Gene Variant Confirmed as Strong Predictor of Lung Disease in RA

Ted Bosworth

June 05, 2021

Dr Antti Palomäki

Patients with rheumatoid arthritis who carry a specific allele of the gene MUC5B have about double the risk of developing interstitial lung disease when compared with noncarriers, according to a large Finnish biobank study presented at the annual European Congress of Rheumatology.

"The risk difference [or carriers relative to noncarriers] started at about age 65, with a bigger difference [for] men than women," reported Antti Palomäki, MD, PhD, of the center for rheumatology and clinical immunology at Turku (Finland) University.

The gain-of-function MUC5B variant, which encodes mucin 5B, was first linked to RA-associated interstitial lung disease (ILD) more than 3 years ago. At that time, it was already a known genetic risk factor for idiopathic pulmonary fibrosis in the general population. The new data confirm the association in a longitudinal analysis of a large biobank and suggest the association might have clinical utility.

"This is not ready for clinical practice at the moment. We do not yet know whether we can change therapy to reduce risk," Palomäki said, adding "in the future we can look."

One question that might be asked in clinical studies using MUC5B as a tool to assess and modify risk of ILD in patients with RA is whether one therapy is better than another in avoiding or delaying development of lung fibrosis. Palomäki noted that biologics, for example, might be a more favorable choice in patients with RA who are at high risk of developing ILD.

The association of the MUC5B variant with increased ILD incidence in patients with RA was drawn from a data set known as FinnGen, a biobank collection of epidemiologic cohorts and hospital samples with genotypes of about 10% of the Finnish population. Follow-up extends to 46 years in some of these individuals.

When 248,4000 individuals in this data set were evaluated, 5,534 had a diagnosis of RA. Of these, 178 (3.2%) developed ILD. About 20% of both those with and without RA were MUC5B variant carriers, meaning the remainder were not.

Sex and Age Factor Into Lifetime Risk

In patients with RA, the lifetime rate of ILD among MUC5B variant carriers was 16.8% versus only 6.1% among noncarriers. This finding translated into a hazard ratio for ILD of 2.27 (95% confidence interval, 1.75–2.96) for variant carriers versus noncarriers.

The lifetime rate of ILD in patients with RA was greater in men versus women regardless of carrier status (18.5% vs. 8.5%). For women, the lifetime rate was lower for carriers, although the difference relative to female noncarriers was greater (14.5% vs. 4.7%).

ILD, whether in the general population or in patients with RA, is a disease of advancing age. When Palomäki showed a graph, the rise in ILD incidence did not start in any population, whether those with or without RA and regardless of carrier status, until about age 55. In those without RA and in noncarriers of the variant, ILD incidence remained low and began a discernible climb at around age 70.

In those who did not have RA but were positive for the variant, the rates rose more than twice as fast, particularly after age 70. In people who had RA but not the variant, the rate of ILD was greater than in patients who carried the variant without RA, starting the climb earlier and rising more steeply with age. In those with RA and the variant, the climb in ILD incidence rose rapidly after age 65 years even though the incidence remained fairly similar between all of these groups at age 60.

Putting the Findings Into Context

The need to develop ways to prevent ILD in RA is urgent. ILD is one of the most common extraarticular manifestations of RA, developing in up to 60% of patients with RA in older age groups when evaluated with imaging, according to Palomäki. Although it develops into a clinically significant complication in only about 10% of these patients, ILD still is a significant cause of illness and death in elderly patients with RA.

In the 2018 study that first linked the MUC5B variant to RA-ILD, the investigators also found that the variant was associated with an increased likelihood of developing the usual interstitial pneumonia type of ILD on imaging. David Schwartz, MD, professor of medicine, pulmonary sciences, and critical care and chair of the department of medicine at the University of Colorado at Denver, Aurora, was a senior author of that study. He said these findings build on the 2018 study.

"While the gain-of-function MUC5B promoter variant is important in predicting who will develop RA-ILD, these findings also suggest that MUC5B may be involved in the etiology of RA-ILD, at least for those with the MUC5B variant," he said.

"The study also raises the possibility that there are several subtypes of RA-ILD, and the subtype that is driven by MUC5B may respond differently to RA biologics or therapeutic agents to treat ILD," he added.

In the discussion following the presentation by Palomäki, others agreed, with that statement including Palomäki. He expressed interest in clinical studies comparing different classes of RA therapies for their relative impact on the risk of developing ILD.Palomäki reported financial relationships with AbbVie, Merck, Pfizer, and Sanofi. Schwartz is the founder of Eleven P15, which is developing methods for early diagnosis and treatment of pulmonary fibrosis.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

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