Virtual Workshop on Rheumatoid Arthritis, Asthma & COPD: Characterization of the Patients, New Evidence, Research Needs and Opportunities

Background

Lung disease is a well-known comorbidity in rheumatoid arthritis (RA). Although interstitial lung disease (ILD) is the primary manifestation of RA in the lungs, there is strong emerging evidence that airway diseases including asthma and chronic obstructive pulmonary disease (COPD) affect both the course and mortality of RA. The ‘pre-RA’ period in which genetic and environmental factors combine to trigger and propagate autoimmunity before arthritis develops is also actively being investigated; indeed, there are several ongoing trials worldwide set to explore methods to prevent RA. Mucosal processes, including lung/airway immuno-pathobiology, are thought to play a key role in pre-RA and could represent an area to target for disease prevention and/or treatment.

Workshop Goals

• Describe the type, prevalence and impact of airway disease in RA.
• Describe the evidence supporting a possible role for airway disease in the etiopathogenesis of RA development, even in the pre-RA phase.
• Compare and contrast the biology and risk factors for airway disease in RA as well as non-RA conditions to identify potential shared mechanisms of disease that could be leveraged to improve diagnosis and treatment.
• Identify imaging and non-imaging methods and biomarkers for assessing airway disease in RA.
• Understand current and pipeline therapies for asthma and COPD and airway disease in RA, and how known therapies, or gaps, may help to move the field toward better treatments for airway disease with or without RA.
• Develop a meeting summary that can be published and used to drive forward research in the area of airway disease across the spectrum of RA development.

Discussions

The workshop presentations and discussions centered around the following key issues:

Epidemiology and Clinical Manifestations of RA-Airway Disease

Epidemiological studies conducted to date in adult populations provide evidence that airway diseases, including both asthma and COPD, are associated with increased incidence of RA. However, the studies overall had limitations, including problems with classification of both asthma and RA; limited adjustment for important confounders, particularly smoking duration/intensity; few prospective longitudinal studies; statistical heterogeneity and limited power. RA can be associated with a variety of manifestations in the thorax, including ILD and airway disease [1]. There is a broad variety of airway disease patterns, including cricoarytenoid arthritis, bronchiectasis, cellular or follicular bronchiolitis, and constrictive bronchiolitis [2, 3]. RA-ILD and airway disease generally can be found in combination in the same patient, a finding that favors the diagnosis of rheumatoid lung disease.

Risk factors for RA-Airway Disease

There is research linking risk factors for the development of RA and airway disease independently. While many studies have investigated asthma as a risk factor for RA [4], less is known about how RA and asthma contribute to clinical outcomes [5]. Across these independent studies, shared risk factors for RA and airway disease were determined to include older age, cigarette smoking, lower socioeconomic status, infections and microbial dysbiosis, occupational exposures and air pollutants, and poor nutrition [6, 7]. However, of these shared risk factors, only older age, cigarette smoking, and occupational exposures have been specifically investigated as risk factors for airway disease among patients with RA. Overall, the existing literature demonstrates that RA is associated with excess respiratory mortality; this may be due in part to chronic airway disease and is not explained by smoking. Both RA and airway disease are also recognized to have genetic and environmental interactions that predispose to their development.

Initiation of RA-Airway Disease

The airways could play a role in the development of RA at multiple steps and via multiple potential mechanisms. The airways are a site of interaction between an individual’s genetics and inhaled environmental exposures associated with increased RA risk, such as smoking. Data also support that the airways can be a site of RA-related autoantibody generation, including anti-citrullinated protein antibodies (ACPA) [8]. Potential mechanisms that could also initiate RA-related autoantibodies in the airways, but need further study, include inflammation and tissue damage leading to citrullinated proteins, immune cell activation, neutrophil extracellular trap (NET) formation, and changes in the lung microbiome. In addition to initiation of autoimmunity, the airways may also be involved in the evolution of RA-related autoimmunity and in transitions from systemic autoimmunity to inflammatory arthritis that is classifiable as RA. Additional studies are needed to understand the mechanisms by which the airways could contribute to transitions from systemic autoimmunity to inflammatory arthritis.

Shared Immunologic Pathways in RA-Airway Disease

Although type 2 (T2) inflammation is not typically thought of as relevant to RA, the epithelial cytokines that initiate T2 inflammation at the airway mucosa (IL-33, TSLP, and IL-25) can in some instances have pleiotropic effects and therefore could induce RA-associated inflammatory cascades. Furthermore, T2 inflammation itself could link to RA-relevant inflammatory pathways. For example, alveolar macrophages in T2-high asthma have increased tumor necrosis factor alpha (TNF-a) expression [9], Also, Charcot-Leyden (Galectin 10) crystals are produced by eosinophils in asthma and activate the NLRP3 inflammasome [10], and eosinophils can produce extracellular DNA traps (aka EETosis), which could lead to chronic inflammation. COPD pathogenesis involves inciting events and subsequent perpetuating cycles of injury, dysregulated repair, senescence and inflammation [11]. The inciting events (smoke, second hand smoke, infections, pollution) can induce RA-associated chemokine/cytokine production by alveolar macrophages [12, 13]. Autoimmunity may perpetuate COPD pathogenesis [14], and if a break in immune tolerance occurs due to the long-term effects of smoking, this could link directly to RA-relevant autoimmunity. These observations regarding biomarkers and biological processes underlying asthma and COPD suggest several ways in which the inhaled exposures that initiate these diseases (e.g., smoke, pollution, allergen, infections) and the ongoing inflammatory processes that perpetuate these diseases (e.g., non-T2 pathways of adaptive immunity, inflammasome activation, autoimmunity) could contribute to RA-relevant biology. Further research into these possible interconnected pathways is warranted.

Establishing RA-Airway disease Using Imaging and Biomarkers

Establishing an accurate estimate of the incidence and prevalence of airway disease in RA is complicated by the variable definition of airway disease and the mode of diagnosis. The diagnosis and quantification of airway disease can be accomplished through imaging (high-resolution computed tomography of the chest, HRCT), physiology (pulmonary function testing with bronchodilator challenge) and symptoms (wheezing, cough, breathlessness). The current definitions of the major airway syndromes (asthma, COPD, bronchiolitis, bronchiectasis) have significant overlap, hindering their utility in population estimates in individuals with RA. The current literature suggests that the prevalence of “obstructive lung disease”, as defined by radiographs and physiology, is increased in RA. The prevalence in patients without previously documented lung disease is 32% and clinically significant disease in never-smokers is 14-30%. When highly sensitive screening modalities are utilized (e.g. HRCT), the prevalence is reported at 66-92%.

Quantitative imaging of the airways has been investigated extensively for pulmonary diseases such as asthma and COPD. As such, these techniques potentially could help to investigate airway abnormality in rheumatologic diseases. Further, in COPD, small airways abnormality is thought to be an early lesion preceding the development of emphysema [15]. It is possible a similar abnormality is present earlier in conditions such as RA than previously appreciated. Airway diseases are clinically and biologically heterogeneous. One application of biomarkers in airway disease is “molecular phenotyping,” which can help link these various clinical phenotypes to their molecular underpinnings. In asthma, biomarkers have been used to connect certain clinical phenotypes to molecular processes related to T2 inflammation. Established biomarkers of RA-airway disease are lacking. However, the presence of RA autoantibodies including anti-citrullinated protein antibodies, rheumatoid factor, and anti-malondialdehyde acetaldehyde (anti-MAA) antibodies may be associated with the presence of airway disease in RA, as well as parenchymal lung diseases [16-18].

Treatment of Airway disease: Potential Therapeutics for RA-Airway Disease

Treatments in COPD are targeted to dampening airway inflammation. Inhaled corticosteroid in combination with long-acting beta-2 agonists (ICS/LABA) has been shown to reduce airway inflammation in COPD patients [19], decrease risk of exacerbations [20] and may even increase survival [21], though the latter concept remains controversial. The use of biologics in COPD has been largely disappointing (but instructive). Together, these data suggest that biologics that are effective in RA may not be efficacious in COPD and may even lead to harm in some cases. Asthma is a heterogeneous disease consisting of different molecular phenotypes that respond to overlapping, yet different, treatment approaches. Complete inhibition of T2/Th2 pathways in some individuals could lead to immune shifts towards type 1 immunity of relevance to rheumatologic disease.

COPD and asthma occur with greater than expected frequency in RA, suggesting that these entities share some overlapping disease pathways. Of note, the increased mortality in patients with co-existing RA and airway disease underscores the need for better recognition of these associations and newer treatment modalities that can address both disease components. Unfortunately, there are no clinical trials to date targeting patients with both RA and COPD/asthma. As a result, we can only extrapolate from existing trials in RA or COPD/asthma for agents such as TNF inhibitors that have been largely ineffective in the treatment of the latter airway diseases. Because these and other trials have not revealed common therapeutic targets, improved understanding of disease pathways and disease subsets/endotypes is critical in defining targetable mediators playing key pathophysiological roles in both the airway and autoimmune components of disease. Potential candidate agents include IL-6/IL-6R antagonists and JAK/STAT inhibitors. Other more theoretical therapeutic agents that might be effective in both RA and COPD/asthma include adenosine 2a receptor (A2aR) agonists as well as IL-37 (a natural competitor for IL-18 mediated inflammatory pathways). Based on the emerging paradigm that airway disease may promote citrullination and other protein post-translational modifications that lead to the breakdown of immune tolerance and systemic autoimmunity that is characteristic of RA, airway-targeted therapies may be most effective in the pre-RA period. Ultimately, however, controlled clinical trials will be required to resolve these questions and establish biologically plausible strategies for treatment of co-existing RA and airway disease.

Research Opportunities and Critical Gaps:

The workshop identified the following opportunities and gaps:

Critical Research Gaps:

• What is the true prevalence and incidence of large and small airway disease in RA?
• What subtypes of airway disease are most prevalent in RA?
• What subtypes of airway disease in RA are linked to the pathogenesis of RA?
• What is currently the most accurate way to diagnose airway disease in RA?
• Are there shared mechanisms (genetic variants, exposures, T2 inflammation, immune tolerance, citrullinated antibodies, changes in microbiome, etc.) that are associated with RA-airway disease?

Research Opportunities:

• Determining the extent and nature of airway disease in RA, particularly in early disease and before the development of pulmonary symptoms. This will likely require more extensive characterization of an RA cohort, examining a variety of metrics to understand the types of airway abnormalities are present in these cohorts and their relationship to disease activity as well as progression of both systemic and pulmonary focused disease.
• Determining the clinical impact of airway disease on choice and escalation of disease-modifying anti-RA drugs, including propensity for infection such as pneumonia, articular disease activity, patient-reported outcomes, underlying lung disease, and mortality.
• Collaborative studies to evaluate lung-related mechanisms in the early initiation and propagation of RA-related autoimmunity prior to the development of inflammatory arthritis, efforts could include leveraging current studies, as well as creating large-scale studies that provide optimal information.
• Evaluating the natural history of RA-related lung inflammation and autoimmunity from pre-RA through clinically apparent articular disease to identify key pathways that lead to the development of clinically important lung disease.
• Assessing sex differences in the immune response in the airways and how those might contribute to development of autoimmunity in RA-airway disease.
• Using animal models of combination exposures to provide mechanistic insights and the opportunity to develop targeted therapies.

Publication Plans

The meeting participants will develop a workshop report, highlighting the meeting’s main objectives and scientific opportunities identified, for publication in a peer-reviewed journal.