IPF and Interstitial Lung Disease in Rheumatoid Arthritis Share Genetic Risk Factor

A mutation associated with the mucous-producing gene MUC5B, a known genetic risk factor for idiopathic pulmonary fibrosis (IPF), also is prevalent in rheumatoid arthritis patients with interstitial lung disease (ILD), according to a study led by researchers from the University of Colorado School of Medicine.

The study, “MUC5B Promoter Variant and Rheumatoid Arthritis with Interstitial Lung Disease,” was published in The New England Journal Of Medicine.

Rheumatoid arthritis (RA) is an autoimmune inflammatory condition that affects the joints in the body. However, it also can damage the lungs, heart, and blood vessels. According to the Arthritis Foundation, about 10% of RA patients develop an ILD condition such as pulmonary fibrosis.

Previous studies have shown the involvement of a gene encoding for mucin 5B (MUC5B) in IPF development. The gene results in the production of mucin, a key component that makes up the mucus.

Every gene has a promoter region that helps initiate the synthesis of a product from that gene. A mutation in the promoter region of the gene MUC5B results in a variant (alternative form) of the promoter — rs35705950 — which enables increased production of mucus in the lungs. This mutation has been noted in 50% of IPF patients, and increased their risk of disease progression by up to 30%, making this variant a strong genetic risk factor for the disease.

Since the promoter variant of MUC5B is a known genetic risk factor for IPF, researchers hypothesized that it could be a common factor in the genetics of both IPF and RA-ILD. To investigate this hypothesis, the team screened RA patients with and without ILD to determine if this genetic variant is also a risk factor for RA-ILD.

The study included 620 patients with RA-ILD, 614 RA patients without ILD, and 5,448 unaffected controls without ILD or RA. Participants were recruited from the United States, Greece, the Netherlands, Japan, France, Mexico, and China.

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Researchers found that the frequency of the MUC5B promoter variant in the unaffected group was 10.9% compared to 32.6% in the RA-ILD group. Likewise, the team observed a significantly higher expression of the MUC5B gene with a variant promoter in the RA-ILD group compared with the unaffected control group.

To determine if the promoter variant contributed to the risk of ILD in RA patients, the team compared the presence of MUC5B rs35705950 promoter variant in RA patients with and without ILD. They found that the chances of the promoter variant being present in RA-ILD patients was 3.1 times higher compared with RA patients without ILD.

Also, the odds of MUC5B promoter variant being present in RA-ILD patients with usual interstitial pneumonia (UIP, a progressive ILD condition) was six times higher than in RA patients without ILD.

“We found that the MUC5B promoter variant rs35705950, the strongest genetic risk factor for idiopathic pulmonary fibrosis, was also a strong risk factor for RA-ILD, especially among patients with evidence of a UIP pattern on imaging,” the researchers wrote.

“By uncovering this link in the genetic background between these conditions, we now know that rheumatoid arthritis associated-interstitial lung disease and idiopathic pulmonary fibrosis have similar causes and may prove to have similar treatments,” Joyce Lee, MD, associate professor at CU School of Medicine and the first author of the study, said in a press release.

David Schwartz, MD, chair of the department of medicine at the CU School of Medicine and senior author of the study, added: “These findings will enable us to identify those with rheumatoid arthritis who are at risk of pulmonary fibrosis and design interventions to potentially prevent patients with rheumatoid arthritis from developing progressive pulmonary fibrosis.”