The underlying systemic disease may be under control, even as pulmonary fibrosis continues to progress. This pattern characterizes progressive pulmonary fibrosis (PPF), a phenotype in which tissue remodeling advances independently of the original disease trigger. Approximately 30% of patients with fibrotic interstitial lung disease (ILD) experience this course. Delayed recognition may leave patients receiving immunosuppressive treatment, which no longer prevents functional decline.

What links systemic sclerosis, rheumatoid arthritis, myositis, and chronic hypersensitivity pneumonitis is not the origin of the disease but rather what happens when the lungs are affected.

Speaking with Medscape’s Portuguese edition, Maria Raquel Soares, MD, pulmonologist with experience in ILD in the Division of Respiratory Diseases, Department of Internal Medicine, Hospital São Paulo, Universidade Federal de São Paulo, São Paulo, Brazil, said, “The convergence of such distinct pathogenic mechanisms toward the common final pathway of interstitial lung disease occurs because these different stimuli trigger a dysregulated tissue repair response that, once initiated, becomes self-sustaining. Whether the initial trigger is exposure to inhaled antigens or a systemic autoimmune attack, the initial epithelial injury stimulates the proliferation of fibroblasts and myofibroblasts resistant to apoptosis. The critical point in idiopathic pulmonary fibrosis (IPF) is that, once fibrogenesis is established, tissue remodeling progresses autonomously, regardless of whether the inflammation has been controlled.”

However, autonomous fibrogenesis does not imply that inflammation and fibrosis develop independently. “In the vast majority of cases, inflammatory mechanisms and the progression to fibrosis occur simultaneously. There is no clear-cut, surgical-like division where inflammation stops abruptly and fibrosis begins in isolation,” said Bruno Guedes Baldi, MD, PhD, pulmonologist in the Division of Pulmonology at the Instituto do Coracao, Hospital das Clínicas, Faculty of Medicine, University of São Paulo.

Recognizing Progression and Monitoring Disease Activity

The overlap between inflammation and fibrosis complicates clinical assessment, particularly for connective tissue diseases. ILD affects up to 70% of patients with systemic sclerosis and is the leading cause of disease-related death. Approximately one third of these patients develop a progressive phenotype, consistent with estimates published in The New England Journal of Medicine in 2020.

“Monitoring with high-resolution computed tomography, symptom assessment, and pulmonary function testing should be performed regularly in all patients. Factors such as the diffuse cutaneous form, male sex, and the presence of the anti-topoisomerase I (anti-Scl-70) antibody increase the risk and require even more intensive screening in the first few years after diagnosis,” said Cristiane Kayser, MD, PhD, rheumatologist and coordinator of the Systemic Sclerosis Outpatient Clinic in the Rheumatology Division at the Escola Paulista de Medicina, Federal University of São Paulo.

Criteria for Progression

Joint guidelines published in 2022 by the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Asociación Latinoamericana de Tórax define PPF in patients with ILD other than IPF as the presence of at least two of the following three criteria within the previous year, without an alternative explanation:

• Worsening respiratory symptoms.
• An absolute decline in forced vital capacity (FVC) ≥ 5 percentage points of the predicted value or a decline in diffusing capacity for carbon monoxide (DLCO) ≥ 10 percentage points.
• Radiologic progression on high-resolution CT, such as increased traction bronchiectasis, new honeycombing, or more extensive reticulation.

A Brazilian retrospective multicenter cohort study provides additional evidence relevant to clinical practice in the country’s Unified Health System (SUS). Conducted at six referral centers and presented in a doctoral dissertation at the Escola Paulista de Medicina in 2025, the study analyzed 380 patients with fibrotic ILD. During follow-up, a peripheral oxygen saturation level below 90% at rest had prognostic significance comparable to that of a decline in FVC and was associated with a higher risk for disease progression (hazard ratio, 5.81; 95% CI, 3.49-9.70). This finding may be particularly useful in settings where DLCO testing is not readily available.

Follow-Up Before Functional Decline Becomes Irreversible

Waiting 12 months to confirm a decline in pulmonary function may allow the functional reserve to deteriorate irreversibly.

“There is a consensus that, at least in the first 2 years after a diagnosis of ILD, follow-up should occur every 3-6 months with serial measurements of FVC and DLCO,” Soares said. “The criteria in the guidelines refer to the last year, but that doesn’t mean we have to wait 12 months in every case. In patients with more rapid disease progression, we scheduled earlier follow-up visits to intervene before catastrophic loss [of functional reserve] occurred,” Baldi added.

A central diagnostic challenge is distinguishing an active inflammatory flare from established fibrotic remodeling. “The dissociation between systemic control and pulmonary progression is a classic warning sign,” Soares said. “The patient may have good control of joint or skin symptoms but continue to experience worsening dyspnea and functional decline.”

High-resolution CT can help distinguish between the two processes. Ground glass opacities outside fibrotic areas may indicate potentially reversible inflammation, whereas increased architectural distortion, widening of alveolar walls, and loss of lobar volume suggest established fibrosis. Serum biomarkers, such as KL-6 and CCL18, are being investigated for early risk stratification. In systemic sclerosis, changes detected using periungual capillaroscopy can provide additional information.

Antifibrotic Treatment and Integrated Care

Once PPF is confirmed, intensifying immunosuppressive treatment may not prevent further functional decline and can expose patients to substantial toxicity without altering disease progression. Therefore, treatment may need to shift toward inhibiting profibrotic pathways.

“In autoimmune diseases with persistent systemic activity, such as myositis and systemic sclerosis, an antifibrotic is often added to the maintenance immunosuppressive regimen,” Soares said. “Agents such as mycophenolate, rituximab, or tocilizumab remain necessary to control extrapulmonary manifestations.”

Evidence for Antifibrotic Therapy

Evidence supporting antifibrotic treatment in PPF includes the INBUILD trial published in The New England Journal of Medicine in 2019. This trial evaluated 663 patients with progressive fibrosing ILD, other than IPF. Nintedanib reduced the annual rate of decline in FVC by 107 mL compared with placebo, with a consistent effect across diagnostic subgroups. These findings led Brazil’s Health Regulatory Agency (Anvisa) and the FDA to approve nintedanib for this indication.

Clinical evidence also supports the safety of combining antifibrotic and immunosuppressive treatments. The SENSCIS trial, which included patients with systemic sclerosis-associated ILD, found that nintedanib combined with mycophenolate mofetil had an acceptable gastrointestinal and hepatic tolerability profile, without evidence of substantial additional toxicity, Kayser noted.

In July 2026, Anvisa approved nerandomilast (sold under the brand name Jascayd), a selective phosphodiesterase 4B inhibitor, on the basis of phase 3 studies from the FIBRONEER program published in The New England Journal of Medicine in 2025. In the FIBRONEER-IPF and FIBRONEER-ILD trials, nerandomilast significantly reduced FVC decline over 52 weeks and showed evidence of a lower risk for death than placebo. The discontinuation rates due to adverse events were similar in the treatment and placebo groups. According to the source, nerandomilast was the first new therapeutic option for IPF in more than 5 years.

Managing Adverse Effects

The management of adverse effects begins before treatment commences. “We instruct patients to take nintedanib strictly with or immediately after main meals, and we prescribe fast-acting antidiarrheals, such as loperamide, right at the start of treatment for use at the first sign of loose stools,” Soares said.

Regular monitoring of the liver function is also required. “Liver function should be monitored using transaminase levels at the start of treatment, continued monthly for the first 3 months, and subsequently every 3 months or every 4-8 weeks,” Kayser said.

Antifibrotic treatment appears to have a more consistent effect when initiated during the mild-to-moderate stages of the disease. “Although there is no absolute cutoff point, studies have focused on patients with FVC above 45% and DLCO above 30% of predicted values. Below these thresholds, we enter a scenario of very severe disease, in which the likelihood of a therapeutic response and functional recovery is drastically reduced,” Baldi warned.

Rehabilitation and Nutritional Support

Cardiopulmonary rehabilitation should begin early during the course of the disease. “Rehabilitation should be offered as soon as exercise intolerance or functional limitation is identified. It should not be delayed until advanced or end-stage disease because early intervention helps preserve functional reserve,” Soares emphasized.

Nutritional support is an integral part of care. The hypercatabolic state associated with advanced disease accelerates the loss of lean body mass, making high-protein supplementation and individualized caloric adjustments important management components.

Barriers to Treatment Access in Brazil

Disparities in access complicate the implementation of these strategies in Brazil’s public healthcare system. Access to antifibrotic drugs for PPF through the SUS remains fragmented, depending on state-specific protocols or court orders.

“With monthly costs range from 8000-13,000 Brazilian reais, the unavailability of the drug in the public health system often leaves the patient’s inclusion in clinical research protocols conducted by leading university centers as the only alternative,” Baldi said.

Coordinated Care Across Specialties

Reducing treatment delays requires direct and efficient communication between specialties. “We recommend establishing institutional priority referral pathways and holding regular clinical meetings between rheumatology and pulmonology to discuss cases involving rapid functional decline before irreversible deterioration occurs,” Soares said.

“Networking and shared decision-making through multidisciplinary discussions directly improve clinical outcomes,” Kayser concluded. “Close monitoring by both specialties for the first signs of imaging or functional decline is the only tool capable of changing the patient’s prognosis.”

Daniela Barros is a Brazilian journalist specializing in social journalism at the Pontifical Catholic University of São Paulo and is a master’s student in the Department of Social Medicine at the Ribeirão Preto Medical School in Ribeirão Preto, Brazil. She has been involved in medicine for 23 years and has contributed to several specialized publications.

This story was translated from Medscape’s Portuguese edition.