Editorial: Rheumatoid Arthritis and Chronic Obstructive Pulmonary Disease: Pathogenesis and Treatment Challenges

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disorder primarily affecting the joints, leading to pain, swelling, and functional impairment. Epidemiological data indicate that RA affects approximately 0.5%–1% of the global population, with a higher prevalence in women, typically manifesting in middle age. There are numerous extraarticular manifestations (EAMs) in RA, among which lung damage, especially interstitial lung disease (ILD), deteriorate the evolution and survival of these patients [1]. The prevalence of RA-ILD was approximately 18.7%, and the risk for RA-ILD including male sex, older age, having a smoking history, pulmonary comorbidities, older age of RA onset, longer RA duration, positive RF, positive ACPA, higher ESR, moderate and high DAS28 (≥ 3.2), rheumatoid nodules, leflunomide use, and steroid use. Additionally, biological agent use was a protective factor [2].

Chronic obstructive pulmonary disease (COPD), characterized by chronic airway inflammation and progressive airflow limitation, is a debilitating respiratory condition often resulting from long-term exposure to harmful substances such as tobacco smoke and environmental pollutants. This disease leads to the gradual destruction of lung tissue, significantly impairs patients' daily activities and quality of life, and is a leading cause of morbidity and mortality worldwide. The disease's progression is typically marked by exacerbations, which are acute episodes of worsening respiratory symptoms, often triggered by infections or environmental factors. These exacerbations further contribute to impaired lung function and a decline in overall health status [3]. Comprehensive management strategies, including smoking cessation, pharmacotherapy, and pulmonary rehabilitation, are crucial in mitigating the impact of COPD on patients' lives.

Both RA and COPD have high prevalence rates and impose substantial social and medical burdens and considerable pressure on patients' quality of life and healthcare systems [4]. Compared to ILD, which gets more attention in RA patients, COPD is rarely discussed in the lung complications of RA; maybe this is because COPD is more prevalent in older men with a smoking history, and RA is more prevalent in middle-aged women without smoking. Although COPD and ILD have distinct clinical features, both diseases may coexist in a patient because they share similar risk factors, such as smoking, male sex, and old age [5].

Recently, increasing evidence suggests that RA patients are at an elevated risk of developing COPD. A nationwide retrospective cohort study reported that RA was shown to be associated with an increased risk of COPD development, augmented by seropositivity [6]. Cao et al. [6] reported the causal association of RA and COPD from a Mendelian randomization study. Kai et al. [7] also reported that a significant bidirectional association exists between RA and COPD, with five inflammatory factors mediating the RA → COPD path and CRP mediating the COPD → RA path, implicating that the disease activity may be related to the incidence of another disease. As ILD is related to RA, the association between RA and COPD may be linked to shared risk factors and pathophysiological mechanisms, such as chronic inflammation and immune system dysregulation.

Rheumatoid arthritis and COPD may share common mechanisms, such as chronic inflammation, immune dysregulation, and oxidative stress, as suggested by multiple studies. The pathogenic role of antibodies against citrullinated protein antigens (ACPAs) has been found in synovial lesions and is related to worse RA parenchymal lung disease. ACPAs are believed to originate from the mucosal surfaces of the respiratory tract and are crucial in the development of RA. The sequence of inflammation, citrullination, ACPA production, and autoimmune reactions leads to the manifestation of clinical RA and may also influence the emergence of pulmonary abnormalities.

Consequently, individuals with elevated ACPA levels might have a higher likelihood of developing COPD, even before the clinical onset of RA [8]. From Chung's study, seropositive RA patients reveal a significantly higher incidence of COPD than seronegative RA patients [9].

Similarly, the chronic airway inflammation characteristic of COPD can exacerbate systemic inflammation, potentially triggering or worsening RA symptoms. Packard et al. found that COPD patients could produce autoantibodies reactive to a broad spectrum of self-antigens. Further, the level and reactivities of these antibodies, or autoantibody profile, correlated with disease phenotype [10]. Shared genetic predispositions and environmental exposures, such as smoking, which is a known risk factor for both conditions, may also play a crucial role in this association. A phenome-wide association study found suggestive evidence of an association between the rs207488 single nucleotide polymorphism of HLA-C and increased risk of RA and type 1 diabetes and bronchiectasis in COPD patients [11]. Other COPD susceptibility genes like HHIP may increase RA risk through worsened pulmonary function, resulting in chronic lung injury, inducing local inflammatory milieu, and promoting RA-related autoimmunity [12]. Gene-smoking interactions are also described in both RA and COPD, which may explain bidirectional associations of both diseases increasing risk for each other [13].

Other possible underlying mechanisms for causal relationships between RA and COPD have involved infections or pneumonia. Changes in lung bacterial taxa and inflammatory mediators during RA and COPD have been reported with a decreased burden of Prevotella copri and overrepresentation of Pseudomonas [14, 15]. Reduced microbial diversity in the lungs and outgrowth of specific taxa were thought to be associated with IL-17-mediated immunity in RA, stimulating the production of IL-1b, IL-6, and IL-23 to promote the pathogenesis of COPD-related inflammation [14].

Among the CD4⁺ T-cell subsets involved in RA, T helper 1 (Th1) and Th17 cells have been identified as prominent contributors. Therefore, RA treatment primarily relies on immunosuppressive therapies focused on Th1 inflammation, including disease-modifying antirheumatic drugs (DMARDs), biologics including tumor necrosis factor inhibitor (TNFi), interleukin (IL)-1 inhibitor, IL-6 inhibitor, CD20 inhibitor, cytotoxic T-lymphocyte associated antigen (CTLA) 4 inhibitor, and Janus Kinase (JAK) inhibitors [16]. These medications effectively control RA inflammation and reduce joint damage, significantly improving patient outcomes.

In most COPD patients, the predominant inflammation is type 1 (T1), with neutrophils as the predominant cell. However, up to 40% of patients may have overlapping type 2 (T2) inflammation features, with increased eosinophil counts orchestrated by Th2 lymphocytes and innate lymphoid cell type 2 (ILC2) [17]. The type 1 and type 2 inflammation may overlap in many COPD patients. Based on these findings, it is reasonable that treatment for RA cannot be applied entirely to the treatment for COPD.

Different monoclonal antibodies, such as IL-1 inhibitor, IL-17A inhibitor, or TNFi, have been tested for treating COPD with disappointing results or significant adverse effects. More encouraging results were from studies with monoclonal antibodies approved for treating high T2 asthma that are being investigated in COPD patients [18]. Among DMARDs, MTX therapy in COPD patients is associated with a lower risk of severe exacerbations requiring hospitalization, especially within the first 6 months [19]. MTX is an immunosuppressive drug primarily inhibiting immune cell proliferation and DNA synthesis. Previous studies have also found that MTX exposure is negatively associated with the development of RA-ILD. Compared to never-users, those who had used MTX had a significantly lower risk of ILD and delayed ILD detection [20]. These findings suggest that MTX could be included in the management strategies for COPD patients with frequent exacerbations, providing an alternative to long-term corticosteroid therapy, which has several adverse effects and may further decrease the incidence of RA.

Several studies have indicated that ILD and COPD may share similar inflammatory mechanisms, such as chronic inflammatory responses and immune system dysregulation [5]. Therefore, treatment in RA-ILD may also improve the possible progression to COPD. The impact of RA treatments on COPD patients varies, necessitating a balanced approach to managing these patients to optimize treatment outcomes and minimize adverse effects. For example, corticosteroids, commonly used in RA management, can worsen COPD by increasing the risk of pneumonia and other respiratory infections. Understanding the specific impacts of each therapy on COPD progression is crucial for guiding clinicians in tailoring treatments to optimize overall patient health and mitigate risks.

Patients with RA must consider the elevated risk of COPD. Understanding the interrelationship between RA and COPD, their shared risk factors, and pathophysiological mechanisms is essential for better diagnosis, development of integrated treatment, and managing both diseases. Individualized treatment plans should be developed based on the severity of the disease and past medical history, balancing RA inflammation control and reducing COPD risk. Close collaboration between rheumatologists and pulmonologists is essential to ensure comprehensive patient care. Regularly monitoring lung function, infection markers, and other relevant parameters is crucial to detecting and addressing potential side effects or disease progression early. Future research should focus on elucidating the precise mechanisms linking RA and COPD and developing targeted therapies that can effectively manage both conditions without compromising patient safety.

C.-H.H. conceptualized the article, C.-H.H., L.-Y.L., and A.-P.H. wrote it, and all authors contributed to revising it and approving the final version.

The authors declare no conflicts of interest.