleep disturbances are common, particularly in middle aged women. Prescription medications for this indication are increasingly used, despite uncertain safety. This study assessed prescription medication use for sleep among a cohort of women with and without sleep disturbances. Methods We examined reports of sleep disturbance and sleep medication use among pre- and early peri-menopausal womenassessed annually or biennially since 1996. Women self-reported medications at visits, and we identified medications that have been used primarily for sleep disturbances. They reported on difficulties falling and staying asleep, and early morning wakening. Sleep medication use across 20 years of follow-up was examined for all women and by race/ethnicity. Women who reported data for both sleep disturbance and sleep medication use were included in the analyses.. Results Among participants in a cohort of 3302 women who were enrolled prior to their menopause transition, 3082 women were included in the analytic sample and 2531 (82%) reported sleep disturbances. They were more likely to endorse higher anxiety and pain scores and more comorbid conditions than women without sleep disturbances. Baseline characteristics were similar among women who did and did not use sleep medications. Among women reporting a sleep disturbance at baseline, 2.5% reported sleep medication use, increasing to 8% over 20 years. However, the proportion of women reporting sleep medication use who did not report a sleep disturbance remained low, approximately 1% to 2% over the entire follow-up. Increases in sleep medication use was observed across women of all race/ethnicities. Conclusions The use of sleep medications among women reporting sleep disturbance grew over the last 20 years. Growth was observed across women of all race/ethnicities.

Erosion healing in rheumatoid arthritis (RA) is difficult to demonstrate. This extension study aimed to determine whether 2 years of teriparatide (TPTD) produces erosion healing. Subjects in a prev...

OBJECTIVE Methotrexate (MTX) increases the risk of alopecia and stomatitis, but the prevalence of these adverse events among rheumatic patients taking MTX is poorly defined. We conducted a systematic literature review and meta-analysis to estimate the prevalence of alopecia and stomatitis with MTX in rheumatic diseases. METHODS We searched PubMed, The Cochrane Library, and CINAHL databases for double-blind randomized controlled trials (RCTs) with an MTX monotherapy arm. Alopecia, stomatitis, and oral/mouth ulcers data were extracted. The quality of trials was assessed by 2 authors. We included trials published since 1990 that used at least 10 mg of MTX weekly, coadministered with folic or folinic acid. We estimated the prevalence using random-effects models because heterogeneity was anticipated. Two estimates of prevalence were included; the lower bound estimate included all trials (assuming no alopecia and stomatitis if not mentioned), and the upper bound estimate included only those that specifically described prevalence estimates of alopecia or stomatitis. RESULTS Of 3,954 studies identified, 20 RCTs were included, with a total of 24 MTX monotherapy arms, of which 10 reported the prevalence of alopecia (n = 1,113), and 21 reported stomatitis or mouth/oral ulcers (n = 2,056). The prevalence of alopecia was between 1.0% and 4.9%. The prevalence of stomatitis was between 5.7% and 8.0%. CONCLUSION This meta-analysis gives more precise estimates of mucocutaneous adverse events that occur in rheumatic disease patients taking MTX. These estimates will help inform patient decision-making regarding MTX.

The past decade in rheumatology has seen tremendous innovation in digital health technologies, including the electronic health record, virtual visits, mobile health, wearable technology, digital therapeutics, artificial intelligence and machine learning. The increased availability of these technologies offers opportunities for improving important aspects of rheumatology, including access, outcomes, adherence and research. However, despite its growth in some areas, particularly with non-health-care consumers, digital health technology has not substantially changed the delivery of rheumatology care. This Review discusses key barriers and opportunities to improve application of digital health technologies in rheumatology. Key topics include smart design, voice enablement and the integration of electronic patient-reported outcomes. Smart design involves active engagement with the end users of the technologies, including patients and clinicians through focus groups, user testing sessions and prototype review. Voice enablement using voice assistants could be critical for enabling patients with hand arthritis to effectively use smartphone apps and might facilitate patient engagement with many technologies. Tracking many rheumatic diseases requires frequent monitoring of patient-reported outcomes. Current practice only collects this information sporadically, and rarely between visits. Digital health technology could enable patient-reported outcomes to inform appropriate timing of face-to-face visits and enable improved application of treat-to-target strategies. However, best practice standards for digital health technologies do not yet exist. To achieve the potential of digital health technology in rheumatology, rheumatology professionals will need to be more engaged upstream in the technology design process and provide leadership to effectively incorporate the new tools into clinical care. Digital health technologies (DHTs) have a variety of interesting current and possible future applications in rheumatology. In this article, the authors describe some of the key barriers that prevent DHT integration into rheumatology care and discuss ways in which these barriers could be addressed.

Objectives Electronic patient-reported outcomes (ePROs) transmitted digitally allow patients to communicate with their clinicians and track the activity of chronic diseases, such as RA. Several ePRO smartphone apps have been developed in rheumatology, yet few data have been reported regarding patient adherence. We developed a PRO app for RA and assessed adherence over 6 months. Methods We developed an app to deliver daily assessments to participants (RA App v.1.0). The app was tested as part of a randomized controlled trial examining potential clinical benefits. The current analyses focus on the adherence to the ePRO app for patients randomized to receive the app. We recruited RA patients from an academic rheumatology practice in the USA. Patients randomized to receive the app received daily notifications regarding ePROs. We examined adherence to the PRO questionnaires over the 6-month study and examined factors related to adherence. Results Seventy-eight patients received the app and have data included in these analyses: 63 (80.7%) were female, mean age was 55.2 years, 71% had attended college or beyond, and the mean Clinical Disease Activity Index at baseline was 9.7 (low disease activity). Median adherence to the daily questions was 79% (interquartile range 48–90%). Significant predictors of increased adherence were age ≥65 (P = 0.03) and low baseline Clinical Disease Activity Index (P = 0.02). Conclusion We developed and tested an ePRO app for RA over a 6-month study. Adherence to the app was strong. There was correlation between older age and better disease control and increased adherence. Trial registration ClinicalTrials.gov, https://clinicaltrials.gov/, NCT02822521.

Objective We previously derived and validated a risk score for major nonsteroidal anti-inflammatory drug (NSAID) toxicity over 1 year among NSAID users in a randomized controlled trial. This work was extended to examine the risk score's performance in an external population using real-world data. Methods Patients enrolled in the Corrona Rheumatoid Arthritis (RA) Registry were included if they initiated use of an NSAID. We defined the original risk factors previously identified in the risk score for major NSAID toxicity: age; male sex; history of cardiovascular disease, hypertension, and diabetes; tobacco use; statin use; elevated serum creatinine and hematocrit values; and RA. Additionally, we defined the occurrence of major toxicity, including major adverse cardiovascular events, acute kidney injury, significant gastrointestinal events, and mortality. The original risk factors were assessed in Cox regression examining discrimination and calibration. Low (less than 1%), intermediate (1%-4%), and high (more than 4%) risk categories for 1-year risk were applied to the population. Results A total of 5231 patients from Corrona who had a new NSAID exposure period were included. The original risk score model showed good discrimination (C-index 0.70). Not all of the original variables were statistically significant in real-world data. Using the original risk score weights, 1363 (26.1%) patients had predicted risk of less than 1%, 3571 (68.3%) had predicted risk of 1% to 4%, and 297 (5.7%) had predicted risk of more than 4%. Conclusion The original NSAID major toxicity risk score demonstrated good model fit characteristics in this external real-world cohort. These results suggest that such a risk score is valid in typical practice and could be considered for clinical care.

Academic institutions play an essential role in providing physicians with the necessary skills needed to improve the quality and value of care provided. The Accreditation Council for Graduate Medical Education has several milestones in the curriculum of fellowship programs that prioritize involvement in quality improvement (QI) and patient safety efforts. This article reviews the unique benefits and challenges of involving and teaching fellows to conduct QI initiatives. Strategies and resources available to overcome these challenges and develop a successful quality driven training environment are outlined in this article.

Context Discontinuation of denosumab leads to a rapid reversal of its therapeutic effect. However, there are no data regarding how unintended delays or missed injections of denosumab impact bone mineral density (BMD) response. Objective We examined the association of delays in injections of denosumab with BMD change. Design We used electronic medical records from two academic hospitals from 2010 to 2017. Participants Patients older than 45 years of age and used at least 2 doses of 60 mg denosumab. Denosumab adherence was evaluated by the medication coverage ratio (MCR). Good adherence corresponds to a dosing interval ≤7 months (defined by MCR ≥93%), moderate adherence corresponds to an interval of 7 to 10 months (MCR 75%–93%), and poor adherence corresponds to an interval ≥10 months (MCR ≤75%). Outcome Measures Annualized percent BMD change from baseline at the lumbar spine, total hip, and femoral neck. Results We identified 938 denosumab injections among 151 patients; the mean (SD) age was 69 (10) years, and 95% were female. Patients with good adherence had an annualized BMD increase of 3.9% at the lumbar spine, compared with patients with moderate (3.0%) or poor adherence (1.4%, P for trend .002). Patients with good adherence had an annualized BMD increase of 2.1% at the total hip, compared with patients with moderate (1.3%) or poor adherence (0.6%, P for trend .002). Conclusions A longer interval between denosumab injections is associated with suboptimal BMD response at both spine and total hip. Strategies to improve the timely administration of denosumab in real-world settings are needed.

Objective Most patients with rheumatoid arthritis (RA) strive to consolidate their treatment from methotrexate combinations. The objective of this analysis was to identify patients with RA most likely to achieve remission with tocilizumab (TCZ) monotherapy by developing and validating a prediction model and associated remission score. Methods We identified four TCZ monotherapy randomized controlled trials in RA and chose two for derivation and two for internal validation. Remission was defined as a Clinical Disease Activity Index score less than 2.8 at 24 weeks post randomization. We used logistic regression to assess the association between each predictor and remission. After selecting variables and assessing model performance in the derivation data set, we assessed model performance in the validation data set. The cohorts were combined to calculate a remission prediction score. Results The variables selected included younger age, male sex, lower baseline Clinical Disease Activity Index score, shorter RA disease duration, region of the world (Europe and South America [increased odds of remission] versus Asia and North America), no previous exposure to disease-modifying antirheumatic drugs and/or methotrexate, lower baseline Health Assessment Questionnaire Disability Index score, and baseline hematocrit. The area under the receiver operating characteristic curve was 0.739 in the derivation data set and 0.756 in the validation data set. Patients were categorized into three remission prediction categories based on the remission prediction score: 40% in the low (less than 10% probability of remission), 45% in the intermediate (10%-25% probability), and 15% in the moderate remission prediction category (greater than 25% probability). Conclusion We used easily accessible factors to develop a remission prediction score to predict RA remission at 24 weeks after initializing TCZ monotherapy. These results may provide guidance to clinicians tailoring treatment options based on clinical characteristics.

ObjectiveLong-term adherence to evidence-based medications in cardiometabolic diseases remains poor, despite extensive efforts to develop and test interventions and deploy clinician performance incentives. The limited success of interventions may be due to ignored factors such as patients’ experience of medication-taking. Despite being potentially addressable by clinicians, these factors have not been sufficiently explored, which is particularly important as patients use increasing numbers of medications. The aim is to explore patient perspectives on medication-taking, medication properties that are barriers to adherence, and coping strategies for their medication regimen.DesignIndividual, in-person, semistructured qualitative interviews.SettingUrban healthcare system.ParticipantsTwenty-six adults taking ≥2 oral medications for diabetes, hypertension or hyperlipidaemia with non-adherence. Interviews were digitally recorded and transcribed. Data were analysed using developed codes to generate themes. Representative quotations were selected to illustrate themes.ResultsParticipants’ mean age was 55 years, 46% were female and 39% were non-white. Six key themes were identified: (1) medication-taking viewed as a highly inconvenient action (that patients struggle to remember to do); (2) negative implications because of inconvenience or illness perceptions; (3) actual medication regimens can deviate substantially from prescribed regimens; (4) certain medication properties (especially size and similar appearance with others) may contribute to adherence deviations; (5) development of numerous coping strategies to overcome barriers and (6) suggestions to make medication-taking easier (including reducing drug costs, simplifying regimen or dosing frequency and creating more palatable medications).ConclusionPatients with poor adherence often find taking prescription medications to be undesirable and take them differently than prescribed in part due to properties of the medications themselves and coping strategies they have developed to overcome medication-taking challenges. Interventions that reduce the inconvenience of medication use and tailor medications to individual needs may be a welcome development.

In rheumatoid arthritis (RA), there are limited data on risk factors for the clinical heart failure (HF) subtypes of HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). This study examined the association between inflammation and incident HF subtypes in RA. Because inflammation changes over time with disease activity, we hypothesized that the effect of inflammation may be stronger at the 5-year follow-up than at the standard 10-year follow-up from general population studies of cardiovascular risk.We studied an electronic health record (EHR)-based RA cohort with data pre- and post-RA incidence. We applied a validated approach to identify HF and extract ejection fraction to classify HFrEF and HFpEF. Follow-up started from the RA incidence date (index date) to the earliest occurrence of incident HF, death, last EHR encounter, or 10 years. Baseline inflammation was assessed using erythrocyte sedimentation rate or C-reactive protein values. Covariates included demographic characteristics, established HF risk factors, and RA-related factors. We tested the association between baseline inflammation with incident HF and its subtypes using Cox proportional hazards models.We studied 9,087 patients with RA; 8.2% developed HF during 10 years of follow-up. Elevated inflammation was associated with increased risk for HF at both 5- and 10-year follow-ups (hazard ratio [HR] 1.66, 95% confidence interval [95% CI] 1.12-2.46 and HR 1.46, 95% CI 1.13-1.90, respectively), which is also seen for HFpEF at 5 years (HR 1.72, 95% CI 1.09-2.70) and 10 years (HR 1.45, 95% CI 1.07-1.94). HFrEF was not associated with inflammation for either follow-up time.Elevated inflammation early in RA diagnosis was associated with HF; this association was driven by HFpEF and not HFrEF, suggesting a window of opportunity for prevention of HFpEF in RA.

Calcium pyrophosphate deposition (CPPD) disease represents a common crystalline arthritis with a range of manifestations. Our goal was to investigate risks for cardiovascular events in patients with CPPD.We performed a retrospective matched cohort analysis in the Veterans Health Administration Corporate Data Warehouse, 2010-2014. CPPD was defined by ≥1 International Classification of Diseases, Ninth Revision codes for chondrocalcinosis or calcium metabolism disorder. CPPD patients were age- and sex-matched to approximately 4 patients without codes for CPPD; we excluded patients with a cardiovascular event during the 365 days prior to the index date. Demographic information, traditional cardiovascular risk factors, medications, and health care utilization were assessed at baseline. The primary outcome was a major adverse cardiovascular event (MACE: myocardial infarction, acute coronary syndrome, coronary revascularization, stroke, or death). Secondary outcomes included individual components of MACE. Cox proportional hazards models estimated fully adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs).We identified 23,124 CPPD patients matched to 86,629 non-CPPD patients with250,000 person-years of follow-up. The study population was 96% male, mean age was 78 years, and 75% were White. The frequency of traditional cardiovascular risk factors was similar between the 2 cohorts. CPPD was not significantly associated with risk for MACE (HR 0.98 [95% CI 0.94-1.02]) in fully adjusted models, though risks of myocardial infarction, acute coronary syndrome, and stroke were significantly higher in the CPPD cohort compared to the non-CPPD cohort.CPPD did not confer an increased risk for MACE, a composite end point including all-cause mortality. Our results propose CPPD as a novel risk factor for MACE components, including myocardial infarction, acute coronary syndrome, and stroke.

OBJECTIVE To examine the effects of a smartphone application (app) to monitor longitudinal electronic patient-reported outcomes (ePROs) on patient satisfaction and disease activity in patients with rheumatoid arthritis (RA). METHODS We conducted a 6-month randomized controlled trial of care coordination along with an app (intervention) versus care coordination alone (control) in 191 RA patients. Participants in the intervention group were prompted to provide information daily using ePROs. In both the intervention and control groups, a care coordinator contacted participants at 6 and 18 weeks to assess for flares. The main outcome measures were the global satisfaction score from the Treatment Satisfaction Questionnaire for Medication (TSQM), the score from the Perceived Efficacy in Patient-Physician Interactions (PEPPI) Questionnaire, and the Clinical Disease Activity Index (CDAI) score. RESULTS Groups were similar at baseline. The median TSQM score at 6 months was 83.3 in both groups, and the median PEPPI score at 6 months was 50 in both groups. The median CDAI score at 6 months was 8 in the intervention group versus 10 in the control group. No statistically significant group differences in the medians of TSQM, PEPPI, or CDAI scores at 6 months were detected. Of the 67 intervention participants who completed the exit survey, 90% rated their likelihood of recommending the app as ≥7 of 10. Of the 11 physicians who completed the exit survey, 73% agreed/strongly agreed that they wanted to continue offering the app to patients. CONCLUSION A mobile app designed to collect ePRO data on RA symptoms did not significantly improve patient satisfaction or disease activity compared to care coordination alone. However, both patients and physicians reported positive experiences with the app.

Objective.Systemic lupus erythematosus (SLE) is a multisystem chronic inflammatory autoimmune disease with high prevalence of several risk factors for atrial fibrillation/flutter (AF). However, the incidence and risk of AF in SLE have not been well quantified.Methods.We used the United States Medicaid Analytic eXtract from 2007 to 2010 to identify beneficiaries aged 18–65 years, with prevalent SLE, each matched by age and sex to 4 non-SLE general Medicaid recipients. We estimated the incidence rates (IR) per 1000 person-years (PY) for AF hospitalizations and used multivariable Cox regression to estimate the HR for AF hospitalization.Results.We identified 46,876 US Medicaid recipients with SLE, and 187,504 age- and sex-matched non-SLE controls (93% female; mean age 41.5 ± 12.2 yrs). Known AF risk factors such as hypertension (HTN), cardiovascular disease (CVD), and kidney disease were more prevalent in patients with SLE. During a mean followup of 1.9 ± 1.1 years for SLE, and 1.8 ± 1.1 years for controls, the IR per 1000 PY for AF was 1.4 (95% CI 1.1–1.6) among patients with SLE and 0.7 (95% CI 0.6–0.8) among non-SLE controls. In age- and sex-matched and race-adjusted Cox models, the HR for AF was 1.79 (95% CI 1.43–2.24); after adjustment for baseline HTN and CVD, the adjusted HR was reduced to 1.17 (95% CI 0.92–1.48).Conclusion.SLE was associated with a doubled rate of hospitalization for AF compared to age- and sex-matched general Medicaid patients. In a race-adjusted model, the risk was 80% higher. However, the AF risk factors HTN and CVD were more prevalent among patients with SLE and accounted for the excess risk.

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.

Objective Azathioprine (AZA) and mycophenolate mofetil (MMF) are immunosuppressants frequently used in the treatment of moderate-to-severe systemic lupus erythematosus (SLE). We studied longitudinal patterns and predictors of adherence to AZA and MMF in a nationwide US SLE cohort. Methods In the Medicaid Analytic eXtract (2000-2010) database, we identified patients with SLE who initiated AZA or MMF (no use in the prior 6 months) with ≥12 months of continuous follow-up. We dichotomized adherence at 80%, with ≥24 of 30 days per month considered adherent. We used group-based trajectory models to estimate monthly adherence patterns and multivariable multinomial logistic regression to determine the association between demographic, SLE and utilization-related predictors, and the odds ratios (OR) of belonging to a nonadherent versus the adherent trajectory, separately for AZA and MMF. Results We identified 2,309 AZA initiators and 2,070 MMF initiators with SLE. Four-group trajectory models classified 17% of AZA and 21% of MMF initiators as adherent. AZA and MMF nonadherers followed similar trajectory patterns. African American race (OR 1.67 [95% confidence interval (95% CI) 1.20-2.31]) and Hispanic ethnicity (OR 1.58 [95% CI 1.06-2.35]) increased odds of AZA nonadherence; there were no significant associations between race/ethnicity and MMF nonadherence. Male sex and polypharmacy were associated with lower odds of nonadherence to both medications; lupus nephritis was associated with lower odds of nonadherence to MMF (OR 0.74 [95% CI 0.55-0.99]). Conclusion Adherence to AZA or MMF over the first year of use was rare. Race, sex, and lupus nephritis were modestly associated with adherence, but the magnitude, direction, and significance of predictors differed by medication, suggesting the complexity of predicting adherence behavior.

Objectives To examine the rate of incident malignancies excluding non-melanoma skin cancer (NMSC) in patients with rheumatoid arthritis (RA) newly treated with tocilizumab versus other biologic drugs. Methods We conducted a cohort study using data from 3 U.S. insurance claims databases – Medicare (2010–2015), ‘IMS’ PharMetrics Plus (2011–2015) and Truven ‘MarketScan’ (2011–2015). Adults with RA who newly started tocilizumab or a TNF inhibitor (TNFi) after failing a different TNFi, abatacept or tofacitinib were included. The primary outcome was development of any malignancies excluding NMSC. For confounding control, tocilizumab starters were propensity score (PS)-matched to TNFi starters with a variable ratio of 1:3 within each database. Hazard ratios (HR) from the 3 PS-matched cohorts were combined by an inverse variance-weighted, fixed-effects model. We conducted a secondary analysis where we compared tocilizumab initiators with abatacept initiators. Results We included 13,102 tocilizumab initiators PS-matched to 26,727 TNFi initiators in all three databases. The incidence rate of malignancies per 1,000 person-years ranged from 8.27 (IMS) to 23.18 (Medicare) in the tocilizumab group and from 9.64 (MarketScan) to 21.46 (Medicare) in the TNFi group. The risk of incident malignancies was similar between tocilizumab and TNFi initiators across all three databases, with a combined HR of 0.98 (95%CI 0.80–1.19) in tocilizumab versus TNFi. The secondary analysis comparing tocilizumab versus abatacept showed similar results (combined HR 0.97, 95%CI 0.74–1.27). Conclusions This large multi-database cohort study found no difference in the risk of malignancies excluding NMSC in RA patients who newly started tocilizumab compared with TNFi or abatacept.

Summary Objective To examine patterns of prescription opioid use before total joint replacement (TJR) and factors associated with continuous use of opioids before TJR. Design We conducted an observational cohort study among Medicare enrollees aged ≥65 years who underwent TJR between 2010 and 2014. Preoperative opioid use was defined as having any opioid prescription in the 12-month period before TJR. Patients who had an opioid prescription every month for a 12-month period were defined as continuous users. We examined patients' demographics, pain-related conditions, medication use, other comorbidities, healthcare utilization and their association with use of opioids before TJR. Results A total of 473,781 patients underwent TJR:,155,516 THR and 318,265 TKR. Among the total cohort, 60.2% patients had any use of opioids and of those, 12.4% used opioids at least once a month continuously over the 12-month baseline period. Correlates of continuous opioid use included African American race (OR = 2.14, 95% confidence intervals (CI) = 2.01–2.28, compared to White patients), history of drug abuse (OR = 5.18, 95% CI = 3.95–6.79) and back pain (OR = 2.32, 95% CI = 2.24–2.39). Conclusions In this large cohort of patients undergoing TJR, over 60% ever used opioids and 12.4% of them continuously used opioids in the 12-month prior to surgery. Utilization of opioids became more frequent and high-dosed near the surgery. History of drug abuse, back pain, and African American race were strongly associated with continuous use of opioids preoperatively. Further research is needed to determine short-term and long-term risks of preoperative use of opioids in TJR patients and to optimize pre- and post-TJR pain management of patients with arthritis.

While nonsteroidal antiinflammatory drugs (NSAIDs) are commonly used in rheumatology, they can cause major toxicity. Improving the risk/benefit ratio requires a more precise understanding of risk. This study was undertaken to derive and validate a risk score for major toxicity among NSAID users enrolled in a randomized controlled trial.Patients enrolled in a randomized controlled trial who had known cardiovascular disease or risk factors as well as osteoarthritis or rheumatoid arthritis were divided into derivation and validation cohorts. Patients were randomized to receive celecoxib, naproxen, or ibuprofen at typical dosages. The risk score was designed to predict the 1-year occurrence of major toxicity among NSAID users, including major adverse cardiovascular events, acute kidney injury, significant gastrointestinal events, and mortality. Variables significantly associated with major toxicity were candidates for inclusion in the final regression model. After derived models were found to have a similar model fit in the validation set, the cohorts were combined, allowing calculation of a risk score.In the derivation cohort, significant variables included age, male sex, history of cardiovascular disease, hypertension, diabetes mellitus, tobacco use, statin use, elevated serum creatinine level, hematocrit level, and type of arthritis. The C-index was 0.73 in the validation cohort and 0.71 in the total cohort; the model was well calibrated. Of the total population with complete data (n = 23,735), 1,080 participants (4.6%) had a predicted 1-year risk of major toxicity of1%, 16,273 (68.6%) had a predicted risk of 1-4%, and 6,382 (26.9%) had a predicted risk of4%.The risk score accurately categorizes the 1-year risk of major toxicity among NSAID users and may be useful in identifying patients who can safely use these agents.

Purpose In observational research, equipoise concerns whether groups being compared are similar enough for valid inference. Empirical equipoise was previously proposed as a tool to assess patient similarity based on propensity scores (PS). We extended this work for multigroup observational studies. Methods We modified the tool to allow for multinomial exposures such that the proposed definition reduces to the original when there are only two groups. We illustrated how the tool can be used as a method to assess study design within three-group clinical examples. We then conducted three-group simulations to assess how the tool performed in a setting with residual confounding after PS weighting. Results In a clinical example based on rheumatoid arthritis, 44.5% of the sample fell within the region of empirical equipoise when considering first-line biologics, whereas 57.7% did so for second-line biologics, consistent with the expectation that a second-line design results in better equipoise. In a simulation where the unmeasured confounder had the same magnitude of association with the treatment as the measured confounders and a 25% greater association with the outcome, the tool crossed the proposed threshold for empirical equipoise at a residual confounding of 20% on the ratio scale. When the unmeasured variable had a twice larger association with treatment, the tool became less sensitive and crossed the threshold at a residual confounding of 30%. Conclusion Our proposed tool may be useful in guiding cohort identification in multigroup observational studies, particularly with similar effects of unmeasured and measured covariates on treatment and outcome.

Objective Systemic lupus erythematosus (SLE), which is associated with increased stroke risk, is more prevalent and often more severe among Blacks, Asians, and Hispanics than Whites. We examined racial/ethnic variation in stroke rates and risks, overall and by hemorrhagic versus ischemic subtype, among SLE patients. Methods Within Medicaid (2000–2010), we identified patients aged 18–65 with SLE (≥ 3 ICD-9 710.0 codes, ≥ 30days apart) and ≥12 months of continuous enrollment. Subjects were followed from index date to first stroke event, death, disenrollment, or end of follow-up. Race/ethnicity-specific annual event rates were calculated for stroke overall and by subtypes (hemorrhagic vs. ischemic). We used Cox proportional hazard models to estimate hazard ratios (HR) of stroke by race/ethnicity, adjusting for comorbidities and the competing risk of death. Results Of 65,788 SLE patients, 93.1% were female. Racial/ethnic breakdown was 42% Black, 38% White, 16% Hispanic, 3% Asian, and 1% American Indian/Alaska Natives. Mean follow-up was 3.7 ± 3.0years. After multivariable adjustment, Blacks were at increased risk of overall stroke (HR 1.34 [95%CI 1.18–1.53), hemorrhagic stroke (HR 1.42 [1.00–2.01]), and ischemic stroke (HR 1.33 [1.15–1.52]) compared to Whites. Hispanics were at increased risk of overall stroke (HR 1.25 [1.06–1.47)] and hemorrhagic stroke (HR 1.79 [95% CI 1.22–2.61]), but not ischemic stroke, compared to Whites. Conclusion Among SLE patients enrolled in Medicaid, we observed elevated stroke risk (overall and by subtype) among Blacks and Hispanics compared to Whites, suggesting the importance of early recognition and screening for stroke risk factors among Blacks and Hispanics.

Objective The opioid epidemic is a major public health concern. However, little is known about opioid use among rheumatoid arthritis (RA) patients. We undertook this study to examine trends in chronic opioid use in RA patients in 2002-2015 and to identify clinical predictors. Methods RA patients were identified from the Corrona registry. Opioid use was ascertained from surveys obtained at clinical visits as often as every 3 months. Chronic opioid use was defined as any opioid use reported during ≥2 consecutive study visits. Annual prevalence of chronic opioid use was calculated using data from 33,739 RA patients with information on opioid use from ≥2 visits. Among the 26,288 individuals who were not taking opioids at baseline, Cox proportional hazards models identified associations between patient characteristics and incident chronic opioid use. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated. Results Chronic opioid use increased from 7.4% in 2002 to 16.9% in 2015. Severe pain (HR 2.53 [95% CI 2.19-2.92]) and antidepressant use (HR 1.79 [95% CI 1.64-1.92]) were associated with an increased risk of chronic opioid use. High disease activity (HR 1.55 [95% CI 1.30-1.84]) and a high level of disability (HR 1.45 [95% CI 1.27-1.65]) were also associated with chronic opioid use, whereas Asian ethnicity (HR 0.49 [95% CI 0.36-0.68]) was associated with a decreased risk of chronic opioid use. Conclusion Among RA patients, chronic opioid use doubled from 2002 to 2015. Pain and antidepressant use were the strongest predictors of chronic opioid use. To curb the rise in chronic opioid use, strategies for stringent control of RA disease activity and management of pain and depression should be research priorities.

Objective To examine disease-modifying antirheumatic drug (DMARD) treatments and estimate the risk of a subsequent cardiovascular (CV) event following an initial CV event in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), or psoriasis. Methods We analyzed data from MarketScan claims databases (January 1, 2006 to June 30, 2015) for adults with RA, PsA, or psoriasis and an initial/index CV event (acute myocardial infarction, stroke, or coronary revascularization) while receiving DMARDs (tumor necrosis factor inhibitor [TNFi] biologic DMARDs [bDMARDs], conventional synthetic DMARDs [csDMARDs], or non-TNFi bDMARDs). We studied DMARD treatment patterns following the index event and rates of subsequent CV events. We used Cox regression to investigate predictors of DMARD discontinuation and risk factors for subsequent CV events. Results Among 10,254 patients, 15.3% discontinued and 15.5% switched DMARD therapy after the index CV event. Independent predictors of DMARD discontinuation included a psoriasis diagnosis, renal disease, hypertension, heart failure, diabetes mellitus, older age, and baseline csDMARD or non-TNFi bDMARD use (versus TNFi bDMARDs). Rates per 1,000 patient-years of subsequent events were 75.2 (95% confidence interval [95% CI] 54.4-96.0) for patients taking TNFi bDMARDs, 83.6 (95% CI 53.3-113.9) for csDMARDs, and 122.4 (95% CI 60.6-184.3) for non-TNFi bDMARDs. A diagnosis of RA (versus psoriasis) and heart failure at baseline, but not a DMARD pattern after the index event, were independently associated with an increased risk of subsequent CV event. Conclusion In this large nationwide study, nearly one-third of patients with RA, PsA, or psoriasis switched or discontinued DMARD therapy following a CV event. There was no association between DMARD class and the risk of a subsequent CV event.

BACKGROUND: Inflammation is causally related to atherothrombosis. Treatment with canakinumab, a monoclonal antibody that inhibits inflammation by neutralizing interleukin-1β, resulted in a lower rate of cardiovascular events than placebo in a previous randomized trial. We sought to determine whether an alternative approach to inflammation inhibition with low-dose methotrexate might provide similar benefit. METHODS: We conducted a randomized, double-blind trial of low-dose methotrexate (at a target dose of 15 to 20 mg weekly) or matching placebo in 4786 patients with previous myocardial infarction or multivessel coronary disease who additionally had either type 2 diabetes or the metabolic syndrome. All participants received 1 mg of folate daily. The primary end point at the onset of the trial was a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Near the conclusion of the trial, but before unblinding, hospitalization for unstable angina that led to urgent revascularization was added to the primary end point. RESULTS: The trial was stopped after a median follow-up of 2.3 years. Methotrexate did not result in lower interleukin-1β, interleukin-6, or C-reactive protein levels than placebo. The final primary end point occurred in 201 patients in the methotrexate group and in 207 in the placebo group (incidence rate, 4.13 vs. 4.31 per 100 person-years; hazard ratio, 0.96; 95% confidence interval [CI], 0.79 to 1.16). The original primary end point occurred in 170 patients in the methotrexate group and in 167 in the placebo group (incidence rate, 3.46 vs. 3.43 per 100 person-years; hazard ratio, 1.01; 95% CI, 0.82 to 1.25). Methotrexate was associated with elevations in liver-enzyme levels, reductions in leukocyte counts and hematocrit levels, and a higher incidence of non–basal-cell skin cancers than placebo. CONCLUSIONS: Among patients with stable atherosclerosis, low-dose methotrexate did not reduce levels of interleukin-1β, interleukin-6, or C-reactive protein and did not result in fewer cardiovascular events than placebo. (Funded by the National Heart, Lung, and Blood Institute; CIRT ClinicalTrials.gov number, NCT01594333.)

Objectives While tocilizumab may increase serum lipid levels, recent studies do not suggest a link between tocilizumab use and clinical cardiovascular risk in patients with rheumatoid arthritis (RA). Methods To compare cardiovascular safety of tocilizumab with abatacept, we conducted a cohort study using data from Medicare (2010–2013), IMS PharMetrics (2011–2014) and MarketScan (2011-6/2015). RA patients aged ≥18 years who newly started tocilizumab or abatacept entered the cohort on the day of their first use of tocilizumab or abatacept after a continuous enrollment period for ≥365 days. The primary outcome was a composite cardiovascular endpoint of hospitalization for myocardial infarction or stroke. To control for more than 60 confounders, tocilizumab starters were propensity score (PS)-matched to abatacept starters with a variable ratio of 1:3 within each database. A fixed-effects model combined database-specific hazard ratios (HR). Results We included 6237 tocilizumab starters PS-matched to 14,685 abatacept starters in all three databases. Mean age was 72 years in Medicare, 51 in PharMetrics and 53 in MarketScan. The incidence rate of the composite cardiovascular events per 100 person-years ranged from 0.37 (PharMetrics) to 1.64 (Medicare) in the tocilizumab group and from 0.59 (PharMetrics) to 1.69 (Medicare) in the abatacept group. The risk of the composite cardiovascular events was similar between the two groups across all three databases, with a combined HR of 0.82 (95% CI: 0.55–1.22) in tocilizumab versus abatacept starters. Conclusions This multi-database cohort study found no difference in the risk of cardiovascular events in RA patients who newly started tocilizumab versus abatacept.

This randomized trial compares the effects of half-dose conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) vs stable-dose csDMARDs on the risk of flares in patients with rheumatoid arthritis in sustained remission.Importance Sustained remission has become an achievable goal for patients with rheumatoid arthritis (RA) receiving conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), but how to best treat patients in clinical remission remains unclear. Objective To assess the effect of tapering of csDMARDs, compared with continuing csDMARDs without tapering, on the risk of flares in patients with RA in sustained remission. Design, Setting, and Participants ARCTIC REWIND was a multicenter, randomized, parallel, open-label noninferiority study conducted in 10 Norwegian hospital-based rheumatology practices. A total of 160 patients with RA in remission for 12 months who were receiving stable csDMARD therapy were enrolled between June 2013 and June 2018, and the final visit occurred in June 2019. Interventions Patients were randomly assigned to half-dose csDMARDs (n = 80) or stable-dose csDMARDs (n = 80). Main Outcomes and Measures The primary end point was the proportion of patients with a disease flare between baseline and the 12-month follow-up, defined as a combination of Disease Activity Score (DAS) greater than 1.6 (threshold for RA remission), an increase in DAS score of 0.6 units or more, and at least 2 swollen joints. A disease flare could also be recorded if both the patient and investigator agreed that a clinically significant flare had occurred. A risk difference of 20% was defined as the noninferiority margin. Results Of 160 enrolled patients (mean [SD] age, 55.1 [11.9] years; 66% female), 156 received the allocated therapy, of which 155 without any major protocol violations were included in the primary analysis population (77 receiving half-dose and 78 receiving stable-dose csDMARDs). Flare occurred in 19 patients (25%) in the half-dose csDMARD group compared with 5 (6%) in the stable-dose csDMARD group (risk difference, 18% [95% CI, 7%-29%]). Adverse events occurred in 34 patients (44%) in the half-dose group and 42 (54%) in the stable-dose group, none leading to study discontinuation. No deaths occurred. Conclusions and Relevance Among patients with RA in remission taking csDMARD therapy, treatment with half-dose vs stable-dose csDMARDs did not demonstrate noninferiority for the percentage of patients with disease flares over 12 months, and there were significantly fewer flares in the stable-dose group. These findings do not support treatment with half-dose therapy.Question In patients with rheumatoid arthritis in remission taking conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), is reducing the csDMARDs to half dose noninferior to stable csDMARD dosage for the outcome of rheumatoid arthritis flares? Findings In this randomized clinical trial that included 160 patients with rheumatoid arthritis in remission taking csDMARD therapy, treatment with half-dose vs stable-dose csDMARDs resulted in disease flares in 25% vs 6% over 12 months; this did not meet the noninferiority criterion of a 20% difference. There were significantly fewer patients with flares in the stable-dose group. Meaning These findings do not support the use of half-dose treatment in patients with rheumatoid arthritis in remission taking csDMARDs.

BACKGROUND: Low-dose methotrexate (LD-MTX) is contraindicated in advanced CKD, but kidney safety in normal kidney function or mild-to-moderate CKD is less clear. METHODS: We performed a secondary analysis for eGFR and kidney AEs using the randomized double-blind, placebo-controlled Cardiovascular Inflammation Reduction Trial. Adults with cardiovascular disease and diabetes and/or metabolic syndrome were randomly allocated to oral LD-MTX (target dose 15–20 mg/week) or placebo. All participants took folic acid 1 mg 6 days/week. Exclusion criteria included systemic rheumatic disease and creatinine clearance

ObjectiveTocilizumab (TCZ) has shown similar efficacy when used as monotherapy as in combination with other treatments for rheumatoid arthritis (RA) in randomized controlled trials (RCTs). We derived a remission prediction score for TCZ monotherapy (TCZm) using RCT data and performed an external validation of the prediction score using real-world data (RWD).MethodsWe identified patients in the Corrona RA registry who used TCZm (n = 452), and matched the design and patients from 4 RCTs used in previous work (n = 853). Patients were followed to determine remission status at 24 weeks. We compared the performance of remission prediction models in RWD, first based on variables determined in our prior work in RCTs, and then using an extended variable set, comparing logistic regression and random forest models. We included patients on other biologic disease-modifying antirheumatic drug monotherapies (bDMARDm) to improve prediction.ResultsThe fraction of patients observed reaching remission on TCZm by their follow-up visit was 12% (n = 53) in RWD vs 15% (n = 127) in RCTs. Discrimination was good in RWD for the risk score developed in RCTs, with area under the receiver-operating characteristic curve (AUROC) of 0.69 (95% CI 0.62–0.75). Fitting the same logistic regression model to all bDMARDm patients in the RWD improved the AUROC on held-out TCZm patients to 0.72 (95% CI 0.63–0.81). Extending the variable set and adding regularization further increased it to 0.76 (95% CI 0.67–0.84).ConclusionThe remission prediction scores, derived in RCTs, discriminated patients in RWD about as well as in RCTs. Discrimination was further improved by retraining models on RWD.

Background There are numerous non-biologic and biologic disease-modifying anti-rheumatic drugs (bDMARDs) for rheumatoid arthritis (RA). Typical sequences of bDMARDs are not clear. Future treatment policies and trials should be informed by quantitative estimates of current treatment practice. Methods We used data from Corrona, a large real-world RA registry, to develop a method for quantifying sequential patterns in treatment with bDMARDs. As a proof of concept, we study patients who eventually use tocilizumab monotherapy (TCZm), an IL-6 antagonist with similar benefits used as monotherapy or in combination. Patients starting a bDMARD were included and were followed using a discrete-state Markov model, observing changes in treatments every 6 months and determining whether they used TCZm. A supervised machine learning algorithm was then employed to determine longitudinal patient factors associated with TCZm use. Results 7300 patients starting a bDMARD were followed for up to 5 years. Their median age was 58 years, 78% were female, median disease duration was 5 years, and 57% were seropositive. During follow-up, 287 (3.9%) reported use of TCZm with median time until use of 25.6 (11.5, 56.0) months. Eighty-two percent of TCZm use began within 3 years of starting any bDMARD. Ninety-three percent of TCZm users switched from TCZ combination, a TNF inhibitor, or another bDMARD. Very few patients are given TCZm as their first DMARD (0.6%). Variables associated with the use of TCZm included prior use of TCZ combination therapy, older age, longer disease duration, seronegative, higher disease activity, and no prior use of a TNF inhibitor. Conclusions Improved understanding of treatment sequences in RA may help personalize care. These methods may help optimize treatment decisions using large-scale real-world data.

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).

Background: Coronary microvascular disease (CMD) is associated with increased mortality in rheumatoid arthritis (RA). Studies suggest that higher RA disease activity is associated with a higher degree of CMD. However, it is not known whether specific inflammatory pathways implicated in RA play a stronger role than others in the pathogenesis of CMD. The objective of this study was to identify the associations between inflammatory cytokines, CMD, and resultant myocardial injury. Methods: We used baseline data from the first 53 subjects enrolled in a study of RA and CV risk (LiiRA, NCT02714881). LiiRA enrolls RA patients, age>35, prior to TNF inhibitor initiation. All subjects underwent a stress myocardial perfusion PET scan to quantify coronary flow reserve (CFR). CFR is the ratio of myocardial blood flow during maximal hyperemia over that at rest. A lower CFR in the absence of obstructive coronary artery disease (CAD) is indicative of CMD. We tested the association between markers of inflammation and myocardial injury with CFR using the Spearman correlation. Results: Clinical characteristics of LiiRA subjects are shown in Table 1. Baseline cardiac risk factors were uncommon. IL-6, sTNFR2, NT-proBNP were correlated with lower CFR. However, no significant associations were observed between IL-1β, hsCRP, or hs-cTnT (Table 2). Conclusions: Among RA patients with no history of overt CAD, the severity of CMD was correlated with IL-6 and sTNFR2 but not IL-1β or hsCRP. CMD was further associated with increased levels of NT-proBNP but not hs-cTnT. These findings provide potential insight into the mechanisms by which inflammation mediates CMD and resultant myocardial dysfunction.

Some in the medical publishing world have observed an “infodemic” occurring alongside the pandemic. One might define an infodemic as a contagious disease infecting our information culture. As the Editors of A&R, tasked with conducting, reviewing, reporting, and translating science to the rheumatic disease community, we agree with this diagnosis. Herein, we reflect on how the pandemic has impacted A&R, the medical publishing world, and how we may best engage our community to navigate current challenges.

ObjectivesTarget trial emulation is an intuitive design framework that encourages investigators to formulate their comparative effectiveness research (CER) question as a hypothetical randomised controlled trial (RCT). Our aim was to systematically review CER studies in rheumatoid arthritis (RA) to provide examples of design limitations that could be avoided using target trial emulation, and how these limitations might introduce bias.MethodsWe searched for head-to-head CER studies of biologic disease modifying anti-rheumatic drugs (DMARDs) in RA. Study designs were reviewed for seven components of the target trial emulation framework: eligibility criteria, treatment strategies, assignment procedures, follow-up period, outcome, causal contrasts of interest (ie, intention-to-treat (ITT) or per-protocol effect) and analysis plan. Hypothetical trials corresponding to the reported methods were assessed to identify design limitations that would have been avoided with an explicit target trial protocol. Analysis of the primary effectiveness outcome was chosen where multiple analyses were performed.ResultsWe found 31 CER studies, of which 29 (94%) had at least one design limitation belonging to seven components. The most common limitations related to: (1) eligibility criteria: 19/31 (61%) studies used post-baseline information to define baseline eligibility; (2) causal contrasts: 25 (81%) did not define whether ITT or per-protocol effects were estimated and (3) assignment procedures: 13 (42%) studies did not account for confounding by indication or relied solely on statistical confounder selection.ConclusionsDesign limitations were found in 94% of observational CER studies in RA. Target trial emulation is a structured approach for designing observational CER studies that helps to avoid potential sources of bias.

Objectives Methotrexate is widely used at low dosages (LD-MTX) for non-oncologic indications and is associated with a variety of adverse effects (AEs). We sought to determine whether concentrations of the active metabolite, MTX polyglutamates (MTX-PGs) 1–5, correlate with AEs. Method We examined data from the LD-MTX arm of the randomized double-blind Cardiovascular Inflammation Reduction Trial (CIRT). All AEs were blindly adjudicated and monitoring laboratories were tested centrally. The MTX-PGs 1–5 were assessed in one reference laboratory using liquid chromatography–tandem mass spectrometry. Based on prior literature, MTX-PGs 3–5 were chosen as the exposure of interest and quartiles of MTX-PGs 3–5 were assessed for their relationship with all AEs and each pre-specified category of AE using adjusted Cox proportional hazards regression. Results Of the 2391 subjects randomized to LD-MTX, MTX-PG levels were available for 1319 subjects (median dosage 16.1 mg/week) from the 8 month visit. We followed these subjects for a median of 2.2 years [interquartile range (IQR) 1.5–2.9]. Higher MTX-PG3–5 levels were related to an increased risk of anaemia [compared with quartile 1 (Q1); hazard ratio (HR) for Q4 1.27 (95% CI 0.98, 1.65), P for trend = 0.05] and a decreased risk of thrombocytopenia [HR for Q4 0.52 (95% CI 0.32, 0.84), P for trend = 0.05]. MTX-PG3–5 levels >134 nmol/l were associated with an increased risk of liver abnormalities [HR 1.36 (95% CI 1.08, 1.72)]. Conclusions Higher MTX- PG3–5 levels were modestly associated with LD-MTX AEs, including anaemia and liver function abnormalities, but a reduced risk of thrombocytopenia and haemorrhage. Clinical trial registration NCT 01594333.

Objective Low-dose methotrexate (LD-MTX), a cornerstone in the treatment of rheumatoid arthritis, is associated with a moderately increased risk of anemia, leukopenia, and skin cancers, but the risks of myelosuppression and malignancy during LD-MTX use remain incompletely described. We examined the risks of cytopenias and skin cancers among patients taking LD-MTX versus placebo in a large randomized controlled trial (RCT). Methods We prespecified secondary analyses of a double-blind, placebo-controlled RCT that included adults with known cardiovascular disease and diabetes or metabolic syndrome in the United States and Canada. Subjects were randomly allocated to LD-MTX (20 mg/week maximum) or placebo. All subjects received folic acid (1 mg daily for 6days/week). We assessed the frequency of blindly adjudicated hematologic and malignant adverse events (AEs). Results A total of 2391 subjects were randomized to LD-MTX (mean dosage 14.9 mg/week), and 2395 were randomized to placebo. During follow-up, in the LD-MTX arm, simultaneous two-line cytopenias (n = 92 [3.9%]) or pancytopenia (n = 13 [0.54%]) were infrequent. Pancytopenia developed as soon as 4 months and as late as 3.5 years after beginning LD-MTX, though the latter subject had been recently diagnosed with multiple myeloma. Overall skin cancer risk was increased in users of LD-MTX compared with users of placebo, which driven largely by a statistically significant increased risk of squamous cell skin cancer (hazard ratio [HR] 3.31; 95% confidence interval [CI] 1.63-6.71). Melanoma was increased in LD-MTX, but this was not statistically significant (HR 2.33; 95% CI 0.60-9.01). Conclusions Among subjects using LD-MTX, simultaneous two-line cytopenias and pancytopenia were uncommon. We found more cases of skin cancer, particularly squamous cell carcinomas, in the LD-MTX arm than the placebo arm.