Treatment Outcomes for Rheumatoid Arthritis-Associated Interstitial Lung Disease: A Real-World, Multisite Study of the Impact of Immunosuppression on Pulmonary Function Trajectory

Abstract

Background: Rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) is common in patients with RA and leads to significant morbidity and mortality. No randomized, placebo-controlled data are available that support the role of immunosuppression to treat RA-associated ILD, despite being widely used in clinical practice.

Research question: How does immunosuppression impact pulmonary function trajectory in a multisite retrospective cohort of patients with RA-associated ILD?

Study design and methods: Patients with RA who started treatment for ILD with mycophenolate, azathioprine, or rituximab were identified retrospectively from five ILD centers. Change in lung function before and after treatment was analyzed using a linear spline mixed-effect model with random intercept. Prespecified secondary analyses examined the impact of radiologic pattern of ILD (ie, usual interstitial pneumonia [UIP] vs non-UIP) on treatment trajectory.

Results: Two hundred twelve patients were included in the analysis: 92 patients (43.4%) were treated with azathioprine, 77 patients (36.3%) were treated with mycophenolate mofetil, and 43 patients (20.3%) were treated with rituximab. In the combined analysis of all three agents, an improvement in FVC % predicted was found after 12 months of treatment compared with the potential 12-month response without treatment (+3.90%; P ≤ .001; 95% CI, 1.95-5.84). Diffusing capacity of the lungs for carbon monoxide (Dlco) % predicted also improved at 12 months (+4.53%; P ≤ .001; 95% CI, 2.12-6.94). Neither the UIP pattern of ILD nor choice of immunosuppressive agent significantly impacted the pulmonary function trajectory on immunosuppression.

Interpretation: Immunosuppression was associated with an improved trajectory in FVC and Dlco compared with the pretreatment pulmonary function trajectory. Prospective, randomized trials are required to validate these findings.

Keywords: azathioprine; interstitial lung disease; mycophenolate; rheumatoid arthritis; rituximab.

Figure 1

Flow diagram showing cohort formation. AZA = azathioprine; ILD = interstitial lung disease; MMF = mycophenolate mofetil; RTX = rituximab; PFT = pulmonary function test; RA = rheumatoid arthritis.

Figure 2

A, Line graph showing impact of immunosuppression on predicted trajectory of FVC % predicted. The pretreatment trend in FVC is shown from time –24 months to time 0, when RA-associated ILD-specific treatment was initiated. The pretreatment trend (blue dotted line) is projected forward from time 0 to +24 months and compared with the observed FVC trend after treatment initiation. After 12 months of treatment, significant increase in FVC % predicted was achieved compared with the projected trend without treatment (+3.90; P < .001; 95% CI, 1.95-5.84). Gray shading indicates 95% CIs. B, Line graph showing impact of immunosuppression on Dlco. A significant increase in Dlco % predicted after 12 months of treatment was found compared with the projected trend without treatment (+4.53%; P ≤ .001; 95% CI, 2.12-6.94). Dlco = diffusing capacity of the lungs for carbon monoxide.

Figure 3

A, Line graph showing the trajectory of FVC % predicted response before and after immunosuppression treatment (azathioprine, mycophenolate mofetil, or rituximab) for patients with RA without a definite or probable UIP pattern on chest imaging. Compared with the potential response without treatment, the change after 12 months of treatment was +3.36% (P = .012; 95% CI, 0.74-5.98). B, Line graph showing the FVC response for patients with RA with UIP pattern (+4.74%; P = .003; 95% CI, 1.64-7.83). In the overall model, the presence of definite or probable UIP did not significantly impact treatment response at 12 months for FVC % predicted based on the interaction analysis (P = .506). C, Line graph showing the Dlco response for patients with RA without UIP pattern (4.29%; P = .009; 95% CI, 1.08-7.50). D, Line graph showing the Dlco response for patients with RA with UIP pattern (4.68%; P = .014; 95% CI, 0.96-8.40). In the overall model, the presence of definite or probable UIP did not significantly impact treatment response at 12 months for Dlco % predicted based on the interaction analysis (P = .9). Dlco = diffusing capacity of the lungs for carbon monoxide; ILD = interstitial lung disease; RA = rheumatoid arthritis; UIP = interstitial pneumonia.