TNF Inhibitors May Be OK for Treating RA-Associated Interstitial Lung Disease

Doug Brunk

November 14, 2023

SAN DIEGO — Patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD) who start a tumor necrosis factor inhibitor (TNFi) appear to have rates of survival and respiratory-related hospitalization similar to those initiating a non-TNFi biologic disease-modifying antirheumatic drug (bDMARD) or Janus kinase inhibitor (JAKi), results from a large pharmacoepidemiologic study show.

Dr Bryant England

"These results challenge some of the findings in prior literature that perhaps TNFi should be avoided in RA-ILD," lead study investigator Bryant R. England, MD, PhD,  said in an interview. The findings were presented during a plenary session at the American College of Rheumatology (ACR) 2023 Annual Meeting.

England, associate professor of rheumatology and immunology at the University of Nebraska Medical Center, Omaha, said that while RA-ILD carries a poor prognosis, a paucity of evidence exists on the effectiveness and safety of disease-modifying therapies in this population.

It’s a pleasant surprise "to see that the investigators were unable to demonstrate a significant difference in the risk of respiratory hospitalization or death between people with RA-ILD initiating non-TNFi/JAKi versus TNFi. Here is a unique situation where a so called 'negative' study contributes important information. This study provides needed safety data, as they were unable to show that TNFi results in worsening of severe RA-ILD outcomes," Sindhu R. Johnson, MD, PhD, professor of medicine at the University of Toronto, Toronto, Ontario, Canada, said when asked for comment on the study.

Dr Sindhu Johnson

"While this study does not address the use of these medications for the treatment of RA-ILD, these data suggest that TNFi may remain a treatment option for articular disease in people with RA-ILD," said Johnson, who was not involved with the study.

For the study, England and colleagues drew from Veterans Health Administration data between 2006 and 2018 to identify patients with RA-ILD initiating TNFi or non-TNFi biologic/JAKi for the first time. Those who received ILD-focused therapies such as mycophenolate and antifibrotics were excluded from the analysis.

The researchers used validated administrative algorithms requiring multiple RA and ILD diagnostic codes to identify RA-ILD and used 1:1 propensity score matching to compare TNFi and non-TNFi biologic/JAKi factors such as healthcare use, comorbidities, and several RA-ILD factors, such as pretreatment forced vital capacity, obtained from electronic health records and administrative data. The primary outcome was a composite of time to respiratory-related hospitalization or death using Cox regression models.

England reported findings from 237 TNFi initiators and 237 non-TNFi/JAKi initiators. Their mean age was 68 years and 92% were male. After matching, the mean standardized differences of variables in the propensity score model improved, but a few variables remained slightly imbalanced, such as two markers of inflammation, inhaled corticosteroid use, and body mass index. The most frequently prescribed TNFi drugs were adalimumab (51%) and etanercept (37%), and the most frequently prescribed non-TNFi/JAKi drugs were rituximab (53%) and abatacept (28%).

The researchers observed no significant difference in the primary outcome between non-TNFi/JAKi and TNFi initiators (adjusted hazard ratio [aHR], 1.22; 95% CI, 0.92-1.60). They also observed no significant differences in respiratory hospitalization, all-cause mortality, or respiratory-related death at 1 and 3 years. In sensitivity analyses with modified cohort eligibility requirements, no significant differences in outcomes were observed between non-TNFi/JAKi and TNFi initiators.

During his presentation at the meeting, England posed the question: Are TNFi drugs safe to be used in RA-ILD?

"The answer is: It’s complex," he said. "Our findings don’t suggest that we should be systematically avoiding TNFis with every single person with RA-ILD. But that’s different than whether there are specific subpopulations of RA-ILD for which the choice of these therapies may differ. Unfortunately, we could not address that in this study. We also could not address whether TNFis have efficacy at stopping, slowing, or reversing progression of the ILD itself. This calls for us as a field to gather together and pursue clinical trials to try to generate robust evidence that can guide these important clinical decisions that we’re making with our patients."

He acknowledged certain limitations of the analysis, including its observational design. "So, despite best efforts to minimize bias with pharmacoepidemiologic designs and approaches, there could still be confounding and selection," he said. "Additionally, RA-ILD is a heterogeneous disease characterized by different patterns and trajectories. While we did account for several RA- and ILD-related factors, we could not account for all heterogeneity in RA-ILD."

Dr Janet Pope

When asked for comment on the study, session moderator Janet Pope, MD, MPH, professor of medicine in the division of rheumatology at the University of Western Ontario, London, Ontario, Canada, said that the study findings surprised her.

"Sometimes RA patients on TNFis were thought to have more new or worsening ILD vs [those on] non-TNFi bDMARDs, but most [data were] from older studies where TNFis were used as initial bDMARD in sicker patients," she told Medscape Medical News. "So, data were confounded previously. Even in this study, there may have been channeling bias as it was not a randomized controlled trial. We need a definitive randomized controlled trial to answer this question of what the most optimal therapy for RA-ILD is."

England reports receiving consulting fees and research support from Boehringer Ingelheim, and several co-authors reported financial relationships from several pharmaceutical companies and medical publishers. Johnson reports no relevant financial relationships. Pope reports being a consultant for several pharmaceutical companies. She has also received grant/research support from AbbVie/Abbott and Eli Lilly and is an adviser for Boehringer Ingelheim.


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