Association between serum tumor necrosis factor-alpha levels and rheumatoid arthritis-associated interstitial lung disease: a cross-sectional study
TL;DR
Serum TNF-α was associated with RA-ILD in females, exhibiting a nonlinear relationship with a potential inflection point, and the interaction testing did not confirm a statistically significant sex difference, and these findings are exploratory and warrant further prospective validation in larger cohorts.
Abstract
Background Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is one of the most severe extra-articular complications of rheumatoid arthritis (RA). Although tumor necrosis factor-α (TNF-α) plays a central role in RA pathogenesis, its relationship with RA-ILD remains uncertain. This study aimed to investigate the association between serum TNF-α levels and RA-ILD, with a focus on sex-stratified patterns. Methods We performed a cross-sectional study that initially included 1,191 consecutive RA inpatients at Xingtai People’s Hospital between March 2022 and December 2024. Clinical and laboratory data were extracted from electronic medical records. RA-ILD was diagnosed using high-resolution computed tomography, with subtypes classified by consensus. Multivariable logistic regression and generalized additive models were used to assess the association of TNF-α with RA-ILD. Serum TNF-α was natural log-transformed (ln) to improve linearity and reduce the influence of extreme values. Results After exclusions, 790 patients were included in the final analysis, of whom 149 (18.86%) had RA-ILD, with a higher prevalence in males than in females (30.68% vs 15.47%). In sex-stratified analyses, after adjusting for age, disease duration, rheumatoid factor, and anti-citrullinated protein antibody in both sexes, and additionally adjusting for smoking in males, serum TNF-α was associated with RA-ILD in females (highest vs lowest tertile: OR = 1.96, 95% CI: 1.10 – 3.48; P for trend < 0.01). This association followed a nonlinear pattern, with an exploratory inflection point above which elevated TNF-α showed a positive association with increased odds of RA-ILD. In males, no statistically significant association was observed across all models. However, the formal sex ×ln(TNF-α) interaction term was not statistically significant (P = 0.08). Conclusion In sex-stratified analyses, serum TNF-α was associated with RA-ILD in females, exhibiting a nonlinear relationship with a potential inflection point; no statistically significant association was observed in males. However, as the interaction testing did not confirm a statistically significant sex difference, these findings are exploratory and warrant further prospective validation in larger cohorts.