pathogenic links between RA and COPD that include smoking (increasing the risk of RA [27] and inducing the formation of ACPA [44, 150]) and occupational exposures [151]. Patients with RA and COPD have a 47% greater risk of COPD hospitalization compared to COPD patients without RA [152] and the 5-year mortality of patients with RA and COPD is double that of RA alone (41.9% vs. 20.5%) [153], similar to that found in ILD [14, 53]. In a study of mortality in women with RA over 36 years of follow-up, the majority of the deaths (57%) were from COPD [118]. Though a prospective trial of abatacept found a signi cant increase in adverse events in RA patients with COPD [154], a follow-up study utilizing US administrative databases found that biologic agents and targeted synthetic DMARDs were not associated with an increased risk of adverse respiratory events when compared to conventional synthetic DMARDs [155].

Cricoarytenoid Involvement

Cricoarytenoid involvement is common and occurs in as many as 75% of patients though many are asymptomatic [156]. Arthritis of the cricoarytenoid joints can lead to midline adduction of the vocal cords with resultant hoarseness and in some cases symptomatic inspiratory stridor.

Pleural Disease

Pleural disease is one of the most common intra-thoracic manifestations of RA with pleuritis and pleural effusion being the predominant subtypes. In post-mortem studies, pleural involvement is seen in up to 73% of patients with RA [157–159]. In a study looking at chest radiographs, pleural thickening and/or effusion was seen in 24% of men and 16% of women [160]. Pleural effusions have been associated with middle-aged men with rheumatoid nodules [161] and the presence of HLA-B8 antigen [162] and have a reported annual incidence of 1.54% in males and 0.34% in females [163]. Though the prevalence of pleural involvement is high, symptoms are less common. Pleurisy is reported in 20% of RA patients [164] and “clinical” pleural disease, including symptomatic effusions, is seen in less than 5% [161, 165, 166]. Pleural effusions in RA are exudative and sterile with low glucose (80%) and low pH 1 [167]. On cytology, they demonstrate features similar to that seen in rheumatoid nodules and synovitis, namely elongated macrophages and multinucleated giant cells alongside granulomatous debris [168]. They can rarely pre-date the onset of RA and RA-associated effusions often spontaneously resolve over time. When they are discovered, infection and malignancy need to be ruled out if appropriate.

Conclusion

RA can affect all pulmonary compartments but most commonly manifests as ILD, RA-AD, and pleural disease. RA-ILD is a prevalent and morbid condition with an increasing prevalence and a signi cant adverse impact on patients’ quality of life. Its etiology is unknown, there are no FDA approved therapies and current treatment regimens are based on retrospective and open-label studies. RA-AD is also prevalent and can be clinically silent. The predominate types of airway involvement include bronchiolitis, bronchiectasis, and COPD and all can lead to excess morbidity and early mortality when severe. Treatment of RA-AD is based on case reports and case series and should be individualized. Finally, pleural disease is common, but often has minimal clinical impact and can show spontaneous resolution.

Clinical Vignette

A 65-year-old female presents with progressive breathlessness. She has had rheumatoid arthritis for 30 years and has been on various medications since her diagnosis such as prednisone, gold, penicillamine, and methotrexate. She recently has had good joint control on infiximab for the last 4 years. Six months ago, she had the gradual onset of breathlessness that started with activity and evolved to breathlessness at rest with a dry cough. She saw her primary care provider 3 months ago and had a workup that included a normal cardiac electrocardiograph, desaturation on a cardiac exercise treadmill, and a plain chest-radiograph showing basilar-­predominate interstitial changes. A follow-up chest computed tomography showed a basilar and peripheral process consisting of reticulation and mild honeycombing without signi cant ground glass opacity in a usual interstitial pneumonia pattern. Her pulmonary physiology showed mild restriction with a total lung capacity of 78% predicted, a forced vital capacity (FVC) of 71% predicted, and a diffusing capacity for carbon monoxide (DLCO) of 63% predicted. She desaturated to 87% on a 6-min walk test. She has no other occupational or environmental causes for ILD and has no family history of ILD. In conjunction with her rheumatologist, she is changed from etanercept to rituximab every 6 months and an antibrotic is added to her regimen. Follow-up after 6 months of therapy showed gradual progression of her lung disease as evidenced by mild reductions in both her FVC and DLCO. She had no evidence of active synovitis on follow-up. Her regimen was continued and she was referred for lung transplant evaluation.

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