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Purpose We evaluated associations between adiponectin and the risk of diabetes among patients with rheumatoid arthritis (RA), a systemic inflammatory disease associated with metabolic disturbance. Methods This prospective cohort study included adults with RA from the Veterans Affairs Rheumatoid Arthritis Registry. Adiponectin and inflammatory cytokines/chemokines were measured at enrollment on stored serum samples. Adiponectin levels were categorized, and clinical variables were described across categories (<10 μg/mL; 10-40 μg/mL; >40 μg/mL). Multivariable Cox proportional hazard models evaluated associations between adiponectin and incident diabetes adjusting for age, sex, race, smoking status, body mass index (BMI), disease-modifying therapy use, calendar year, and comorbidity. Testing for modification of effect in the context of elevated cytokines/chemokines was performed. Results Among 2595 patients included in the analysis, those with adiponectin levels >40 μg/mL (N = 379; 15%) were older and had lower BMI. There were 125 new cases of diabetes among 1689 patients without prevalent disease at enrollment. There was an inverse association between adiponectin and incident diabetes; however, the association was positive among patients with adiponectin levels >40 μg/mL. Patients with levels >40 μg/mL were at higher risk compared to those with levels 10-40 μg/mL (HR: 1.70 [1.34, 2.16] P <.001). Those with adiponectin levels >40 μg/mL had significantly higher levels of inflammatory cytokines with evidence of a modified effect of adiponectin on diabetes risk in the setting of inflammation. Conclusion The relationship between adiponectin and incident diabetes risk is U-shaped in RA. Patients with very high adiponectin levels have greater systemic inflammation and an altered relationship between adiponectin and diabetes risk. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study is 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 US 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 enzyme‐linked immunosorbent assay. 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 participants with RA (88% male, mean age of 64 years), there were 114 with prevalent and 136 with incident RA‐ILD (average time to diagnosis: 6.6 years). Higher IgM anti–MAA‐collagen (per 1 SD: adjusted odds ratio [aOR] 1.28, 95% confidence interval [CI] 1.02–1.61), IgA anti–MAA‐fibrinogen (aOR 1.48, 95% CI 1.14–1.92), and IgA (aOR 1.78, 95% CI 1.34–2.37) and IgG (aOR 1.48, 95% CI 1.14–1.92) anti–MAA‐vimentin antibodies were associated with prevalent RA‐ILD. In incident analyses, higher IgA (per one SD: adjusted hazards ratio [aHR] 1.40, 95% CI 1.11–1.76) and IgM (aHR 1.29, 95% CI 1.04–1.60) anti–MAA‐albumin antibody concentrations were associated with increased ILD risk. Participants with IgA (aHR 2.13, 95% CI 1.16–3.90) or IgM (aHR 1.98, 95% CI 1.08–3.64) anti–MAA‐albumin antibody concentrations in the highest quartile had an approximately two‐fold increased risk of incident RA‐ILD. Across all isotypes, anti–MAA‐fibrinogen, anti–MAA‐collagen, and anti–MAA‐vimentin antibodies were not significantly associated with incident RA‐ILD. Conclusion: 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: To develop a natural language processing (NLP) tool to extract forced vital capacity (FVC) values from electronic health record (EHR) notes in patients with rheumatoid arthritis‐interstitial lung disease (RA‐ILD). Methods: We selected RA‐ILD patients (n = 7485) in the Veterans Health Administration (VA) between 2000 and 2020 using validated ICD‐9/10 codes. We identified numeric values in proximity to FVC string patterns from clinical notes in the EHR. Subsequently, we performed processing steps to account for variability in note structure, related pulmonary function test (PFT) output, and values copied across notes, then assigned dates from linked administrative procedure records. NLP‐derived FVC values were compared to values recorded directly from PFT equipment available on a subset of patients. Results: We identified 5911 FVC values (n = 1844 patients) from PFT equipment and 15 383 values (n = 4982 patients) by NLP. Among 2610 date‐matched FVC values from NLP and PFT equipment, 95.8% of values were within 5% predicted. The mean (SD) difference was 0.09% (5.9), and values strongly correlated (r = 0.94, p < 0.001), with a precision of 0.87 (95% CI 0.86, 0.88). NLP captured more patients with longitudinal FVC values (n = 3069 vs. n = 1164). Mean (SD) change in FVC %‐predicted per year was similar between sources (−1.5 [30.0] NLP vs. −0.9 [16.6] PFT equipment; standardized response mean = 0.05 for both). Conclusions: NLP of EHR notes increases the capture of accurate, longitudinal FVC values by three‐fold over PFT equipment. Use of this NLP tool can facilitate pharmacoepidemiologic research in RA‐ILD and other lung diseases by capturing this critical measure of disease severity. [ABSTRACT FROM AUTHOR]

Objective: To examine temporal trends in all‐cause and cause‐specific mortality in patients with rheumatoid arthritis (RA) in the Veterans Health Administration (VHA). Methods: We conducted a matched cohort study in the VHA from January 1, 2000 to December 31, 2017. Incident RA patients were matched up to 1:10 on age, sex, and VHA enrollment year to non‐RA patients, then followed until death or end of study period. Cause of death was obtained from the National Death Index. Multivariable Cox regression models stratified by RA diagnosis years were used to examine trends in RA‐related risk of all‐cause and cause‐specific mortality. Results: Among 29,779 incident RA patients (matched to 245,226 non‐RA patients), 9,565 deaths occurred. RA patients were at increased risk of all‐cause (adjusted hazard ratio [HRadj] 1.23 [95% confidence interval (95% CI) 1.20–1.26]), cardiovascular (HRadj 1.19 [95% CI 1.14–1.23]), cancer (HRadj 1.19 [95% CI 1.14–1.24]), respiratory (HRadj 1.46 [95% CI 1.38–1.55]), and infection‐related mortality (HRadj 1.59 [95% CI 1.41–1.80]). Interstitial lung disease was the cause of death most strongly associated with RA (HRadj 3.39 [95% CI 2.88–3.99]). Nearly 70% of excess deaths in RA were attributable to cardiopulmonary disease. All‐cause mortality risk related to RA was lower among those diagnosed during 2012–2017 (HRadj 1.10 [95% CI 1.05–1.15]) compared to 2000–2005 (HRadj 1.31 [95% CI 1.26–1.36]), but still higher than for non‐RA controls (P < 0.001). Cause‐specific mortality trends were similar. Conclusion: Excess RA‐related mortality was driven by cardiovascular, cancer, respiratory, and infectious causes, particularly cardiopulmonary diseases. Although our findings support that RA‐related mortality risk is decreasing over time, a mortality gap remains for all‐cause and cause‐specific mortality in RA. [ABSTRACT FROM AUTHOR]

Objective: To compare all‐cause and cause‐specific mortality risk between patients with gout and patients without gout in the Veteran's Health Administration (VHA). Methods: We performed a matched cohort study, identifying patients with gout in the VHA from January 1999 to September 2015 based on the presence of ≥2 International Classification of Diseases, Ninth Revision codes for gout (274.X). Gout patients were matched up to 1:10 on birth year, sex, and year of VHA enrollment with patients without gout and followed until death or end of study (December 2017). Cause of death was obtained from the National Death Index. Associations of gout with all‐cause and cause‐specific mortality were examined using multivariable Cox regression. Results: Gout (n = 559,243) and matched non‐gout controls (n = 5,428,760) had a mean age of 67 years and were 99% male. There were 246,291 deaths over 4,250,371 patient‐years in gout patients and 2,000,000 deaths over 40,441,353 patient‐years of follow‐up in controls. After matching, gout patients had an increased risk of death (hazard ratio [HR] 1.09 [95% confidence interval (95% CI) 1.08–1.09]), which was no longer present after adjusting for comorbidities (HR 0.98 [95% CI 0.97–0.98]). The strongest association of gout with cause‐specific mortality was observed with genitourinary conditions (HR 1.50 [95% CI 1.47–1.54]). Gout patients were at lower risk of death related to neurologic (e.g., Alzheimer's disease and Parkinson's disease) (HR 0.63 [95% CI 0.62–0.65]) and mental health (HR 0.66 [95% CI 0.65–0.68]) conditions. Conclusion: A higher risk of death among gout patients in the VHA was related to comorbidity burden. While deaths attributable to neurologic and mental health conditions were less frequent among gout patients, genitourinary conditions were the most overrepresented causes of death. [ABSTRACT FROM AUTHOR]

Objective: Patients with rheumatoid arthritis (RA) have an increased risk of select cancers, including lymphoma and lung cancer. Whether RA influences prostate cancer risk is uncertain. We aimed to determine the risk of prostate cancer in patients with RA compared to patients without RA in the Veterans Health Administration (VA). Methods: We performed a matched (up to 1:5) cohort study of male patients with and without RA in the VA from 2000 to 2018. RA status, as well as covariates, were obtained from national VA databases. Prostate cancer was identified through linked VA cancer databases and the National Death Index. Multivariable Cox models compared prostate cancer risk between patients with RA and patients without RA, including models that accounted for retention in the VA system. Results: We included 56,514 veterans with RA and 227,284 veterans without RA. During 2,337,104 patient‐years of follow‐up, 6,550 prostate cancers occurred. Prostate cancer incidence (per 1,000 patient‐years) was 3.50 (95% confidence interval [95% CI] 3.32–3.69) in patients with RA and 2.66 (95% CI 2.58–2.73) in patients without RA. After accounting for confounders and censoring for attrition of VA health care, RA was modestly associated with a higher prostate cancer risk (adjusted HR [HRadj] 1.12 [95% CI 1.04–1.20]). There was no association between RA and prostate cancer mortality (HRadj 0.92 [95% CI 0.73–1.16]). Conclusion: RA was associated with a modestly increased risk of prostate cancer, but not prostate cancer mortality, after accounting for relevant confounders and several potential sources of bias. However, even minimal unmeasured confounding could explain these findings. [ABSTRACT FROM AUTHOR]

Objective: Recognizing that the interrelationships between chronic conditions that complicate rheumatoid arthritis (RA) are poorly understood, we aimed to identify patterns of multimorbidity and to define their prevalence in RA through machine learning. Methods: We constructed RA and age‐ and sex‐matched (1:1) non‐RA cohorts within a large commercial insurance database (MarketScan) and the Veterans Health Administration (VHA). Chronic conditions (n = 44) were identified from diagnosis codes from outpatient and inpatient encounters. Exploratory factor analysis was performed separately in both databases, stratified by RA diagnosis and sex, to identify multimorbidity patterns. The association of RA with different multimorbidity patterns was determined using conditional logistic regression. Results: We studied 226,850 patients in MarketScan (76% female) and 120,780 patients in the VHA (89% male). The primary multimorbidity patterns identified were characterized by the presence of cardiopulmonary, cardiometabolic, and mental health and chronic pain disorders. Multimorbidity patterns were similar between RA and non‐RA patients, female and male patients, and patients in MarketScan and the VHA. RA patients had higher odds of each multimorbidity pattern (odds ratios [ORs] 1.17–2.96), with mental health and chronic pain disorders being the multimorbidity pattern most strongly associated with RA (ORs 2.07–2.96). Conclusion: Cardiopulmonary, cardiometabolic, and mental health and chronic pain disorders represent predominant multimorbidity patterns, each of which is overrepresented in RA. The identification of multimorbidity patterns occurring more frequently in RA is an important first step in progressing toward a holistic approach to RA management and warrants assessment of their clinical and predictive utility. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objectives: To compare the onset and trajectory of multimorbidity between individuals with and without rheumatoid arthritis (RA).Methods: A matched, retrospective cohort study was completed in a large, US commercial insurance database (MarketScan) from 2006 to 2015. Using validated algorithms, patients with RA (overall and incident) were age-matched and sex-matched to patients without RA. Diagnostic codes for 44 preidentified chronic conditions were selected to determine the presence (≥2 conditions) and burden (count) of multimorbidity. Cross-sectional comparisons were completed using the overall RA cohort and conditional logistic and negative binomial regression models. Trajectories of multimorbidity were assessed within the incident RA subcohort using generalised estimating equations.Results: The overall cohort (n=277 782) and incident subcohort (n=61 124) were female predominant (76.5%, 74.1%) with a mean age of 55.6 years and 54.5 years, respectively. The cross-sectional prevalence (OR 2.29, 95% CI 2.25 to 2.34) and burden (ratio of conditions 1.68, 95% CI 1.66 to 1.70) of multimorbidity were significantly higher in RA than non-RA in the overall cohort. Within the incident RA cohort, patients with RA had more chronic conditions than non-RA (β 1.13, 95% CI 1.10 to 1.17), and the rate of accruing chronic conditions was significantly higher in RA compared with non-RA (RA × follow-up year, β 0.21, 95% CI 0.20 to 0.21, p<0.001). Results were similar when including the pre-RA period and in several sensitivity analyses.Conclusions: Multimorbidity is highly prevalent in RA and progresses more rapidly in patients with RA than in patients without RA during and immediately following RA onset. Therefore, multimorbidity should be aggressively identified and targeted early in the RA disease course. [ABSTRACT FROM AUTHOR]

Objective Methods Results Conclusion We aimed to evaluate lung cancer risk in patients with rheumatoid arthritis (RA) and RA‐interstitial lung disease (ILD).We performed a retrospective, matched cohort study of RA and RA‐ILD within the Veterans Health Administration (VA) between 2000 and 2019. Patients with RA and RA‐ILD were identified with validated administrative‐based algorithms, then matched (up to 1:10) on age, gender, and VA enrollment year to individuals without RA. Lung cancers were identified from a VA oncology database and the National Death Index. Conditional Cox regression models assessed lung cancer risk adjusting for race, ethnicity, smoking status, Agent Orange exposure, and comorbidity burden among matched individuals. Several sensitivity analyses were performed.We matched 72,795 patients with RA with 633,937 patients without RA (mean age 63 years; 88% male). Over 4,481,323 patient‐years, 17,099 incident lung cancers occurred. RA was independently associated with an increased lung cancer risk (adjusted hazard ratio [aHR] 1.58 [95% confidence interval (CI) 1.52–1.64]), which persisted in never smokers (aHR 1.65 [95% CI 1.22–2.24]) and in those with incident RA (aHR 1.54 [95% CI 1.44–1.65]). Compared to non‐RA controls, prevalent RA‐ILD (n = 757) was more strongly associated with lung cancer risk (aHR 3.25 [95% CI 2.13–4.95]) than RA without ILD (aHR 1.57 [95% CI 1.51–1.64]). Analyses of both prevalent and incident RA‐ILD produced similar results (RA‐ILD vs non‐RA aHR 2.88 [95% CI 2.45–3.40]).RA was associated with a >50% increased risk of lung cancer, and those with RA‐ILD represented a particularly high‐risk group with an approximate three‐fold increased risk. Increased lung cancer surveillance in RA, and especially RA‐ILD, may be a useful strategy for reducing the burden posed by the leading cause of cancer death. [ABSTRACT FROM AUTHOR]