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BACKGROUND: Patients hospitalised for COVID-19 are at risk for multiorgan failure and death. Sodium-glucose co-transporter-2 (SGLT2) inhibitors provide cardiovascular and kidney protection in patients with cardiometabolic conditions and could provide organ protection during COVID-19. We aimed to investigate whether SGLT2 inhibitors can reduce the need for organ support in patients hospitalised for COVID-19. METHODS: This pragmatic, multicentre, open-label, randomised, controlled, platform trial was conducted across 63 sites in the USA, Spain, Brazil, Italy, and Mexico. Patients aged at least 18 years hospitalised for COVID-19 (moderate or severe illness) were randomly assigned (1:1), via an interactive voice system or web-response system, to receive locally available SGLT2 inhibitor (administered orally, once daily) plus standard-of-care or standard-of-care for 30 days. The primary outcome was organ support-free days evaluated through 21 days, assessed using intention-to-treat approach. This trial is registered on ClinicalTrials.gov, NCT04505774. FINDINGS: The first patient was randomly assigned to the SGLT2 inhibitor domain on Dec 3, 2021. On March 31, 2023, at the recommendation of the data and safety monitoring board, enrolment in the SGLT2 inhibitor domain for both moderately and severely ill hospitalised patients was stopped prematurely for futility due to a low likelihood of finding a treatment benefit. The final randomised population consisted of 575 patients (mean age 72 years [SD 13], 242 (42%) female and 154 (27%) Hispanic; 504 in the moderate illness group and 71 in the severe illness group). 573 patients had a known 21-day outcome; 215 (75%) of 285 patients in the SGLT2 inhibitor plus standard-of-care group did not require respiratory or cardiovascular organ support versus 231 (80%) of 288 patients in the standard-of-care group. The adjusted odds ratio (OR) for an SGLT2 inhibitor effect on organ support-free days was 0·74 (95% Credible Interval [CrI] 0·48-1·13; where OR higher than 1 indicated treatment benefit, yielding a posterior probability of futility P(OR <1·2) of 99% and a posterior probability of inferiority P(OR<1·0) of 91%). There were 37 deaths (13%) in the SGLT2 inhibitor plus standard-of-care group and 42 deaths (15%) in the standard-of-care group at 90 days (hazard ratio 0·91 [95% CrI 0·58-1·43], probability of hazard ratio <1 of 66%). No safety concerns were observed with SGLT2 inhibitors, including no cases of ketoacidosis. INTERPRETATION: SGLT2 inhibitors did not significantly increase days free of organ support or reduce mortality in patients hospitalised with COVID-19. SGLT2 inhibitors were well tolerated with no observed safety concerns. Overall, these findings do not support the use of SGLT2 inhibitors as standard care in patients hospitalised with COVID-19. FUNDING: National Institutes of Health.

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INTRODUCTION: Patterns of treatment response can inform clinical decision-making. This study assessed the course and impact of achieving minimal clinically important improvement (MCII) in clinical measures and patient-reported outcomes (PROs) with guselkumab in patients with active psoriatic arthritis (PsA). METHODS: Post hoc analyses evaluated 1120 patients with PsA receiving guselkumab every 4 or 8 weeks (Q4W/Q8W) or placebo from DISCOVER-1 (31% tumor necrosis factor inhibitor-experienced) and DISCOVER-2 (biologic-naïve). Achievement of MCII in clinical Disease Activity Index for PsA (cDAPSA), patient global assessment (PtGA) of arthritis, PtGA of psoriasis, patient-reported pain, Functional Assessment of Chronic Illness Therapy-Fatigue, Health Assessment Questionnaire-Disability Index, 36-item Short-Form Health Survey Physical Component Summary score, PtGA Arthritis + Psoriasis, and PsA Disease Activity Score (PASDAS) was compared between the guselkumab and placebo groups using Cox regression. Logistic regression adjusting for baseline factors evaluated associations between early (W4/W8) MCII achievement and stringent response (≥%50/%70 improvement in American College of Rheumatology response criteria, cDAPSA low disease activity [LDA], PASDAS LDA, and minimal disease activity) at W24/W52 among guselkumab-randomized patients. RESULTS: Among patients with highly active PsA (baseline cDAPSA = 44.1-45.0, PASDAS = 6.4-6.5), times to MCII were significantly faster for guselkumab vs. placebo (hazard ratios 1.3-2.5; P < 0.05). Across measures, at first timepoint assessed, MCII rates were significantly higher with guselkumab (Q4W/Q8W 28-68%/29-65%) vs. placebo (19-47%; both P < 0.05). Early (W4/W8) MCII with guselkumab associated with higher odds of achieving stringent responses at W24/W52 (odds ratios 1.4-17.2/1.4-5.4). CONCLUSIONS: In a mixed PsA population, significant proportions of patients treated with guselkumab achieved early (W4/W8) MCII across clinical and PRO measures, which associated with a higher likelihood of attaining clinically relevant improvements and low levels of disease activity at W24/W52. TRIAL REGISTRATION: DISCOVER-1 (NCT03162796). DISCOVER-2 (NCT03158285).

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The Veterans Health Administration (VHA) listed the infliximab (IFX) biosimilar, IFX-dyyb (Inflectra), on the Veterans Affairs National Formulary (VANF) in May 2017. In September 2018, biosimilar IFX-abda (Renflexis) became the VANF IFX product. The recommended formulary changes from one IFX biosimilar to another provided a unique opportunity to study IFX utilization patterns in IFX-naïve Veterans with Inflammatory Bowel Disease (IBD). This study aimed to describe IFX and healthcare utilization during the 365 days after initiation with IFX reference product (RP) or biosimilars IFX-dyyb and IFX-adba. This descriptive study was performed using the VHA Corporate Data Warehouse. All Veterans initiated on IFX-RP (Remicade) or biosimilars IFX-dyyb and IFX-adba between September 1, 2016 and December 30, 2019 were included and followed for 365 days. Veterans enrolled in the VHA for at least 365 days with no evidence of IFX before their index date were considered IFX-naïve. Continuous data on IFX use, laboratory measurements, and healthcare utilization were reported with means, 95% confidence interval (CI), medians, and interquartile ranges. Frequency, proportions, and 95% CIs were presented for categorical variables. Statistical tests included ANOVA and Kruskal-Wallis for continuous outcomes, Poisson regression for count-based outcomes (i.e., healthcare utilization visits), and Chi-square for dichotomous outcomes. The study identified 1763 IFX-naïve patients with IBD, and 785, 441, and 537 was indexed to RP, IFX-dyyb, and IFX-adba, respectively. Statistical differences were observed in IFX utilization measures related to dosing, adherence, and persistence. The proportion of days covered (PDC) during the 365-day follow-up period varied among the IFX groups: IFX-RP at 66%, IFX-dyyb at 60%, and IFX-abda at 69% (P value < .001). Persistence with the index IFX product during the 365-day follow-up period also varied: IFX-RP at 43%, IFX-dyyb at 32%, and IFX-abda at 51% (P value < .001). Healthcare utilization and laboratory findings were similar among the IFX groups. IFX utilization and laboratory patterns were clinically similar among the IFX biosimilars and RP groups, suggesting that providers did not modify their practice with biosimilars. Statistically significant differences in IFX utilization patterns are explained by formulary dynamics when the VANF product switched from IFX-dyyb to IFX-abda.

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OBJECTIVE: To assess the impact of baseline rheumatoid factor (RF) level on drug concentrations and efficacy of certolizumab pegol (CZP; tumour necrosis factor inhibitor [TNFi] without a crystallisable fragment [Fc]) and adalimumab (ADA; Fc-containing TNFi) in patients with rheumatoid arthritis (RA). METHODS: The phase 4 EXXELERATE study (NCT01500278) was a 104-week, randomised, single-blind (double-blind until week 12; investigator-blind thereafter), head-to-head study of CZP vs ADA in patients with RA. In this post hoc analysis, we report drug concentration and efficacy outcomes stratified by baseline RF quartile (≤Q3 or >Q3). RESULTS: Baseline data by RF quartiles were available for 453 CZP-randomised and 454 ADA-randomised patients (≤Q3: ≤204 IU/ml; >Q3: >204 IU/ml). From week 12, the area under the curve (AUC) of ADA concentration was lower in patients with RF > 204 IU/ml vs patients with RF ≤ 204 IU/ml; the AUC of CZP concentration was similar in patients with RF ≤ 204 IU/ml and >204 IU/ml. For patients with RF ≤ 204 IU/ml, disease activity score (DAS28)-C-reactive protein (CRP) was similar between CZP- and ADA-treated patients through week 104. For patients with RF > 204 IU/ml, mean DAS28-CRP was lower in CZP- vs ADA-treated patients at week 104. The proportion of patients with RF > 204 IU/ml achieving DAS28-CRP low disease activity at week 104 was greater in CZP- vs ADA-treated patients. CONCLUSION: CZP was associated with maintained drug concentration and efficacy in patients with RA and high RF and may therefore be a more suitable therapeutic option than TNFis with an Fc fragment in these patients.

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Rationale: Identification and validation of circulating biomarkers for lung function decline in COPD remains an unmet need. Objective: Identify prognostic and dynamic plasma protein biomarkers of COPD progression. Methods: We measured plasma proteins using SomaScan from two COPD-enriched cohorts, the Subpopulations and Intermediate Outcomes Measures in COPD Study (SPIROMICS) and Genetic Epidemiology of COPD (COPDGene), and one population-based cohort, Multi-Ethnic Study of Atherosclerosis (MESA) Lung. Using SPIROMICS as a discovery cohort, linear mixed models identified baseline proteins that predicted future change in FEV1 (prognostic model) and proteins whose expression changed with change in lung function (dynamic model). Findings were replicated in COPDGene and MESA-Lung. Using the COPD-enriched cohorts, Gene Set Enrichment Analysis (GSEA) identified proteins shared between COPDGene and SPIROMICS. Metascape identified significant associated pathways. Measurements and Main Results: The prognostic model found 7 significant proteins in common (p < 0.05) among all 3 cohorts. After applying false discovery rate (adjusted p < 0.2), leptin remained significant in all three cohorts and growth hormone receptor remained significant in the two COPD cohorts. Elevated baseline levels of leptin and growth hormone receptor were associated with slower rate of decline in FEV1. Twelve proteins were nominally but not FDR significant in the dynamic model and all were distinct from the prognostic model. Metascape identified several immune related pathways unique to prognostic and dynamic proteins. Conclusion: We identified leptin as the most reproducible COPD progression biomarker. The difference between prognostic and dynamic proteins suggests disease activity signatures may be different from prognosis signatures.

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The biological mechanisms leading some tobacco-exposed individuals to develop early-stage chronic obstructive pulmonary disease (COPD) are poorly understood. This knowledge gap hampers development of disease-modifying agents for this prevalent condition. Accord-ingly, with National Heart, Lung and Blood Institute support, we initiated the SPIROMICS Study of Early COPD Progression (SOURCE), a multicenter observational cohort study of younger individuals with a history of cigarette smoking and thus at-risk for, or with, early-stage COPD. Our overall objectives are to identify those who will develop COPD earlier in life, characterize them thoroughly, and by contrasting them to those not developing COPD, define mechanisms of disease progression. SOURCE utilizes the established SPIROMICS clinical network. Its goal is to enroll n=649 participants, ages 30-55 years, all races/ethnicities, with ≥10 pack-years cigarette smoking, in either Global Initiative for Chronic Obstructive Lung Disease (GOLD) groups 0-2 or with Preserved Ratio Impaired Spirometry (PRISm); and an additional n=40 never-smoker controls. Participants undergo baseline and three-year follow-up visits, each including high-resolution computed tomography; respiratory oscillometry and spirometry (pre- and post-bronchodilator administration), exhaled breath condensate (baseline only); and extensive biospecimen collection, including sputum induction. Symptoms, interim healthcare utilization, and exacerbations are captured every six months via follow-up phone calls. An embedded bronchoscopy sub-study involving n=100 participants (including all never-smokers) will allow collection of lower airway samples for genetic, epigenetic, genomic, immunological, microbiome, mucin analyses, and basal cell culture. SOURCE should provide novel insights into the natural history of lung disease in younger individuals with a smoking history, and its biological basis.

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OBJECTIVE: To assess the association of trimethoprim sulfamethoxazole (TMP-SMX) prophylaxis with serious infections in rituximab-treated patients with granulomatosis with polyangiitis (GPA). METHODS: This retrospective cohort study included adults with GPA (2011-2020) within the United States Merative™ Marketscan® Research Databases with ≥6 months enrolment prior to first (index) rituximab treatment. We defined TMP-SMX prophylaxis as a ≥28-day prescription dispensed after or overlapping the index date. Serious infection was a hospital primary diagnosis for infection (excluding viral or mycobacterial codes). Secondary outcomes were outpatient infection, PJP, and adverse events potentially attributable to TMP-SMX. Cox proportional hazards regression assessed the association of time-varying TMP-SMX with outcomes of interest, adjusting for potential confounders. Individuals were followed until the outcome of interest, end of database enrolment, or Dec 31, 2020. RESULTS: Among 919 rituximab-treated individuals (53% female), mean age was 52.1 years (SD 16) and 281 (31%) were dispensed TMP-SMX within 30 days of index date. Over a median of 496 (IQR 138, 979) days, 130 serious infections occurred among 104 individuals (incidence 6.1 [95% CI 5.0-7.4] per 100 person-years). Time-varying TMP-SMX was negatively associated with serious infection (adjusted HR 0.5; 95% CI 0.3-0.9). The aHR for outpatient infections was 0.8 (95% CI 0.6-1.1). The estimate for PJP was imprecise (13 events, unadjusted HR 0.2; 95% CI 0.03-1.8). TMP-SMX was potentially associated with adverse events (aHR 1.3; 95% CI 0.9-1.9). CONCLUSIONS: TMP-SMX prophylaxis was associated with reduced serious infections in rituximab-treated GPA, but may increase adverse events, warranting further study of optimal prophylaxis strategies.

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BACKGROUND: Cardiovascular disease (CVD) is the main cause of mortality in Rheumatoid Arthritis (RA). OBJECTIVE: To investigate the effect of biologic disease modifying anti-rheumatic drugs (bDMARDs) on lipids and CVD risk and evaluate associations with changes in systemic inflammation. METHODS: Patients with RA initiating a bDMARD were evaluated at baseline, 3 and 6 months later. Longitudinal mixed effects models examined the association of individual biologics with changes in lipid levelsm Reynolds Risk Score (RRS) and Framingham risk score. Mediation by CRP, clinical disease activity index (CDAI) or swollen joint count on lipid changes were modeled using structural equation models. The correlation between CRP changes and LDL changes was estimated. Changes of LDL-C at 6 months among patients with low baseline LDL-C (<90 mg/dl) vs higher baseline LDL-C(90-130, and >130 mg/dl) were compared. The association between LDL-C changes across baseline LDL-C groups and disease activity improvement was evaluated. RESULTS: 1698 bDMARD initiations were analyzed. Patients initiating tocilizumab had a significant increase in lipid levels but RRS at 3 and 6 months was similar across all biologics. Framingham risk score increased for patients treated with tocilizumab. Mediator analyses were statistically significant for the effects of CRP on lipid levels. Increases in LDL-C from baseline were independent of clinical response. An association of changes from baseline CRP and LDL-C were observed across all of the bDMARDs studied. CONCLUSION: Moderate increases in lipid levels on bDMARD treatment were not associated with an increased CVD risk by RRS regardless of the bDMARD initiated. Changes in CRP were significantly associated with changes in lipids in a mediator analysis.

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OBJECTIVES: Immune checkpoint inhibitor (ICI) associated inflammatory arthritis (ICI-IA) occurs in 4-6% of ICI-treated patients based on one observational study. We identified cases of ICI-IA using administrative claims to study its incidence and characteristics at the population level. METHODS: We used the Medicare 5% sample to identify patients initiating ICIs. Cancer patients were identified by having ≥ 2 ICD-9/10-CM diagnosis codes from an oncologist for lung cancer, melanoma, or renal/urothelial cancer. ICI-IA was defined as having two Medicare claims ≥ 30 days apart with combinations of ICD-9/10-CM diagnosis codes that favored specificity. ICI-IA was identified in patients with a musculoskeletal diagnosis after ICI initiation, who had i.) no inflammatory arthritis or inflammatory rheumatic disease before ICI initiation ever, and ii) no musculoskeletal complaint in the one year prior to ICI. We examined DMARD utilization and visits to rheumatology in patients with ICI-IA. Landmark analysis and a time varying Cox proportional hazards model for overall survival was constructed. RESULTS: The incidence of ICI-IA was 7.2 (6.1-8.4) per 100 patient years. Patients with ICI-IA were mean (SD) age 73.5(7.0) years, 48% women, 91% white. Median(IQR) time from ICI initiation to first ICI-IA diagnosis was 124(56, 252) days. Only 24(16%) received care from a rheumatologist, and 24(16%) were prescribed a DMARD (46% by a rheumatologist). The HR for mortality in patients with ICI-IA was 0.86 (95% CI 0.59-1.26, p= 0.45). CONCLUSIONS: The incidence of ICI-IA identified in claims data is similar to that reported in observational studies, however, few patients are treated with a DMARD or see a rheumatologist. There was no difference in overall survival between ICI-treated patients with and without ICI-IA.

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Objectives: To examine determinants of tofacitinib discontinuation due to voluntary (i.e. patient-driven) or involuntary reasons (i.e. protocol mandated) in long-term extension (LTE) studies of patients with RA to inform clinical practice, clinical study execution and data capture. Methods: This post hoc analysis used pooled data from patients receiving tofacitinib 5 or 10 mg twice daily (BID) in LTE studies. Outcomes included time to voluntary/involuntary discontinuation (and baseline predictors), including by geographic region. Exposure-adjusted event rates (EAERs) were calculated for adverse events (AEs), serious AEs (SAEs) and discontinuations due to AEs/SAEs. Results: Of 4967 patients, 2463 (49.6%) discontinued [1552/4967 (31.2%) voluntarily, 911/4967 (18.3%) involuntarily] and 55 (1.1%) died over the course of 9.5 years. When involuntary discontinuation was present as a competing risk for voluntary discontinuation, patients who stayed on combination therapy and with higher patient-assessed pain were significantly more likely to discontinue for voluntary reasons (P < 0.05). Older patients, those enrolled in Asia, Europe or Latin America (vs USA or Canada) or with RF+/anti-CCP+ status were significantly less likely to discontinue for voluntary reasons (P < 0.05). Small numeric differences in disease activity were observed between geographic regions in patients who discontinued or completed the studies. EAERs were generally higher for tofacitinib 10 vs 5 mg BID, irrespective of discontinuation reason. Conclusion: The factors associated with voluntary/involuntary discontinuation of tofacitinib suggest that treatment persistence in RA studies is partly predictable, which may be reflected in clinical practice. Applying these results may improve our understanding of attrition and inform future study design/execution. Trial registrations: ClinicalTrials.gov (http://clinicaltrials.gov): NCT00413699 and NCT00661661.

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Rationale: Genetic variants and gene expression predict risk of chronic obstructive pulmonary disease (COPD), but their effect on COPD heterogeneity is unclear. Objectives: Define high-risk COPD subtypes using both genetics (polygenic risk score, PRS) and blood gene expression (transcriptional risk score, TRS) and assess differences in clinical and molecular characteristics. Methods: We defined high-risk groups based on PRS and TRS quantiles by maximizing differences in protein biomarkers in a COPDGene training set and identified these groups in COPDGene and ECLIPSE test sets. We tested multivariable associations of subgroups with clinical outcomes and compared protein-protein interaction networks and drug repurposing analyses between high-risk groups. Measurements and Main Results: We examined two high-risk omics-defined groups in non-overlapping test sets (n=1,133 NHW COPDGene, n=299 African American (AA) COPDGene, n=468 ECLIPSE). We defined "High activity" (low PRS/high TRS) and "severe risk" (high PRS/high TRS) subgroups. Participants in both subgroups had lower body-mass index (BMI), lower lung function, and alterations in metabolic, growth, and immune signaling processes compared to a low-risk (low PRS, low TRS) reference subgroup. "High activity" but not "severe risk" participants had greater prospective FEV 1 decline (COPDGene: -51 mL/year; ECLIPSE: - 40 mL/year) and their proteomic profiles were enriched in gene sets perturbed by treatment with 5-lipoxygenase inhibitors and angiotensin-converting enzyme (ACE) inhibitors. Conclusions: Concomitant use of polygenic and transcriptional risk scores identified clinical and molecular heterogeneity amongst high-risk individuals. Proteomic and drug repurposing analysis identified subtype-specific enrichment for therapies and suggest prior drug repurposing failures may be explained by patient selection.

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OBJECTIVE: Many guidelines recommend limiting glucocorticoids in patients with rheumatoid arthritis (RA), but 40% of patients remain on glucocorticoids long term. We evaluated the cardiovascular risk of long-term glucocorticoid prescription by studying patients on stable disease-modifying antirheumatic drugs (DMARDs). METHODS: Using two claims databases, we identified patients with RA on stable DMARD therapy for >180 days. Proportional hazards models with inverse-probability weights and clustering to account for multiple observations were used to estimate the effect of glucocorticoid dose on composite cardiovascular outcomes (stroke or myocardial infarction [MI]). RESULTS: There were 135,583 patients in Medicare and 39,272 in Optum's de-identified Clinformatics Data Mart (CDM) database. Medicare and CDM patients had an incidence of 1.3 and 0.8 composite cardiovascular outcomes per 100 person-years, respectively. In the older, comorbid Medicare cohort, glucocorticoids were associated with a dose-dependent increase in composite cardiovascular outcomes in adjusted models with predicted one-year incidence of 1.4% (95% confidence interval [CI] 1.2%-1.6%) for ≤5 mg, 1.6% (95% CI 1.4%-1.9%) for >5 to 10 mg, and 1.8% (95% CI 1.2%-2.5%) for >10 mg versus 1.1% (95% CI 1.1%-1.2%) among patients not receiving glucocorticoids. There was no significant association among the CDM cohort. However, in the subgroup of younger patients with RA and higher cardiovascular risk, glucocorticoids were associated with a dose-dependent increase in composite cardiovascular outcomes. CONCLUSION: Among older patients with more comorbidities and younger patients with higher cardiovascular risk with RA on stable DMARD therapy, glucocorticoids were associated with a dose-dependent increased risk of MI and stroke, even at doses ≤5 mg/day. By contrast, no association was noted among younger, healthier patients with RA.

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RATIONALE: While many studies have examined gene expression in lung tissue, the gene regulatory processes underlying emphysema are still not well understood. Finding efficient non-imaging screening methods and disease-modifying therapies has been challenging, but knowledge of the transcriptomic features of emphysema may help in this effort. OBJECTIVES: Our goals were to identify emphysema-associated biological pathways through transcriptomic analysis of bulk lung tissue, to determine the lung cell types in which these emphysema-associated pathways are altered, and to detect unique and overlapping transcriptomic signatures in blood and lung samples. METHODS: Using RNA-sequencing data from 446 samples in the Lung Tissue Research Consortium (LTRC) and 3,606 blood samples from the COPDGene study, we examined the transcriptomic features of chest computed tomography-quantified emphysema. We also leveraged publicly available lung single-cell RNA-sequencing data to identify cell types showing COPD-associated differential expression of the emphysema pathways found in the bulk analyses. MEASUREMENTS AND MAIN RESULTS: In the bulk lung RNA-seq analysis, 1,087 differentially expressed genes and 34 dysregulated pathways were significantly associated with emphysema. We observed alternative splicing of several genes and increased activity in pluripotency and cell barrier function pathways. Lung tissue and blood samples shared differentially expressed genes and biological pathways. Multiple lung cell types displayed dysregulation of epithelial barrier function pathways, and distinct pathway activities were observed among various macrophage subpopulations. CONCLUSIONS: This study identified emphysema-related changes in gene expression and alternative splicing, cell-type specific dysregulated pathways, and instances of shared pathway dysregulation between blood and lung.

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OBJECTIVE: Quality of care (QoC) delivery in rheumatoid arthritis (RA) continues to suffer from various challenges (eg, delay in diagnosis and referral) that can lead to poor patient outcomes. This study aimed to identify good practice interventions that address these challenges in RA care in North America. METHODS: The study was conducted in three steps: (1) literature review of existing publications and guidelines (April 2005 to April 2021) on QoC in RA; (2) in-person visits to >50 individual specialists and health care professionals across nine rheumatology centers in the United States and Canada to identify challenges in RA care and any corresponding good practice interventions; and (3) collation and organization of findings of the two previous methods by commonalities to identify key good practice interventions, followed by further review by RA experts to ensure key challenges and gaps in RA care were captured. RESULTS: Several challenges and eight good practice interventions were identified in RA care. The interventions were prioritized based on the perceived positive impact on the challenges in care and ease of implementation. High-priority interventions included the use of technology to improve care, streamlining specialist treatment, and facilitating comorbidity assessment and care. Other interventions included enabling patient access to optimal medication regimens and improving patient self-management strategies. CONCLUSION: Learnings from the study can be implemented in other rheumatology centers throughout North America to improve RA care. Although the study was completed before the COVID-19 pandemic, the findings remain relevant.

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Rationale: Accelerated biological aging has been implicated in the development of interstitial lung disease (ILD) and other diseases of aging but remains poorly understood. Objectives: To identify plasma proteins that mediate the relationship between chronological age and survival association in patients with ILD. Methods: Causal mediation analysis was performed to identify plasma proteins that mediated the chronological age-survival relationship in an idiopathic pulmonary fibrosis discovery cohort. Proteins mediating this relationship after adjustment for false discovery were advanced for testing in an independent ILD validation cohort and explored in a chronic obstructive pulmonary disease cohort. A proteomic-based measure of biological age was constructed and survival analysis performed, assessing the impact of biological age and peripheral blood telomere length on the chronological age-survival relationship. Measurements and Main Results: Twenty-two proteins mediated the chronological age-survival relationship after adjustment for false discovery in the idiopathic pulmonary fibrosis discovery cohort (n = 874), with 19 remaining significant mediators of this relationship in the ILD validation cohort (n = 983) and one mediating this relationship in the chronic obstructive pulmonary disease cohort. Latent transforming growth factor-ß binding protein 2 and ectodysplasin A2 receptor showed the strongest mediation across cohorts. A proteomic measure of biological age completely attenuated the chronological age-survival association and better discriminated survival than chronological age. Results were robust to adjustment for peripheral blood telomere length, which did not mediate the chronological age-survival relationship. Conclusions: Molecular measures of aging completely mediate the relationship between chronological age and survival, suggesting that chronological age has no direct effect on ILD survival.

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Although clinical trials have shown that denosumab significantly increases bone mineral density at key skeletal sites more than oral bisphosphonates, evidence is lacking from head-to-head randomized trials evaluating fracture outcomes. This retrospective cohort study uses administrative claims data from Medicare fee-for service beneficiaries to evaluate the comparative effectiveness of denosumab vs alendronate in reducing fracture risk among women with PMO in the US. Women with PMO ≥ 66 yr of age with no prior history of osteoporosis treatment, who initiated denosumab (n = 89 115) or alendronate (n = 389 536) from 2012 to 2018, were followed from treatment initiation until the first of a specific fracture outcome, treatment discontinuation or switch, end of study (December 31, 2019), or other censoring criteria. A doubly robust inverse-probability of treatment and censoring weighted function was used to estimate the risk ratio associated with the use of denosumab compared with alendronate for hip, nonvertebral (NV; includes hip, humerus, pelvis, radius/ulna, other femur), non-hip nonvertebral (NHNV), hospitalized vertebral (HV), and major osteoporotic (MOP; consisting of NV and HV) fractures. Overall, denosumab reduced the risk of MOP by 39%, hip by 36%, NV by 43%, NHNV by 50%, and HV fractures by 30% compared with alendronate. Denosumab reduced the risk of MOP fractures by 9% at year 1, 12% at year 2, 18% at year 3, and 31% at year 5. An increase in the magnitude of fracture risk reduction with increasing duration of exposure was also observed for other NV fracture outcomes. In this cohort of almost half-a-million treatment-naive women with PMO, we observed clinically significant reductions in the risk of MOP, hip, NV, NHNV, and HV fractures for patients on denosumab compared with alendronate. Patients who remained on denosumab for longer periods of time experienced greater reductions in fracture risk.

Osteoporosis-related fractures can have a significant impact on the health and quality of life of women with postmenopausal osteoporosis, as well as pose a significant burden to society. Although clinical trials have shown that denosumab is more effective at increasing bone mineral density compared with alendronate, there is a lack of evidence evaluating the fracture risk between these 2 commonly used osteoporosis therapies. In this study using Medicare claims data for almost 500 000 women with postmenopausal osteoporosis with no prior history of osteoporosis medication use, we compared the risk of fracture­an important outcome to patients and health care providers­between denosumab and alendronate. Advanced analytic methods were implemented to ensure the study results were valid and were not unduly influenced by biases common in observational studies. We observed clinically meaningful reductions (from 30% up to 50%) in the risk of hip, nonvertebral, non-hip nonvertebral, hospitalized vertebral, and major osteoporotic fractures for patients treated with denosumab compared with alendronate. Patients who remained on denosumab for longer periods of time experienced greater reductions in fracture risk than those who remained on alendronate.

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OBJECTIVE: The objective of this study was to ascertain pegloticase persistence and adverse events associated with concomitant immunomodulatory drug treatment in patients with gout. METHODS: We conducted a retrospective analysis of patients with gout using the American College of Rheumatology's Rheumatology Informatics System for Effectiveness registry from January 2016 through June 2020. The first pegloticase infusion defined the index date. Based on concomitant immunomodulatory drug treatment, we identified three exposure groups: (1) immunomodulatory drug initiators (patients initiating an immunomodulatory prescription ±60 days from the index date), (2) prevalent immunomodulatory drug recipients (patients receiving their first immunomodulatory drug prescription >60 days before the index date with at least one prescription within ±60 days of the index date), and (3) immunomodulatory nonrecipients (patients receiving pegloticase without concomitant immunomodulatory drugs). We calculated the proportion of patients who achieved serum urate levels ≤6 mg/dL and who had laboratory abnormalities (white blood cell count <3.4 x 109/L, platelet count <135,000, hematocrit level <30%, alanine aminotransferase or aspartate aminotransferase level ≥1.5 times the upper limit normal value) within 180 days after the index date. Cox regression analyzed time to pegloticase discontinuation, controlling for potential confounders. RESULTS: We identified 700 pegloticase recipients (91 immunomodulatory drug initiators, 33 prevalent immunomodulatory drug recipients, and 576 nonrecipients), with a median follow-up of 14 months. Immunomodulatory drug recipients were less likely to discontinue pegloticase. The adjusted hazard ratios of pegloticase discontinuation associated with concomitant immunomodulatory drug initiation and prevalent treatment were 0.52 (95% confidence interval [CI] 0.37-0.75) and 0.69 (95% CI 0.42-1.16), respectively. Laboratory abnormalities were uncommon (<5%) and were not higher in concomitant immunomodulatory drug treatment. CONCLUSION: Consistent with clinical trials, results from this large observational registry suggest that concomitant immunomodulatory drug treatment improves pegloticase persistence.

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Chronic obstructive pulmonary disease (COPD) is characterized by infiltration of the airways and lung parenchyma by inflammatory cells. Lung pathology results from the cumulative effect of complex and aberrant interactions between multiple cell types. However, three cell types, natural killer cells (NK), dendritic cells (DCs), and regulatory T cells (Tregs), are understudied and underappreciated. We propose that their mutual interactions significantly contribute to the development of COPD. Here, we highlight recent advances in NK, DC, and Treg biology with relevance to COPD, discuss their pairwise bidirectional interactions, and identify knowledge gaps that must be bridged to develop novel therapies. Understanding their interactions will be crucial for therapeutic use of autologous Treg, an approach proving effective in other diseases with immune components.

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