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
Rheumatoid arthritis (RA) and its treatments are associated with an increased risk of infection, but it remains unclear whether these factors have an impact on the risk or severity of ...COVID‐19. The present study was undertaken to assess the risk and severity of COVID‐19 in a US Department of Veterans Affairs (VA) cohort of patients with RA and those without RA.
Methods
A matched cohort study using national VA data was conducted. Patients diagnosed as having RA were identified among nondeceased individuals who were active in the VA health care system as of January 1, 2020 and who had received care in a VA medical center in 2019; patients for whom no RA diagnostic code was indicated were matched to the RA patients (1:1) by age, sex, and VA site (non‐RA controls). Patients diagnosed as having COVID‐19 and those with severe COVID‐19 (defined as requiring hospitalization or leading to death) were ascertained from a national VA COVID‐19 surveillance database through December 10, 2020. Multivariable Cox models were used to compare the risk of COVID‐19 and COVID‐19 hospitalization or death between RA patients and non‐RA controls, after adjusting for demographic characteristics, comorbidities, health care utilization and access, and county‐level COVID‐19 incidence rates.
Results
This VA cohort of RA patients and non‐RA controls (n = 33,886 subjects per group) predominantly comprised male patients (84.5%), and the mean age was 67.8 years. During follow‐up, 1,503 patients in the cohort were diagnosed as having COVID‐19; among them, 388 patients had severe COVID‐19 (hospitalization or death), while in 228 patients, the deaths were not related to COVID‐19. In the multivariable model, RA was associated with a higher risk of COVID‐19 (adjusted hazard ratio HR 1.25 95% confidence interval (95% CI) 1.13–1.39) and a higher risk of COVID‐19 hospitalization or death (adjusted HR 1.35 95% CI 1.10–1.66) as compared to non‐RA controls. Use of disease‐modifying antirheumatic drugs and prednisone, as well as self‐reported Black race, self‐reported Hispanic ethnicity, and presence of several chronic conditions, but not seropositivity for RA autoantibodies, were each associated with risk of COVID‐19 and severe COVID‐19 (hospitalization or death).
Conclusion
Patients with RA are at higher risk of developing COVID‐19 and severe COVID‐19 (leading to hospitalization or death) compared to those without RA. With a risk of COVID‐19 that approaches that of other recognized chronic conditions, these findings suggest that RA patients should be prioritized for COVID‐19 prevention and management strategies.
Aldehyde dehydrogenase 2 (ALDH2) is the major enzyme that metabolizes acetaldehyde produced from alcohol metabolism. Approximately 40‐50% of East Asians carry an inactive ALDH2 gene and exhibit ...acetaldehyde accumulation after alcohol consumption. However, the role of ALDH2 deficiency in the pathogenesis of alcoholic liver injury remains obscure. In the present study, wild‐type and ALDH2−/− mice were subjected to ethanol feeding and/or carbon tetrachloride (CCl4) treatment, and liver injury was assessed. Compared with wild‐type mice, ethanol‐fed ALDH2−/− mice had higher levels of malondialdehyde‐acetaldehyde (MAA) adduct and greater hepatic inflammation, with higher hepatic interleukin (IL)‐6 expression but surprisingly lower levels of steatosis and serum alanine aminotransferase (ALT). Higher IL‐6 levels were also detected in ethanol‐treated precision‐cut liver slices from ALDH2−/− mice and in Kupffer cells isolated from ethanol‐fed ALDH2−/− mice than those levels in wild‐type mice. In vitro incubation with MAA enhanced the lipopolysaccharide (LPS)‐mediated stimulation of IL‐6 production in Kupffer cells. In agreement with these findings, hepatic activation of the major IL‐6 downstream signaling molecule signal transducer and activator of transcription 3 (STAT3) was higher in ethanol‐fed ALDH2−/− mice than in wild‐type mice. An additional deletion of hepatic STAT3 increased steatosis and hepatocellular damage in ALDH2−/− mice. Finally, ethanol‐fed ALDH2−/− mice were more prone to CCl4‐induced liver inflammation and fibrosis than ethanol‐fed wild‐type mice. Conclusion: ALDH2−/− mice are resistant to ethanol‐induced steatosis but prone to inflammation and fibrosis by way of MAA‐mediated paracrine activation of IL‐6 in Kupffer cells. These findings suggest that alcohol, by way of acetaldehyde and its associated adducts, stimulates hepatic inflammation and fibrosis independent from causing hepatocyte death, and that ALDH2‐deficient individuals may be resistant to steatosis and blood ALT elevation, but are prone to liver inflammation and fibrosis following alcohol consumption. (Hepatology 2014;60:146–157)
Objective
The co‐occurrence of rheumatoid factor (RF) and anti–citrullinated protein antibody (ACPA) positivity in rheumatoid arthritis (RA) is well described. However, the mechanisms underlying the ...potential interaction between these 2 distinct autoantibodies have not been well defined. The aim of this study was to evaluate the epidemiologic and molecular interaction of ACPAs and RF and its association with both disease activity and measures of RA‐associated inflammation.
Methods
In a cohort of 1,488 US veterans with RA, measures of disease activity and serum levels of cytokines and multiplex ACPAs were compared between the following groups of patients: double‐negative (anti–cyclic citrullinated peptide anti‐CCP−/RF−), anti‐CCP+/RF−, anti‐CCP−/RF+, or double‐positive (anti‐CCP+/RF+). Additional studies were performed using an in vitro immune complex (IC) stimulation assay in which macrophages were incubated with ACPA ICs in the presence or absence of monoclonal IgM‐RF, and tumor necrosis factor α production measured as a readout of macrophage activation.
Results
Compared with the double‐negative subgroup (as well as each single‐positive subgroup), the double‐positive subgroup exhibited higher disease activity as well as higher levels of C‐reactive protein and inflammatory cytokines (all P < 0.001). In vitro stimulation of macrophages by ACPA ICs increased cytokine production, and the addition of monoclonal IgM‐RF significantly increased macrophage tumor necrosis factor α production (P = 0.003 versus ACPA ICs alone).
Conclusion
The combined presence of ACPAs and IgM‐RF mediates increased proinflammatory cytokine production in vitro and is associated with increased systemic inflammation and disease activity in RA. Our data suggest that IgM‐RF enhances the capacity of ACPA ICs to stimulate macrophage cytokine production, thereby providing a mechanistic link by which RF enhances the pathogenicity of ACPA ICs in RA.
PURPOSE OF REVIEWThis article reviews recent literature on the origin and pathogenic role of anticitrullinated protein antibodies (ACPAs) in rheumatoid arthritis (RA).
RECENT FINDINGSACPAs and ...ACPA-immune complexes interact with immune cells to facilitate articular inflammation. Findings from recent in vitro and in vivo studies are congruent with epidemiologic observations in RA supporting a pathogenic role of ACPAs.
SUMMARYACPAs target proteins/peptides with citrullinated epitopes and serve as informative RA biomarkers. ACPAs are generated within synovium and possibly at extra-articular sites prior to disease onset. Proximate to RA onset, critical qualitative and quantitative changes to ACPAs occur that drive proinflammatory responses. Unable to induce arthritis alone, the administration of ACPAs enhances the development and severity of inflammation in mice when a mild synovitis is already present. In vitro studies have elucidated several possible mechanisms linking ACPA to disease progression includingfirst, activation of inflammatory cells by ACPA-immune complexes; second, ACPA-mediated neutrophil cell death producing neutrophil extracellular traps, which drives inflammation and autoimmunity by releasing citrullinated autoantigen; and finally, direct binding of ACPAs to osteoclasts and resulting osteoclastogenesis. Together, these recent investigations have begun to elucidate the different mechanisms by which ACPAs may be directly pathogenic in RA.
Objective
Malondialdehyde‐acetaldehyde (MAA) adducts are a product of oxidative stress associated with tolerance loss in several disease states. This study was undertaken to investigate the presence ...of MAA adducts and circulating anti‐MAA antibodies in patients with rheumatoid arthritis (RA).
Methods
Synovial tissue from patients with RA and patients with osteoarthritis (OA) were examined for the presence of MAA‐modified and citrullinated proteins. Anti‐MAA antibody isotypes were measured in RA patients (n = 1,720) and healthy controls (n = 80) by enzyme‐linked immunosorbent assay. Antigen‐specific anti–citrullinated protein antibodies (ACPAs) were measured in RA patients using a multiplex antigen array. Anti‐MAA isotype concentrations were compared in a subset of RA patients (n = 80) and matched healthy controls (n = 80). Associations of anti‐MAA antibody isotypes with disease characteristics, including ACPA positivity, were examined in all RA patients.
Results
Expression of MAA adducts was increased in RA synovial tissue compared to OA synovial tissue, and colocalization with citrullinated proteins was found. Increased levels of anti‐MAA antibody isotypes were observed in RA patients compared to controls (P < 0.001). Among RA patients, anti‐MAA antibody isotypes were associated with seropositivity for ACPAs and rheumatoid factor (P < 0.001) in addition to select measures of disease activity. Higher anti‐MAA antibody concentrations were associated with a greater number of positive antigen‐specific ACPA analytes (expressed at high titer) (P < 0.001) and a higher ACPA score (P < 0.001), independent of other covariates.
Conclusion
MAA adduct formation is increased in RA and appears to result in robust antibody responses that are strongly associated with ACPAs. These results support speculation that MAA formation may be a cofactor that drives tolerance loss, resulting in the autoimmune responses characteristic of RA.
There is a growing body of evidence to suggest that autoimmunity in patients with rheumatoid arthritis (RA) is initiated outside the joint. This is supported by the observation that circulating ...autoantibodies, including both rheumatoid factor and anti-citrullinated protein antibody, can be detected in many subjects years before the development of initial joint symptoms leading to an RA diagnosis. Of the potential extra-articular sites implicated in disease initiation, mucosal tissues have garnered increasing attention. Several lines of investigation have separately implicated mucosal tissues from varying anatomic locations as possible initiating sites for RA, including those from the lung and oral cavity. In this review we summarize recent reports incriminating these mucosal tissues as the initial site of autoantibody generation and inflammation in patients with RA.
Scavenger receptors constitute a large family of proteins that are structurally diverse and participate in a wide range of biological functions. These receptors are expressed predominantly by myeloid ...cells and recognize a diverse variety of ligands including endogenous and modified host-derived molecules and microbial pathogens. There are currently eight classes of scavenger receptors, many of which have multiple names, leading to inconsistencies and confusion in the literature. To address this problem, a workshop was organized by the United States National Institute of Allergy and Infectious Diseases, National Institutes of Health, to help develop a clear definition of scavenger receptors and a standardized nomenclature based on that definition. Fifteen experts in the scavenger receptor field attended the workshop and, after extensive discussion, reached a consensus regarding the definition of scavenger receptors and a proposed scavenger receptor nomenclature. Scavenger receptors were defined as cell surface receptors that typically bind multiple ligands and promote the removal of nonself or altered-self targets. They often function by mechanisms that include endocytosis, phagocytosis, adhesion, and signaling that ultimately lead to the elimination of degraded or harmful substances. Based on this definition, nomenclature and classification of these receptors into 10 classes were proposed. This classification was discussed at three national meetings and input from participants at these meetings was requested. The following manuscript is a consensus statement that combines the recommendations of the initial workshop and incorporates the input received from the participants at the three national meetings.
Objective
To examine the degree to which shared risk factors explain the relationship of periodontitis (PD) to rheumatoid arthritis (RA) and to determine the associations of PD and Porphyromonas ...gingivalis with pathologic and clinical features of RA.
Methods
Patients with RA (n = 287) and patients with osteoarthritis as disease controls (n = 330) underwent a standardized periodontal examination. The HLA–DRB1 status of all participants was imputed using single‐nucleotide polymorphisms from the extended major histocompatibility complex. Circulating anti–P gingivalis antibodies were measured using an enzyme‐linked immunosorbent assay, and subgingival plaque was assessed for the presence of P gingivalis using polymerase chain reaction (PCR). Associations of PD with RA were examined using multivariable regression.
Results
Presence of PD was more common in patients with RA and patients with anti–citrullinated protein antibody (ACPA)–positive RA (n = 240; determined using the anti–cyclic citrullinated peptide 2 anti–CCP‐2 test) than in controls (35% and 37%, respectively, versus 26%; P = 0.022 and P = 0.006, respectively). There were no differences between RA patients and controls in the levels of anti–P gingivalis or the frequency of P gingivalis positivity by PCR. The anti–P gingivalis findings showed a weak, but statistically significant, association with the findings for both anti–CCP‐2 (r = 0.14, P = 0.022) and rheumatoid factor (RF) (r = 0.19, P = 0.001). Presence of PD was associated with increased swollen joint counts (P = 0.004), greater disease activity according to the 28‐joint Disease Activity Score using C‐reactive protein level (P = 0.045), and higher total Sharp scores of radiographic damage (P = 0.015), as well as with the presence and levels of anti–CCP‐2 (P = 0.011) and RF (P < 0.001). The expression levels of select ACPAs (including antibodies to citrullinated filaggrin) were higher in patients with subgingival P gingivalis and in those with higher levels of anti–P gingivalis antibodies, irrespective of smoking status. Associations of PD with established seropositive RA were independent of all covariates examined, including evidence of P gingivalis infection.
Conclusion
Both PD and P gingivalis appear to shape the autoreactivity of RA. In addition, these results demonstrate an independent relationship between PD and established seropositive RA.
Chronic inflammation plays a critical role in the pathogenesis of atherosclerosis. Currently, the mechanism(s) by which inflammation contributes to this disease are not entirely understood. ...Inflammation is known to induce oxidative stress, which can lead to lipid peroxidation. Lipid peroxidation can result in the production of reactive by-products that can oxidatively modify macromolecules including DNA, proteins, and lipoproteins. A major reactive by-product of lipid peroxidation is malondialdehyde (MDA). MDA can subsequently break down to form acetaldehyde (AA). These two aldehydes can covalently interact with the epsilon (ε)-amino group of lysines within proteins and lipoproteins leading to the formation of extremely stable, highly immunogenic malondialdehyde/acetaldehyde adducts (MAA-adducts). The aim of this study was to investigate the inflammatory response to MAA-modified human serum albumin (HSA-MAA) and low-density lipoprotein (LDL-MAA). We found that animals injected with LDL-MAA generate antibodies specific to MAA-adducts. The level of anti-MAA antibodies were further increased in an animal model of atherosclerosis fed a Western diet. An animal model that combined both high fat diet and immunization of MAA-modified protein resulted in a dramatic increase in antibodies to MAA-adducts and vascular fat accumulation compared with controls. In vitro exposure of endothelial cells and macrophages to MAA-modified proteins resulted in increased fat accumulation as well as increased expression of adhesion molecules and pro-inflammatory cytokines. The expression of cytokines varied between the different cell lines and was unique to the individual modified proteins. The results of these studies demonstrate that different MAA-modified proteins elicit unique responses in different cell types. Additionally, the presence of MAA-modified proteins appears to modulate cellular metabolism leading to increased accumulation of triglycerides and further progression of the inflammatory response.
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