Rheumatoid arthritis is a systemic inflammatory disorder that most commonly affects the joints, causing progressive destruction of the cartilage and the bone, which reduces mobility and can lead to severe functional disabilities. Apart from the musculoskeletal disease, one of the main manifestations driving its mortality is interstitial lung disease (ILD) widely known to be associated with a worse outcome in this context (1).

Patients suffering from RA typically have circulating antibodies, the most common being rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP). Antibodies onset may precede the disease onset and may be associated with the development of RA-associated lung disease. Physiopathologically, there is growing evidence that RA begins in the lung with active citrullination of vimentin peptides induced by tobacco exposure (2, 3). Similarly, epidemiological data showed that in a global RA population, most of the patients were presenting a tobacco abuse history (former smokers or ex-smokers) (4).

Out of this context, chronic smoking abuse is widely recognized to induce chronic obstructive pulmonary disease (COPD) and emphysema. COPD is an obstructive lung disease (OLD) where airflow limitation is not fully reversible (5). Functional definition is based on spirometry and a post-bronchodilator FEV1/FVC ratio (Tiffeneau index) of less than 70%, which is the usually recommended cut-off (5). The origin of airflow obstruction is thought to be related to persistent bronchial inflammation due to noxious particles and gas.

The most frequently incriminated etiologic factor is tobacco smoking and environmental exposure. In opposition, RA is frequently associated with ILD and is clinically significant in up to 10% of the global RA population which leads to a restrictive syndrome defined as a reduced total lung capacity (TLC) (6–10). Some patients can experience an association of those two conditions that can modify the overall morbi-mortality of those patients (1, 6–8, 10). According to different studies, the percentages of RA patients with COPD vary from 3 to 10% (10), patients with bronchiectasis, from 2 to 58% (11, 12), and patients with ILD (either nonspecific interstitial pneumonia (NSIP) or usual interstitial pneumonia (UIP)) from 6 to 56% (9, 12).

Therefore, the evaluation of OLD associated with RA is a key question to determine its impact on patient mortality. It is important to note that patients suffering from RA can underestimate respiratory symptoms due to a significant reduction in their mobility induced by arthritis and inflammatory symptoms.

This descriptive and explorative study aimed to describe RA patients exhibiting OLD (O-RA) phenotype and their functional characteristics compared to those without obstruction.

The current study provides a comprehensive analysis of a cohort of patients suffering from RA retrospectively analyzed to better qualify the specific subgroup of those suffering from obstructive lung disease (O-RA). We found that obstruction is an independent risk factor for increased mortality. Knowing that lung disease is recognized as one of the major comorbidities in RA, and even if smoking abuse is widely known to be associated with an increased risk of RA, we cannot exclude that COPD can act as an isolated factor contributing to RA-associated morbimortality (8, 15, 16) through neutrophilic inflammation associated with this condition. Whereas more than 70% of our O-RA population had a significant smoking history, RA can probably also independently lead to obstruction through autonomous bronchiolar inflammation.

In our study, approximately two-thirds of the O-RA population could be described as suffering from COPD. We identified that in a cohort of 309 RA patients that benefited from PFT during their clinical follow-up, 33% of them were suffering from OLD. Those O-RA patients were displaying a higher TLC with hyperinflation based on RV evaluation associated with per definition a reduced FEV1/FVC ratio (17). DLCO was also significantly lower in the O-RA cohort compared to the other patients. The O-RA patients were also presenting a reduced specific conductance (sGaw) with increased FRC. Focusing on the mortality, O-RA patients presenting an overall increased mortality with a median survival of 11.8 years (HR 2.50, 95% CI 1.52–4.10) confirmed by the multivariate analysis (HR 2.20; 95% CI 1.23–3.92).

Several studies have identified that COPD was an independent risk factor for developing RA. This observation suggests that mucosal airway inflammation may increase the risk of RA (18). Of interest, a case-control study previously showed that both RA and COPD were exhibiting similar morbidities (18, 19). In a meta-analysis evaluating previous studies, it has been described that RA patients have a significantly increased risk of suffering from COPD with a pooled RR of 1.82 (95% CI = 1.55 to 2.10, p < 0.001) (10). This meta-analysis showed a prevalence of COPD in RA of 6.2% (95% CI = 4.1 to 8.3%). Of note, few have compared the mortality of these patients longitudinally. Our prevalence is probably higher than in other studies due to the retrospective aspect of our study, considering that PFT has probably been performed in symptomatic patients only.

We have recently shown in a 1,500 RA patients cohort that patients with ILD had a higher mortality risk compared to non-ILD RA patients (9). This study confirms that ILD is an independent predictor of mortality also for patients with O-RA.

The association of RA with COPD may have affected the severity of the disease. Indeed, COPD causes high mortality and may play a decisive role in all patients with various chronic diseases, including RA. Currently, we are prospectively evaluating whether COPD may be an interfering factor in the control of RA in a systematic manner.

Interestingly, we identified that patients with O-RA were exhibiting increased levels of CRP. As it was previously described in other studies, increased CRP and fibrinogen levels are known to be associated with increased overall mortality in COPD (20, 21) as well as with the risk of cardiovascular events (22). There is evidence that the inflammatory process in COPD is relevant to the development of cardiovascular disease and lung cancer (23). Therefore, we cannot avoid that common physiopathological processes may be shared by both COPD and O-RA patients.

Whereas COPD is known to be the major cause of OLD, we cannot certify that in our cohort none of them was suffering from obliterans bronchiolitis (also previously referred to as constrictive bronchiolitis), which is clinically known to be more severe and often quickly fatal in RA.

The retrospective aspect of this study must be disclosed as a significant bias. Indeed, patients who have undergone PFT are thought to be more symptomatic than others or are suspected of suffering from an OLD. Therefore, the prevalence of O-RA might have been overestimated. We cannot avoid that some of them can also experience bronchiolitis associated with RA (15). This can overestimate the proportion of O-RA patients in a RA cohort. This bias was mitigated in our study as the non-O-RA cohort was similarly recruited.

Surprisingly, in our O-RA cohort, we found that only 41.4% of the population was treated with bronchodilators, which are the cornerstone of COPD treatment. Thus, COPD patients in this RA cohort were under-treated. However, the majority of O-RA patients aerosol-treated would have benefited in our study from those therapies based on the GOLD recommendation. COPD and RA have similar complications over time. Indeed, it appears that these two situations lead to progressive musculoskeletal degradation linked to a significant deterioration in the quality of life and a functional decline. In this context, both drug management and musculoskeletal rehabilitation remain imperative to minimize long-term complications.

One other limitation of this study out of its retrospective aspect is the lack of information concerning the occurrence of incidental respiratory infection favored by immunosuppressive therapies. COPD patients are at higher risk to develop lower respiratory tract infections. In this specific population, adding bronchodilator therapy is a key factor to reduce acute exacerbations. The multivariate analysis did not include immunosuppressive status since patients had benefited from multiple specific therapies that can modify the interpretability of those results. Moreover, we did not have information on the cardiovascular status of the patients, which is known to be also associated with an increased risk of mortality. We were not able to retrieve from the medical records frequent comorbidities such as diabetes, renal or hepatic insufficiency, and arterial hypertension, because this study was retrospective, and we did not have a reliable and dedicated evaluation of these parameters.

Many patients were referred to our center, which is a tertiary clinical center where the patients did not benefit from other examinations than rheumatologic ones, during which these points were not systematically identified as present or absent.

In conclusion, patients with combined obstructive lung disease and rheumatoid arthritis exhibit a characteristic functional profile with reduced FEV-1, small airway involvement, reduced sGaw, hyperinflation, and lower carbon monoxide diffusing capacity of the lung. Our study identified that patients with O-RA were at higher risk of death compared to other RA patients. OLD in RA seems to be an independent risk factor of mortality based on our data potentially associated with an underlying inflammatory process similar to what is seen in COPD.

Therefore, patients with RA have to be considered for specific and dedicated pulmonary evaluation to treat both ILD and OLD. Spirometry is a key indicator of RA-associated lung disease that can modify a patient’s outcome. Further prospective longitudinal studies will have to determine its implication in patients’ management and follow-up and particularly the need for an early diagnosis to propose appropriate bronchodilator therapy.

The datasets generated and/or analyzed during the current study are not publicly available because these data are considered sensitive but are available from the corresponding author upon reasonable request.

The studies involving human participants were reviewed and approved by Ethics Committee of the University Hospital of Liège (Belgian Number: B707201422832; ref.: 2022/52). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

JG, MM, and RL conceived the study. JG, ME, and LS developed the study methodology. MH and MT collected data and validated the data. AD, A-NF, FG, PC, CR, OM, LG, and OG acquired data. JG, M-SN, PM, and J-LC analyzed the data. MH, ME, and LS made the statistical analysis. JG, MH, ME, LS, and MW wrote the manuscript. MM and RL coordinated the research activity. All authors contributed to the article and approved the submitted version.

JG reports personal fees for the advisory board, work, and lectures from Boehringer Ingelheim, Janssens, GSK, Roche, AstraZeneca, and Chiesi, non-financial support for meeting attendance from AstraZeneca, Chiesi, Roche, Boehringer Ingelheim, and Janssens. He is in the permanent SAB of Radiomics (Oncoradiomics SA) for the SALMON trial without any specific consultancy fee for this work. He is a co-inventor of one issued patent on radiomics licensed to Radiomics (Oncoradiomics SA).

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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