Validation of a Genetic Risk Score Combined with Clinical Variables for Predicting Pulmonary Fibrosis in early Rheumatoid Arthritis

Objectives Pulmonary fibrosis (PF) is a severe extra‐articular manifestation of rheumatoid arthritis (RA). The study aimed to externally validate a genetic risk score (GRS) and a combined risk score for predicting the risk of RA‐associated PF in an independent cohort of early‐RA patients. Methods This study utilized an inception cohort of 1118 patients diagnosed with RA from northern Sweden between 1996 and 2016. Clinical data were systematically collected, and genotyping was performed for 12 single‐nucleotide polymorphisms (SNPs) associated with idiopathic pulmonary fibrosis. Statistical analyses, including logistic regression and area under the curve (AUC) assessments, were conducted to evaluate the performance of the GRS and in combination with clinical data as combined risk score in predicting RA‐PF development. Results Of the 1115 patients with complete data, 60 (5.6%) were diagnosed with PF. PF was significantly associated with age, rheumatoid factor positivity, disease activity, and MUC5B (rs35705950) and FAM13A (rs2609255) SNPs. The GRS demonstrated a significant association with RA‐PF (odds ratio 2.6, (95%CI 1.6, 4.5), while the combined risk score exhibited superior performance (AUC 0.75, p<0.001) compared to the GRS alone (AUC 0.62). The combined risk score outperformed the GRS in discriminating RA‐PF, indicating its potential utility in clinical practice. Conclusion This study provides external validation of the VARA‐ILD‐GRS and VARA‐ILD combined risk score in an RA cohort, demonstrating their generalizability and effectiveness in identifying high‐risk individuals for RA‐ILD. The findings support the integration of genetic and clinical data in risk stratification models, which could significantly improve screening strategies for RA patients at risk of developing PF. image