Respiratory Trials·org

Topic

Interstitial lung disease

Antifibrotics in IPF and progressive fibrosing ILD, and what immunosuppression does.

Antifibrotics slow the slope; they do not reverse fibrosis. Pirfenidone (ASCEND) and nintedanib (INPULSIS) were published together in 2014 and ended the era in which IPF had no treatment. Neither individually demonstrated a mortality benefit. That distinction is the substance of every honest conversation with a newly diagnosed patient.

The regimen they replaced had itself been endorsed by a positive trial. Acetylcysteine added to prednisone and azathioprine slowed decline in vital capacity and DLCO (IFIGENIA) — but both arms received that background regimen, so the trial never tested it.

Then came the most important negative trial in the field. The standard regimen of prednisone, azathioprine and N-acetylcysteine — recommended for decades on reasoning about inflammation — produced eight deaths against one and 23 hospitalisations against seven at the halfway point, with no benefit (PANTHER-IPF). Immunosuppression is not universally wrong in ILD; it is wrong in IPF.

The field then stopped enrolling by diagnosis and started enrolling by behaviour. INBUILD took fibrosis that was progressing, whatever its cause, and found nintedanib slowed decline anyway — creating progressive pulmonary fibrosis as a treatable entity. Nintedanib also works in scleroderma-associated ILD, though the result there is fragile under sensitivity analysis and nothing outside the lung improved (SENSCIS).

Newer agents add to what patients already take, which is the real advance. Nerandomilast slowed FVC decline in IPF with three quarters of participants on background antifibrotics (FIBRONEER-IPF) and in progressive pulmonary fibrosis (FIBRONEER-ILD). Inhaled treprostinil did the same in IPF without requiring pulmonary hypertension (TETON-2).

Immunosuppression has not disappeared. In inflammatory NSIP-pattern disease, adding rituximab to mycophenolate improved lung function and progression-free survival, at the cost of viral infection (EVER-ILD). In pulmonary sarcoidosis, methotrexate matched prednisone as first-line treatment, so the choice can now be made on side effects (PREDMETH).

Antifibrotics beyond IPF

Trial Year Therapy Effect Finding
FIBRONEER-ILD 2025 Nerandomilast Nerandomilast slowed FVC decline in progressive pulmonary fibrosis, including on top of nintedanib
INBUILD subgroups subgroup analysis 2020 Nintedanib Nintedanib's benefit in progressive fibrosing ILD held across diagnoses, though no subgroup was individually powered
INBUILD 2019 Nintedanib Nintedanib slowed FVC decline across progressive fibrosing ILD, whatever the underlying diagnosis
SENSCIS 2019 Nintedanib Nintedanib slowed lung function decline in scleroderma ILD, but the result is fragile and skin disease was unchanged

Antifibrotics in IPF

Trial Year Therapy Effect Finding
TETON-2 2026 Inhaled treprostinil Inhaled treprostinil slowed FVC decline in IPF, in patients mostly already on antifibrotics
FIBRONEER-IPF 2025 Nerandomilast Nerandomilast slowed FVC decline on top of existing antifibrotics — the first genuinely additive agent in IPF
ASCEND 2014 Pirfenidone Pirfenidone slowed FVC decline and improved progression-free survival in IPF
INPULSIS 2014 Nintedanib Nintedanib roughly halved the annual rate of FVC decline in IPF, at the cost of diarrhoea

Immunosuppression in IPF

Trial Year Therapy Effect Finding
PANTHER-IPF 2012 Prednisone, azathioprine and N-acetylcysteine The standard immunosuppressive regimen for IPF was killing patients
IFIGENIA 2005 N-acetylcysteine Acetylcysteine slowed lung function decline when added to prednisone and azathioprine — a background regimen later shown to be lethal

Obtaining a tissue diagnosis

Trial Year Therapy Effect Finding
COLD 2024 Step-up cryobiopsy strategy Cryobiopsy first, surgery only if needed, matched immediate surgery with less burden
COLDICE 2020 Transbronchial lung cryobiopsy Cryobiopsy agreed closely with surgical lung biopsy, especially when the diagnosis was made with high confidence

How IPF progresses

Trial Year Therapy Effect Finding
Martinez 2005 2005 Observation within a randomised trial IPF killed a fifth of patients while their lung function looked stable, often after an acute deterioration

Immunosuppression in connective tissue ILD

Trial Year Therapy Effect Finding
EVER-ILD 2023 Rituximab plus mycophenolate Adding rituximab to mycophenolate improved lung function in NSIP-pattern ILD, with more viral infection

Treating pulmonary sarcoidosis

Trial Year Therapy Effect Finding
PREDMETH 2025 Methotrexate Methotrexate matched prednisone as first-line treatment for pulmonary sarcoidosis, with a different side-effect profile

Key references

Guidelines, standards and reviews for this topic.