Study: Are TNF Inhibitors Safe for Patients with RA-ILD?

In roughly 10% of patients with rheumatoid arthritis (RA), interstitial lung disease (ILD) can develop and become clinically significant, leading to chronic inflammation and progressive scarring of the lung tissue that profoundly complicates treatment strategies.¹ The poor prognosis for patients with RA-associated ILD—who have a median survival of three to eight years—has underscored the need for more clarity on effective interventions and modifiable risk factors.

Anecdotal reports linking ILD development or exacerbation to treatment with tumor necrosis factor (TNF) inhibitors have cast a shadow over a potent anti-inflammatory drug often used to treat more severe cases of RA. The reports haven’t been able to disentangle causality from correlation, however, given that TNF inhibitor-treated patients tend to have more severe RA, which could hasten ILD.

Bryant England, MD, PhD, an asso­ci­ate professor of medicine in the Division of Rheumatology and Immunology, the University of Nebraska Medical Center, Omaha, and the VA Nebraska-Western Iowa Health Care System, says advice on using TNF inhibitors for RA-ILD has been a mixed bag. Even some medical societies have expressed concern that patients “could have an increased risk of exacerbation of [ILD] and potentially even a worse prognosis, meaning shorter survival, if they were treated with a TNF inhibitor,” he says.

Dr. Bryant England

In one of the largest observational studies to date, Dr. England and colleagues found no difference in deaths or respiratory hospitalizations between patients with RA-ILD who took TNF inhibitors and counterparts who took non-TNF biologic or targeted synthetic disease-modifying anti-rheumatic drugs (DMARDs).²

The null results, he says, add new data to arguments that TNF inhibitors need not be avoided for such patients. “We have our toolbox of medicines to take care of people with rheumatoid arthritis, and when you go to take care of a patient with RA-ILD, you don’t have to reach into your toolbox, take all those TNF inhibitors, and throw them away,” Dr. England says.

Among a group of largely male U.S. veterans diagnosed with RA-ILD, the study in The Lancet Rheumatology matched 237 patients who started taking TNF inhibitors with 237 counterparts who started taking non-TNF biologic or targeted synthetic disease-modifying anti-rheumatic drugs. The study found no statistically significant difference in respiratory hospitalizations (adjusted hazard ratio [HR] of 1.27), all-cause mortality (adjusted HR of 1.15) or respiratory mortality (adjusted HR of 1.38).

A Framework to Minimize Bias

A few observational studies had previously pointed to associations between TNF inhibitors and ILD exacerbation or shorter survival, but Dr. England maintains most of them were relatively small and generated imprecise risk estimates. “Therefore, you couldn’t make definitive conclusions,” he says. “Then, as with all observational studies, the potential for selection bias or confounding bias is a huge problem, and so that left some trepidation about whether the findings were real and causal.”