Rheumatoid Arthritis Extra-Articular Manifestations: Challenges of Interstitial Lung Disease

The systemic inflammation that characterizes rheumatoid arthritis (RA) is associated with a spectrum of extra-articular manifestations (EAMs) that are ultimately major predictors of increased morbidity and mortality.^1,2 Among the various EAMs, pulmonary diseases are common, reported in 60% to 80% of patients with RA and accounting for 10% to 20% of all RA-related mortality.³ A major challenge to the timely management of pulmonary-related complications is the sometimes subclinical, asymptomatic presentation that may precede the clinical manifestation of RA joint symptoms.³ Furthermore, poor functional status from RA-associated chronic inflammation can mask symptoms of pulmonary disease, further delaying prompt diagnosis and treatment. These challenges emphasize the importance of targeting the earliest phase, if possible, the pre-RA phase, to prevent comorbidities that are often poorly responsive to treatment once they develop.^1,4

Specific to RA-associated lung diseases, several have been documented along the entire length of the thoracic cavity, including interstitial lung disease (ILD), airway disease, pleural disease, rheumatoid long nodules, and pulmonary vascular nodules.^1,3 These thoracic complications can range from nonsevere (eg, subcutaneous nodules) to severe and potentially life-threatening (eg, vasculitis, pachymeningitis, and parenchymal involvement, in the form of RA-associated ILD [RA-ILD]). In addition, drug-induced lung diseases have been described following treatment with agents used as standard of care for the treatment of RA, including sulfasalazine, methotrexate, and biologic and synthetic disease-modifying antirheumatic drugs.^3,5 Since the introduction of biologics more than 2 decades ago, mortality rates specific to the RA disease have steadily declined; however, the mortality rate from RA-ILD has shown an increasing trend.³ Some observational studies have suggested a higher rate of severe EAMs with tumor necrosis factor inhibitors,⁴ including their contribution to the progression of ILD⁶; however, other studies have also suggested that these agents do not cause an increased risk for RA-ILD.⁷ In the absence of robust studies, currently the jury is out on the true effect of RA therapies on lung disease.

Among the severe EAMs, RA-ILD is common; however, the disease etiology and course are poorly understood.² It has been postulated that most patients with RA have some underlying genetic predisposition to fibrosis that may be triggered by some form of injury to the lung. In support of this hypothesis, a mouse model of RA suggests that both genetic predisposition and lung injury with inflammation are required for the development of ILD in RA.⁷ Older age, prolonged RA disease activity, decreased functional capacity, and the presence of other nonpulmonary extra-articular disease activity have been reported as risk factors for RA-ILD.^3,7 Furthermore, a strong correlation between anti-citrullinated protein antibodies and RA-ILD has been reported, which has been strongly associated with a history of smoking exposure.^3.4

The treatment of RA-ILD is nonspecific. This may reflect the several subtypes of RA-ILD recognized. The most common subtypes are the usual interstitial pneumonia pattern (UIP) and the nonspecific IP. Others include organizing pneumonia, lymphocytic interstitial pneumonia, desquamative interstitial pneumonia, and diffuse alveolar damage.³ Unlike RA that has a higher prevalence in women, a prevalence rate of RA-ILD of 4 times higher in men than women has been reported.⁴ Patients with RA-ILD and a UIP pattern appear to have a worse survival compared with patients without a UIP pattern.^3,7 Data suggest that RA-ILD with a UIP pattern may have a distinct clinical phenotype, natural history, and disease course compared with the other subtypes, potentially complicating a diagnostic and treatment approach.^7,8

The increased risk for death from RA-associated lung diseases requires effective management; outcomes, however, remain poor. Screening, diagnostic evaluation, treatment options, and management strategy remain uncertain.³ The diagnosis of RA-ILD follows a systematic approach.

“The current diagnosis starts with symptoms; these are usually shortness of breath and dry cough,” said Jon T Giles, MD, MPH, professor of medicine in the division of rheumatology at Columbia University College of Physicians & Surgeons. “Based on the findings, the rheumatologist may be prompted to check pulmonary function tests. A [computed tomography] scan of the chest may be indicated if the pulmonary function tests are abnormal.”

Dr Giles added, “The findings for RA-ILD are distinct from asthma, [chronic obstructive pulmonary disease], and cancer, so they can be distinguished, [however], there are some conditions that look a lot like RA-ILD, the most prominent of which is hypersensitivity pneumonitis.”

Differential diagnosis can be challenging.

“Sometimes you need a lung biopsy to tell these apart, and sometimes even then you may not be sure that the ILD is caused by RA; however, for the most part, the initial workup will reveal whether ILD is present or not,” concluded Dr Giles.