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Genetic Risk Score Improves Prediction of Lung Disease in Rheumatoid Arthritis Patients
A new combined risk score incorporating genetic factors offers a more precise way to identify rheumatoid arthritis (RA) patients at high risk of developing pulmonary fibrosis (PF), potentially leading to earlier screening and intervention. Published online November 14, 2025, in Arthritis Care & Research, the findings validate a tool developed by Veterans Affairs researchers and suggest genetic analysis shoudl play a larger role in assessing risk for those with RA.
Approximately one in ten individuals with RA will experience RA-associated interstitial lung disease (RA-ILD), a severe complication affecting the lungs. However, pinpointing which patients will develop this condition has proven challenging. “Despite the identification of several clinical risk factors…there remains a lack of standardized tools for risk stratification in RA-ILD,” researchers wrote.
This gap prompted examination into genetic predispositions. Last year, a team developed a clinical and genetic risk score-the VARA RA-ILD genetic risk score (GRS)-using data from the Veterans Affairs Rheumatoid Arthritis (VARA) registry. This initial score demonstrated superior performance compared to relying solely on clinical factors. The recent study aimed to confirm its effectiveness in a different patient population.
Researchers analyzed data from 1,118 patients with early-onset RA diagnosed in northern Sweden between 1996 and 2016. they collected clinical information and conducted genotyping to analyze 12 single-nucleotide polymorphisms linked to idiopathic pulmonary fibrosis (IPF). After excluding three patients with incomplete data, the team identified 60 individuals who were afterward diagnosed with PF.
The study confirmed that established clinical risk factors-age, disease activity, and rheumatoid factor positivity-were associated with PF risk. Importantly, the MUC5B (rs35705950) and FAM13A (rs2609255) single nucleotide polymorphisms also showed a critically important association with PF growth.
The VARA GRS demonstrated an association with RA-PF, with an odds ratio of 2.6 (95% CI, 1.6, 4.5). However,mirroring the initial VARA study,the predictive power of the score was enhanced when combined with clinical factors. The combined risk score achieved an area under the curve (AUC) of 0.75 (P < 0.001), compared to an AUC of 0.62 for the GRS alone. .
Notably,the Swedish cohort differed from the original VARA cohort,which comprised primarily male patients,while the swedish group had a higher proportion of females. Smoking rates were also higher in the VARA cohort. Despite these differences, the researchers found the performance of both the GRS and the combined risk score remained consistent.
“Thus, this RA-ILD combined risk score appears to be a promising tool for use to risk-stratify RA-ILD and inform RA-ILD screening approaches,” the authors concluded. More broadly,they emphasized the importance of considering genetic factors-beyond customary demographic and clinical features-when evaluating risk for individuals with RA. This research underscores a shift toward personalized medicine in the management of RA and its associated complications.
References
Brink M, Wheeler A, England BR, Rantapää-Dahlqvist S. Validation of a genetic risk score combined with clinical variables for predicting pulmonary fibrosis in early rheumatoid arthritis. Arthritis Care Res (Hoboken). Published online November 14, 2025.doi:10.1002/acr.25696
Wheeler AM, Baker JF, Riley T, et al. Development and internal validation of a clinical and genetic risk score for rheumatoid arthritis-associated interstitial lung disease. Rheumatology (Oxford).2025;64(1):268-275. doi:10.1093/rheumatology/keae001
