Genetic, Clinical Variables Can Predict Pulmonary Fibrosis Risk in Early Rheumatoid Arthritis

A new combined risk score that incorporates genetic factors may give clinicians a better idea of which patients with rheumatoid arthritis (RA) are most at risk for pulmonary fibrosis (PF).

The authors of the new report say they hope their findings can help improve screening strategies to identify patients at a significant risk of developing PF. The study was published in Arthritis Care & Research.1

The authors explained that about 1 in 10 patients with RA experience RA-associated interstitial lung disease (RA-ILD), which is considered a severe extra-articular manifestation of the disease. Yet, they said it is difficult to precisely predict which patients will be affected.

The data show that genetic factors, and not simply demographic or clinical features, should play an important role in assessing risk factors for people with RA. | Image credit: Dr_Microbe - stock.adobe.com

“Despite the identification of several clinical risk factors, such as older age, male sex, smoking history, severe articular disease, and autoantibody seropositivity, particularly in usual interstitial pneumonia, there remains a lack of standardized tools for risk stratification in RA-ILD,” the authors wrote.

That gap has led some to begin analyzing genetic risk factors as a means to better identify high-risk patients. The investigators noted that the MUC5B rs35705950 promoter variant, in particular, has been identified as a possible genetic risk factor for RA-ILD.

Last year, a team of investigators developed a clinical and genetic risk score using the Veterans Affairs Rheumatoid Arthritis (VARA) registry, which the score’s developers said outperformed risk stratification based solely on clinical factors.2 In the new report, researchers sought to externally validate the Veterans Affairs risk score—known as the VARA RA-ILD genetic risk score (GRS)—as a tool to predict PF among patients with RA.

The investigators used a cohort of 1,118 patients with early RA who were from northern Sweden and diagnosed with the disease between 1996 and 2016. They collected clinical data and then performed genotyping for 12 single-nucleotide polymorphisms associated with idiopathic pulmonary fibrosis (IPF).

After excluding 3 patients with incomplete data, the investigators found that 60 patients in their cohort were eventually diagnosed with PF. Factors such as age, disease activity, and rheumatoid factor positivity were significantly associated with PF risk. However, the investigators also found that the MUC5B (rs35705950) and FAM13A (rs2609255) single nucleotide polymorphisms were also associated with PF risk.

The investigators calculated that the VARA GRS was associated with RA-PF, with an odds ratio of 2.6 (95% CI, 1.6, 4.5). However, as with the earlier VARA study, they found that combining the genetic risk score with clinical factors improved the predictive value of the score. The combined risk score had an area under the curve (AUC) of 0.75 (P < 0.001), while the GRS alone had an AUC of 0.62.

The authors noted that there were significant differences between their cohort and the VARA cohort. For instance, the VARA cohort was made up predominantly of men, while the Swedish cohort had a higher proportion of females. In addition, while both cohorts had high percentages of patients with a history of smoking cigarettes, the VARA cohort had a higher percentage.

“Despite the differences in these cohorts, the performance of the GRS and combined risk score were similar,” they wrote. “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.”

More broadly, the researchers explained that the data show that genetic factors, and not simply demographic or clinical features, should play an important role in assessing risk factors for people with RA.

References

1. 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
2. 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