Christine Kilgore

March 06, 2025

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Elizabeth R. Volkmann, MD, MS

The prevalence of interstitial lung disease (ILD) across connective tissue disorders (CTDs) and its persistent standing as a leading cause of death in patients with CTDs challenge rheumatologists to play an increasingly proactive role not only in screening and diagnosis but also in treatment and monitoring as well, Elizabeth R. Volkmann, MD, MS, said at the 2025 Rheumatology Winter Clinical Symposium (RWCS 2025).

“I don’t leave monitoring [for progression] solely up to the pulmonologist,” particularly when caring for patients with early ILD related to CTD, who often have minimal symptoms and may not be followed as closely, said Volkmann, co-director of the CTD-ILD program at University of California Los Angeles (UCLA) and director of its scleroderma program, in a session on personalized care for CTD-ILD.

“We want to approach monitoring more aggressively,” she said, adding that the rheumatologist also has the advantage of understanding how the patient’s extra-pulmonary disease manifestations may affect the interpretation of respiratory assessments.

Regarding treatment itself, “I recommend treating all patients with new-onset ILD,” she said, considering that fibrosis is difficult to reverse and losses in lung function are difficult to regain once they’ve occurred. Some patients with long-standing, seemingly stable CTD-ILD may not need treatment but must be followed vigilantly for progression, she said.

In another session that addressed systemic sclerosis (SSc)-associated ILD specifically, Volkmann cautioned that too often, clinicians start therapy when a patient has signs of disease progression. “I find this often with my pulmonary colleagues. They won’t treat the patient unless the patient is showing signs of their disease getting worse,” she said.

The problem is, “our traditional ways of measuring progression, like FVC [forced vital capacity] and HRCT [high-resolution CT] are less measures of disease activity and more measures of disease damage,” said Volkmann, whose patients with CTD-ILD include “many young women.” By the time a patient experiences progression per these measures, the patient may have accrued irreversible lung damage.

“The therapies we have now [for SSc-ILD] work better earlier in the course of disease when there’s more inflammation and less fibrosis,” she said.

During RWCS 2025, Volkmann also provided updates on investigational therapies and candidate biomarkers for prognosis and treatment response in SSc-ILD.

Advice on Screening, Communication With Radiology, Treatment

For patients with SSc, mixed connective tissue disease, and myositis — CTDs with the highest prevalence of ILD (52%-65%, 40%-65%, and 30%-50%, respectively) — Volkmann said she proposes that “all these patients be screened” for ILD, regardless of underlying risk factors.

The 2023 American College of Rheumatology (ACR)/American College of Chest Physicians (CHEST) guideline for the screening and monitoring of ILD in people with systemic autoimmune rheumatic diseases (SARDs), another name for CTDs, lists disease-specific risk factors, recommends shared decision-making for screening, and says screening for ILD “should not necessarily be limited only to those with these risk factors.”

“We know there are certain risk factors that portend a greater or lesser risk” for ILD in patients with SSc, for instance, “but none of these clinical factors will perfectly predict who will and will not get ILD,” she said, noting that ILD is still the leading cause of SSc-related death.

With RA, where the prevalence of ILD “isn’t quite as high [6%-17%], I don’t think all patients should be screened,” she said. Before ordering a HRCT scan in a seropositive patient without pulmonary symptoms, “I’d look for at least one additional risk factor for ILD, such as a history of smoking, older age, male sex,” she said.

Early signs of ILD can be “quite subtle,” such as fatigue during a walk without dyspnea, Volkmann said. “Sometimes patients [with CTD-ILD] are completely asymptomatic and this is usually because they’ve started to already modify their lifestyle to avoid uncomfortable symptoms.” 

These patients can still progress, she emphasized, noting that a post hoc analysis of patients with SSc-ILD in the placebo group of the SENSCIS trial, which studied the drug nintedanib, found that patients without dyspnea had a similar decline in FVC over 52 weeks compared with those with dyspnea (−95.8 and −87.7 mL/y, respectively).

A noncontrast HRCT ordered with a note about suspicion of ILD is the optimal screening tool. “We don’t use pulmonary function tests [PFTs] to screen,” she said, “because early in the course [of CTD-ILD] your PFTs can be in the normal range…and you also don’t know what the historical PFTs have been.” 

As part of evaluating exercise tolerance, Volkmann said she has moved from reliance on the 6-minute walk test and toward asking patients about their daily step count. Walking distance can be influenced by nonpulmonary factors, she explained, and step counts “help me understand how they’re making changes to their lifestyle to accommodate their symptoms.”

Across the spectrum of CTD-ILD, the predominant radiologic pattern is that of nonspecific interstitial pneumonia (NSIP), with the exception of RA-ILD, in which the more common pattern is that of usual interstitial pneumonia. NSIP is characterized by ground glass opacity, reticulation, traction bronchiectasis, subpleural sparing, and a “symmetric process that starts in the lower lobes and usually ascends up the lungs,” she said.

NSIP related to CTD is more common than idiopathic NSIP, she emphasized. So “if you see a patient referred by the pulmonologist [with concern about possible autoimmune disease], and they have a NSIP pattern, it’s more likely to be related to an autoimmune disease than idiopathic NSIP.”

Volkmann said she encourages rheumatologists who are evaluating patients for CTD-ILD to acquire the ordered images and communicate with the radiologist. “Oftentimes, radiologists will divulge more [in a conversation] than they will on the radiology report,” she said, “and they welcome communication.”

Nailing down a diagnosis of CTD-ILD can improve chances of survival over other diagnoses such as idiopathic pulmonary fibrosis, she emphasized. “You may be asked, does the patient have an underlying autoimmune disease that could explain their ILD? And your impression can make a huge difference in how the pulmonologist and you go about treating the patient,” said Volkmann, who emphasized the importance of multidisciplinary care.

“I commonly see…that rheumatologists will comment ‘doesn’t meet classification criteria for lupus or myositis,’ for instance. But that’s not really the question,” she said. “Maybe they have a high titer ANA [antinuclear antibodies], Raynaud’s, some arthritis…[But] even if they don’t meet full criteria, they may still have underlying autoimmune disease.”

Broadly assessing patients with serology tests, rather than ordering targeted batteries based on clinical suspicion of specific diagnoses, is warranted in cases of ILD and questions of underlying autoimmunity, she emphasized.

Asked when progression of CTD-ILD is significant enough to consider switching treatment, and when treatment can be stopped, Volkmann said it’s reasonable to meet the definition of progressive pulmonary fibrosis (PPF) as defined in a 2022 guideline by the American Thoracic Society and partner organizations.

“If this happens after at least a 6-month trial of a treatment, I’d switch at that point,” she said. “[To stop treatment] I take this really seriously because if they flare up, usually we can’t get back to our baseline again. So I’d wait for a patient to be quite stable for a couple years, then I’d taper therapy.” 

SSc-ILD Investigational Drugs and Candidate Biomarkers for Prognosis, Treatment Response

Joining the 2023 ACR/CHEST guideline for the treatment of ILD in people with SARDs is a 2024 guideline from the American Thoracic Society (ATS) focused on treatment of SSc-ILD.

“You now have in your toolbox a lot of options,” from mycophenolate mofetil to rituximab, said Volkmann, an author of the ATS SSc-ILD guideline. “But even though we now have these therapies, which have proven efficacy, survival rates have largely not improved in the last 50 years.”

Volkmann pointed to several knowledge gaps. “We don’t have consensus about when to start therapy, and when we start it, we don’t know what the right time to change it is,” she said. Additionally, “we have to really use research to define how we can enrich SSc-ILD trial cohorts” to increase the probability of success and advance precision medicine.

There is an unmet need for prognostic, predictive, and treatment response biomarkers, she said, noting that it is unclear whether stable HRCT findings signify active or inactive fibrosis.

Post hoc analyses of treatment trials, including an analysis presented at EULAR 2024 of data from the SENSCIS trial, suggest that serum KL-6 predicts ILD progression, making it a potential prognostic biomarker. Patients with higher baseline levels of KL-6, a glycoprotein expressed on pneumocytes, had a greater rate of FVC decline, she said.

KL-6 also predicted SSc-PPF in a 2024 published analysis of patients in the Scleroderma Lung Study II receiving either mycophenolate mofetil (MMF) or cyclophosphamide (CYC) for SSc-ILD, making it a potential treatment response biomarker. Those with an increase in KL-6 were more likely to develop PPF than those with a decrease in KL-6.

C-reactive protein was also analyzed and was found to predict SSc-PPF in the MMF treatment group but not in the CYC group, suggesting that certain response biomarkers may be treatment specific, Volkmann said.

KL-6 is routinely measured in Japan in patients with scleroderma, she noted. “Patients know their KL-6 levels in the same way they know their FVCs,” she said. “This could be something we hopefully do in the future.”

At UCLA, researchers are studying functional imaging as a potential biomarker of treatment response. Past research showed that uptake on PET imaging of a ⁶⁸Ga-labeled tracer targeting fibroblast activation protein inhibitor (FAPI) predicted FVC decline in SSc-ILD patients treated with nintedanib. And a small study published last year by Volkmann and her colleagues found that FAPI PET uptake correlated with histopathology findings in patients with advanced ILD, which “gives us hope that what we’re seeing on the PET imaging signifies something going on biologically.”

Promising investigational therapies, Volkmann said at the RWCS, include soluble guanylate cyclase (SGC) activators, which stimulate the production of cyclic guanosine monophosphate — thus inhibiting fibrosis — and agents that inhibit B cell survival and differentiation. A phase 2 trial of an SGC activator in progressive SSc is currently underway, and a phase 2 study of belimumab vs placebo in diffuse cutaneous SSc has recently been completed. In both studies, FVC is a primary endpoint.

Overall, for SSc and other autoimmune diseases, chimeric antigen receptor–based cellular therapies hold promise for more sustained remission and an opportunity to prevent the need for lifelong immunomodulatory therapy, Volkmann noted, referencing a 2024 published study.

Volkmann disclosed consulting for AbbVie, Boehringer Ingelheim, and GSK; speaking for Boehringer Ingelheim; and receiving grants from AstraZeneca, GSK, and other companies.

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