Progression of radiographic fibrosis in rheumatoid arthritis-associated interstitial lung disease

Background and objectives Preclinical interstitial lung disease (pILD) may represent the early stages of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). However, the characteristics, clinical outcomes, and risk factors associated with fibrosis progression in RA-ILD, including pILD and ILD, remain poorly understood. Methods Baseline data were compared between patients with RA-ILD and those with RA alone. Multivariate logistic regression and Cox regression analyses were performed to identify risk factors associated with the prevalence and imaging progression of RA-ILD, respectively. Results Among the 371 enrolled RA patients, 32.3% had RA-ILD. Multiple logistic regression analyses identified age over 60.0 years (OR 2.22), smoking (OR 2.09), diabetes mellitus (DM) (OR 3.09), mixed connective tissue disease (MCTD) (OR 2.98), serum lactate dehydrogenase (LDH) levels exceeding 250.0 U/L (OR 6.73), and positive anti-cyclic citrullinated peptide (anti-CCP) antibody (OR 2.06) as independent risk factors for RA-ILD (p< 0.05 or 0.01). Among the 98 RA-ILD patients who underwent follow-up for a median duration of 19.1 months, 51.0% demonstrated fibrotic progression on high-resolution computed tomography (HRCT). Multiple Cox regression analysis identified DM (HR 2.03), Disease Activity Score in 28 joints-Erythrocyte Sedimentation Rate (DAS28-ESR) greater than 5.1 (HR 2.21), and baseline HRCT scores exceeding 5.0 (HR 2.30) as independent risk factors for fibrosis progression in RA-ILD (p< 0.05 or 0.01). Conclusion Nearly one-third of RA patients in this cohort had prevalent pILD or ILD, and half of them demonstrated imaging progression during follow-up. DM, higher DAS28-ESR, and advanced HRCT scores were identified as independent risk factors for progressive fibrosis in RA-ILD.

Table S1 Demographics and baseline characteristics of RA-pILD and RA-ILD 8 Table S2 Chest HRCT changes during follow-up Table S3 Therapeutic regimen of patients in RA-ILD Table S4 Therapeutic regimen of progressors and nonprogressors in RA-ILD Table S5 Logistic regression analysis for risk factors of the prevalence of RA-ILD Table S6 Cox regression analysis for risk factors of the progression of RA-ILD Figure S1 HRCT manifestations of a patient with progression of radiographic fibrosis in RA-pILD Pulmonary function test Pulmonary function tests (PFTs) were conducted by certified technicians in accordance with the guidelines set by the American Thoracic Society (ATS) and European Respiratory Society (ERS).These tests included spirometry, whole-body plethysmography, and single-breath diffusing capacity for carbon monoxide measurements.The PFT data were analyzed and reported following the recommendations provided by the ATS/ERS guidelines. 1 Chest high-resolution computed tomography (HRCT) HRCT was performed using a GE Brightspeed 64-slice spiral CT scanner.The patient was positioned in a supine position with both hands raised over the head to maximize chest exposure and scapular spread.Continuous inhalation was performed during scanning, covering the lung apex to the costophrenic recess, followed by breath-holding.The scanning parameters were set as follows: voltage of 140 kV, current of 300 mA, scanning layer thickness of 5 mm, high-resolution layer thickness of 0.625 mm, spacing of 10 mm, bone algorithm reconstruction, and specific window settings for lung and mediastinal windows.The lung window had a window width of 1500 HU and a window position of 700 HU, while the mediastinal window had a window width of 400 HU and a window position of 40 HU.Two independent physicians interpreted the CT images, and any discrepancies were resolved through discussion to reach a consensus.

Description and scoring of chest HRCT
The chest HRCT images were described and scored by two blinded and experienced pulmonologists who were unaware of the clinical data.Interstitial lung disease (ILD) was categorized according to the idiopathic interstitial pneumonia (IIP) classification and 2018 IPF clinical practice guidelines, including usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), organizing pneumonia (OP), NSIP+OP, and unclassified interstitial pneumonia (uIP). 2,3Additionally, preclinical interstitial lung disease (pILD) was further divided into non-subpleural non-fibrotic, subpleural non-fibrotic, and subpleural fibrotic patterns based on the 2020 Fleischner Society Position Paper. 4 Each lung was divided into three zones by the levels of the inferior aortic arch and right inferior pulmonary vein.The degree of abnormal imaging was scored semiquantitatively based on the percentage of abnormal findings in each lung zone, using a scoring system ranging from 0 to 4 points for each zone, with a total score range of 0 to 24 points.The scoring method was consistent with previous studies, ensuring comparability. 5The interobserver agreement, as measured by weighted kappa, was 0.83.

Laboratory findings
Laboratory tests included the detection of rheumatoid factor (RF) using an ELISA method with an RF IgM detection kit, and the testing of anti-citrullinated cyclic peptide (anti-CCP) antibodies using an ELISA method with an anti-CCP IgG detection kit.

Figure S1 .
Figure S1.HRCT manifestations of a patient with progression of radiographic fibrosis in RA-pILDA 73-year-old male with a 16-year history of rheumatoid arthritis (RA) was included in this study.Upon enrollment, the patient underwent chest high-resolution computed tomography (HRCT), revealing distinct imaging findings at three different levels (A, C, E).The HRCT images demonstrated prominent bronchovascular bundles and thickened interlobular septa in both lungs.Additionally, multiple fine reticulations were observed in the subpleural region, indicating a subpleural fibrotic pattern.Following a 30-month follow-up period, the patient underwent a repeat chest HRCT (B, D, F), which showed worsening abnormalities compared to the initial assessment.Specifically, the lower lung zone exhibited an imaging pattern consistent with usual interstitial pneumonia.

Table S1 Demographics and baseline characteristics of RA-pILD and RA-ILD
a Seronegative RA represented RA patients with both negative RF and anti-CCP.bMCTD, representing systemic autoimmune diseases other than RA, included Sjögren 's syndrome (n=22), systemic lupus erythematosus (n=4), idiopathic inflammatory myopathy (n=7), and systemic sclerosis (n=2) in this study.