LUNG DISEASES IN RHEUMATOID ARTHRITIS – EXPERIENCES OF A TERTIARY CENTRE

KLJUČNE RIJEČI: ARTRITIS, REUMATOIDNI, PLUĆNE BOLESTI, INTERSTICIJSKEINTRODUCTION

Rheumatoid arthritis (RA) is a systemic autoimmune disease whose prevalence is slightly less than 1% in developed countries (1). The most common extra-articular manifestation of RA is involvement of the lung parenchyma and pleura, primarily interstitial lung disease (ILD), with an estimated prevalence between 1.8% and 67% (2). In most patients, lung disease occurs within the period of nine years since RA diagnosis, although respiratory symptoms may precede the occurrence of joint disease in 2.3% to 10% of patients (3, 4). Pleuropulmonary diseases in patients with RA include parenchymal lung diseases such as ILD and nodular lung disease, followed by airway diseases such as bronchiolitis, bronchiectasis, and chronic small airways obstruction, and pleural diseases such as pleurisy, pleural effusion, and pleural thickening. Chronic infections of the respiratory system can also be the cause of lung disease, particularly bronchiectasis. The impact of immunomodulators that increase the risk of developing infections, but can have a direct toxic effect on the lung parenchyma, is also important (4, 5). Lung diseases present with symptoms such as exertion intolerance, chest pains and cough, but they can also be asymptomatic. Since pleuropulmonary diseases are responsible for 10–20% of mortality cases in patients with RA, clinical, functional and radiological monitoring is necessary in order to identify patients with progressive lung disease in the earliest possible stage (6, 7). Factors that increase mortality include old age, male gender, history of smoking, low values of pulmonary function tests, pattern of usual interstitial pneumonia (UIP) shown on high-resolution computed tomography (HRCT), presence of emphysema, and acute exacerbation of ILD (8). Methotrexate (MTX) treatment is recommended as a first-line treatment for RA, as it effectively reduces disease activity, morbidity, mortality, and the occurrence of RA-related ILD (RA-ILD) (9, 10).

The aim of our study was to present the clinical features of patients with pleuropulmonary manifestations as part of RA, in a sample of patients treated with biologics or targeted synthetic disease-modifying antirheumatic drugs (DMARDs).

SUBJECTS AND METHODS

This retrospective observational study was conducted during the course of 2022 on patients with RA, who were treated with biologics and targeted synthetic DMARDs, at the Division of Rheumatology, Allergy and Clinical Immunology of the University Hospital Centre Split. Data taken from the medical records archived at the outpatient clinic, inpatient unit and day-care hospital of the Division were used in the study. Moreover, the study included patients older than 18 years of age who met the 2010 EULAR/ACR classification criteria for RA, which was the inclusion criterion for the participation in the study. The exclusion criteria included the presence of another inflammatory rheumatic disease other than RA and known lung disease, the occurrence of which is not dependent on the presence of RA. Lung involvement was based on the findings of the high-resolution CT (HRCT) of the chest. Age and gender of the subjects, presence of rheumatoid factor (RF) and antibodies to anti-cyclic citrullinated peptide (anti-CCP), disease duration, history of smoking, pleuropulmonary manifestations and therapy were analysed.

Methods of descriptive statistics were used in the analysis of the results.

RESULTS

A total of 188 patients with RA who were treated with biologics and targeted synthetic DMARDs were included in the study. There were 18 (9.6%) patients with pleuropulmonary manifestations of RA, whose average age was 66.5 (range: 48–85), and 13 of these patients were women (72.2%). 6 patients were smokers (33.3%) and four of them were women (66.6%). 12 patients were diagnosed with seropositive RA (66.6%), and four of these patients were smokers (33.3%). According to disease duration, we divided the subjects into three groups (<10 years, 10–20 years, >20 years), with 6 patients in each group (33.3%). Patients with seropositive RA and associated pleuropulmonary manifestations had the shortest disease duration (<10 years), and there were five of them (83.3%), with four of them being smokers (66.6%). Nodular lung disease was found in 12 patients (66.6%), and 9 of these patients had seropositive RA (75%). Bronchiectasis was found in 8 patients (44.4%) and pleural thickening in three patients (16,6%). ILD was radiologically diagnosed in 10 patients (55.5%), and 7 of them had seropositive RA (70%). The pattern of usual interstitial pneumonia (UIP) was present in 8 patients (80%), while the pattern of non-specific interstitial pneumonia (NSIP) was found in two patients (20%) (Table 1). 8 patients (44.4%) were treated with rituximab, while four patients were treated with TNF-α and IL-6 inhibitors (22.2% in both cases), and two patients were treated with Janus kinase (JAK) inhibitors (11.1%). 10 patients (55.5%) were treated with concomitant therapy with methotrexate (MTX).

DISCUSSION

Pleuropulmonary diseases occur in 30–40% of patients with RA and are the second main cause of mortality, right after cardiovascular diseases (11). There are several factors associated with the development of lung disease in RA. It has been confirmed that lung disorders are associated with the male gender, seropositive RA, smoking and mucin-5B (MUC-5B) gene mutation. The MUC-5B polymorphism leads to inefficient removal of inhaled particles and pathogens in the respiratory mucosa, thus increasing the risk of RA-ILD development (3, 4, 12, 13). The most common patterns found on chest HRCT in patients with RA-ILD are usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), lymphocytic interstitial pneumonia (LIP), organizing pneumonia (OP), acute interstitial pneumonia (AIP), and desquamative interstitial pneumonia (DIP) (6).

In our study, the proportion of patients with pleuropulmonary disorders in RA was 9.6%, with an average age of 66.5, which is in accordance with data from the literature. The subjects were predominantly female (72.2%), while in some studies, male predominance was established (3–5, 7).

Smoking was present in 6 patients (33.3%), which is slightly less than in the researched literature, where smokers comprised more than 50% of subjects, especially with RA-ILD pattern found on chest HRCT (3, 4). In our study, the majority of smokers were female (66.6%), while in the multicentre study conducted by Kelly et al., a larger proportion of smokers were male (3). The RA-ILD pattern found on chest HRCT was present in all subjects who used tobacco products, in contrast to the aforementioned study conducted by Kelly and colleagues, which did not establish that smoking is a risk factor for the development of RA-ILD in women (3). The mentioned deviation may be a consequence of the smaller number of subjects in our study. It is believed that smoking induces the formation of enzymes that promote the modification of peptides in the lung parenchyma, that is, the conversion of arginine into citrulline, which binds to human leukocyte antigen II (HLA II) on antigen-presenting cells (the so-called “common epitope” HLA-DRB1). This type of a more immunogenic, citrullinated peptide is presented to T lymphocytes and leads to the formation of anti-CCP antibodies, activation of cytokines and growth factors (vascular endothelial growth factor — VEGF, platelet-derived growth factor — PDGF) that contribute to fibroblast proliferation (5, 11, 13, 14).

Patients with RA have elevated values of circulating RF and anti-CCP antibodies, which can be present in the serum several years before the clinical onset of the disease. Both antibodies may be associated with the development of lung disease in RA, especially anti-CCP which is primarily associated with the development of RA-ILD (5, 13). In our study, 12 patients were diagnosed with seropositive RA (66.6%), which is in accordance with data from the literature (3, 4). However, we found that in the case of 5 patients (83.3%) with seropositive RA there was a significantly shorter period until the diagnosis of lung disease (<10 years) and that four of them were smokers (66.6%). This data shows that seropositivity and smoking lead to an earlier onset of pulmonary manifestations in patients with RA.

In our study, the most common disease of the lung parenchyma was nodular lung disease, which was found in 12 patients (66.6%), which is slightly more than in the available literature, where the prevalence was between 1% and 32% (4, 15–17). This deviation in our results may be related to a smaller number of subjects in our study. The second most common disease of the lung parenchyma was RA-ILD, which was found in 10 subjects (55.5%), and 7 of them (70%) had seropositive RA. According to the available literature, the probability that patients with RA will develop ILD is nine times higher than in the general population, and the prevalence of RA-ILD in other studies was as high as 67% (2, 4–6, 15–17). In our study, the most common RA-ILD pattern found on chest HRCT was the UIP pattern (80%), which is slightly higher than in the available studies, which could be a consequence of late diagnosis of pulmonary manifestations (4, 15, 17). Bronchiectasis was the most common manifestation of respiratory diseases and was present in 8 patients (44.4%), four of whom were smokers (50%). In other studies, the prevalence of bronchiectasis was somewhat lower and was up to 30% (5, 15–17). More frequent bronchiectasis are probably caused by smoking and chronic inflammation. The most common manifestation of pleural involvement was pleural thickening, which was present in 3 subjects (16.6%). All subjects with involvement of the pleura also had nodular lung disease. In other studies, a slightly lower frequency of involvement of the pleura was demonstrated, approximately between 3 and 5%, and this primarily includes pleural effusions (5, 15–17). It should be noted that it was difficult to make an estimation of prevalence due to the great heterogeneity among studies and the imaging methods used for the purpose of making a diagnosis. Given that malignant diseases can present with symptoms that are similar to those of nodular lung disease, the importance of multidisciplinary collaboration with pulmonologists should be highlighted.

In patients with RA, it is important to immediately evaluate the presence of pulmonary manifestations, the severity of the disease, and identify patients with progressive disease through further monitoring. Factors suggestive of progressive disease are worsening symptoms, low values of pulmonary function tests (PFTs), and/or radiological progression. It is recommended to perform pulmonary function tests in all patients who are newly diagnosed with RA. In asymptomatic patients, pulmonary function tests should be performed once a year, and in the case of RA-ILD confirmed through HRCT, they should be repeated every 6 months (18). Disease severity and progression are two major factors to consider when deciding on immunomodulatory treatment in patients with RA-ILD. Among other things, it is necessary to consider other factors, such as age and comorbidities, as well as the patient’s wishes when it comes to making decisions regarding treatment (15, 18). In our study, 10 patients received concomitant treatment with methotrexate (55.5%). In their study, Juge et al also reported similar data, which included between 55.3% and 66.7% of subjects treated with methotrexate, and they proved a reduced incidence of RA-ILD in these patients (10). In addition to conventional therapy, 8 subjects in our study were treated with rituximab (44.4%), four of them were treated with TNF-α and IL-6 inhibitors (22.2% in both cases) and two subjects were treated with JAK inhibitors (11.1%). In a UK cohort study, rituximab showed a satisfactory safety profile in patients with RA-ILD, with stable or improved lung function over a 10-year follow-up period, which is similar to the results of a smaller study conducted by Fui et al (19, 20). A study conducted by Detorakis et al. which included 82 subjects with RA, showed an effective and favourable safety profile of TNF-α inhibitors in these patients. Therefore, no new ILDs or exacerbations of already existing ILDs were found in the studied population (21). Treatment with tocilizumab has also shown a potential role in the stabilization of lung disease (6, 22). In a retrospective cohort study conducted by Baker et al. RA patients treated with a JAK inhibitor had the lowest incidence of ILD compared to patients treated with biologics (23). Therefore, JAK inhibitors are introduced as the drug of choice in patients with ILD as part of RA.

CONCLUSION

In our sample of patients with RA who were treated with biologics or targeted synthetic DMARDs, a higher prevalence of nodular and interstitial lung diseases was found in seropositive patients than in seronegative patients. Therefore, it is necessary to conduct more intensive clinical, functional and radiological monitoring of patients with seropositive RA, especially smokers, in order to prevent the progression of lung disease. The most common radiological pattern of RA-ILD was usual interstitial pneumonia (UIP).

Acknowledgments: The authors report no acknowledgments.

Funding: For this work authors did not receive any funding.

Conflict of interest statement: The authors declare no conflict of interest.

REFERENCES / LITERATURA

<jrn>1. Hunter TM, Boytsov NN, Zhang X, Schroeder K, Michaud K, Araujo AB. Prevalence of rheumatoid arthritis in the United States adult population in healthcare claims databases, 2004–2014. Rheumatol Int. 2017;37(9):1551–7.PubMedhttps://doi.org/10.1007/s00296-017-3726-1</jrn>

<jrn>2. Fazeli MS, Khaychuk V, Wittstock K, Han X, Crocket G, Lin MJ, et al. Rheumatoid arthritis-associated interstitial lung disease: epidemiology, risk/prognostic factors, and treatment landscape. Clin Exp Rheumatol. 2021;39(5):1108–18.PubMedhttps://doi.org/10.55563/clinexprheumatol/h9tc57</jrn>

<jrn>3. Kelly CA, Saravanan V, Nisar M, Arthanari S, Woodhead FA, Price-Forbes AN, et al. Rheumatoid arthritis-related interstitial lung disease: associations, prognostic factors and physiological and radiological characteristics – a large multicentre UK study. Rheumatology. 2014;53:1676–82.PubMedhttps://doi.org/10.1093/rheumatology/keu165</jrn>

<jrn>4. Duarte AC, Porter JC, Leandro MJ. The lung in a cohort of rheumatoid arthritis patients-an overview of different types of involvement and treatment. Rheumatology (Oxford). 2019;58(11):2031–8.PubMedhttps://doi.org/10.1093/rheumatology/kez177</jrn>

<jrn>5. Shaw M, Collins BF, Ho LA, Raghu G. Rheumatoid arthritis-associated lung disease. Eur Respir Rev. 2015;24(135):1–16.PubMedhttps://doi.org/10.1183/09059180.00008014</jrn>

<jrn>6. Cassone G, Manfredi A, Vacchi C, Luppi F, Coppi F, Salvarani C, et al. Treatment of rheumatoid arthritis-associated interstitial lung disease: lights and shadows. J Clin Med. 2020;9(4):1082.PubMedhttps://doi.org/10.3390/jcm9041082</jrn>

<jrn>7. Hyldgaard C, Hilberg O, Pedersen AB, Ulrichsen SP, Løkke A, Bendstrup E, et al. A population-based cohort study of rheumatoid arthritis-associated interstitial lung disease: comorbidity and mortality. Ann Rheum Dis. 2017;76(10):1700–6.PubMedhttps://doi.org/10.1136/annrheumdis-2017-211138</jrn>

<jrn>8. Qiu M, Jiang J, Nian X, Wang Y, Yu P, Song J, et al. Factors associated with mortality in rheumatoid arthritis-associated interstitial lung disease: a systematic review and meta-analysis. Respir Res. 2021;22(1):264.PubMedhttps://doi.org/10.1186/s12931-021-01856-z</jrn>

<jrn>9. Smolen JS, Landewé RBM, Bergstra SA, Kerschbaumer A, Sepriano A, Aletaha D, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Ann Rheum Dis. 2023;82(1):3–18.PubMedhttps://doi.org/10.1136/ard-2022-223356</jrn>

<jrn>10. Juge PA, Lee JS, Lau J, Kawano-Dourado L, Serrano JR, Sebastiani M, et al. Methotrexate and rheumatoid arthritis associated interstitial lung disease. Eur Respir J. 2021;57(2):2000337.PubMedhttps://doi.org/10.1183/13993003.00337-2020</jrn>

<jrn>11. Figus FA, Piga M, Azzolin I, McConnell R, Iagnocco A. Rheumatoid arthritis: extra-articular manifestations and comorbidities. Autoimmun Rev. 2021;20(4):102776.PubMedhttps://doi.org/10.1016/j.autrev.2021.102776</jrn>

Table 1 Pulmonary diseases in patients with rheumatoid arthritis

Legend / Legenda: RF – Rheumatoid factor / reumatoidni faktor, anti-CCP – Anti-Cyclic Citrullinated Peptide Antibody / antitijela na ciklički citrulirani peptid, ILD/IBP – interstitial lung disease / intersticijska bolest pluća