Antibodies to Malondialdehyde-Acetaldehyde Adduct Are Associated with Prevalent and Incident Rheumatoid Arthritis-Associated Interstitial Lung Disease in U.S. Veterans.

OBJECTIVE: To determine the associations of protein-specific anti-malondialdehyde acetaldehyde (MAA) antibodies with prevalent and incident rheumatoid arthritis-interstitial lung disease (RA-ILD). METHODS: Within a multicenter, prospective cohort of U.S. Veterans with RA, RA-ILD was validated by medical record review of clinical diagnoses, chest imaging, and pathology. Serum antibodies to MAA-albumin, MAA-collagen, MAA-fibrinogen, and MAA-vimentin (IgA, IgM, and IgG) were measured by a standardized ELISA. Associations of anti-MAA antibodies with prevalent and incident RA-ILD were assessed using multivariable regression models adjusting for established RA-ILD risk factors. RESULTS: Among 2,739 RA participants (88% male, mean age 64 years), there were 114 prevalent and 136 incident RA-ILD cases (average time to diagnosis: 6.6 years). Higher IgM anti-MAA-collagen (per 1 SD: aOR 1.28 [1.02-1.61]), IgA anti-MAA-fibrinogen (aOR 1.48 [1.14-1.92]), and IgA (aOR 1.78 [1.34-2.37]) and IgG (aOR 1.48 [1.14-1.92]) anti-MAA-vimentin antibodies were associated with prevalent RA-ILD. In incident analyses, higher IgA (per 1 SD: aHR 1.40 [1.11-1.76]) and IgM (aHR 1.29 [1.04-1.60]) anti-MAA-albumin antibody concentrations were associated with increased ILD risk. Participants with IgA (aHR 2.13 [1.16-3.90]) or IgM (aHR 1.98 [1.08-3.64]) anti-MAA-albumin antibody concentrations in the highest quartile had an approximate 2-fold increased risk of incident RA-ILD. Across all isotypes, anti-MAA-fibrinogen, -collagen, and -vimentin antibodies were not significantly associated with incident RA-ILD. CONCLUSIONS: Protein-specific anti-MAA antibodies to collagen, fibrinogen, and vimentin were associated with prevalent RA-ILD. IgA and IgM anti-MAA-albumin antibodies were associated with a higher risk of incident RA-ILD. These findings suggest that MAA-modifications and resultant immune responses may contribute to RA-ILD pathogenesis.

Development and Internal Validation of a Clinical and Genetic Risk Score for Rheumatoid Arthritis-Associated Interstitial Lung Disease.

OBJECTIVE: Although clinical and genetic risk factors have been identified for rheumatoid arthritis-associated interstitial lung disease (RA-ILD), there are no current tools allowing for risk stratification. We sought to develop and validate an ILD risk model in a large, multicentre, prospective RA cohort. METHODS: Participants in the Veterans Affairs RA (VARA) registry were genotyped for 12 single nucleotide polymorphisms (SNPs) associated with idiopathic pulmonary fibrosis. ILD was validated through systematic record review. A genetic risk score (GRS) was computed from minor alleles weighted by effect size with ILD, using backward selection. The GRS was combined with clinical risk factors within a logistic regression model. Internal validation was completed using bootstrapping, and model performance was assessed by the area under the receiver operating curve (AUC). RESULTS: Of 2,386 participants (89% male, mean age 69.5 years), 9.4% had ILD. Following backward selection, five SNPs contributed to the GRS. The GRS and clinical factors outperformed clinical factors alone in discriminating ILD (AUC 0.675 vs 0.635, p< 0.001). The shrinkage-corrected performance for combined and clinical-only models was 0.667 (95% CI 0.628, 0.712) and 0.623 (95% CI 0.584, 0.651), respectively. Twenty percent of the cohort had a combined risk score below a cut-point with >90% sensitivity. CONCLUSION: A clinical and genetic risk model discriminated ILD in a large, multicentre RA cohort better than a clinical-only model, excluding 20% of the cohort from low-yield testing. These results demonstrate the potential utility of a GRS in RA-ILD and support further investigation into individualized risk stratification and screening.

Plasma Matrix Metalloproteinase Concentrations and Risk of Interstitial Lung Disease in a Prospective Rheumatoid Arthritis Cohort.

OBJECTIVE: To evaluate the associations of plasma matrix metalloproteinases (MMPs) with prevalent and incident interstitial lung disease (ILD) in people with rheumatoid arthritis (RA). METHODS: Within a multicenter, prospective cohort of US veterans with RA, we performed a cross-sectional study of prevalent ILD and cohort study of incident ILD. ILD diagnoses were validated by medical record review of provider diagnoses and chest imaging and/or pathology reports. MMP-1, 3, 7, and 9 concentrations were measured in plasma samples, then standardized and categorized into quartiles. The associations of MMPs with prevalent and incident ILD were assessed with logistic (prevalent) and Cox (incident) regression models adjusted for RA-ILD risk factors. RESULTS: Among 2,312 participants (88.9% male; mean age 63.8 years), 96 had prevalent ILD. Incident ILD developed in 130 participants over 17,378 person-years of follow-up (crude incidence rate 7.5/1,000 person-years). Participants with the highest quartile of MMP-7 concentrations had a nearly four-fold increased odds of prevalent ILD (adjusted odds ratio 3.78 [95% confidence interval (95% CI) 1.86-7.65]) and over two-fold increased risk of incident ILD (adjusted hazard ratio 2.33 [95% CI 1.35-4.02]). Higher MMP-9 concentrations were also associated with prevalent and incident ILD, as well as negatively correlated with forced vital capacity among those with prevalent ILD (r = -0.30, P = 0.005). CONCLUSION: MMP-7 and MMP-9 were strongly associated with both prevalent and incident ILD in this large, multicenter RA cohort after adjustment for other RA-ILD risk factors. These population-level findings further support a potential pathogenic role for MMPs in RA-ILD and suggest that their measurement could facilitate RA-ILD risk stratification.

Serum alarmins and the risk of incident interstitial lung disease in rheumatoid arthritis.

OBJECTIVES: To quantify associations of serum alarmins with risk of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). METHODS: Using serum collected at enrolment, three alarmins (interleukin [IL]-33, thymic stromal lymphopoietin [TSLP], and IL-25) were measured in a multicentre prospective RA cohort. ILD was classified using systematic medical record review. Cross-sectional associations of log-transformed (IL-33, TSLP) or quartile (IL-25) values with RA-ILD at enrolment (prevalent RA-ILD) were examined using logistic regression, while associations with incident RA-ILD developing after enrolment were examined using Cox proportional hazards. Covariates in multivariate models included age, sex, race, smoking status, RA disease activity score, and anti-cyclic citrullinated antibody positivity. RESULTS: Of 2,835 study participants, 115 participants (4.1%) had prevalent RA-ILD at baseline and an additional 146 (5.1%) developed incident ILD. There were no associations between serum alarmin concentrations and prevalent ILD in unadjusted or adjusted logistic regression models. In contrast, there was a significant inverse association between IL-33 concentration and the risk of developing incident RA-ILD in unadjusted (HR 0.73 per log-fold increase; 95% CI 0.57-0.95; p= 0.018) and adjusted (HR 0.77; 95% CI 0.59-1.00, p= 0.047) models. No significant associations of TSLP or IL-25 with incident ILD were observed. CONCLUSIONS: In this study, we observed a significant inverse association between serum IL-33 concentration and the risk of developing incident RA-ILD, but no associations with prevalent ILD. Additional investigation is required to better understand the mechanisms driving this relationship and how serum alarmin IL-33 assessment might contribute to clinical risk stratification in patients with RA.

Associations of Cost Sharing With Rheumatoid Arthritis Disease Burden.

OBJECTIVE: To evaluate the regional variation of cost sharing and associations with rheumatoid arthritis (RA) disease burden in the US. METHODS: Patients with RA from rheumatology practices in Northeast, South, and West US regions were evaluated. Sociodemographics, RA disease status, and comorbidities were collected, and Rheumatic Disease Comorbidity Index (RDCI) score was calculated. Primary insurance types and copay for office visits (OVs) and medications were documented. Univariable pairwise differences between regions were conducted, and multivariable regression models were estimated to evaluate associations of RDCI with insurance, geographical region, and race. RESULTS: In a cohort of 402 predominantly female, White patients with RA, most received government versus private sponsored primary insurance (40% vs. 27.9%). Disease activity and RDCI were highest for patients in the South region, where copays for OVs were more frequently more than $25. Copays for OVs and medications were less than $10 in 45% and 31.8% of observations, respectively, and more prevalent in the Northeast and West patient subsets than in the South subset. Overall, RDCI score was significantly higher for OV copays less than $10 as well as for medication copays less than $25, both independent of region or race. Additionally, RDCI was significantly lower for privately insured than Medicare individuals (RDCI -0.78, 95% CI [-0.41 to -1.15], P < 0.001) and Medicaid (RDCI -0.83, 95% CI [-0.13 to -1.54], P = 0.020), independent of region and race. CONCLUSION: Cost sharing may not facilitate optimum care for patients with RA, especially in the Southern regions. More support may be required of government insurance plans to accommodate patients with RA with a high disease burden.

Geographic Variation in Disease Burden and Mismatch in Care of Patients With Rheumatoid Arthritis in the United States.

OBJECTIVE: Our objective was to evaluate the factors associated with regional variation of rheumatoid arthritis (RA) disease burden in the US. METHODS: In a retrospective cohort analysis of Rheumatology Informatics System for Effectiveness (RISE) registry data, seropositivity, RA disease activity (Clinical Disease Activity Index [CDAI], Routine Assessment of Patient Index Data-version 3 [RAPID3]), socioeconomic status (SES), geographic region, health insurance type, and comorbidity burden were recorded. An Area Deprivation Index score of more than 80 defined low SES. Median travel distance to practice sites' zip codes was calculated. Linear regression was used to analyze associations between RA disease activity and comorbidity adjusting for age, sex, geographic region, race, and insurance type. RESULTS: Enrollment data for 184,722 patients with RA from 182 RISE sites were analyzed. Disease activity was higher in African American patients, in those from Southern regions, and in those with Medicaid or Medicare coverage. Greater comorbidity was prevalent in patients in the South and those with Medicare or Medicaid coverage. There was moderate correlation between comorbidity and disease activity (Pearson coefficient: RAPID3 0.28, CDAI 0.15). High-deprivation areas were mainly in the South. Less than 10% of all participating practices cared for more than 50% of all Medicaid recipients. Patients living more than 200 miles away from specialist care were located mainly in Southern and Western regions. CONCLUSION: A disproportionately large portion of socially deprived, high comorbidity, and Medicaid-covered patients with RA were cared for by a minority of rheumatology practices. Studies are needed in high-deprivation areas to establish more equitable distribution of specialty care for patients with RA.

Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio as Biomarkers in Axial Spondyloarthritis: Observational Studies From the Program to Understand the Longterm Outcomes in Spondyloarthritis Registry.

OBJECTIVES: This study was conducted to assess the utility of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in predicting radiographic sacroiliitis and active disease in axial spondyloarthritis (SpA) and to explore the association between use of a tumor necrosis factor inhibitor (TNFi) and these laboratory values compared with traditional inflammatory markers. METHODS: Observational data from the Program to Understand the Longterm Outcomes in Spondyloarthritis (PULSAR) registry were analyzed. We generated receiver operating characteristic curves to calculate laboratory cutoff values; we used these values in multivariable logistic regression models to identify associations with radiographically confirmed sacroiliitis and active disease. We also used logistic regression to determine the likelihood of elevated laboratory values after initiation of TNFi. RESULTS: Most study participants (n = 354) were White, male, and HLA-B27 positive. NLR (odds ratio [OR] 1.459, P = 0.034), PLR (OR 4.842, P < 0.001), erythrocyte sedimentation rate (OR 4.397, P < 0.001), and C-reactive protein (CRP) level (OR 2.911, P = 0.001) were independent predictors of radiographic sacroiliitis. Models that included PLR with traditional biomarkers performed better than those with traditional biomarkers alone. NLR (OR 6.931, P = 0.002) and CRP (OR 2.678, P = 0.004) were predictors of active disease, but the model that included both NLR and CRP performed better than CRP alone. TNFi use reduced the odds of elevated NLR (OR 0.172, P < 0.001), PLR (OR 0.073, P < 0.001), erythrocyte sedimentation rate (OR 0.319, P < 0.001), and CRP (OR 0.407, P < 0.001), but models that included NLR or PLR and traditional biomarkers performed best. CONCLUSIONS: These findings demonstrate an association between NLR and PLR and sacroiliitis and disease activity, with NLR and PLR showing response after TNFi treatment and adding useful clinical information to established biomarkers, thus perhaps assisting in management of axial SpA.

Hydroxychloroquine and Risk of Long QT Syndrome in Rheumatoid Arthritis: A Veterans Cohort Study With Nineteen-Year Follow-up.

OBJECTIVE: Recent evidence suggests that hydroxychloroquine use is not associated with higher 1-year risk of long QT syndrome (LQTS) in patients with rheumatoid arthritis (RA). Less is known about its long-term risk, the examination of which was the objective of this study. METHODS: We conducted a propensity score-matched active-comparator safety study of hydroxychloroquine in 8,852 veterans (mean age 64 ± 12 years, 14% women, 28% Black) with newly diagnosed RA. A total of 4,426 patients started on hydroxychloroquine and 4,426 started on another nonbiologic disease-modifying antirheumatic drug (DMARD) and were balanced on 87 baseline characteristics. The primary outcome was LQTS during 19-year follow-up through December 31, 2019. RESULTS: Incident LQTS occurred in 4 (0.09%) and 5 (0.11%) patients in the hydroxychloroquine and other DMARD groups, respectively, during the first 2 years. Respective 5-year incidences were 17 (0.38%) and 6 (0.14%), representing 11 additional LQTS events in the hydroxychloroquine group (number needed to harm 403; [95% confidence interval (95% CI)], 217-1,740) and a 181% greater relative risk (95% CI 11%-613%; P = 0.030). Although overall 10-year risk remained significant (hazard ratio 2.17; 95% CI 1.13-4.18), only 5 extra LQTS occurred in hydroxychloroquine group over the next 5 years (years 6-10) and 1 over the next 9 years (years 11-19). There was no association with arrhythmia-related hospitalization or all-cause mortality. CONCLUSIONS: Hydroxychloroquine use had no association with LQTS during the first 2 years after initiation of therapy. There was a higher risk thereafter that became significant after 5 years of therapy. However, the 5-year absolute risk was very low, and the absolute risk difference was even lower. Both risks attenuated during longer follow-up. These findings provide evidence for long-term safety of hydroxychloroquine in patients with RA.

Genetic, social, and environmental risk factors in rheumatoid arthritis-associated interstitial lung disease.

OBJECTIVE: MUC5B and TOLLIP single nucleotide polymorphisms (SNPs) and cigarette smoking were associated with rheumatoid arthritis-interstitial lung disease (RA-ILD) in a predominantly Northern European population. We evaluated whether RA-ILD is associated with these genetic variants and HLA-DRB1 shared epitope (SE) alleles in a large RA cohort stratified by race and smoking history. METHODS: HLA-DRB1 SE alleles and MUC5B rs35705950 and TOLLIP rs5743890 SNPs were genotyped in U.S. veterans with RA. ILD was validated through medical record review. Genetic associations with ILD were assessed in logistic regression models overall and in subgroups defined by race and smoking status, with additive interactions assessed by the relative excess risk of interaction (RERI). RESULTS: Of 2,556 participants (88% male, 77% White), 238 (9.3%) had ILD. The MUC5B variant was associated with ILD (OR 2.25 [95% CI 1.69, 3.02]), whereas TOLLIP and HLA-DRB1 SE were not. The MUC5B variant was less frequent among Black/African American participants (5.8% vs. 22.6%), though its association with RA-ILD was numerically stronger (OR 4.23 [1.65, 10.86]) compared to all other participants (OR 2.32 [1.70, 3.16]). Those with the MUC5B variant and a smoking history had numerically higher odds of ILD (OR 4.18 [2.53, 6.93]) than non-smokers (OR 2.41 [1.16, 5.04]). Additive interactions between MUC5B-race and MUC5B-smoking were not statistically significant. CONCLUSION: In this large RA cohort, the MUC5B promoter variant was associated with >2-fold higher odds of RA-ILD. While this variant is less common among Black/African American patients, its presence in this population carried >4-fold higher odds of RA-ILD.

Protocol for a multi-center randomized controlled trial to evaluate the benefits of exercise incentives and corticosteroid injections in osteoarthritis of the knee (MOVE-OK).

BACKGROUND: Knee osteoarthritis (KOA) is a high-priority problem among the aging population. While exercise has been shown to be beneficial in management of the disease, scalable and low-cost interventions to improve exercise in this population are lacking. Recent controversy over the value of corticosteroid injections for palliation has also arisen. Therefore, we designed a randomized, double-blind, placebo-controlled clinical trial with a 2-period crossover design to study (1) behavioral incentives to promote exercise and (2) corticosteroid injections to reduce pain and improve function in patients with KOA when compared to lidocaine only. METHODS: The study design is a pragmatic factorial and crossover randomized clinical trial. Patients with KOA who are deemed eligible by their provider to receive knee injections and are able to walk without assistive devices will be recruited from clinical practices at four sites within the Veterans Affairs (VA) Health System in the USA. In total, 220 participants will be randomized to receive social incentives with gamification (i.e., incorporation of game elements) to promote exercise and compared to controls that receive a Fitbit but no incentive. Each patient will also be assigned to receive a blinded corticosteroid injection and a lidocaine-only injection in random order. The primary outcomes are the change in average daily step counts from baseline and the change in Knee Osteoarthritis Outcome Score (KOOS) from baseline. The study team will continuously collect step count, heart rate, and sleep data using activity monitors and patient-reported outcomes using the Way to Health (WTH) platform at two four-week intervals over eight months of follow-up. Mixed effects regression incorporating all available data points will be used for analysis. DISCUSSION: The "Marching on for Veterans with Osteoarthritis of the Knee" (MOVE-OK) trial will take a pragmatic approach to evaluate (1) whether incentives based on behaviorally enhanced gamification can improve physical activity in this patient population and (2) whether corticosteroids injections reduce pain and disability in patients with KOA. Results of this trial will help to direct clinical practice and inform management guidelines. TRIAL REGISTRATION: ClinicalTrials.gov NCT05035810 . Registered on 5 September 2021.

Association of rheumatoid arthritis with mortality in chronic kidney disease: a cohort study.

BACKGROUND: Rheumatoid arthritis (RA) is associated with an increased risk of cardiovascular disease (CVD) as well as with an increased risk of chronic kidney disease (CKD), also a known cardiovascular risk factor. However, it is not known if RA is a predictor of adverse outcomes in patients with CKD. We hypothesized that among a cohort of patients with CKD, RA would be associated with an increased risk of mortality. MATERIALS AND METHODS: We conducted a retrospective study of 3939 participants with CKD from the prospective Chronic Renal Insufficiency Cohort (CRIC) study. The primary outcome of interest was all-cause mortality. Secondary outcomes included CKD progression (defined as end-stage kidney disease or 50% decline in estimated glomerular filtration rate), cardiovascular endpoints, and composite of myocardial infarction, cerebrovascular accident, heart failure, or death. Multivariable Cox proportional hazards regression was utilized, adjusting for potential confounders including age, sex, race/ethnicity, body mass index, current smoker, and education. RESULTS: The study cohort included 83 participants with RA on a disease modifying anti-rheumatic drug (DMARD). In the adjusted analysis, CKD-RA status was significantly associated with an increased risk of death (adjusted HR, aHR, 1.73 (1.27, 2.35)) and composite outcome (aHR 1.65 (1.27-2.15)) even after adjusting for traditional risk factors. Similar statistically significant associations were observed between CKD-RA and other secondary outcomes except for CKD progression. CONCLUSION: RA was associated with higher mortality among individuals with CKD but not progressive renal decline. Further studies evaluating the mechanisms behind this association are needed. Key Points • Rheumatoid arthritis (RA) is associated with an increased risk of cardiovascular disease (CVD) as well as with an increased risk of chronic kidney disease (CKD), also a known cardiovascular risk factor. However, it is not known if RA is an independent predictor of adverse outcomes in patients with CKD • In this study, we observed that CKD patients with RA experience higher mortality as well as an increased risk of CVD compared to patients with CKD without comorbid RA • These data provide rationale for more aggressive monitoring for CVD in patients with CKD and RA. They also underscore the need for determining which interventions can help decrease the burden of mortality in these patients.

The impact of disease severity measures on survival in U.S. veterans with rheumatoid arthritis-associated interstitial lung disease.

OBJECTIVES: To determine whether RA and interstitial lung disease (ILD) severity measures are associated with survival in patients with RA-ILD. METHODS: We studied US veterans with RA-ILD participating in a multicentre, prospective RA cohort study. RA disease activity (28-joint DAS [DAS28-ESR]) and functional status (multidimensional HAQ [MDHAQ]) were collected longitudinally while pulmonary function tests (forced vital capacity [FVC], diffusing capacity for carbon monoxide) were obtained from medical records. Vital status and cause of death were determined from the National Death Index and administrative data. Predictors of death were assessed using multivariable Cox regression models adjusting for age, sex, smoking status, ILD duration, comorbidity burden and medications. RESULTS: We followed 227 RA-ILD participants (93% male and mean age of 69 years) over 1073 person-years. Median survival after RA-ILD diagnosis was 8.5 years. Respiratory diseases (28%) were the leading cause of death, with ILD accounting for 58% of respiratory deaths. Time-varying DAS28-ESR (adjusted hazard ratio [aHR] 1.21; 95% CI: 1.03, 1.41) and MDHAQ (aHR 1.85; 95% CI: 1.29, 2.65) were separately associated with mortality independent of FVC and other confounders. Modelled together, the presence of either uncontrolled disease activity (moderate/high DAS28-ESR) or FVC impairment (<80% predicted) was significantly associated with mortality risk. Those with a combination of moderate/high disease activity and FVC <80% predicted had the highest risk of death (aHR 4.43; 95% CI: 1.70, 11.55). CONCLUSION: Both RA and ILD disease severity measures are independent predictors of survival in RA-ILD. These findings demonstrate the prognostic value of monitoring the systemic features of RA-ILD.

Adipocytokines and achievement of low disease activity in rheumatoid arthritis.

PURPOSE: To determine if adipocytokines are independently associated with the achievement of low disease activity (LDA) over long-term follow-up in a large rheumatoid arthritis (RA) registry. METHODS: This cohort study evaluated adults with RA from the Veteran's Affairs RA Registry. Adipocytokines (adiponectin, leptin, and fibroblast growth factor [FGF]-21) and inflammatory cytokines were measured as part of a multi-analyte panel on banked serum from enrollment. Covariates were derived from medical record, biorepository, and registry databases. Multivariable Cox proportional hazard models evaluated associations between adipocytokines and rates of 1) DAS28 LDA and remission, 2) individual Boolean remission criteria and 3) initiation of a new bDMARD or tsDMARD. RESULTS: There were 1,276 participants with a DAS28 >3.2 at enrollment. Of these, 827 achieved LDA and 598 achieved remission over 2,287 and 4,096 person-years, respectively. Patients in the highest quartile of adiponectin had lower rates LDA before and after adjustment [aHR Q4: 0.68 (0.53,0.87) p<0.001]. Those in the highest quartile of leptin and FGF-21 also had lower rates of LDA. Higher quartiles of adipocytokines were also associated with lower rates of achieving a low patient/evaluator global scores and low tender joint counts. Among 1,236 biologic-naïve participants, values above the median for adiponectin [HR: 1.67 (1.23,1.26) p = 0.001] and FGF-21 [HR: 1.27 (1.09,1.47) p = 0.002] were associated with a greater likelihood of initiating a b/tsDMARD. CONCLUSIONS: Adipocytokines may serve as prognostic biomarkers of a more severe RA disease course. Additional study is needed to determine whether adipocytokines are phenotypic markers or whether they actively promote disease progression.

Elevations in adipocytokines and mortality in rheumatoid arthritis.

OBJECTIVES: This study assessed whether circulating levels of adiponectin and leptin are associated with higher mortality in patients with RA. METHODS: Participants were adults from the Veterans Affairs RA Registry. Adipokines and inflammatory cytokines were measured as part of a multi-analyte panel on banked serum at enrolment. Dates and causes of death were derived from the Corporate Data Warehouse and the National Death Index. Covariates were derived from medical record, biorepository and registry databases. Multivariable Cox proportional hazard models evaluated associations between biomarkers and all-cause and cause-specific mortality. RESULTS: A total of 2583 participants were included. Higher adiponectin levels were associated with older age, male sex, white race, lower BMI, autoantibody seropositivity, radiographic damage, longer disease duration, prednisone use and osteoporosis. Higher adiponectin concentrations were also associated with higher levels of inflammatory cytokines but not higher disease activity at enrolment. Leptin was primarily associated with greater BMI and comorbidity. The highest quartile of adiponectin (vs lowest quartile) was associated with higher all-cause mortality [hazard ratio (HR): 1.46 (95% CI: 1.11, 1.93), P = 0.009] and higher cardiovascular mortality [HR: 1.85 (95% CI: 1.24, 2.75), P = 0.003], after accounting for covariates. Higher leptin levels were also associated with greater all-cause and cancer mortality. CONCLUSIONS: Elevations in adipokines are associated with age, BMI, comorbidity and severe disease features in RA and independently predict early death. Associations between adiponectin and inflammatory cytokines support the hypothesis that chronic subclinical inflammation promotes metabolic changes that drive elevations in adipokines and yield adverse health outcomes.

Tumor necrosis factor inhibitor (TNFi) persistence and reasons for discontinuation in a predominantly male cohort with axial spondyloarthritis.

Although tumor necrosis factor inhibitors (TNFi) have favorably altered the treatment landscape for patients with axial spondyloarthritis (axSpA), there is limited data regarding TNFi persistence and reasons for discontinuation. This is an observational time-to-event study utilizing data collected for a prospective multiple-disease registry of US Veterans with axSpA treated with TNFi therapies and recruited over a 10 year period. Clinical, serological, and comorbid parameters were collected. Corporate Data Warehouse Pharmacy files provided courses of the 5 TNFi agents, and response to treatment was documented. Individual TNFi persistence was established utilizing univariate and multivariate Cox proportional models, and reasons for discontinuation were obtained by physician chart review. Two-hundred and fifty-five axSpA patients received 731 TNFi courses. A majority of patients (84.3%) had TNFi persistence at 12 months; 63.5% and 47.1% at 24 and 36 months, respectively. Compared to adalimumab, infliximab demonstrated greater persistence, certolizumab the least. Age, smoking status, BMI, comorbidity burden, inflammatory markers and HLA-B27 did not predict TNFi persistence or discontinuation. Stroke and peripheral arterial disease increased the probability of TNFi discontinuation. Secondary non-response (SNR) was the most common reason for discontinuation (46% of all courses); non-adherence (6%) and clinical remission (2%) were uncommon. Pain score at enrollment, myocardial infarction, African American race and inflammatory bowel disease (IBD) predicted TNFi response. While initial persistence of TNFi treatment was high, a large proportion of the patients discontinued initial TNFi therapy by 3 years, primarily due to loss of efficacy. While further research identifying potential predictors of TNFi discontinuation in axSpA is warranted, access to alternate disease-modifying therapies is needed.

Increasing Advocacy Awareness in Early Career Rheumatologists: A Web-Based Educational Tool.

OBJECTIVE: To evaluate the utility of a web-based advocacy training tool in increasing advocacy awareness. METHODS: Early career rheumatologists who attended 2019 American College of Rheumatology Advocacy 101 were invited to participate. A web-based tool consisting of 9 cases covering various aspects of advocacy was developed and included the opportunity for continuing medical education credit. A preparticipation questionnaire surveyed prior involvement, knowledge, and willingness to participate in an advocacy program. Participants rated cases based on educational quality, relevance of content, achievement of training goals, competency, and evidence of bias. Two web-based conferences were held to address technical questions, review, and discussion of cases and responses, and to obtain feedback. RESULTS: Twenty-one early career rheumatologists from 9 academic institutions enrolled, with 15 (75%) completing all cases. Correct continuing medical education answers were scored on 85% of cases. Overall educational quality of content received a mean rating of 4.3 of 5. Seven cases achieved positive ratings for relevance of case content, achievement of training goals, objectivity, and competency. All cases were assessed free of bias. Feedback indicated that 30 minutes were dedicated to each case, and that a combination of skill set and content learning were most effective. Pre- and postquestionnaire scores indicated significant improvement in knowledge of advocacy matters (P < 0.0001). CONCLUSION: A web-based advocacy training tool was successful in significantly improving awareness and knowledge of advocacy matters among early career rheumatologists. This innovative educational tool may play a vital role in shaping the future of rheumatology for both patients and physicians.

2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis.

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.