Mechanisms of Rheumatoid Arthritis-Associated Interstitial Lung Disease

Interstitial lung disease (ILD), a common complication of rheumatoid arthritis (RA), often leads to deteriorating health. For example, in a cohort of 167 RA-ILD patients, progressive decline occurred in 22% to 40%. RA-ILD also increases risk of death. However, the heterogeneity of the condition makes determining a prognosis challenging in specific patients.

Although several key risk factors for RA-ILD have been identified in many populations worldwide, factors that predict progression from subclinical to clinical RA-ILD are unclear. What’s more, the quality of studies supporting current management strategies is substandard; treatment depends on findings from retrospective studies and cases, not well-designed and controlled prospective trials.

In the last few years, however, much has been learned to answer the many remaining questions regarding RA-ILD. Cheilonda Johnson, MD, MHS, (pictured) of the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, recently reviewed key findings from the latest literature on RA-ILD.

According to Johnson, the main risk factors for RA-ILD are advancing age, male sex, greater RA disease activity, rheumatoid factor (RF) positivity, and elevated titers of anticitrullinated protein antibodies such as anticyclic citrullinated peptide. Cigarette smoking also appears to increase risk of RA-ILD, especially in patients with human leukocyte antigen DRB1.

A recently published retrospective study by a team from Beijing Chao-Yang Hospital in Beijing, China, supported three of the risk factors Johnson listed for RA-ILD and identified an additional risk factor. In that study of 550 RA patients, logistic regression analysis of data collected on the 237 (43%) with ILD revealed that age, smoking, RF positivity, and elevated lactate dehydrogenase closely correlated with ILD.

The Beijing study also reported the appearance of ILD relative to RA onset in their cohort. ILD occurred before RA onset in 13%, within 10 years of RA onset in 70%, and more than 10 years after RA onset in 17%.

According to Johnson, adding assessment of recently identified biomarkers of RA-ILD to predictive models could improve diagnostic sensitivity substantially early in the course of the disease. One notable biomarker is the tumor marker carbohydrate antigen 125, whose elevation was associated with greater risk of RA-ILD in an adjusted model in a study of 111 RA patients in which 28 (25%) had ILD.

Recent studies have also identified risk factors for disease progression and mortality. A retrospective study of 167 patients with RA-ILD determined that the usual interstitial pneumonia (UIP) pattern on high-resolution computed tomography (HRCT) was a risk factor for progression, as were severe disease upon diagnosis and rate of change in pulmonary function test results in the first 6 months after diagnosis.

A study of 59 RA-ILD patients found no median survival difference between those with the UIP pattern and those without it. But the UIP group had more deaths, hospital admissions, need for supplemental oxygen, and decline in lung function.

In contrast, a larger study (n = 137) found that mean survival was 3.4 years shorter in those with UIP than in those without it. Median survival in the 108 patients with UIP (44%) was 10.2 years, but in the 29 without UIP (24%), it was 13.6 years.

That larger study also found that those with UIP were more likely to die than those without it. However, after adjustment, UIP was not associated with mortality, but low forced vital capacity percentage (FVC%) or a 10% decrease in FVC% at any time during follow-up were.

CALIPER, a computer-based computed tomography analysis tool, identified pulmonary vessel volume as a better predictor of progression than results of adjusted pulmonary function testing or visual inspection. However, CALIPER must be externally validated before it can be used clinically as a prognostic tool.

Corticosteroids are the basis of RA-ILD treatment, and using these agents to treat patients with ILD related to connective tissue disease stabilizes lung function. Moreover, the infection rate associated with their use in RA-ILD is similar to the infection rate in RA patients without ILD.

In clinical studies in RA-ILD patients, rituximab (Rituxan/Biogen) had no effect on lung function, and tocilizumab (Actemra/Roche) caused acute exacerbations of RA-ILD. In contrast, a one-year study of 82 RA patients found that tumor necrosis factor inhibitors (TNFi) such as adalimumab (Humira/AbbVie), etanercept (Enbrel/Amgen), and infliximab (Remicade/Janssen) were not associated with progression or exacerbation in patients with RA-ILD or with the development of new ILD in RA patients.

The study team also found that TNFi treatment improved bronchial walls and air trapping with time.

The review article, “Recent advances in the pathogenesis, prediction, and management of rheumatoid arthritis-associated interstitial lung disease,” is being published in the May, 2017, issue of Current Opinion in Rheumatology. The Beijing report, “Retrospective study of the clinical characteristics and risk factors of rheumatoid arthritis-associated interstitial lung disease,” appears in the April, 2017, issue of Clinical Rheumatology.