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.”

The relative risk was further mud­died by the potential for toxic pul­monary effects associated with all DMARDs. “Essentially, every single medicine that is approved for the treatment of rheumatoid arthritis has been implicated in causing a hyper­sensitivity pneumonitis, which is basically an allergic-type reaction to the drug that happens within the lungs,” Dr. England says. “It’s just that for RA-ILD, there are a couple medicines out there that people were particularly concerned about.”

On the basis of the limited preliminary evidence, Dr. England and his colleagues initially hypothesized that treatment with non-TNF inhibitors would be more effective and associated with improved survival and fewer respiratory hospitalizations than treatment with TNF inhibitors. Their results to the contrary, however, left him only “modestly” surprised, he says. “The careful design often can lead to a result that is different than what a less stringently defined observational study produces.”

To minimize the potential for bias that often plagues observational studies, the research team used a target trial emulation framework, which Dr. England calls an important advance in pharmaco-epidemiology. “The prin­ciple is that when we do an observational study, we should approach it with the rigor and the strategy that we would if we designed this as a clinical trial,” he says.

Among the critical questions are which patient populations should be included in a trial, which participants should receive which therapies and how, and what the best outcome measures would be. The target trial emulation framework then specifies that the same approaches taken for a clinical trial should be applied to observational data. “Ultimately, you can’t pull it off perfectly because in a trial you have randomization: You can flip the coin and give one drug to one person, the other drug to another,” he concedes. Instead, observational studies can use statistical techniques like propensity score-based methods to reduce bias by estimating the probability that a particular participant would have received a particular treatment.

Questions of Interpretation

The study results yielded additional questions that will likely require more follow-up to fully resolve, like how to interpret the null results when comparing the two patient groups. “One of the questions is, is it null because for every single person in that study it didn’t matter which drug you gave them?” Dr. England says. Alternatively, a subset of patients in each group may have done better if they had received the other drug, effectively canceling each other out in the statistical analysis.

The interpretation challenge is especially hard for RA-ILD, given its wide range of types and disease patterns. “There’s the usual interstitial pneumonia, there’s non-specific interstitial pneumonia, there are disease trajectories that tend to stay pretty stable, there are some that slowly progress over time, and there are a few unlucky ones that rapidly progress,” Dr. England says. Compounding the difficulty, ILD can occur roughly 7 to 10 years into the course of RA, with intervening drug interventions and comorbidities adding further variability to the mix.

From prior observational studies, doctors have at least learned a few key lessons, such as the importance of controlling RA from the start.³ “If we get good control of rheumatoid arthritis and lower their disease activity, similar to what we learned with cardiovascular disease years ago, that seems to be the thing that can help prevent interstitial lung disease,” Dr. England says.

To hone the preventive strategy, a prospective RA-ILD study that takes disease patterns, trajectories, bio­molecular signatures, and other factors into account could help determine whether rheumatologists can more precisely select the right therapy for the right person. Although that precision medicine goal may be years away, Dr. England’s study suggests that in the meantime, TNF inhibitors shouldn’t be scrapped from the roster of potential interventions.

“It doesn’t mean that’s the perfect choice for everyone. It doesn’t mean that we can tell a patient, we know that this medicine is going to improve their lungs because we don’t,” he says. “But it still remains that for many people, these can still be effective medicines that will help control their rheumatoid arthritis, and we don’t have strong evidence that it’s going to cause them harm in their lungs.”

Bryn Nelson, PhD, is a medical journalist based in Seattle.

References

1. Kadura S, Raghu G. Rheumatoid arthritis-interstitial lung disease: Manifestations and current concepts in pathogenesis and management. Eur Respir Rev. 2021 Jun 23;30(160):210011.
2. England BR, Baker JF, George MD, et al. Advanced therapies in US veterans with rheumatoid arthritis-associated interstitial lung disease: A retrospective, active-comparator, new-user, cohort study. Lancet Rheumatol. 2025 Mar;7(3):e166–e177.
3. Huang S, Kronzer VL, Dellaripa PF, et al. Rheumatoid arthritis-associated interstitial lung disease: Current update on prevalence, risk factors, and pharmacologic treatment. Curr Treatm Opt Rheumatol. 2020 Dec;6(4):337–353.