As the goal in rheumatoid arthritis (RA) management shifts toward the prevention of joint disease, it is important to consider the role of mucosal sites in the pathogenesis of RA because they may be ...potential targets for preventive interventions. Multiple mucosal sites demonstrate immune dysregulation and inflammation in individuals with classifiable RA as well as, importantly, in individuals with systemic autoimmunity related to RA. The lung, gingival, and gastrointestinal mucosae are most strongly implicated in RA pathogenesis and may be sites where autoimmunity in RA initially develops. Targeting the exact site where the initial immune dysregulation in RA occurs is an appealing approach to prevention because it could avoid unwanted side effects of systemic therapies. However, several challenges must be addressed before mucosa-targeted interventions are a readily available option for RA prevention. Studies are needed to determine whether all RA-related immune dysregulation at mucosal sites will progress to joint disease and whether one or multiple mucosal sites demonstrate dysregulation prior to the development of classifiable RA. These areas of future research are likely to provide crucial pieces in the understanding of RA pathogenesis and ultimately RA prevention.
Genetic and environmental risk factors for rheumatoid arthritis Deane, Kevin D.; Demoruelle, M. Kristen; Kelmenson, Lindsay B. ...
Best practice & research. Clinical rheumatology,
February 2017, 2017-02-00, 20170201, Letnik:
31, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Multiple genetic and environmental factors have been associated with an increased risk for rheumatoid arthritis (RA). Of these, the strongest associations have been seen with female sex, a family ...history of RA, the genetic factor the “shared epitope,” and exposure to tobacco smoke. There is also renewed interest in mucosal inflammation and microbial factors as contributors to the development of RA. However, the identification of a “preclinical” period of RA that can be defined as local or systemic autoimmunity as measured by autoantibodies and other biomarkers prior to the development of clinically apparent synovitis suggests that the risk factors for RA are acting long prior to first clinical evidence of IA. As such, a major challenge to the field will be to investigate the full spectrum of the development of RA, from initiation and propagation of autoimmunity during preclinical RA and transition to clinically apparent synovitis and classifiable RA, to determine which genetic and environmental factors are important at each stage of disease development. Understanding the exact role and timing of action of risk factors for RA is especially important given the advent of prevention trials in RA, and the hope that a full understanding of genetic and environmental factors in RA could lead to effective preventive interventions.
Individuals at high risk of developing seropositive rheumatoid arthritis (RA) can be identified for translational research and disease prevention studies through the presence of highly informative ...and predictive patterns of RA-related autoantibodies, especially anti-citrullinated protein antibodies (ACPAs), in the serum. In serologically positive individuals without arthritis, designated ACPA positive at risk, the presence of mucosal inflammatory processes associated with the presence of local ACPA production has been demonstrated. In other at-risk populations, local RA-related autoantibody production is present even in the absence of serum autoantibodies. Additionally, a proportion of at-risk individuals exhibit local mucosal ACPA production in the lung, as well as radiographic small-airway disease, sputum hypercellularity and increased neutrophil extracellular trap formation. Other mucosal sites in at-risk individuals also exhibit autoantibody production, inflammation and/or evidence of dysbiosis. As the proportion of individuals who exhibit such localized inflammation-associated ACPA production is substantially higher than the likelihood of an individual developing future RA, this finding raises the hypothesis that mucosal ACPAs have biologically relevant protective roles. Identifying the mechanisms that drive both the generation and loss of externally focused mucosal ACPA production and promote systemic autoantibody expression and ultimately arthritis development should provide insights into new therapeutic approaches to prevent RA.
Airway Disease in Rheumatoid Arthritis Matson, Scott M; Demoruelle, M Kristen; Castro, Mario
Annals of the American Thoracic Society,
03/2022, Letnik:
19, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Rheumatoid arthritis (RA) is a common condition affecting approximately 1% of the general population. RA is a multisystem disorder that causes progressive articular destruction through synovial ...inflammation. One of the most common extraarticular manifestations of RA is pulmonary involvement, where all compartments of the pulmonary system can be impacted (e.g., pulmonary vasculature, pleura, parenchyma, and the airways). Although it has been known for decades that a portion of patients with RA develop interstitial lung disease, and recent advancements in understanding the genetic risk and treatment for RA-interstitial lung disease have drawn attention, more recent data have begun to highlight the significance of airway disease in patients with RA. Yet, little is known about the underlying pathogenesis, clinical impact, or optimal treatment strategies for airway disease in RA. This review will focus on airway disease involvement in patients with RA by highlighting areas of clinical inquiry for pulmonologists and rheumatologists and discuss areas for future research. Finally, we discuss a potential screening algorithm for providers when approaching patients with RA with respiratory complaints.
Interstitial lung disease (ILD) is a common pulmonary manifestation of rheumatoid arthritis. There is lack of clarity around predictors of mortality and disease behaviour over time in these ...patients.We identified rheumatoid arthritis-related interstitial lung disease (RA-ILD) patients evaluated at National Jewish Health (Denver, CO, USA) from 1995 to 2013 whose baseline high-resolution computed tomography (HRCT) scans showed either a nonspecific interstitial pneumonia (NSIP) or a "definite" or "possible" usual interstitial pneumonia (UIP) pattern. We used univariate, multivariate and longitudinal analytical methods to identify clinical predictors of mortality and to model disease behaviour over time.The cohort included 137 subjects; 108 had UIP on HRCT (RA-UIP) and 29 had NSIP on HRCT (RA-NSIP). Those with RA-UIP had a shorter survival time than those with RA-NSIP (log rank p=0.02). In a model controlling for age, sex, smoking and HRCT pattern, a lower baseline % predicted forced vital capacity (FVC % pred) (HR 1.46; p<0.0001) and a 10% decline in FVC % pred from baseline to any time during follow up (HR 2.57; p<0.0001) were independently associated with an increased risk of death.Data from this study suggest that in RA-ILD, disease progression and survival differ between subgroups defined by HRCT pattern; however, when controlling for potentially influential variables, pulmonary physiology, but not HRCT pattern, independently predicts mortality.
Connective tissue disease associated interstitial lung disease (CTD-ILD) is a heterogenous collection of conditions with a diverse spectrum of interstitial lung disease (ILD) manifestations. ...Currently, clinical practice of lung-directed immunosuppression in CTD-ILD is supported by several randomized, placebo-controlled trials (RCTs) in patients with scleroderma and several observational, retrospective studies in other autoimmune conditions. However, given the harm of immunosuppression in idiopathic pulmonary fibrosis, there is an urgent need for RCTs of immunosuppression and antifibrotic agents in fibrotic CTD-ILD populations as well as the study of intervention in patients with subclinical CTD-ILD.
Objective
The disease process in rheumatoid arthritis (RA) starts years before the clinical diagnosis is made, and elevated levels of disease‐specific autoantibodies can be detected during this ...period. Early responses to known or novel autoantigens likely drive the eventual production of pathogenic autoimmunity. Importantly, the presence of disease‐specific autoantibodies can identify individuals who are at high risk of developing RA but who do not currently have arthritis. The goal of the current study was to characterize plasmablasts from individuals at risk of developing RA.
Methods
We investigated antibody‐secreting plasmablasts derived from a well‐characterized cohort of individuals who were at risk of developing RA, based on RA‐related serum autoantibody positivity, as compared to patients with early (<1 year) seropositive RA as well as healthy control subjects. The plasmablast antibody repertoires of at‐risk subjects were analyzed using DNA barcode–based methods with paired heavy‐ and light‐chain gene sequencing. Cells were single‐cell sorted, the cell‐ and plate‐specific DNA barcodes were sequentially added, and next‐generation sequencing was performed.
Results
Total plasmablast levels were similar in the antibody‐positive (1%) and control (0.4–1.6%) groups. However, increased frequencies of IgA+ versus IgG+ plasmablasts were observed in the antibody‐positive group (39% IgA+ and 37% IgG+) as compared to other groups (1–9% IgA+ and 71‐87% IgG+). Paired antibody sequences from antibody‐positive subjects revealed cross‐isotype clonal families and similar sequence characteristics in the IgA and IgG plasmablast repertoires. Antibody‐positive individuals also demonstrated elevated serum levels of IgA isotype anti–cyclic citrullinated peptide 3 antibodies.
Conclusion
The IgA plasmablast dominance in these antibody‐positive individuals suggests that a subset of RA‐related autoantibodies may arise from mucosal immune responses and may be involved in early disease pathogenesis in individuals who are at risk of developing RA.
PDF
