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Objective Randomized controlled trials (RCTs) in biologic-naïve rheumatoid arthritis (RA) patients with high disease activity and inadequate response/intolerance to methotrexate have shown interleukin-6 (IL-6) receptor inhibitors (IL-6Ri) to be superior to tumor necrosis factor inhibitors (TNFi) as monotherapy. This observational study aimed to compare the effectiveness of TNFi vs IL-6Ri as mono- or combination therapy in biologic/targeted synthetic (b/ts) -experienced RA patients with moderate/high disease activity. Methods Eligible b/ts-experienced patients from the CorEvitas RA registry were categorized as TNFi and IL-6Ri initiators, with subgroups initiating as mono- or combination therapy. Mixed-effects regression models evaluated the impact of treatment on Clinical Disease Activity Index (CDAI), patient-reported outcomes, and disproportionate pain (DP). Unadjusted and covariate-adjusted effects were reported. Results Patients initiating IL-6Ri (n = 286) vs TNFi monotherapy (n = 737) were older, had a longer RA history and higher baseline CDAI, and were more likely to initiate as third-line therapy; IL-6Ri (n = 401) vs TNFi (n = 1315) combination therapy initiators had higher baseline CDAI and were more likely to initiate as third-line therapy. No significant differences were noted in the outcomes between TNFi and IL-6Ri initiators (as mono- or combination therapy). Conclusion This observational study showed no significant differences in outcomes among b/ts-experienced TNFi vs IL-6Ri initiators, as either mono- or combination therapy. These findings were in contrast with the previous RCTs in biologic-naïve patients and could be explained by the differences in the patient characteristics included in this study. Further studies are needed to help understand the reasons for this discrepancy in the real-world b/ts-experienced population. Key Points• Patients with rheumatoid arthritis (RA) often require switching between biologics or targeted synthetic (b/ts) disease-modifying anti-rheumatic drugs (DMARDs) to achieve their treatment target.• Head-to-head randomized controlled trials (RCTs) in biologic-naïve RA patients with high disease activity and inadequate response/intolerance to methotrexate have shown interleukin-6 receptor inhibitors (IL-6Ri) to be superior to tumor necrosis factor inhibitors (TNFi) as monotherapy; however, there are no RCTs comparing these therapies in a population previously treated with b/tsDMARDs (i.e., b/ts-experienced patients).• This observational study compared the effectiveness of TNFi vs IL-6Ri (as mono- or combination therapy) in b/ts-experienced RA patients with moderate or high disease activity and found no significant differences in clinical outcomes for the two treatments.• A discrepancy is noted between our study and RCTs, which have shown superiority of IL-6Ri therapy (albeit in biologic-naïve patients). Further analyses may help elucidate the reason for this discrepancy in the real-world b/ts-experienced population.

PURPOSE Fluctuations in weight have been linked to cardiovascular (CV) outcomes in the general population. We evaluated whether weight fluctuation was independently predictive of CV events in patients with rheumatoid arthritis (RA). METHODS We studied patients with RA from the Corrona registry. Weight change was categorized as loss of ≥10%, loss of 5-10%, stable, gain of 5-10%, and gain of ≥10%. We also categorized patients by quintile of variability in weight in prior observation periods. Cox proportional hazard models explored independent associations between time-varying weight change and weight variability and risk of CV events before and after adjusting for CV risk factors, RA disease features, and disability. RESULTS Among 31,381 participants, those that lost or gained 10% of their weight had greater disease activity, worse physical function, and were more likely to smoke, have diabetes, use corticosteroids, and be disabled. In adjusted models, a greater risk of CV events was observed in those that experienced 10% weight loss [HR: 1.18 (1.03,1.36) p=0.02] or weight gain [HR 1.20 (1.04,1.38) p=0.01]. The association between weight change and CV events was stronger among participants with BMI

BackgroundTargeting interleukin (IL)-6 has become a major therapeutic strategy in the treatment of immune-mediated inflammatory disease. Interference with the IL-6 pathway can be directed at the specific receptor using anti-IL-6Rα antibodies or by directly inhibiting the IL-6 cytokine. This paper is an update of a previous consensus document, based on most recent evidence and expert opinion, that aims to inform on the medical use of interfering with the IL-6 pathway.MethodsA systematic literature research was performed that focused on IL-6-pathway inhibitors in inflammatory diseases. Evidence was put in context by a large group of international experts and patients in a subsequent consensus process. All were involved in formulating the consensus statements, and in the preparation of this document.ResultsThe consensus process covered relevant aspects of dosing and populations for different indications of IL-6 pathway inhibitors that are approved across the world, including rheumatoid arthritis, polyarticular-course and systemic juvenile idiopathic arthritis, giant cell arteritis, Takayasu arteritis, adult-onset Still’s disease, Castleman’s disease, chimeric antigen receptor-T-cell-induced cytokine release syndrome, neuromyelitis optica spectrum disorder and severe COVID-19. Also addressed were other clinical aspects of the use of IL-6 pathway inhibitors, including pretreatment screening, safety, contraindications and monitoring.ConclusionsThe document provides a comprehensive consensus on the use of IL-6 inhibition to treat inflammatory disorders to inform healthcare professionals (including researchers), patients, administrators and payers.

Introduction Timely matching of patients to beneficial targeted therapy is an unmet need in rheumatoid arthritis (RA). A molecular signature response classifier (MSRC) that predicts which patients with RA are unlikely to respond to tumor necrosis factor-α inhibitor (TNFi) therapy would have wide clinical utility. Methods The protein–protein interaction map specific to the rheumatoid arthritis pathophysiology and gene expression data in blood patient samples was used to discover a molecular signature of non-response to TNFi therapy. Inadequate response predictions were validated in blood samples from the CERTAIN cohort and a multicenter blinded prospective observational clinical study (NETWORK-004) among 391 targeted therapy-naïve and 113 TNFi-exposed patient samples. The primary endpoint evaluated the ability of the MSRC to identify patients who inadequately responded to TNFi therapy at 6 months according to ACR50. Additional endpoints evaluated the prediction of inadequate response at 3 and 6 months by ACR70, DAS28-CRP, and CDAI. Results The 23-feature molecular signature considers pathways upstream and downstream of TNFα involvement in RA pathophysiology. Predictive performance was consistent between the CERTAIN cohort and NETWORK-004 study. The NETWORK-004 study met primary and secondary endpoints. A molecular signature of non-response was detected in 45% of targeted therapy-naïve patients. The MSRC had an area under the curve (AUC) of 0.64 and patients were unlikely to adequately respond to TNFi therapy according to ACR50 at 6 months with an odds ratio of 4.1 (95% confidence interval 2.0–8.3, p value 0.0001). Odds ratios (3.4–8.8) were significant (p value, Plain Language Summary A blood-based molecular signature response classifier (MSRC) integrating next-generation RNA sequencing data with clinical features predicts the likelihood that a patient with rheumatoid arthritis will have an inadequate response to TNFi therapy. Treatment selection guided by test results, with likely inadequate responders appropriately redirected to a different therapy, could improve response rates to TNFi therapies, generate healthcare cost savings, and increase rheumatologists’ confidence in prescribing decisions and altered treatment choices. The MSRC described in this study predicts the likelihood of inadequate response to TNFi therapies among targeted therapy-naïve and TNFi-exposed patients in a multicenter, 24-week blinded prospective clinical study: NETWORK-004. Patients with a molecular signature of non-response are less likely to have an adequate response to TNFi therapies than those patients lacking the signature according to ACR50, ACR70, CDAI, and DAS28-CRP with significant odds ratios of 3.4–8.8 for targeted therapy-naïve patients and 3.3–26.6 for TNFi-exposed patients. This MSRC provides a solution to the long-standing need for precision medicine tools to predict drug response in rheumatoid arthritis—a heterogeneous and progressive disease with an abundance of therapeutic options. These data validate the performance of the MSRC in a blinded prospective clinical study of targeted therapy-naïve and TNFi therapy-exposed patients. Supplementary Information The online version contains supplementary material available at 10.1007/s40744-021-00330-y.

Introduction Anti-cyclic citrullinated peptide (anti-CCP) antibodies are associated with poor prognosis in patients with rheumatoid arthritis (RA). Previous data from randomized controlled trials and clinical practice have shown anti-CCP-positive (+) patients had a better response to treatment with abatacept or tumor necrosis factor inhibitor (TNFi) treatment than those who were anti-CCP negative. This study assessed the association between baseline anti-CCP2 [a surrogate for anti-citrullinated protein antibody (ACPA)] concentration and 6-month treatment responses to abatacept or TNFi in patients with RA. Methods This real-world analysis included biologic-experienced patients from CERTAIN (Comparative Effectiveness Registry to study Therapies for Arthritis and Inflammatory CoNditions) who initiated abatacept or TNFi, had prior biologic disease-modifying drug exposure and baseline anti-CCP2 concentration/serostatus and serum samples (baseline and 6 months). Baseline demographics and disease characteristics were compared. Change from baseline at 6 months in Clinical Disease Activity Index (CDAI) score and patient-reported outcomes [PROs: pain, fatigue, patient global assessment (PtGA), modified Health Assessment Questionnaire (mHAQ) score], by baseline anti-CCP2 quartile and binary cut-off (> 10–250 and > 250 U/ml), were evaluated separately in the abatacept and TNFi groups using a linear regression model adjusted for age, sex, CDAI/PROs, comorbidity index, and methotrexate use. Results Included were 138 abatacept and 137 TNFi initiators who were anti-CCP2+. At baseline, there were significant differences between anti-CCP2 quartiles and mean CDAI, swollen joint count 28, C-reactive protein (CRP), Disease Activity Score 28 (CRP), rheumatoid factor (RF), mHAQ and physician global assessment among abatacept initiators, and in mean RF, mHAQ, and PtGA among TNFi initiators. Among abatacept (but not TNFi) initiators, CDAI numerically improved (p = 0.208) and PROs significantly improved (p, Plain Language Summary Rheumatoid arthritis (RA) is an autoimmune disease – a disease that causes the immune system to attack an individual’s own body. A key feature of RA is the presence of proteins called autoantibodies in the blood. While antibodies help protect against external threats such as viruses, autoantibodies mistakenly target an individual’s own tissues and organs. One type of autoantibody often found in patients with RA is called anti-cyclic citrullinated peptide (anti-CCP). Studies have shown that patients with RA with anti-CCP antibodies may experience worse physical symptoms, function, disease activity, and outcomes than patients with RA without anti-CCP antibodies. Clinical trials suggest that some drugs may be more effective than others at managing symptoms of RA in patients who have anti-CCP in their blood. It is important to study this further to give doctors a sense of how patients respond to drug therapy in the ‘real world’, without clinical trial constraints. This study examined real-world patient data to see whether the presence of anti-CCP in patients’ blood impacted how their RA symptoms responded to treatment with two different drugs: abatacept or a tumor necrosis factor inhibitor (TNFi). This study found that patients with higher levels of anti-CCP at the start of the study, compared with patients with lower levels of anti-CCP, experienced less disease activity and greater improvement in physical function after 6 months of treatment with abatacept. The study found no relationship between anti-CCP and treatment response after 6 months of treatment with a TNFi. Supplementary Information The online version contains supplementary material available at 10.1007/s40744-021-00310-2.

Introduction Understanding the durability of response to treatment and factors associated with failure to maintain response in a real-world setting can inform treatment decisions for patients with rheumatoid arthritis (RA). The aim of this study was to analyze durability of response to tocilizumab (TCZ) and factors associated with durability among US patients with RA in routine clinical practice. Methods TCZ initiators in the Corrona RA Registry were included. Durability of response was defined as maintaining continuous TCZ treatment and either an improvement of at least minimum clinically important difference (MCID) in Clinical Disease Activity Index (CDAI) score or low disease activity (LDA). Secondary analyses included patients treated with intravenous (IV) TCZ and excluded those who discontinued TCZ without reporting reasons for discontinuation. Durability was calculated with Kaplan–Meier survival analysis. Cox proportional hazards modeling identified factors associated with durability. Results Among 1789 TCZ initiators, 466, 272, and 162 were persistent (with or without durable response) with follow-up visits at 1, 2, and 3 years, respectively. Median MCID durability of response in CDAI was > 50% after 36 months overall, 26 months for TCZ-IV, and > 50% after 36 months for those with known reasons for discontinuation; longer durability was associated with increased duration of RA and higher baseline CDAI score and shorter durability with history of malignancy and history of diabetes. Median LDA durability of response was 13.0 months overall, for TCZ-IV, and for those with known reasons for discontinuation; shorter durability was associated with history of malignancy, history of diabetes, and higher baseline CDAI score. Conclusions Median durability of response to TCZ in RA was > 3 years when defined as maintenance of MCID in CDAI score and > 1 year with the more stringent criteria of maintenance of LDA. Trial Registration ClinicalTrials.gov identifier, NCT01402661

Tumor necrosis factor inhibitor (TNFi) therapies are often the first biologic therapy used to treat rheumatoid arthritis (RA) patients. However, a substantial fraction of patients do not respond adequately to TNFi therapies. A test with the ability to predict response would inform therapeutic decision-making and improve clinical and financial outcomes. A 32-question decision-impact survey was conducted with 248 rheumatologists to gauge the perceived clinical utility of a novel test that predicts inadequate response to TNFi therapies in RA patients. Participants were informed about the predictive characteristics of the test and asked to indicate prescribing decisions based on four result scenarios. Overall, rheumatologists had a favorable view of the test: 80.2% agreed that it would improve medical decision-making, 92.3% said it would increase their confidence when making prescribing decisions, and 81.5% said it would be useful when considering TNFi therapies. Rheumatologists would be more likely to prescribe a TNFi therapy when the test reported that no signal of non-response was detected (79.8%) and less likely to prescribe a TNFi therapy when a signal of non-response was detected (11.3%–25.4%). Rheumatologists (84.7%) agreed that payers should provide coverage for such a test. This study shows that rheumatologists support the clinical need for a test to predict inadequate response to TNFi therapies. Test results were perceived to lead to changes in prescribing behaviors as results instill confidence in the ordering rheumatologist. Electronic supplementary material The online version of this article (10.1007/s00296-020-04746-7) contains supplementary material, which is available to authorized users.

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

ObjectivesTofacitinib is a Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ulcerative colitis, and has been investigated in psoriasis (PsO). Routine pharmacovigilance of an ongoing, open-label, blinded-endpoint, tofacitinib RA trial (Study A3921133; NCT02092467) in patients aged ≥50 years and with ≥1 cardiovascular risk factor identified a higher frequency of pulmonary embolism (PE) and all-cause mortality for patients receiving tofacitinib 10 mg twice daily versus those receiving tumour necrosis factor inhibitors and resulted in identification of a safety signal for tofacitinib. Here, we report the incidence of deep vein thrombosis (DVT), PE, venous thromboembolism (VTE; DVT or PE) and arterial thromboembolism (ATE) from the tofacitinib RA (excluding Study A3921133), PsA and PsO development programmes and observational studies. Data from an ad hoc safety analysis of Study A3921133 are reported separately within.MethodsThis post-hoc analysis used data from separate tofacitinib RA, PsO and PsA programmes. Incidence rates (IRs; patients with events per 100 patient-years’ exposure) were calculated for DVT, PE, VTE and ATE, including for populations stratified by defined baseline cardiovascular or VTE risk factors. Observational data from the US Corrona registries (including cardiovascular risk factor stratification), IBM MarketScan research database and the US FDA Adverse Event Reporting System (FAERS) database were analysed.Results12 410 tofacitinib-treated patients from the development programmes (RA: n=7964; PsO: n=3663; PsA: n=783) were included. IRs (95% CI) of thromboembolic events among the all tofacitinib cohorts’ average tofacitinib 5 mg and 10 mg twice daily treated patients for RA, respectively, were: DVT (0.17 (0.09–0.27) and 0.15 (0.09–0.22)); PE (0.12 (0.06–0.22) and 0.13 (0.08–0.21)); ATE (0.32 (0.22–0.46) and 0.38 (0.28–0.49)). Among PsO patients, IRs were: DVT (0.06 (0.00–0.36) and 0.06 (0.02–0.15)); PE (0.13 (0.02–0.47) and 0.09 (0.04–0.19)); ATE (0.52 (0.22–1.02) and 0.22 (0.13–0.35)). Among PsA patients, IRs were: DVT (0.00 (0.00–0.28) and 0.13 (0.00–0.70)); PE (0.08 (0.00–0.43) and 0.00 (0.00–0.46)); ATE (0.31 (0.08–0.79) and 0.38 (0.08–1.11)). IRs were similar between tofacitinib doses and generally higher in patients with baseline cardiovascular or VTE risk factors. IRs from the overall Corrona populations and in Corrona RA patients (including tofacitinib-naïve/biologic disease-modifying antirheumatic drug-treated and tofacitinib-treated) with baseline cardiovascular risk factors were similar to IRs observed among the corresponding patients in the tofacitinib development programme. No signals of disproportionate reporting of DVT, PE or ATE with tofacitinib were identified in the FAERS database.ConclusionsDVT, PE and ATE IRs in the tofacitinib RA, PsO and PsA programmes were similar across tofacitinib doses, and generally consistent with observational data and published IRs of other treatments. As expected, IRs of thromboembolic events were elevated in patients with versus without baseline cardiovascular or VTE risk factors, and were broadly consistent with those observed in the Study A3921133 ad hoc safety analysis data, although the IR (95% CI) for PE was greater in patients treated with tofacitinib 10 mg twice daily in Study A3921133 (0.54 (0.32–0.87)), versus patients with baseline cardiovascular risk factors treated with tofacitinib 10 mg twice daily in the RA programme (0.24 (0.13–0.41)).

Introduction The PrismRA® test identifies rheumatoid arthritis (RA) patients who are unlikely to respond to anti-tumor necrosis factor (anti-TNF) therapies. This study evaluated the clinical and financial outcomes of incorporating PrismRA into routine clinical care of RA patients. Methods A decision-analytic model was created to evaluate clinical and economic outcomes in the 12-month period following first biologic treatment. Two treatment strategies were compared: (1) observed clinical decision-making based on a 175-patient cohort receiving an anti-TNF therapy as their first biologic after failure of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and (2) modeled clinical decision-making of the same population using PrismRA results to inform first-line biologic treatment choice. Modeled costs include biologic drug pharmacy, non-biologic pharmacy, and total medical costs. The odds of inadequate response to anti-TNF therapies and various components of patient care were calculated based on PrismRA results. Results Identifying predicted inadequate responders to anti-TNF therapies resulted in a modeled 38% increase in ACR50 response to first-line biologic therapies. The fraction of patients who achieved an ACR50 response to any therapy (TNFi and others) within the 12-month period was 33% higher in the PrismRA-stratified population than in the unstratified population (59 vs. 44%, respectively). When therapy prescriptions were modeled according to PrismRA results, cost savings were modeled for all financial variables: overall costs (4% decreased total, 19% decreased on ineffective treatments), total biologic drug pharmacy (4% total, 23% ineffective), non-biologic pharmacy (2% total, 19% ineffective), and medical costs (6% total, 19% ineffective). Female sex was the clinical metric that showed the greatest association with inadequate response to anti-TNF therapies (odds ratio 2.42, 95% confidence interval 1.20, 4.88). Conclusions If PrismRA is implemented into routine clinical care as modeled, predicting which RA patients will have an inadequate response to anti-TNF therapies could save > $7 million in overall ineffective healthcare costs per 1000 patients tested and increase targeted DMARD response rates in RA. Electronic Supplementary Material The online version of this article (10.1007/s40744-020-00226-3) contains supplementary material, which is available to authorized users.

Objectives: For rheumatoid arthritis (RA) patients failing to achieve treatment targets with conventional synthetic disease-modifying antirheumatic drugs, tumor necrosis factor (TNF)-α inhibitors (...

ObjectivesThis study evaluated the comparative effectiveness of a tumour necrosis factor inhibitor (TNFi) versus a non-TNFi (biological disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs)) as the first-line treatment following conventional synthetic DMARDs, as well as potential modifiers of response, observed in US clinical practice.MethodsData were from a large US healthcare registry (Consortium of Rheumatology Researchers of North America Rheumatoid Arthritis Registry). The analysis included patients (aged ≥18 years) with a documented diagnosis of rheumatoid arthritis (RA), a valid baseline Clinical Disease Activity Index (CDAI) score of >2.8 and no prior bDMARD or tsDMARD use. Outcomes were captured at 1-year postinitiation of a TNFi (adalimumab, etanercept, certolizumab pegol, golimumab or infliximab) or a non-TNFi (abatacept, tocilizumab, rituximab, anakinra or tofacitinib) and included CDAI, 28-Joint Modified Disease Activity Score, patient-reported outcomes (including the Health Assessment Questionnaire Disability Index, EuroQol-5 Dimension score, sleep, anxiety, morning stiffness and fatigue) and rates of anaemia. Groups were propensity score-matched at baseline to account for potential confounding.ResultsThere were no statistically significant differences observed between the TNFi and non-TNFi treatment groups for outcomes assessed, except the incidence rate ratio for anaemia, which slightly favoured the TNFi group (19.04 per 100 person-years) versus the non-TNFi group (24.01 per 100 person-years, p=0.03). No potential effect modifiers were found to be statistically significant.ConclusionsThe findings of no significant differences in outcomes between first-line TNF versus first-line non-TNF groups support RA guidelines, which recommend individualised care based on clinical judgement and consideration of patient preferences.

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.

Objective Patients with rheumatoid arthritis (RA) have higher incidence of cardiovascular diseases (CVDs) compared with age- and sex-matched controls. The objective of our study was to measure the knowledge of patients with RA about the association between their disease and cardiovascular (CV) risk and to measure the frequency of counseling by physicians based on patient report. Methods A telephone survey was conducted among patients with RA enrolled in the Consortium of Rheumatology Researchers of North America RA registry to collect data on medical and social history and on knowledge about CVD risk in RA and how they learned about that risk. Multivariable logistic regression models were performed to determine the factors associated with patients' knowledge and factors influencing likelihood of physician counseling. The odds ratios (ORs) represent adjusted multivariable results. Results Of 185 patients with RA included in the study, 87 patients (47%) were aware that RA was a CV risk factor. Older age (OR 0.6; 95% confidence interval [CI] 0.4-0.8 per decade) and smoking (OR 0.4; 95% CI 0.1-0.9) were associated with low awareness, whereas disease duration of more than 10 years (OR 5.2; 95% CI 2.2-12.1) was positively associated with patient knowledge. Counseling by physicians, mostly rheumatologists, on CV risk in RA was reported by 47 patients (25%). Disease duration of more than 10 years (OR 3.9; 95% CI 1.2-13.1) was positively associated with patient-reported counseling. Patients with hypertension were less likely to report counseling (OR 0.4; 95% CI 0.2-0.9). Conclusion Our study demonstrated low patient awareness of CV risk with RA and low rates of patient-reported counseling by physicians. This is an unmet need in clinical practice, which may be overcome by multimodal approaches such as developing websites, organizing symposiums, and involving health care providers at various levels.

Introduction Similar outcomes have been observed between patients with rheumatoid arthritis (RA) responding to tocilizumab (TCZ) with methotrexate (MTX) who discontinued vs. continued MTX and between patients receiving MTX who added TCZ vs. switched to TCZ monotherapy. This study examined MTX discontinuation and dose decreases in patients with RA initiating TCZ in a real-world setting. Methods TCZ-naïve patients enrolled in the Corrona RA registry who initiated TCZ in combination with MTX and had a 6-month follow-up visit without TCZ discontinuation were included. Patients were grouped by MTX dose at the time of TCZ initiation (≤ 10 mg, > 10 to ≤ 15 mg, > 15 to ≤ 20 mg, > 20 mg). The primary outcome was the proportion of patients with changes in MTX use at 6 months, with a secondary analysis at 12 months. Changes in disease activity [Clinical Disease Activity Index (CDAI)] and patient-reported outcomes (PROs) at 6 and 12 months were summarized descriptively. Results Of 444 included patients, 82.7% were female and 83.7% white, with mean (SD) disease duration of 11.6 (9.3) years, baseline CDAI score of 24.0 (15.4), and baseline MTX dose of 17.7 (5.8) mg. At 6 months, 139 patients (31.3%) discontinued or decreased their MTX dose. All MTX dose groups and patients who discontinued, decreased, maintained, or increased their MTX dose displayed improvements in CDAI scores and PROs at 6 months. Similar patterns and results were observed at 12 months. Conclusions A considerable proportion of patients initiating TCZ discontinued or decreased their MTX dose after TCZ initiation. Improvements in disease activity and functionality were observed in patients who decreased or stopped MTX. This real-world study confirmed prior observations that discontinuing or decreasing MTX may be a treatment strategy for patients initiating TCZ combination therapy. Trial Registration ClinicalTrials.gov identifier, NCT01402661., Plain Language Summary Rheumatoid arthritis (RA) is a long-term disease that causes joint swelling, stiffness, and pain. Unless RA is treated quickly, patients can experience joint damage and disability. Patients with RA often take methotrexate (MTX) as their first treatment, but many patients do not have sufficient improvement with MTX alone. For these patients, doctors often add another medicine called a biologic to their existing treatment. However, taking more medications is associated with toxic effects and can make it harder for patients to stay on their therapy. Tocilizumab (TCZ) is a biologic that is used to treat RA. In one clinical trial, reported by Kremer et al., patients whose RA improved when they were taking TCZ plus MTX were subsequently able to stop taking MTX and their RA remained well controlled (Arthritis Rheumatol 70(8):1200–1218, 2018). However, researchers had not looked at whether patients outside of a clinical trial (in the “real world”) can stop taking MTX or take less MTX after they start taking TCZ. This study used real-world data to examine if patients who start taking TCZ subsequently stop taking or take less MTX. This study showed that many patients were able to stop taking or take less MTX during the year after they started taking TCZ. Patients who stopped or decreased their MTX dose had less-active RA and reported that they felt better and had fewer symptoms. These results suggest that it is common for patients in the real world to stop taking or take less MTX after they start taking TCZ.

The objectives of this analysis were to assess the prevalence of Sjögren’s syndrome (SS) associated with rheumatoid arthritis (RA) and to compare baseline characteristics of patients with RA with and without SS. Adult patients with RA from a large observational US registry (Corrona RA), with ≥ 1 visit for assessment of SS status between 22 April 2010 and 28 February 2018, were considered. Patients with RA with versus without SS were compared. SS status was determined from a yes/no variable and reported at enrollment into the Corrona RA registry and follow-up visits. Outcomes were unadjusted prevalence of SS in patients with RA, prevalence of SS by RA disease duration, and baseline characteristics in patients with RA by SS status. Of 24,528 eligible patients, 7870 (32.1%) had a diagnosis of RA and SS. The unadjusted overall rate for SS prevalence in patients with RA was 0.30 (95% confidence interval 0.29, 0.31). SS prevalence increased with increasing RA duration. Patients with RA with versus without SS were more likely to be older, female, and seropositive; had a longer RA duration; higher disease activity; and a higher incidence of comorbidities (hypertension, cardiovascular disease, malignancies, and serious infections), erosive disease, and subcutaneous nodules at index date. Patients with RA and SS had a higher disease burden than those with RA only. The prevalence of SS increased as duration of RA increased. RA with SS was associated with seropositivity, more severe RA, extra-articular manifestations, and comorbidities.Key Points• The overall prevalence of SS among patients with RA was 30%.• The prevalence of SS increased with increasing RA disease duration.• Identifying specific clinical characteristics of patients with RA with SS, such as a greater incidence of extra-articular manifestations and comorbidities, may help clinicians to better characterize this patient population.

The term “immuno-autonomics” has been coined to describe an emerging field evaluating the interaction between stress, autonomic nervous system (ANS), and inflammation. The field remains largely unknown among practicing rheumatologists. Our objective was to evaluate the perspectives of rheumatologists regarding the role of stress in the activity and management of rheumatoid arthritis (RA). A 31-item survey was conducted with 231 rheumatologists. Rheumatologists were asked to assess the role of stress in rheumatoid arthritis (RA) disease activity and were provided with information regarding immuno-autonomics. They were asked to consider how immuno-autonomics resonated with their patient management needs. The majority of rheumatologists are eager to better understand non-response, believe that stress biology and ANS dysfunction interfere with disease activity, and embrace the theory that measurement of ANS via next-generation HRV may be able to evaluate autonomic dysfunction and the biology of stress. Rheumatologists are open to the idea that quantitative measurement of ANS function using next-generation HRV can be a helpful tool to RA practice. The majority agree that ANS state influences RA disease control and that quantitative measures of ANS state are helpful to RA practice. Rheumatologists also agree that patients with poor ANS function may be at risk for not responding adequately to conventional, biologic, or targeted synthetic DMARDs. Almost all would use an in-office test to quantitatively measure ANS using next-generation HRV. This study shows that rheumatologists are open to embracing evaluation of ANS function as a possible tool in the management and treatment of RA.

We performed a study of tumor necrosis factor inhibitors (TNFi) compared to non-TNFi biologic therapies in rheumatoid arthritis to test whether body mass index (BMI) modified the effect of each therapy.We utilized data from CorEvitas. We studied 3 clinical outcomes based on the Clinical Disease Activity Index (CDAI) at 6 months from therapy initiation: 1) achievement of low disease activity (LDA); 2) a change as large as the minimum clinically important difference (MCID); and 3) the absolute change. We categorized BMI and utilized restricted cubic splines to consider nonlinear associations. We used linear and logistic regression to evaluate associations with response, adjusting for confounders. To determine if comparative effectiveness of therapy varied by BMI, we tested for interactions between BMI and class of therapy.The sample included 2,891 TNFi and 3,010 non-TNFi initiators. Among all initiators, those with severe obesity experienced lower odds of achieving LDA or MCID and less improvement in CDAI score, although associations were attenuated with adjustment. Low BMI was associated with reduced response rates in adjusted models including lower odds of LDA (odds ratio 0.32 [95% confidence interval (95% CI) 0.15, 0.71], P = 0.005). Analyses stratified by TNFi and non-TNFi therapies demonstrated no differences in clinical response rates for TNFi versus non-TNFi across BMI categories (all P for interaction0.05). Estimates for non-TNFi biologics fit within the 95% CI for TNFi.This study observed lower response rates among obese and underweight patients and no evidence of a superior effect of non-TNFi therapy over TNFi therapy in particular BMI categories.

Objective Accurate prediction of treatment responses in rheumatoid arthritis (RA) patients can provide valuable information on effective drug selection. Anti-tumor necrosis factor (anti-TNF) drugs are an important second-line treatment after methotrexate, the classic first-line treatment for RA. However, patient heterogeneity hinders identification of predictive biomarkers and accurate modeling of anti-TNF drug responses. This study was undertaken to investigate the usefulness of machine learning to assist in developing predictive models for treatment response. Methods Using data on patient demographics, baseline disease assessment, treatment, and single-nucleotide polymorphism (SNP) array from the Dialogue on Reverse Engineering Assessment and Methods (DREAM): Rheumatoid Arthritis Responder Challenge, we created a Gaussian process regression model to predict changes in the Disease Activity Score in 28 joints (DAS28) for the patients and to classify them into either the responder or the nonresponder group. This model was developed and cross-validated using data from 1,892 RA patients. It was evaluated using an independent data set from 680 patients. We examined the effectiveness of the similarity modeling and the contribution of individual features. Results In the cross-validation tests, our method predicted changes in DAS28 (ΔDAS28), with a correlation coefficient of 0.405. It correctly classified responses from 78% of patients. In the independent test, this method achieved a Pearson's correlation coefficient of 0.393 in predicting ΔDAS28. Gaussian process regression effectively remapped the feature space and identified subpopulations that do not respond well to anti-TNF treatments. Genetic SNP biomarkers showed small contributions in the prediction when added to the clinical models. This was the best-performing model in the DREAM Challenge. Conclusion The model described here shows promise in guiding treatment decisions in clinical practice, based primarily on clinical profiles with additional genetic information.

Introduction No published studies exist comparing the effectiveness of tofacitinib with other advanced therapies for the treatment of rheumatoid arthritis (RA) in real-world clinical practice. Here, we report differences in effectiveness of tofacitinib compared with standard of care, tumor necrosis factor inhibitors (TNFi), with or without concomitant methotrexate (MTX), using US Corrona registry data. Methods This observational cohort study included RA patients receiving tofacitinib (from 6 November 2012; N = 558) or TNFi (from 1 November 2001; N = 8014) with or without MTX until 31 July 2016. Efficacy outcomes at 6 months included modified American College of Rheumatology 20% responses, Clinical Disease Activity Index (CDAI) and Pain. Outcomes were compared between patients receiving TNFi and tofacitinib with or without MTX and by line of therapy. Outcomes within therapy lines were compared using propensity-score matching; between-group differences were estimated using mixed-effects regression models. Results Patients receiving tofacitinib had longer RA duration and a greater proportion had previously received biologics than those receiving TNFi; other baseline characteristics were comparable. In patients receiving second- and third-line TNFi therapy, CDAI low disease activity/remission response rates were significantly better with concomitant MTX. Too few patients received tofacitinib as second line for meaningful assessment. No significant differences were observed in outcomes between tofacitinib as monotherapy and tofacitinib with concomitant MTX. Conclusions In clinical practice, TNFi efficacy is improved with concomitant MTX in the second and third line. In the third/fourth line, patients are likely to achieve similar efficacy with tofacitinib monotherapy, or TNFi or tofacitinib in combination with MTX. Funding Pfizer Inc Electronic supplementary material The online version of this article (10.1007/s40744-019-00177-4) contains supplementary material, which is available to authorized users.

Introduction This study aimed to characterize disease burden among patients with rheumatoid arthritis (RA) with moderate-to-high disease activity who had received conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) monotherapy for ≥ 6 months but had not advanced to a biologic therapy. Methods Patients enrolled in the US Corrona RA Registry between June 1, 2014, and January 30, 2018, with 6 months of continuous csDMARD monotherapy, with moderate-to-high disease activity, who remained biologic naive, and who had ≥ 1 follow-up visit were identified. Disease activity was assessed among patients with a 6-month follow-up visit (± 3 months). Descriptive statistics were used to compare demographics and disease characteristics between patients with or without treatment advancement. Results The study included 409 patients with a disease activity assessment at 6 months (mean (SD) age 65.9 (12.6) years; mean duration of csDMARD therapy 407 (221) days). Of those patients, more than half (54%, n = 219) remained in moderate-to-high disease activity. Patients remaining in moderate-to-high vs. remission-to-low disease activity had higher baseline swollen (6.1) and tender joint counts (6.8). Over the 6-month period, treatment advancement occurred in 29% of patients. Those who advanced treatment (n = 118) vs. did not advance treatment (n = 291) were younger, had a shorter duration of RA, had higher disease activity, and reported higher levels of pain and fatigue. Conclusions The substantial number of patients with persistent moderate-to-high disease on csDMARDs over a 6-month period and who did not advance treatment indicates that there is considerable need for a treat-to-target approach to care for patients with RA. Key Points•For patients with RA and an inadequate response to treatment with initial csDMARD monotherapy, guidelines recommend treatment advancement; however, this may not be occurring in real-world clinical settings.•In the current study, a substantial proportion of patients (54%) on csDMARDs had persistent moderate-to-severe disease activity at the 6-month (± 3 months) follow-up visit; however, only 29% of patients had their medication treatment advanced, indicating that there is considerable need for a treat-to-target approach to care for patients with RA.•Patients with younger age, shorter RA duration, and higher disease activity were more likely to have their medication treatment advanced, which suggests that potentially more aggressive treatment of disease activity is needed across the whole RA population.

Background The goal of this study is to use comprehensive molecular profiling to characterize clinical response to anti-TNF therapy in a real-world setting and identify reproducible markers differentiating good responders and non-responders in rheumatoid arthritis (RA). Methods Whole-blood mRNA, plasma proteins, and glycopeptides were measured in two cohorts of biologic-naïve RA patients (n = 40 and n = 36) from the Corrona CERTAIN (Comparative Effectiveness Registry to study Therapies for Arthritis and Inflammatory coNditions) registry at baseline and after 3 months of anti-TNF treatment. Response to treatment was categorized by EULAR criteria. A cell type-specific data analysis was conducted to evaluate the involvement of the most common immune cell sub-populations. Findings concordant between the two cohorts were further assessed for reproducibility using selected NCBI-GEO datasets and clinical laboratory measurements available in the CERTAIN database. Results A treatment-related signature suggesting a reduction in neutrophils, independent of the status of response, was indicated by a high level of correlation (ρ = 0.62; p n = 1962) from the CERTAIN database confirmed the observation (odds ratio of good/moderate response = 1.20 [95% CI = 1.03–1.41, p = 0.02]). Conclusion Differences in innate/adaptive immune cell type composition at baseline may be a major contributor to response to anti-TNF treatment within the first 3 months of therapy.

Introduction Prednisone is frequently administered in combination with other therapies for the treatment of rheumatoid arthritis (RA); however, its chronic use is associated with an increased risk of comorbidities and mortality. The objective of this analysis was to evaluate changes in prednisone use among patients with RA treated with tocilizumab (TCZ) in routine US clinical practice. Methods TCZ-naïve patients in the Corrona RA registry who initiated TCZ were included. The primary outcome was the proportion of patients with changes in prednisone use over 12 months (primary analysis) and 6 months (secondary analysis). Changes in disease activity over 6 and 12 months (± 3 months) were assessed using the Clinical Disease Activity Index (CDAI). Outcomes were assessed in the overall population and separately for patients receiving TCZ monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs. Results Of patients receiving prednisone at baseline (mean [SD] dose: 7.7 [5.2] mg/day), 30.6% discontinued prednisone over 12 months; among patients receiving > 7.5 mg of prednisone at the time of TCZ initiation, 63.0% discontinued prednisone or decreased their dose by ≥ 5 mg over 12 months. In secondary analyses, 29.7% of patients receiving prednisone at baseline had discontinued prednisone over 6 months; among those receiving > 7.5 mg of prednisone at baseline, 51.3% discontinued or decreased their dose by ≥ 5 mg over 6 months. Changes in prednisone use and improvement from baseline in CDAI score over 6 and 12 months were comparable between patients who initiated TCZ monotherapy vs. TCZ combination therapy. Conclusions In this real-world analysis, many patients initiating TCZ monotherapy or combination therapy were able to discontinue or decrease their prednisone dose over 12 months. Similar changes in prednisone dose were observed over 6 months. Trial Registration ClinicalTrials.gov identifier, NCT01402661. Funding Corrona, LLC and Genentech, Inc. Plain Language Summary Plain language summary available for this article., Plain Language Summary Rheumatoid arthritis (RA) is a chronic autoimmune disease that can lead to joint damage and disability. The steroid prednisone is a fast-acting and effective treatment for RA and is often prescribed alongside disease-modifying antirheumatic drugs (DMARDs). The health risks associated with the long-term use of prednisone have led to recommendations to minimize prednisone dose and duration of treatment. Few studies have examined the extent to which biologic DMARDs allow rheumatologists to reduce or discontinue the use of prednisone. The objective of this study was to evaluate changes in prednisone dose while receiving tocilizumab (TCZ) in patients with RA seen in routine US clinical practice. Patients who were enrolled in the Corrona RA registry and were beginning treatment with TCZ were included. Changes in prednisone use were evaluated 12 months after starting treatment. Of patients receiving prednisone at study initiation, 30.6% had discontinued prednisone over 12 months; among patients receiving > 7.5 mg of prednisone at the time of TCZ initiation, 63.0% discontinued prednisone or decreased the dose by ≥ 5 mg over 12 months. In secondary analyses, 29.7% of patients receiving prednisone at study initiation had discontinued prednisone over 6 months; among those receiving > 7.5 mg of prednisone at baseline, 51.3% discontinued or decreased the dose by ≥ 5 mg over 6 months. Changes in prednisone use and improvement in disease activity over 6 and 12 months were comparable between patients who initiated TCZ monotherapy or combination therapy with other DMARDs.

Objective.To assess differences in joint damage and inflammation using magnetic resonance imaging (MRI) between patients with rheumatoid arthritis (RA) who achieved low disease activity with tocilizumab (TCZ) + methotrexate (MTX) and subsequently continued or discontinued MTX.Methods.In the COMP-ACT trial, US patients with RA received subcutaneous TCZ 162 mg + MTX. Those who achieved 28-joint count Disease Activity Score calculated with erythrocyte sedimentation rate (DAS28-ESR) ≤ 3.2 at Week 24 were randomized 1:1 (double-blind) to discontinue MTX (TCZ monotherapy; mono) or continue TCZ + MTX until Week 52. In a subset of patients, 1.5-Tesla MRI was used to obtain images of bilateral hands and wrists at weeks 24 and 40. Outcomes included changes in MRI-assessed synovitis, osteitis, erosion, and cartilage loss from Week 24 to Week 40, and in the proportion of patients with progression of each score.Results.Of 296 patients who achieved DAS28-ESR ≤ 3.2 at Week 24, 79 were enrolled in the pilot MRI substudy and randomized to TCZ mono (n = 38) or TCZ + MTX (n = 41). Treatment with either TCZ mono or TCZ + MTX suppressed erosion progression, synovitis, osteitis, and cartilage loss. The proportion of patients with no progression in each outcome measure was similar between groups (range, TCZ mono: 84.8–97.0%; TCZ + MTX: 92.3–100%).Conclusion.In a subset of patients who achieved low disease activity with TCZ + MTX, MRI changes were minimal in intraarticular inflammation and damage measures in patients who discontinued MTX versus those who continued TCZ + MTX.

Dose escalation of infliximab in both primary and secondary nonresponders is widely reported; however, the usefulness of dose escalation has been disputed. The objective of this analysis is to evaluate trends in clinical efficacy following multiple infliximab dose escalations in patients with rheumatoid arthritis (RA). Patients enrolled in a US RA registry were included if they initiated infliximab at 3 mg/kg every 8 weeks, received ≥ 1 infliximab dose escalation within 12 months of initiation, and had ≥ 1 visit following dose escalation. Trends in mean Clinical Disease Activity Index (CDAI) and Health Assessment Questionnaire (HAQ) scores from visits following dose escalations were evaluated. In patients who received 2 or 3 dose escalations, the initial (1 or 2) dose escalations resulted in reduced mean CDAI scores, but subsequent escalations did not further reduce disease activity. In patients who received ≥ 4 dose escalations, mean CDAI scores did not further reduce disease activity over time. Mean HAQ scores were stable over time in patients who received 2 or 3 dose escalations. In patients who received ≥ 4 dose escalations, mean HAQ scores decreased following 1 dose escalation but progressively increased following subsequent dose escalations. Initial dose escalations (from 3 mg/kg to the equivalent of approximately 5 to 7 mg/kg) may be useful in controlling disease activity; however, there may be diminishing clinical benefit of further escalations, which can also increase the potential risk for infection and increase incremental drug costs. • Initial infliximab dose escalations (1 to 2) may be useful in lowering disease activity in patients with rheumatoid arthritis. • There does not appear to be a clinical benefit in infliximab dose escalations above the equivalent of 5 to 7 mg/kg.

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.

Introduction Anti-citrullinated protein antibodies (ACPAs) are highly specific serological biomarkers that are indicative of a poor prognosis in patients with rheumatoid arthritis (RA). The effectiveness of biologic disease-modifying antirheumatic drugs (bDMARDs) with different mechanisms of action may vary, based on patients’ serostatus. The aim of this study is to compare the effectiveness of abatacept versus tumor necrosis factor inhibitors (TNFis) in patients with RA who were anti-cyclic citrullinated peptide antibody positive (anti-CCP+). Methods Abatacept or TNFi initiators with anti-CCP+ status (≥ 20 U/ml) at or prior to treatment initiation were identified from a large observational US cohort (1 December 2005–31 August 2016). Using propensity score matching (1:1), stratified by prior TNFi use (0, 1 and ≥ 2), effectiveness at 6 months after initiation was evaluated. Primary outcome was mean change in Clinical Disease Activity Index (CDAI) score. Secondary outcomes included achievement of remission (CDAI ≤ 2.8), low disease activity/remission (CDAI ≤ 10), modified American College of Rheumatology 20/50/70 responses and mean change in modified Health Assessment Questionnaire score. Results After propensity score matching, the baseline characteristics between 330 pairs of abatacept and TNFi initiators (biologic naïve, n = 97; TNFi experienced, n = 233) were well balanced with absolute value standardized differences of ≤ 0.1. Both overall, and in the biologic-naïve cohort, there were no significant differences in mean change in CDAI score at 6 months. However, in the TNFi-experienced cohort, there was a significantly greater improvement in CDAI score at 6 months with abatacept versus TNFi initiators (p = 0.033). Secondary outcomes showed similar trends. Conclusions Improvements in clinical disease activity were seen in anti-CCP+ abatacept and TNFi initiators. TNFi-experienced anti-CCP+ patients with RA had more improvement in disease activity with abatacept versus TNFis, whereas outcomes were similar between treatments in the overall population and in biologic-naïve patients. Trial Registration ClinicalTrials.gov identifier: NCT01625650. Funding This study is sponsored by Corrona, LLC and funded by Bristol-Myers Squibb. Bristol-Myers Squibb funded the publication of this manuscript. Electronic supplementary material The online version of this article (10.1007/s40744-019-0149-3) contains supplementary material, which is available to authorized users.

Guidelines and recommendations developed and/or endorsed by the American College of Rheumatology (ACR) are intended to provide general guidance for commonly encountered clinical scenarios. The recommendations do not dictate the care for an individual patient. The ACR considers adherence to the recommendations described in this guideline to be voluntary, with the ultimate determination regarding their application to be made by the clinicians in light of each patient’s individual circumstances. Guidelines and recommendations are intended to promote beneficial or desirable outcomes but cannot guarantee any specific outcome. Guidelines and recommendations developed and endorsed by the ACR are subject to periodic revision as warranted by the evolution of medical knowledge, technology, and practice. ACR recommendations are not intended to dictate payment or insurance decisions, or drug formularies or other third-party analyses. Third parties that cite ACR guidelines should state that these recommendations are not meant for this purpose. These recommendations cannot adequately convey all uncertainties and nuances of patient care. The American College of Rheumatology is an independent, professional, medical and scientific society that does not guarantee, warrant, or endorse any commercial product or service. OBJECTIVE. To develop updated guidelines for the pharmacologic management of rheumatoid arthritis. METHODS. We developed clinically relevant population, intervention, comparator, and outcomes (PICO) questions. After conducting a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to rate the certainty of evidence. A voting panel comprising clinicians and patients achieved consensus on the direction (for or against) and strength (strong or conditional) of recommendations. RESULTS. The guideline addresses treatment with disease-modifying antirheumatic drugs (DMARDs), including conventional synthetic DMARDs, biologic DMARDs, and targeted synthetic DMARDs, use of glucocorticoids, and use of DMARDs in certain high-risk populations (i.e., those with liver disease, heart failure, lymphoproliferative disorders, previous serious infections, and nontuberculous mycobacterial lung disease). The guideline includes 44 recommendations (7 strong and 37 conditional). CONCLUSION. This clinical practice guideline is intended to serve as a tool to support clinician and patient decision-making. Recommendations are not prescriptive, and individual treatment decisions should be made through a shared decision-making process based on patients’ values, goals, preferences, and comorbidities.

ObjectivesRheumatoid arthritis (RA), along with glucocorticoid use, is associated with cardiovascular disease. Cardiovascular safety of glucocorticoids in RA is controversial and may be related to dose and duration of use. We determined if initiating glucocorticoids in steroid-naive RA patients would increase cardiovascular event (CVE) risk in a dose and duration-dependent manner over short-term intervals.MethodsPatients enrolled in CorEvitas (formerly Corrona) RA registry. Cox proportional-hazards models estimated adjusted HRs (aHR) for incident CVE in patients who initiated glucocorticoid treatment, adjusting for RA duration, traditional cardiovascular risk factors and time-varying covariates: Clinical Disease activity Index, disease-modifying antirheumatic drugs use and prednisone-equivalent use. Glucocorticoid use assessed current daily dose, cumulative dose and duration of use over rolling intervals of preceding 6 months and 1 year.Results19 902 patients met criteria. 1106 CVE occurred (1.66/100 person-years). Increased aHR occurred at current doses of ≥5–9 mg 1.56 (1.18–2.06) and ≥10 mg 1.91 (1.31–2.79), without increased risk at 0–4 mg 1.04 (0.55–1.59). Cumulative dose over preceding 6 months showed increased aHR at 751–1100 mg 1.43 (1.04–1.98) and >1100 mg 2.05 (1.42–2.94), without increased risk at lower doses; duration of use over preceding 6 months exhibited increased aHR for >81 days of use 1.54 (1.08–2.32), without increased risk at shorter durations. One-year analyses were consistent.ConclusionsOver preceding 6-month and 1-year intervals, initiating glucocorticoids in steroid-naïve RA patients is associated with increased risk of CVE at daily doses ≥5 mg and increased cumulative dose and duration of use. No association with risk for CVE was found with daily prednisone of ≤4 mg or shorter cumulative doses and durations.

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

Rheumatoid arthritis (RA) increases the risk for cardiovascular disease (CVD) and the risk is related to disease activity1,2,3,4. Groundbreaking studies on the etiology of CVD have shown that there is a strong relationship with inflammation5,6. Given that a core therapeutic goal in RA is to control inflammation, it is appropriate to determine if therapeutic interventions for disease activity may also favorably affect the incidence of CVD. Because of the association of inflammation with CVD, a large therapeutic trial was conducted to determine if methotrexate (MTX) treatment in patients with a history of CVD could actually prevent new vascular events. The Cardiovascular Inflammation Reduction Trial (CIRT) was conducted in patients with a history of CVD (without RA or any other inflammatory disease) to determine if weekly MTX was associated with a decrease in new cardiovascular (CV) events7. The study was discontinued due to the lack of benefits of MTX on CVD reduction in this population. However, there has been much speculation regarding the reason(s) for the absence of MTX effect, including the fact that these patients did not have systemic inflammation with elevated C-reactive protein (CRP)8. Given the inflammatory nature of RA, it is certainly logical to posit that therapeutic interventions directed at the treatment of the underlying disease would also favorably affect the incidence of CVD in that population. Indeed, studies have shown that inhibition of both tumor necrosis factor (TNF)9,10 and MTX11,12,13,14,15 significantly diminishes the incidence of CVD in patients with RA. In this issue of The Journal of Rheumatology , Xie and colleagues have demonstrated that MTX is also incrementally beneficial for the prevention of CVD when used in combination … Address correspondence to Dr. J. Kremer, 521 Sir Charles Way, Albany, NY 12203, USA. Email: jkremer{at}corrona.org.

OBJECTIVE Comparative effectiveness research can inform treatment decisions regarding the choice of biologics for rheumatoid arthritis (RA). The objective of this study is to compare the efficacy of tumor necrosis factor inhibitors (TNFis) and non-TNFis (nTNFis) in real-world patients with RA and past TNFi experience. METHODS Comparative Effectiveness Registry to study Therapies for Arthritis and Inflammatory Conditions (CERTAIN) was nested within the United States Corrona registry. Adult patients with RA with moderate to high disease activity (Clinical Disease Activity Index [CDAI] >10) with exposure to one or more prior TNFis who were switching to a new TNFi or nTNFi (choice of therapy per physician choice) were enrolled. The primary outcome was the achievement of low disease activity (LDA) at 12 months (CDAI ≤10; disease activity score in 28 joints based on C-reactive protein [DAS28-CRP]

ObjectivesJanus kinase inhibitors (JAKi) have been approved for use in various immune-mediated inflammatory diseases. With five agents licensed, it was timely to summarise the current understanding of JAKi use based on a systematic literature review (SLR) on efficacy and safety.MethodsExisting data were evaluated by a steering committee and subsequently reviewed by a 29 person expert committee leading to the formulation of a consensus statement that may assist the clinicians, patients and other stakeholders once the decision is made to commence a JAKi. The committee included patients, rheumatologists, a gastroenterologist, a haematologist, a dermatologist, an infectious disease specialist and a health professional. The SLR informed the Task Force on controlled and open clinical trials, registry data, phase 4 trials and meta-analyses. In addition, approval of new compounds by, and warnings from regulators that were issued after the end of the SLR search date were taken into consideration.ResultsThe Task Force agreed on and developed four general principles and a total of 26 points for consideration which were grouped into six areas addressing indications, treatment dose and comedication, contraindications, pretreatment screening and risks, laboratory and clinical follow-up examinations, and adverse events. Levels of evidence and strengths of recommendations were determined based on the SLR and levels of agreement were voted on for every point, reaching a range between 8.8 and 9.9 on a 10-point scale.ConclusionThe consensus provides an assessment of evidence for efficacy and safety of an important therapeutic class with guidance on issues of practical management.

ObjectivesTo determine the effect of hydroxychloroquine on the incidence of new respiratory infections in a large registry of rheumatoid arthritis (RA) patients compared with a matched cohort receiving other conventional disease-modifying antirheumatic drugs (csDMARDs).MethodsWe reviewed physician-reported infections including upper respiratory infections (URI), bronchitis and pneumonia in the Corrona RA registry from June 2008 to February 2020 with the goal of comparing infections in biologic/targeted synthetic (b/ts) DMARDs naive HCQ starts compared with starts of other csDMARDs and no HCQ. Patients on different interventions were compared using time-varying adjusted Cox models adjusting for age, sex, duration of RA, BMI, disease activity, smoking status, concurrent medications, season of the year, year of onset and history of serious infections, diabetes or cardiovascular disease (CVD). A secondary analysis in a set of propensity-matched starts were also compared adjusting for time-varying covariates. The analysis was repeated including URI and bronchitis only and also for serious respiratory infections only.ResultsNo evidence of differences was found in the incidence of any respiratory infection (URI, bronchitis, pneumonia) in patients receiving HCQ compared with other csDMARDs: HR=0.87 (0.70 to1.07) in adjusted analyses and HR=0.90 (0.70 to 1.17) in adjusted matched analysis. Similar results were found in the analysis of URI and bronchitis only and for serious respiratory infections only.ConclusionsIn patients with RA, the risk for respiratory infections was similar among patients using HCQ as compared to other non-biologic DMARDs.