Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is one of the most serious extra-articular manifestations of rheumatoid arthritis (RA). “Studies show that clinically severe RA-ILD affects 3% to 15% of patients with RA and the median survival after RA-ILD diagnosis is only 5 years,” explains Jeffrey A. Sparks, MD, MMSc. Several RA-ILD risk factors have been identified in clinical research, including older age, male sex, cigarette smoking, later onset RA, and longer RA duration, among others. “Considering the devastating impact of this disease, identifying modifiable risk factors for RA-ILD is of crucial importance.”

New Research

According to Dr. Sparks, rheumatologists treat RA by lowering levels of systemic inflammation, which may affect the natural history of RA-ILD prior to clinical detection. For a study published in Arthritis & Rheumatology, Dr. Sparks and colleagues assessed if RA disease activity was associated with a subsequent risk of RA-ILD. The large secondary analysis used prospectively collected data from an RA cohort. Repeated measures of disease activity and chest CT scans were used to identify incident RA-ILD. “We hypothesized that higher levels of RA disease activity would be associated with increased risk for incident RA-ILD,” Dr. Sparks says.

For the study, annually updated Disease Activity Scores in 28 joints (DAS28) data were used to estimate hazard ratios (HRs) for RA‐ILD. These data were adjusted for known RA‐ILD risk factors, including age, sex, smoking status, RA duration, and serologic status. A diagnosis of RA‐ILD was determined after reviewing images from chest CT scans. The investigators also adjusted for use of disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids, as well as the presence of bone erosions and rheumatoid nodules.

Key Findings

Of the 1,419 participants assessed in the study, 85 incident cases of RA‐ILD were identified during an average follow-up duration of nearly 9 years per patient. “We found that higher RA disease activity levels were associated with increased risk of developing future RA-ILD,” says Dr. Sparks. “Patients with moderate or high RA disease activity had an approximately 2-fold increased risk of RA-ILD compared with those with low disease activity or in remission.”

Specifically, patients in the moderate/high disease activity group had a multivariable HR of 2.22 for RA‐ILD when compared with the remission/low disease activity group. The risk of RA‐ILD increased across disease activity categories, with HRs of 1.41 for low disease activity, 2.08 for moderate disease activity, and 3.48 for high disease activity (Table). For each unit increase in the DAS28, the risk of RA‐ILD increased by 35%. Results were similar in analyses that included follow‐up for missing DAS28 data and adjusted for use of DMARDs and glucocorticoid, as well as the presence of bone erosions or rheumatoid nodules.

“Our results imply that measures of joint inflammation may be related to subclinical pulmonary inflammation,” Dr. Sparks says. “Systemic inflammation appears to contribute to the pathogenesis of RA-ILD. Treating patients to a target of low disease activity or remission may alter the natural history of RA-ILD and could prevent or delay its onset.”

A Critical Need

According to the study, more than one-third of patients who developed RA-ILD died by the end of the follow-up period. This finding underscores the importance of gaining a better understanding of the natural history of RA-ILD prior to its manifestation. Enhanced knowledge of the disease pathogenesis could further improve efforts to develop interventions intended to delay or prevent the onset of RA-ILD or alter its course. Studies are needed to firmly establish whether RA activity affects the onset and course of RA-ILD and to better understand the role that particular DMARDs may play in its pathogenesis. In the meantime, the study results emphasize the need to decrease inflammation by treating RA signs and symptoms. These data could provide additional motivation to achieve and maintain remission or low disease activity in order to potentially reduce future risk of developing RA-ILD.