New Insights into Managing Interstitial Lung Disease

Chicago—Interstitial lung diseases (ILD) are challenging for the rheumatologist because there is little high-quality evidence to guide treatment decisions. A presentation at ACR Convergence 2025 titled The Many Faces of ILD addressed some of these issues.

“Treating ILD feels like a bit of pick your own adventure,” said Erin Wilfong, MD, PhD, of Vanderbilt University Medical Center. “That’s because there are multiple options that, for a given patient with their particular disease, there may be reasonable and the right choice.”

Articular Involvement Treatment

Dr. Wilfong first discussed rheumatoid arthritis with ILD (RA-ILD). Articular involvement is an important treatment variable because of an impact on mortality. A moderate to high clinical disease activity index is linked to changes in the survival curves with or without abnormal pulmonary function testing (PFT).¹

There are many choices available. Methotrexate (MTH) is not absolutely contraindicated in RA-ILD. A study by Dr. England, et. al found no differences in outcomes between TNF-inhibitors (TNF-I) and non-TNF inhibitors in hospitalizations, mortality or respiratory mortality.² Dr. Wilfong suggests there is no reason to avoid these therapies without contraindications or continuing progression.

What medications are useful if initial treatment proves ineffective? Azathioprine, mycophenobate (MMF) and rituximab have been shown to stabilize RA-ILD. This is true even for patients with a usual interstitial pneumonia (UIP) pattern.³

“If you treat the joints, you help the lungs,” said Dr. Wilfong. “There is no one right answer. The right answer is what works for your patient.”

SSc-ILD Treatment Data

Systemic sclerosis with ILD (SSc-ILD) is different from systemic autoimmune rheumatic disease (SARD)-ILDs because there are high-quality data informing treatment decisions. In the Scleroderma Lung Study II, both MMF and oral cyclophosphamide worked with the former being better tolerated. This study enrolled all comers, making it applicable to all SSc-ILD patients.⁴

Other options include tocilizumab, rituximab and nintedanib. All may be combined with MMF, and a subgroup analysis from the SENSCI trial indicates MMF and nintedanib may work synergistically.⁵

Manage ASyS Quickly

If you suspect anti-synthetase syndrome (ASyS), quick treatment is important. Even with a UIP pattern, patients still benefit from immunosuppression. If treated with immunosuppression, progression-free survival improves and medial transplant-free survival increases 10-fold.⁶

“Remember that a transplant only lasts for 5–7 years,” said Dr. Wilfong. “We need to treat people early to buy time before starting their transplant clock.”

Multiple Therapies for MDA5

Anti-melanoma differentiation association gene 5 (MDA5) dermatomyositis is a subset of myositis-related ILD that must be caught early and treated aggressively. When rapidly progressing, ACR guidelines call for IV glucocorticoids and two additional therapies, such as rituximab, cyclophosphamide, IVIG, calcineur inhibitor or JAK inhibitors.⁷

“Which two you pick will be a mix of what your institution or the patient’s insurance company lets you have, what you are comfortable using and what is right for your patient,” said Dr. Wilfong. “There is literature supporting all of three.”

She cautions that aggressive immunosuppression can increase infection and worsen outcomes, so this therapy may not be appropriate for all patients.

ILD in Pregnancy

A group that needs attention are women who are pregnant or desire a pregnancy.

“When we think about pregnancy, it is critical our patients feel safe talking to us about having a child,” said Dr. Wilfong. “At the end of the day, they can get pregnant with or without us. It is safer for both mom and baby if done as a team.”

The first concern is reevaluating medications and moving away from teratogens. These should be addressed before pregnancy to ensure the disease remains stable.

Depending on the mom’s disease severity, counseling should note that as ILD severity, so does the risk of miscarriages and preterm births. It is imperative the mother is evaluated for pulmonary hypertension, which increases mortality and morbidity in both the mother and the fetus.⁸

In addition to reevaluating medication regimens, it is important the rheumatologist stays in close consultation with the other physicians. Also plan to increase pulmonary monitoring because the goal for oxygen saturation in pregnancy is 95%.

She suggests her patients get a pulse oximeter for home, which makes it possible to gather information on what happens, for instance, when a patient walks up the stairs or other real-world situations.

How to Define PPF?

There is some controversy in deciding on a definition for progressive pulmonary fibrosis (PPF). For example, the INBUILD study criteria included a ≥ 10% decline in force vital capacity (FVC), a ≥ 5% FVC decline with worsening respiratory symptoms, a ≥ 5% FVC decline with worsening HRCT, or worsening of both respiratory symptoms and HRCT.⁹

“We need to acknowledge upfront that the most important indicator of PPF is FVC decline of greater than 10%,” said Justin Oldham, MD, PhD, an associate professor at the University of Michigan. “Many studies of different processes show FVC had very strong prognostic significance compared to other markers.”

Research suggests patients with interstitial pulmonary fibrosis (IPF) do the worst while autoimmune diseases like SARD do the best. When an FVC decline of ≥ 10% was factored in, the transplant-free survival curves were the same across diseases. When other markers were looked at following removal of FVC decline, few were found to be prognostically useful.¹⁰

“What we find when we look at how well these measures predict death or transplant over the next year is that we are really good at identifying those who won’t die from PPF,” said Dr. Oldham. “But using current criteria, we are doing a bad job of finding those who will die.”

Biomarker Indicators

In an attempt to find better indicators, Dr. Oldham and others used machine learning to look for a composite biomarker. They completed a proof-of-concept study using a 12-protein signature. When applied to the validation cohort, the low-risk signature had a < 10% chance of progression. The high-risk signature was more ambiguous.¹¹

“For a patient with a small chance of progressing, I would be comfortable using these biomarkers to monitor them over the next year,” he said. “We are working on finding additional proteins and moving it to a quantitive panel for use in the clinic.”

When Initial Management Doesn’t Work

Some studies guide initial management, but when things go wrong, PPF comes into play. It is important to think of PPF as a failure of traditional management.

Nintedanib has been the only option for treating PPF. Compared to placebo, nerandomilast in both 9 mg and 18 mg doses slowed FVC decline over time. There was also a survival benefit in not only the overall cohort but in the autoimmune subgroup as well.¹²

“I think this data could easily change the way we treat this condition,” said Dr. Oldham. “This is a big step up over what we have been able to offer over the last six years.”

Kurt Ullman is a freelance writer based in Indiana.

Disclosures

Dr. Wilfong is a consultant for Allogene, Capstan Therapeutics and AstraZeneca; an advisor, review panel member and consultant for Boehringer-Ingelheim; and a former advisor/review panel member for Merck/MSD.

Dr. Oldham is a consultant for GlaxoSmithKline and Roche, and an advisor, speaker or review panel member for Boehringer-Ingelheim.

References

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