Impact of Janus kinase inhibitors and methotrexate on interstitial lung disease in rheumatoid arthritis patients

Abstract

Objectives: Little is known about how various treatments impact the progression of interstitial lung disease (ILD) in rheumatoid arthritis (RA) patients. Here, we compared ILD progression in RA patients treated with Janus kinase inhibitors (JAKi) or biological disease-modifying anti-rheumatic drugs (bDMARDs). In vitro experiments were also performed to evaluate the potential effects of the drugs on epithelial-mesenchymal transition (EMT), a key event in pulmonary fibrosis.

Methods: This retrospective study included 93 RA-ILD patients who initiated treatment with JAKi, tumour necrosis factor inhibitors (TNFi), or abatacept between 2017 and 2020. Worsening ILD was quantified by changes in chest computed tomography (CT) scans between baseline and follow-up (mean 14 months, range 6-51 months). Response to treatment was evaluated using Disease Activity Score-28 with erythrocyte sedimentation rate (DAS28-ESR). Expression of the EMT marker N-cadherin in A549 lung cells was assessed by western blotting.

Results and discussion: Worsening ILD was detected in 19.4% (7/36), 16.7% (5/30), and 22.2% (6/27) of patients treated with JAKi, abatacept, and TNFi, respectively. Multivariate analysis identified female gender (P=0.043) and >10% fibrotic lesions (P=0.015) as significant predictors of worsening ILD. DAS28-ESR-based non-responder status was also significantly associated with worsening ILD (P=0.0085). In vitro, combination treatment with methotrexate and baricitinib significantly impeded EMT progression. Worsening ILD was associated with more extensive fibrotic lesions at baseline and female gender in RA patients treated with JAKi or bDMARDs. JAKi and methotrexate co-treatment may prove beneficial in modifying key events underlying the pathogenesis of RA-ILD.

Keywords: JAK inhibitors; RA-ILD; epithelial-mesenchymal transition; interstitial lung disease; methotrexate; rheumatoid arthritis.

Figure 1

Selection of rheumatoid arthritis patients with interstitial lung disease for this study. Flowchart of the selection process. The initial pool comprised total 468 patients with rheumatoid arthritis (RA) who started treatment with JAK inhibitors (JAKi), T cell co-stimulation inhibitor (CTLA4-Ig), or TNF inhibitors (TNFi) between 2017 and 2020. Patients were excluded if (i) treatment duration was <6 months, (ii) chest high-resolution computed tomography (HRCT) images were unavailable at either baseline or follow-up, (iii) interstitial lung disease was not noted on baseline HRCT images, (iv) bronchiolitis or emphysema was the main lesion, and (v) organizing pneumonia (OP) pattern was diagnosed.

Figure 2

Comparison of inflammatory and fibrotic lesion changes between good/moderate responders and non-responders. Change from baseline to follow-up in the good/moderate responder group (n=58) and non-responder group (n=21) based on EULAR response criteria and DAS28-ESR scores. Data are presented as the mean and standard deviation; circles represent individual patients. ** P <0.01.

Figure 3

Cumulative probability plots of change from baseline in CT scores. Change from baseline to follow-up (ΔCT score) for (A) all patients and (B, C) patients with pulmonary fibrosis lesions in ≤10% of the total lung field who were treated with (B) or without (C) concomitant methotrexate (MTX). Circles represent individual patients.

Figure 4

Effects of MTX and baricitinib treatment on IL-6-induced N-cadherin expression in A549 cells. (A–C) Western blot analysis (left panels) and relative quantification (right panels) of N-cadherin expression in A549 cells pre-treated with various concentrations of methotrexate (MTX) for 48 h (A), baricitinib (Bari) for 3 h (B), or 0.2 μM Bari and/or 0.3 μM MTX for 48 h and 3 h, respectively (C) and then stimulated with 50 ng/mL IL-6 for 24 h Data are expressed as the mean of duplicates (a and b) or the mean ± standard error of quadruplicates (C). *P<0.001 compared to the control group, †P<0.01 compared to the IL-6 group, and §P<0.05 compared to the IL-6+Bari group.