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Multicenter Study
. 2025 Jan 1;64(1):268-275.
doi: 10.1093/rheumatology/keae001.

Development and internal validation of a clinical and genetic risk score for rheumatoid arthritis-associated interstitial lung disease

Austin M Wheeler  1   2 , Joshua F Baker  3 , Thomas Riley  3 , Yangyuna Yang  2 , Punyasha Roul  2 , Katherine D Wysham  4 , Grant W Cannon  5 , Gary Kunkel  5 , Gail Kerr  6 , Dana P Ascherman  7 , Paul Monach  8 , Andreas Reimold  9 , Jill A Poole  2 , Tony R Merriman  10 , Ted R Mikuls  1   2 , Bryant R England  1   2
Affiliations
Multicenter Study

Development and internal validation of a clinical and genetic risk score for rheumatoid arthritis-associated interstitial lung disease

Austin M Wheeler et al. Rheumatology (Oxford). .

Abstract

Objective: Although clinical and genetic risk factors have been identified for rheumatoid arthritis-associated interstitial lung disease (RA-ILD), there are no current tools allowing for risk stratification. We sought to develop and validate an ILD risk model in a large, multicentre, prospective RA cohort.

Methods: Participants in the Veterans Affairs RA (VARA) registry were genotyped for 12 single nucleotide polymorphisms (SNPs) associated with idiopathic pulmonary fibrosis. ILD was validated through systematic record review. A genetic risk score (GRS) was computed from minor alleles weighted by effect size with ILD, using backward selection. The GRS was combined with clinical risk factors within a logistic regression model. Internal validation was completed using bootstrapping, and model performance was assessed by the area under the receiver operating curve (AUC).

Results: Of 2386 participants (89% male, mean age 69.5 years), 9.4% had ILD. Following backward selection, five SNPs contributed to the GRS. The GRS and clinical factors outperformed clinical factors alone in discriminating ILD (AUC 0.675 vs 0.635, P < 0.001). The shrinkage-corrected performance for combined and clinical-only models was 0.667 (95% CI 0.628, 0.712) and 0.623 (95% CI 0.584, 0.651), respectively. Twenty percent of the cohort had a combined risk score below a cut-point with >90% sensitivity.

Conclusion: A clinical and genetic risk model discriminated ILD in a large, multicentre RA cohort better than a clinical-only model, excluding 20% of the cohort from low-yield testing. These results demonstrate the potential utility of a GRS in RA-ILD and support further investigation into individualized risk stratification and screening.

Keywords: genetic polymorphism; genetic risk score; interstitial lung disease; rheumatoid arthritis.

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Figures

Figure 1.
Figure 1.
Comparison of ROC curves for clinical risk factors and the VARA-ILD Combined Risk Score model for presence of RA-ILD. ROC curves, along with their respective AUC, are shown for the clinical risk score and the VARA-ILD Combined Risk Score. A P-value is shown for comparison of the AUCs of the two models, as calculated via the nested likelihood ratio test. AUC: area under the curve; RA-ILD: RA-associated interstitial lung disease; ROC: receiver operating characteristic
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