Lifetime risk of rheumatoid arthritis-associated interstitial lung disease in MUC5B mutation carriers

Abstract

ObjectivesTo estimate lifetime risk of developing rheumatoid arthritis-associated interstitial lung disease (RA-ILD) with respect to the strongest known risk factor for pulmonary fibrosis, a MUC5B promoter variant.MethodsFinnGen is a collection of epidemiological cohorts and hospital biobank samples, integrating genetic data with up to 50 years of follow-up within nationwide registries in Finland. Patients with RA and ILD were identified from the Finnish national hospital discharge, medication reimbursement and cause-of-death registries. We estimated lifetime risks of ILD by age 80 with respect to the common variant rs35705950, a MUC5B promoter variant.ResultsOut of 293 972 individuals, 1965 (0.7%) developed ILD by age 80. Among all individuals in the dataset, MUC5B increased the risk of ILD with a HR of 2.44 (95% CI: 2.22 to 2.68). Out of 6869 patients diagnosed with RA, 247 (3.6%) developed ILD. In patients with RA, MUC5B was a strong risk factor of ILD with a HR similar to the full dataset (HR: 2.27, 95% CI: 1.75 to 2.95). In patients with RA, lifetime risks of ILD were 16.8% (95% CI: 13.1% to 20.2%) for MUC5B carriers and 6.1% (95% CI: 5.0% to 7.2%) for MUC5B non-carriers. The difference between risks started to emerge at age 65, with a higher risk among men.ConclusionOur findings provide estimates of lifetime risk of RA-ILD based on MUC5B mutation carrier status, demonstrating the potential of genomics for risk stratification of RA-ILD.

Towards clinical significance of the MUC5B promoter variant and risk of rheumatoid arthritis-associated interstitial lung disease

“…6 Presence of the MUC5B promoter variant was strongly associated with ILD risk within RA compared with absence of the variant (HR 2.27, 95% CI 1.75 to 2.95). 6 The lifetime risk of ILD in RA for those with the MUC5B promoter variant was 16.8% (compared with 4.4% in the general population) and seemed to specifically emerge after age of 65 years. 6 Consistent with other studies, men with RA had a higher lifetime risk of ILD than women with RA.…”

“…In Annals of the Rheumatic Diseases, Palomäki and colleagues investigate the lifetime risk of RA-ILD related to the MUC5B promoter variant. 6 RA-ILD is a heterogeneous condition that is notoriously difficult to diagnose. Usual interstitial pneumonia (UIP) is the most common RA-ILD, considered to be fibrotic and progressive.…”

“…13 Palomäki and colleagues used FinnGen to study the relationship of the MUC5B promoter variant with the lifetime risk of RA-ILD. 6 FinnGen was assembled from other prospective studies and linked to nationwide registers in Finland to link genetic and clinical data with up to 50 years of follow-up. They analysed 293 972 individuals to determine presence and dates of RA and ILD, identified using medication reimbursement codes and diagnoses from hospital inpatient and outpatient registries.…”

“…They analysed 293 972 individuals to determine presence and dates of RA and ILD, identified using medication reimbursement codes and diagnoses from hospital inpatient and outpatient registries. 6 They then stratified by presence or absence of the MUC5B promoter variant and also performed separate analyses among men and women. In the entire population, about 20% had at least one copy of the MUC5B promoter variant.…”

“…In the entire population, about 20% had at least one copy of the MUC5B promoter variant. 6 Overall, the estimated risk of ILD was 1.5% by 80 years of age (considered as a surrogate for lifetime risk). Within RA, the lifetime risk of RA-ILD was higher, at 6.1%.…”