Proteomic profiling of bronchoalveolar lavage fluid uncovers protein clusters linked to survival in idiopathic forms of interstitial lung disease.

Background: Idiopathic interstitial pneumonias (IIPs) such as idiopathic pulmonary fibrosis (IPF) and interstitial pneumonia with autoimmune features (IPAF), present diagnostic and therapeutic challenges due to their heterogeneous nature. This study aimed to identify intrinsic molecular signatures within the lung microenvironment of these IIPs through proteomic analysis of bronchoalveolar lavage fluid (BALF). Methods: Patients with IIP (n=23) underwent comprehensive clinical evaluation including pre-treatment bronchoscopy and were compared to controls without lung disease (n=5). Proteomic profiling of BALF was conducted using label-free quantitative methods. Unsupervised cluster analyses identified protein expression profiles which were then analyzed to predict survival outcomes and investigate associated pathways. Results: Proteomic profiling successfully differentiated IIP from controls. k-means clustering, based on protein expression revealed three distinct IIP clusters, which were not associated with age, smoking history, or baseline pulmonary function. These clusters had unique survival trajectories and provided more accurate survival predictions than the Gender Age Physiology (GAP) index (C-index 0.794 vs. 0.709). The cluster with the worst prognosis featured decreased inflammatory signaling and complement activation, with pathway analysis highlighting altered immune response pathways related to immunoglobulin production and B cell-mediated immunity. Conclusions: The unsupervised clustering of BALF proteomics provided a novel stratification of IIP patients, with potential implications for prognostic and therapeutic targeting. The identified molecular phenotypes underscore the diversity within the IIP classification and the potential importance of personalized treatments for these conditions. Future validation in larger, multi-ethnic cohorts is essential to confirm these findings and to explore their utility in clinical decision-making for patients with IIP.

Associations between Adiponectin and the Development of Diabetes in Rheumatoid Arthritis.

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 Veteran's 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 1,689 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 < 0.001]. 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. CONCLUSIONS: 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.

Lower body mass and lower adiposity are associated with differential responses to two treatment strategies for rheumatoid arthritis.

PURPOSE: To determine if body mass index (BMI) and adipokine levels identify rheumatoid arthritis (RA) patients most likely to benefit from initiation of tumour necrosis factor inhibitors (TNFi) after methotrexate inadequate response. METHODS: This is a secondary analysis of the Rheumatoid Arthritis Comparison of Active Treatments (RACAT) trial and the (TEAR) trial. Both studies compared treatment strategies starting with conventional disease-modifying anti-rheumatic drugs (DMARDs) (triple therapy) versus etanercept plus methotrexate. We compared response rates between TNFi and triple therapy among patients with different BMI. Adipokines were measured at enrolment and associations with treatment response were examined using regression, adjusting for age, sex, BMI and baseline disease activity. RESULTS: In RACAT (n=306), participants who were normal/underweight were more likely to benefit from TNFi versus triple therapy, with greater change in Disease Activity Score in 28 and greater ACR20 response (ACR 20: 64% vs 23%, p=0.001). In contrast, overweight/obese participants had similar response to TNFi versus triple therapy (p-for-interaction=0.001). Similarly, but modest patterns were observed in TEAR (n=601; ACR20: 67% vs 52%, p=0.05). In RACAT, adipokine scores consistent with lower adiposity also predicted greater response to TNFi (ACR20: 58% vs 37%, p=0.01) with better model fit compared with BMI alone. CONCLUSIONS: Lower BMI and evidence of lower adiposity based on adipokine profiles were associated with a superior response to TNFi compared with triple therapy. There was no difference between treatments among overweight/obese participants. The results support TNFi being a particularly important therapeutic among normal/underweight patients, with implications for clinical decisions and trial design.

A population-based analysis of rheumatology care patterns for inflammatory arthritis during COVID-19 in Alberta, Canada.

OBJECTIVE: The aim of the study was to understand the impact of the COVID-19 pandemic on inflammatory arthritis (IA) rheumatology care in Alberta, Canada. METHODS: We used linked provincial health administrative datasets to establish an incident cohort of individuals with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and Ankylosing Spondylitis (AS) seen at least once by a rheumatologist. We examined incidence rates (IR) per 100,000 population, and patterns of follow-up care between 2011 and 2022. In a subset of individuals diagnosed five years prior to the pandemic, we report on those lost to follow-up during the pandemic, and those with virtual care visits followed by in-person visit within 30 days. Multivariable logistic regression was used to examine patient characteristics associated with these patterns of care. RESULTS: The IR for RA in 2020 declined compared to previous years (44.6), but not for AS (9.2) or PsA (9.1). In 2021 IRs rose (RA 49.5; AS 11.8; PsA 11.8). Among those diagnosed within 5 years of the pandemic, 632 (6.0 %) were lost to follow-up, with characteristics of those lost to follow-up differing between IA types. 1444 individuals had at least one virtual visit followed within 30 days by an in-person follow-up. This was less common in males (OR 0.69-0.79) and more common for those with a higher frequency of physician visits prior to the pandemic (OR 1.27-1.32). CONCLUSION: Impacts of patterns of care during the pandemic should be further explored for healthcare planning to uphold optimal care access and promote effective use of virtual care.

Anti-citrullinated protein antibody profiles predict changes in disease activity in patients with rheumatoid arthritis initiating biologics.

OBJECTIVES: To determine whether an expanded antigen-specific ACPA profile predicts changes in disease activity in patients with RA initiating biologics. METHODS: The study included participants from a prospective, non-randomized, observational RA cohort. For this sub-study, treatment groups of interest included biologic-naïve initiating anti-TNF, biologic-exposed initiating non-TNF, and biologic-naïve initiating abatacept. ACPAs to 25 citrullinated peptides were measured using banked enrolment serum. Principal component analysis (PCA) was performed and associations of resulting principal component (PC) scores (in quartiles) and anti-CCP3 antibody (≤15, 16-250 or >250 U/ml) with EULAR (good/moderate/none) treatment response at 6 months were examined using adjusted ordinal regression models. RESULTS: Participants (n = 1092) had a mean age of 57 (13) years and 79% were women. At 6 months, 68.5% achieved a moderate/good EULAR response. There were three PCs that cumulatively explained 70% of variation in ACPA values. In models including the three components and anti-CCP3 antibody category, only PC1 and PC2 were associated with treatment response. The highest quartile for PC1 (odds ratio [OR] 1.76; 95% CI: 1.22, 2.53) and for PC2 (OR 1.74; 95% CI: 1.23, 2.46) were associated with treatment response after multivariable adjustment. There was no evidence of interaction between PCs and treatment group in EULAR responses (P-value for interaction >0.1). CONCLUSION: An expanded ACPA profile appears to be more strongly associated with biologic treatment response in RA than commercially available anti-CCP3 antibody levels. However, further enhancements to PCA will be needed to effectively prioritize between different biologics available for the treatment of RA.

Expansion of distinct peripheral blood myeloid cell subpopulations in patients with rheumatoid arthritis-associated interstitial lung disease.

OBJECTIVES: Interstitial lung disease (ILD) is associated with significant mortality in rheumatoid arthritis (RA) patients with key cellular players remaining largely unknown. This study aimed to characterize inflammatory and myeloid derived suppressor cell (MDSC) subpopulations in RA-ILD as compared to RA, idiopathic pulmonary fibrosis (IPF) without autoimmunity, and controls. METHODS: Peripheral blood was collected from patients with RA, RA-ILD, IPF, and controls (N = 60, 15/cohort). Myeloid cell subpopulations were identified phenotypically by flow cytometry using the following markers:CD45,CD3,CD19,CD56,CD11b,HLA-DR,CD14,CD16,CD15,CD125,CD33. Functionality of subsets were identified with intracellular arginase-1 (Arg-1) and inducible nitric oxide synthase (iNOS) expression. RESULTS: There was increased intermediate (CD14++CD16+) and nonclassical (CD14+/-CD16++) and decreased classical (CD14++CD16-) monocytes in RA, RA-ILD, and IPF vs. control. Intermediate monocytes were higher and classical monocytes were lower in RA-ILD vs. RA but not IPF. Monocytic (m)MDSCs were higher in RA-ILD vs. control and RA but not IPF. Granulocytic (g)MDSCs did not significantly differ. In contrast, neutrophils were increased in IPF and RA-ILD patients with elevated expression of Arg-1 sharing similar dimensional clustering pattern. Eosinophils were increased in RA-ILD vs. controls, RA and IPF. Across cohorts, iNOS was decreased in intermediate/nonclassical monocytes but increased in mMDSCs vs. classical monocytes. In RA-ILD, iNOS positive mMDSCs were increased versus classic monocytes. CONCLUSIONS: Myeloid cell subpopulations are significantly modulated in RA-ILD patients with expansion of CD16+ monocytes, mMDSCs, and neutrophils, a phenotypic profile more aligned with IPF than other RA patients. Eosinophil expansion was unique to RA-ILD, potentially facilitating disease pathogenesis and providing a future therapeutic target.

Changes in Characteristics of Patients Initiating and Discontinuing Advanced Therapies for Rheumatoid Arthritis Following the Release of Safety Data.

OBJECTIVE: The objective of this study was to determine the impact of emerging safety data on practice patterns by describing the characteristics of patients initiating and discontinuing advanced therapies for rheumatoid arthritis (RA) before and after January 2021. METHODS: This cohort study evaluated US veterans with RA between April 2019 and September 2022. This period was divided into two 664-day periods before and after January 2021. Eligible patients had ≥1 diagnosis code for RA and initiated a tumor necrosis factor inhibitor (TNFi), non-TNFi biologic, or JAK inhibitor (JAKi). We tested for interaction within regression models to determine whether changes in patient characteristics for tofacitinib recipients were different from changes observed for other therapies. We also evaluated factors associated with therapy discontinuation in Cox models adjusted for age, sex, and duration on therapy, including assessment for effect modification. RESULTS: When comparing patients with RA initiating tofacitinib before (n = 2,111) with those initiating tofacitinib after (n = 1,664) January 2021, there was a decrease in mean age (64.1 vs 63.0 years) and in the proportion with cardiovascular comorbidities (all P < 0.01). These changes were significantly different from those observed for patients initiating TNFi or non-TNFi biologics. Among active advanced therapy recipients, the likelihood of discontinuation was higher for tofacitinib than TNFi (hazard ratio 1.18, 95% confidence interval 1.10-1.26, P < 0.001). The higher rate of tofacitinib discontinuation was more pronounced in the presence of cardiovascular comorbidities (P < 0.05). CONCLUSION: Recent safety data significantly affected prescribing practices for advanced therapies, with a reduction in JAKi initiation and an increase in JAKi discontinuation among older patients and those at high cardiovascular risk.

Determinants of Achieving Serum Urate Goal with Treat-to-Target Urate-Lowering Therapy in Gout.

OBJECTIVE: Using trial data comparing treat-to-target allopurinol and febuxostat in gout, we examined participant characteristics associated with serum urate (SU) goal achievement. METHODS: Participants with gout and SU ≥6.8 mg/dL were randomized to allopurinol or febuxostat, titrated during weeks 0 to 24, and maintained weeks 25 to 48. Participants were considered to achieve SU goal if the mean SU from weeks 36, 42, and 48 was <6.0 mg/dL or <5 mg/dL if tophi were present. Possible determinants of treatment response were preselected and included sociodemographics, comorbidities, diuretic use, health-related quality of life (HRQoL), body mass index, and gout measures. Determinants of SU response were assessed using multivariable logistic regression with additional analyses to account for treatment adherence. RESULTS: Of 764 study participants completing week 48, 618 (81%) achieved SU goal. After multivariable adjustment, factors associated with a greater likelihood of SU goal achievement included older age (adjusted odds ratio [aOR] 1.40 per 10 years), higher education (aOR 2.02), and better HRQoL (aOR 1.17 per 0.1 unit). Factors associated with a lower odds of SU goal achievement included non-White race (aORs 0.32-0.47), higher baseline SU (aOR 0.83 per 1 mg/dL), presence of tophi (aOR 0.29), and the use of diuretics (aOR 0.52). Comorbidities including chronic kidney disease, hypertension, diabetes, and cardiovascular disease were not associated with SU goal achievement. Results were not meaningfully changed in analyses accounting for adherence. CONCLUSIONS: Several patient-level factors were predictive of SU goal achievement among patients with gout who received treat-to-target urate-lowering therapy (ULT). Approaches that accurately predict individual responses to treat-to-target ULT hold promise in facilitating personalized management and improving outcomes in patients with gout.

Frailty and Risk of Serious Infections in Patients With Rheumatoid Arthritis Treated With Biologic or Targeted-Synthetic Disease-Modifying Antirheumatic Drugs.

OBJECTIVE: It remains unknown whether frailty status portends an increased risk of adverse outcomes in patients with rheumatoid arthritis (RA) initiating biologic or targeted-synthetic (b/ts) disease-modifying antirheumatic drugs (DMARDs). The objective of our study was to evaluate the association between frailty and serious infections in a younger population of patients (<65 years old) with RA who initiated b/tsDMARDs. METHODS: Using MarketScan data, we identified new users of tumor necrosis factor inhibitors (TNFi), non-TNFi biologic DMARDs, or Janus kinase inhibitors (JAKi) between 2008 and 2019 among those with RA. Patients' baseline frailty risk score was calculated using a Claims-Based Frailty Index (≥0.2 defined as frail) 12 months prior to drug initiation. The primary outcome was time to serious infection; secondarily, we examined time-to-any infection and all-cause hospitalizations. We used Cox proportional hazards to estimate adjusted hazard ratios and 95% confidence intervals (95% CIs) and assessed the significance of interaction terms between frailty status and drug class. RESULTS: A total of 57,980 patients, mean (±SD) age 48.1 ± 10.1 were included; 48,139 (83%) started TNFi, 8,111 (14%) non-TNFi biologics, and 1,730 (3%) JAKi. Among these, 3,560 (6%) were categorized as frail. Frailty was associated with a 50% increased risk of serious infections (adjusted hazard ratio [95% CI] 1.5, 1.2-1.9) and 40% higher risk of inpatient admissions (1.4 [1.3-1.6]) compared with nonfrail patients among those who initiated TNFi. Frailty was also associated with a higher risk of any infection relative to nonfrail patients among those on TNFi (1.2 [1.1-1.3]) or non-TNFi (1.2 [1.0-1.4]) or JAKi (1.4 [1.0-2.0]). CONCLUSION: Frailty is an important predictor for the risk of adverse outcomes among patients with RA treated with biologic or targeted-synthetic DMARDs.

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.

Citrullinated and malondialdehyde-acetaldehyde modified fibrinogen activates macrophages and promotes an aggressive synovial fibroblast phenotype in patients with rheumatoid arthritis.

Objective: Post-translational protein modifications with malondialdehyde-acetaldehyde (MAA) and citrulline (CIT) are implicated in the pathogenesis of rheumatoid arthritis (RA). Although precise mechanisms have not been elucidated, macrophage-fibroblast interactions have been proposed to play a central role in the development and progression of RA. The purpose of our study was to evaluate the downstream effects of macrophage released soluble mediators, following stimulation with fibrinogen (FIB) modified antigens, on human fibroblast-like synoviocytes (HFLS). Methods: PMA-treated U-937 monocytes (Mϕ) and macrophage-differentiated peripheral blood mononuclear cells (MP) were stimulated with FIB, FIB-MAA, FIB-CIT, or FIB-MAA-CIT. HFLS-RA cells were stimulated directly with FIB antigens or with supernatants (SN) from macrophages (Mϕ-SN or MP-SN) stimulated with FIB antigens. Genes associated with an aggressive HFLS phenotype, extracellular matrix proteins, and activated signaling pathways were evaluated. Results: HFLS-RA cells treated with Mϕ-SNFIB-CIT and Mϕ-SNFIB-MAA-CIT demonstrated significant increases in mRNA expression of genes associated with an aggressive phenotype at 24-h as compared to direct stimulation with the same antigens. Similar results were obtained using MP-SN. Cellular morphology was altered and protein expression of vimentin (p<0.0001 vs. Mϕ-SNFIB) and type II collagen (p<0.0001) were significantly increased in HFLS-RA cells treated with any of the Mϕ-SN generated following stimulation with modified antigens. Phosphorylation of JNK, Erk1/2, and Akt were increased most substantially in HFLS-RA treated with Mϕ-SNFIB-MAA-CIT (p<0.05 vs Mϕ-SNFIB). These and other data suggested the presence of PDGF-BB in Mϕ-SN. Mϕ-SNFIB-MAA-CIT contained the highest concentration of PDGF-BB (p<0.0001 vs. Mϕ-SNFIB) followed by Mϕ-SNFIB-CIT then Mϕ-SNFIB-MAA. HFLS-RA cells treated with PDGF-BB showed similar cellular morphology to the Mϕ-SN generated following stimulation with modified FIB, as well as the increased expression of vimentin, type II collagen, and the phosphorylation of JNK, Erk1/2 and Akt signaling molecules. Conclusion: Together, these findings support the hypothesis that in response to MAA-modified and/or citrullinated fibrinogen, macrophages release soluble factors including PDGF-BB that induce fibroblast activation and promote an aggressive fibroblast phenotype. These cellular responses were most robust following macrophage activation with dually modified fibrinogen, compared to single modification alone, providing novel insights into the combined role of multiple post-translational protein modifications in the development of RA.

Changes in Patterns of Use of Advanced Therapies Following Emerging Data About Adverse Events in Patients With Rheumatoid Arthritis From the Veterans Affairs Health System.

OBJECTIVE: To determine whether prescribing practices for Janus kinase inhibitors (JAKi), tumor necrosis factor inhibitors (TNFi), and non-TNFi biologic agents changed after the results of the Oral Rheumatoid Arthritis Trial (ORAL) Surveillance trial were released in January 2021. METHODS: This is a retrospective study in adult patients with rheumatoid arthritis (RA) receiving advanced therapies within the Veterans Affairs Health System from January 2012 through September 2022. Eligible patients were required to have at least one diagnosis code for RA and to have received a biologic disease-modifying antirheumatic drug or JAKi. Treatment courses were defined from pharmacy dispensing data and the number of new courses of each advanced therapy was quantified over time. We assessed changes in the use of each therapy before and after the release of safety data (January 2021). RESULTS: A total of 88,253 individual drug courses (in 34,656 unique patients) were included in the study. There was a consistent increase in the number and proportion of new courses of JAKi leading up to January 2021, which was followed by a significant net decrease in JAKi use through September 2022. There was significantly less tofacitinib use after the release of safety data, with a significant difference in the slope of change in use with time. In contrast, whereas TNFi use declined leading up to 2021, its use significantly increased after January 2021. CONCLUSION: Changes in prescribing in response to new evidence emphasize the impact that safety trials have on prescribing practices. Ongoing study in this area, with attention to specific patient characteristics and risk profiles, will help characterize these changes in practice.

Aortic Stenosis Risk in Rheumatoid Arthritis.

Importance: Although an increased risk of ischemic cardiovascular disease has been associated with rheumatoid arthritis (RA), the risk of aortic stenosis (AS) is unknown. Objective: To examine the risk of incident AS, aortic valve intervention, AS-related death, and risk factors for AS development in patients with RA. Design, Setting, and Participants: This cohort study linked data from the Veterans Health Administration (VHA) and Centers for Medicare & Medicaid Services from 2000 to 2019. Patients with RA were matched by age, sex, and VHA enrollment year with up to 10 patients without RA. The cohort was followed until incident AS, aortic valve intervention, or death. Data were analyzed from August 23, 2022, to March 3, 2023. Exposures: the primary exposure was the presence of RA, defined using validated RA algorithms. Main Outcomes and Measures: Aortic stenosis was defined as a composite of inpatient or outpatient diagnoses, surgical or transcatheter aortic valve replacement, or AS-related death using diagnostic and procedural codes. Risk of AS development was assessed with multivariable Cox proportional hazards models adjusted for race, ethnicity, smoking status, body mass index, rurality, comorbidities, and health care use. Results: The cohort included 73 070 patients with RA (64 008 [87.6%] males; mean [SD] age, 63.0 [11.9] years) matched with 639 268 patients without RA (554 182 [86.7%] males; mean [SD] age, 61.9 [11.7] years) and 16 109 composite AS outcomes that occurred over 6 223 150 person-years. The AS incidence rate was 3.97 (95% CI, 3.81-4.13) per 1000 person-years in patients with RA and 2.45 (95% CI, 2.41-2.49) per 1000 person-years in the control patients (absolute difference, 1.52 per 1000 person-years). Rheumatoid arthritis was associated with an increased risk of composite AS (adjusted hazard ratio [AHR], 1.48; 95% CI, 1.41-1.55), aortic valve intervention (AHR, 1.34; 95% CI, 1.22-1.48), and AS-related death (AHR, 1.26; 95% CI, 1.04-1.54). Conclusions and Relevance: In this cohort study, RA was associated with a higher risk of developing AS and the subsequent risks of undergoing aortic valve intervention and suffering from AS-related death. Future studies are needed to confirm whether valvular heart disease, specifically AS, may be an overlooked cardiovascular disease complication in RA.

Multimorbidity Patterns and Rheumatoid Arthritis Disease Outcomes: Findings From a Multicenter, Prospective Cohort.

OBJECTIVE: To determine whether unique multimorbidity patterns are associated with long-term rheumatoid arthritis (RA) disease severity. METHODS: We conducted a cohort study within the Veterans Affairs Rheumatoid Arthritis registry. We applied previously derived multimorbidity patterns based on the presence of diagnostic codes for relevant conditions prior to enrollment using linked administrative data. Disease activity and functional status were assessed longitudinally up to 5 years after enrollment. The association of multimorbidity patterns with disease activity and functional status were assessed using generalized estimating equations models adjusting for relevant confounders. RESULTS: We studied 2,956 participants, of which 88.2% were male, 76.9% reported white race, and 79.3% had a smoking history. Mental health and substance abuse (ß 0.12 [95% confidence interval {CI} 0.00, 0.23]), cardiovascular (ß 0.25 [95% CI 0.12, 0.38]), and chronic pain (ß 0.21 [95% CI 0.11, 0.31]) multimorbidity were associated with higher Disease Activity Score in 28 joints (DAS28) scores. Mental health and substance abuse (ß 0.09 [0.03, 0.15]), cardiovascular (ß 0.11 [95% CI 0.04, 0.17]), and chronic pain multimorbidity (ß 0.15 [95% CI 0.10, 0.20]) were also associated with higher Multidimensional Health Assessment Questionnaire (MDHAQ) scores. The metabolic pattern of multimorbidity was not associated with DAS28 or MDHAQ. The number of multimorbidity patterns present was highly associated with DAS28 and MDHAQ (P trend < 0.001), and patients with all four multimorbidity patterns had the highest DAS28 (ß 0.59 [95% CI 0.36, 0.83]) and MDHAQ (ß 0.27 [95% CI 0.16, 0.39]) scores. CONCLUSION: Mental health and substance abuse, chronic pain, and cardiovascular multimorbidity patterns are associated with increased RA disease activity and poorer functional status. Identifying and addressing these multimorbidity patterns may facilitate achieving RA treatment targets.

Risk of Prostate Cancer in US Veterans With Rheumatoid Arthritis.

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.

A Narrowing Mortality Gap: Temporal Trends of Cause-Specific Mortality in a National Matched Cohort Study in US Veterans With Rheumatoid Arthritis.

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.

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.

Peptidyl arginine deiminase expression and macrophage polarization following stimulation with citrullinated and malondialdehyde-acetaldehyde modified fibrinogen.

OBJECTIVE: Post-translational modifications of extracellular matrix proteins such as fibrinogen may lead to tolerance loss and have been implicated in rheumatoid arthritis (RA) pathogenesis. The purpose of this study was to determine whether fibrinogen (FIB) modified with citrulline (CIT), malondialdehyde-acetaldehyde (MAA) or both leads to altered macrophage polarization, peptidyl arginine deiminase (PAD) expression, or production of citrullinated proteins. METHODS: PMA-treated U-937 cells (M0 cells) were stimulated with MAA, CIT or MAA-CIT modified FIB. Macrophage (M1/M2) phenotypes were evaluated by flow cytometry, RT-PCR, and ELISA. PAD enzyme expression and protein citrullination was evaluated using RT-PCR and Western Blot. RESULTS: Flow cytometry revealed that M0 macrophages stimulated with FIB-MAA-CIT resulted in mixed M1/M2 phenotypes as demonstrated by cell surface expression and mRNA levels of CD14, CD192, CD163, and CD206 (p < 0.001 vs. others), and the release of IL-18, IP-10, CCL22, and IL-13 (p < 0.001 vs. others). While FIB-MAA treated M0 cells demonstrated a mixed M1/M2 phenotype, cytokine and cell surface markers differed from FIB-MAA-CIT. Finally, M0 cells treated with FIB-CIT demonstrated markers and cytokines consistent with only the M1-like phenotype. Exposure of M0 cells to FIB-MAA-CIT (at 48 h) and FIB-MAA (at 24 h) led to increased mRNA expression and protein expression of PAD2 (p < 0.001) with increased protein citrullination. CONCLUSION: These findings suggest that MAA-modification and citrullination of FIB, in isolation or combination, yield specific effects on macrophage polarization, PAD expression and citrullination that ultimately may induce inflammatory and fibrotic responses associated with RA.

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.

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.