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ABSTRACTRheumatoid arthritis is a systemic autoimmune disease characterized by excess morbidity and mortality from cardiovascular disease. Mechanisms linking rheumatoid arthritis and cardiovascular disease include shared inflammatory mediators, post-translational modifications of peptides/proteins and subsequent immune responses, alterations in the composition and function of lipoproteins, increased oxidative stress, and endothelial dysfunction. Despite a growing understanding of these mechanisms and their complex interplay with conventional cardiovascular risk factors, optimal approaches of risk stratification, prevention, and treatment in the context of rheumatoid arthritis remain unknown. A multifaceted approach to reduce the burden posed by cardiovascular disease requires optimal management of traditional risk factors in addition to those intrinsic to rheumatoid arthritis such as increased disease activity. Treatments for rheumatoid arthritis seem to exert differential effects on cardiovascular risk as well as the mechanisms linking these conditions. More research is needed to establish whether preferential rheumatoid arthritis therapies exist in terms of prevention of cardiovascular disease. Ultimately, understanding the unique mechanisms for cardiovascular disease in rheumatoid arthritis will aid in risk stratification and the identification of novel targets for meaningful reduction of cardiovascular risk in this patient population.

Objective Patients with rheumatic diseases such as rheumatoid arthritis (RA) and lupus have increased risk of infection and are treated with medications that may increase this risk yet are also hypothesized to help treat COVID‐19. We set out to understand how the COVID‐19 pandemic has impacted the lives of these patients in the United States. Methods Participants in a US‐wide longitudinal observational registry responded to a supplemental COVID‐19 questionnaire by e‐mail on March 25, 2020, about their symptoms, COVID‐19 testing, health care changes, and related experiences during the prior 2 weeks. Analysis compared responses by diagnosis, disease activity, and new onset of symptoms. Qualitative analysis was conducted on optional free‐text comment fields. Results Of the 7061 participants invited to participate, 530 responded, with RA as the most frequent diagnosis (61%). Eleven participants met COVID‐19 screening criteria, of whom two sought testing unsuccessfully. Six others sought testing, three of whom were successful, and all test results were negative. Not quite half of participants (42%) reported a change to their care in the prior 2 weeks. Qualitative analysis revealed four key themes: emotions in response to the pandemic, perceptions of risks from immunosuppressive medications, protective measures to reduce risk of COVID‐19 infection, and disruptions in accessing rheumatic disease medications, including hydroxychloroquine. Conclusion After 2 weeks, many participants with rheumatic diseases already had important changes to their health care, with many altering medications without professional consultation or because of hydroxychloroquine shortage. As evidence accumulates on the effectiveness of potential COVID‐19 treatments, effort is needed to safeguard access to established treatments for rheumatic diseases.

ObjectivePost-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).MethodsPMA-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.ResultsHFLS-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.ConclusionTogether, 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.

Rheumatoid arthritis (RA)-associated lung disease is a leading cause of mortality in RA, yet the mechanisms linking lung disease and RA remain unknown. Using an established murine model of RA-associated lung disease combining collagen-induced arthritis (CIA) with organic dust extract (ODE)-induced airway inflammation, differences among lung immune cell populations were analyzed by single cell RNA-sequencing. Additionally, four lung myeloid-derived immune cell populations including macrophages, monocytes/macrophages, monocytes, and neutrophils were isolated by fluorescence cell sorting and gene expression was determined by NanoString analysis. Unsupervised clustering revealed 14 discrete clusters among Sham, CIA, ODE, and CIA+ODE treatment groups: 3 neutrophils (inflammatory, resident/transitional, autoreactive/suppressor), 5 macrophages (airspace, differentiating/recruited, recruited, resident/interstitial, and proliferative airspace), 2 T-cells (differentiating and effector), and a single cluster each of inflammatory monocytes, dendritic cells, B-cells and natural killer cells. Inflammatory monocytes, autoreactive/suppressor neutrophils, and recruited/differentiating macrophages were predominant with arthritis induction (CIA and CIA+ODE). By specific lung cell isolation, several interferon-related and autoimmune genes were disproportionately expressed among CIA and CIA+ODE (e.g. Oasl1 , Oas2 , Ifit3 , Gbp2 , Ifi44 , and Zbp1 ), corresponding to RA and RA-associated lung disease. Monocytic myeloid-derived suppressor cells were reduced, while complement genes (e.g. C1s1 and Cfb ) were uniquely increased in CIA+ODE mice across cell populations. Recruited and inflammatory macrophages/monocytes and neutrophils expressing interferon-, autoimmune-, and complement-related genes might contribute towards pro-fibrotic inflammatory lung responses following airborne biohazard exposures in setting of autoimmune arthritis and could be predictive and/or targeted to reduce disease burden.

Objective The objective of this study is to examine the risk of serious infections (SIs) associated with biological disease‐modifying antirheumatic drugs (bDMARDs) compared with conventional synthetic disease‐modifying antirheumatic drugs (csDMARDs) in patients with rheumatoid arthritis (RA). Methods We studied patients with RA who initiated bDMARDs or csDMARDs from 2001 to 2016 in FORWARD–The National Databank for Rheumatic Diseases. Disease‐modifying antirheumatic drugs (DMARDs) were categorized into three groups: (1) csDMARDs (bDMARD‐naïve; reference), (2) tumor necrosis factor α inhibitors (TNFis), and (3) non‐TNFi biologics (abatacept, rituximab, tocilizumab, and anakinra). SIs were defined as those requiring intravenous antibiotics or hospitalization or those resulting in death. We calculated the propensity score (PS), which reflected the probability of receiving a specific DMARD group, and estimated the hazard ratio (HR) (with the 95% confidence interval [CI]) for SI from multivariable Cox models, adjusting for PS and time‐varying confounders. Results A total of 694 (5.9%) first SIs were identified in 11 623 patients with RA during 27 552 patient‐years of follow‐up. The SI incidence rate per 1000 patient‐years was 22.4 (95% CI 19.2‐26.1) for csDMARDs, 26.9 (95% CI 24.5‐29.6) for TNFis, and 23.3 (95% CI 19.0‐28.5) for non‐TNFi bDMARDs. Adjusted HRs for SIs were 1.33 (95% CI 1.05‐1.68) for TNFis and 1.48 (95% CI 1.02‐2.16) for non‐TNFi bDMARDs, compared with csDMARDs. The SI risk with non‐TNFi bDMARDs versus TNFis was not different. Other risk factors for SI were older age, higher comorbidity burden (particularly pulmonary disease), higher weighted cumulative prednisone dose, disability and disease activity, and number of prior csDMARD failures. Conclusion TNFis and non‐TNFi bDMARDs were associated with an increased SI risk compared with csDMARDs in RA, even after accounting for risk‐associated patient characteristics.

Lung disease is the most overrepresented cause of death in rheumatoid arthritis (RA). Animal studies have demonstrated potentiated autoimmunity, arthritis, and profibrotic/inflammatory lung disease with a combination of airborne exposures and collagen-induced arthritis (CIA), a model that recapitulates features of RA-associated interstitial lung disease (RA-ILD). As patients with RA-ILD demonstrate unique circulating monocyte subpopulations, this study aims to characterize lung infiltrating monocytes/macrophages in a mouse model of RA-ILD and determine whether reducing these cells mitigates the development of lung disease. Autoimmune-prone DBA/1J mice received intranasal inhalation of lipopolysaccharide (LPS) daily for up to 5 weeks and CIA induction. Experimental groups included Sham (saline injection/saline inhalation), CIA (CIA/saline), LPS (saline/LPS), and CIA+LPS (CIA/LPS). Lung disease was assessed by longitudinal imaging, lung function measurements, bronchoalveolar lavage fluid, lung tissues, and lung histopathology. Cell subpopulations were analyzed by single cell RNA-sequencing and flow cytometry. Intravenous clodronate liposome administration was employed to reduce circulating monocytes. Longitudinal imaging demonstrated increased lung volume and tissue density in CIA+LPS mice. Lung function assessment showed reduced compliance and increased airway resistance with dual exposure. Unsupervised clustering revealed 16 discrete clusters among the experimental groups with robust clusters of monocytes/macrophages of overlapping characteristics for both CIA+LPS and CIA. By flow cytometry, dual CIA+LPS exposure induced activated CD11c CD206 CD11b MHC Class II CD80 alveolar macrophages, CD11c CD206 CD11b Ly6C (and Ly6C )MHC Class II CD80 CD86 interstitial macrophages, and CD11c CD11b Ly6C MHC Class II CD80 CD86 monocytic-like cells. MHC Class II -expressing cells across monocyte/macrophage subpopulations of CIA+LPS treated mice were more aligned with CIA than LPS alone. Intravenous clodronate liposome administration reduced CIA+LPS-induced both CD11c CD11b and CD11c CD11b lung macrophages, neutrophils, lymphocytes, inflammatory/pro-fibrotic mediators, and expression of vimentin and citrullinated and malondialdehyde acetaldehyde (MAA)-modified proteins/lung autoantigens. The interaction of inhalation-induced airway inflammation and autoimmune arthritis results in lung disease associated with uniquely activated infiltrating inflammatory interstitial macrophages. Moreover, depletion of circulating monocytes attenuated lung disease. Whereas the induced interstitial macrophage immunophenotype is more aligned to CIA than endotoxin exposure, co-exposure modeling renders unique features that potentially inform the pathogenesis and treatment of RA-ILD.

Substantial progress has been made in understanding the involvement of malondialdehyde-acetaldehyde (MAA) adducts in rheumatoid arthritis (RA) pathogenesis. This systematic review synthesizes current evidence on the role of MAA-modified macromolecules and anti-MAA antibodies in the development, manifestation, and progression of RA. MEDLINE, EMBASE, the Cochrane Library, Scopus, and SciFinder were searched through May 6, 2025. Studies were screened based on predefined inclusion/exclusion criteria. Study characteristics were extracted, and quality assessments were performed. MAA-modified proteins and MAA-specific autoreactive B cells are elevated in synovial and lung tissues of RA patients. Anti-MAA antibodies are enriched in RA-derived synovial fluids compared to serum. Serum levels of anti-MAA IgG and IgA are increased prior to RA onset, and though not RA-specific, were higher in RA patients than those with other conditions. Anti-MAA antibodies do not cross-react with other autoantibodies, such as anti-citrullinated protein autoantibodies, and can be detected in sera from seronegative RA patients. Elevated anti-MAA antibody levels correlate with progression of joint, lung, and cardiovascular complications, as well as biologic treatment responses. Human and animal studies have begun to elucidate mechanisms by which MAA and anti-MAA antibody might contribute to inflammatory and fibrotic changes in RA. This review provides a comprehensive overview of MAA and its involvement in RA pathogenesis. MAA adducts contribute to loss of immune tolerance and promote both inflammation and fibrosis in RA. Given associations of anti-MAA antibodies with RA disease activity and complications, MAA-related pathways hold promise as both biomarkers and treatment targets in RA. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD4202454490.

Immunogenetic as well as environmental and occupational exposures have been linked to the development of rheumatoid arthritis (RA), RA-associated lung disease, and other primary lung disorders. Importantly, various inhalants can trigger post-translational protein modifications, resulting in lung autoantigen expression capable of stimulating pro-inflammatory and/or pro-fibrotic immune responses. To further elucidate gene-environment interactions contributing to pathologic lung inflammation, we exploited an established model of organic dust extract (ODE) exposure with and without collagen-induced arthritis (CIA) in C57BL/6 wild type (WT) versus HLA-DR4 transgenic mice. ODE-induced airway infiltration driven by neutrophils was significantly increased in DR4 versus WT mice, with corresponding increases in bronchoalveolar lavage fluid (BALF) levels of TNF-⍺, IL-6, and IL-33. Lung histopathology demonstrated increased number of ectopic lymphoid aggregates comprised of T and B cells following ODE exposure in DR4 mice. ODE also induced citrullination, malondialdehyde acetaldehyde (MAA) modification, and vimentin expression that co-localized with MAA and was enhanced in DR4 mice. Serum and BALF anti-MAA antibodies were strikingly increased in ODE-treated DR4 mice. Coupling ODE exposure with Type II collagen immunization (CIA) resulted in similarly augmented pro-inflammatory lung profiles in DR4 mice (relative to WT mice) that was accompanied by a profound increase in infiltrating lung CD4 + and CD8 + T cells as well as CD19 + CD11b + autoimmune B cells. Neither modeling strategy induced significant arthritis. These findings support a model in which environmental insults trigger enhanced post-translational protein modification and lung inflammation sharing immunopathological features with RA-associated lung disease in the selected immunogenetic background of HLA-DR4 mice.

Background Biomarkers have been proposed as tools to aid in the identification and prognostication of interstitial lung disease (ILD) in rheumatoid arthritis (RA). We performed a systematic review of studies evaluating peripheral blood biomarkers and their association with RA‐ILD and its prognosis. Methods Medline, Embase, the Cochrane Library, and Scopus were queried for relevant studies, with the final search update on July 12, 2021. We included studies evaluating peripheral blood biomarkers for the identification and/or prognostication of RA‐ILD, extracting the performance of individual biomarkers for identifying RA‐ILD, and predicting prognosis. Modified versions of the Quality Assessment of Diagnostic Accuracy Studies 2 and the Quality in Prognosis Studies tools were used for quality assessment. Results Seventy studies met eligibility criteria. Study and patient characteristics, analytical methods, strength and consistency of associations, and study quality were heterogeneous. A total of 92 biomarkers were positively associated and 12 were negatively associated with RA‐ILD among patients with RA in one or more report. Only a small number of biomarkers were evaluated in multiple cohorts using adjusted analyses. Biomarkers most strongly associated with RA‐ILD overlapped with those identified for idiopathic pulmonary fibrosis. Few prognostic biomarkers of RA‐ILD were identified. Conclusion Several peripheral blood biomarkers are associated with the presence of RA‐ILD, but few have been assessed in multivariable models, have been externally validated, have discriminated RA‐ILD from other lung disease, or have prognosticated the disease course. High‐quality studies investigating and validating peripheral biomarkers in RA‐ILD are needed before they can be employed in clinical care.

ObjectiveStudies of dermatomyositis (DM) are frequently limited to single-centre cohorts. We used two large nationally representative US cohorts to conduct a descriptive epidemiological study of the characteristics, treatments and outcomes of patients with incident DM.MethodsThis retrospective study identified two DM inception cohorts using (1) commercial claims and (2) electronic health record (EHR) data from the Excellence Network in Rheumatology to Innovate Care and High-impact research (ENRICH), a community rheumatology practice-based research network. Patient characteristics, treatments and healthcare utilisation were assessed using the 18 months before and 12 months after diagnosis in claims and the 12 months before and after diagnosis in EHR data.ResultsWe identified 2475 patients (claims) and 1196 patients (EHR) with incident DM. Among 998 patients in the EHR cohort with available laboratory data, 472 had available myositis panel results, with 165 (35.0%) having a positive myositis-specific antibody. Glucocorticoid use was common, 68.7% and 73.8% in the two cohorts, respectively, with initial doses most often >20 mg/day; among glucocorticoid users, mean cumulative dose was 1407 mg in the claims cohort. Hydroxychloroquine, methotrexate and mycophenolate were the most commonly used immunomodulatory therapies. During follow-up in the claims data cohort, incidence per 1000 person-years was 92.2, 15.3, 6.4, 2.9 and 2.1 for all-cause hospitalisation, malignancy, interstitial lung disease, gastrostomy tube placement and myocarditis, respectively.ConclusionAdministrative claims and EHR data can be leveraged to assess treatment patterns and longitudinal outcomes/disease manifestations in incident dermatomyositis cohorts. This study highlights a high burden of glucocorticoid exposure, significant heterogeneity in treatment and high healthcare utilisation in this population.