Care of the patient with a fibrosing interstitial lung disease (ILD) presents constant challenges not just in the diagnosis of ILD but in the choice of treatment. Since the FDA approval of both nintedanib and pirfenidone for the treatment of idiopathic pulmonary fibrosis (IPF) in 2014, interest has grown for their employ in treating other non-IPF ILDs. This is especially true in cases with the pattern of radiographic or histopathological disease is similar to IPF – a usual interstitial pneumonia (UIP) pattern – despite not meeting criteria for an IPF diagnosis due to the identification of a predisposing etiology. As research evolves, clinicians may have more options to fight the vast variety of fibrosing ILDs encountered in practice.
Dr. Corey Kershaw
In 2014, the publication of separate clinical trials of nintedanib and pirfenidone in patients with IPF marked a new beginning in the treatment of this disease. Nintedanib, a tyrosine kinase inhibitor with multiple targets, was shown to decrease progression of disease as measured by the annual rate of decline in forced vital capacity (FVC) (Richeldi L, et al. N Engl J Med. 2014 May;370[22]:2071-82 ). Pirfenidone, whose antifibrotic mechanisms are not completely understood, similarly slowed disease progression via a decrease in the percent change of predicted FVC ( Lederer DJ, et al. N Engl J Med. 2014 May;370[19]:2083-92 ). Clinicians were now armed with two therapeutic options following the subsequent FDA approval of both drugs for the treatment of IPF. This represented a giant leap forward in the management of the disease, as prior to 2014 the only available options were supportive care and lung transplant for appropriate candidates.
As IPF represents but 20% of ILDs in the United States, a significant proportion of diseases were left without an antifibrotic option after the arrival of nintedanib and pirfenidone. (Lederer DJ. N Engl J Med. 2018 May;378:1811-23 ). For the others, such as chronic hypersensitivity pneumonitis and the many connective tissue disease-associated ILDs, treatment revolved around a variety of anti-inflammatory pharmaceuticals. Common treatment choices include corticosteroids, mycophenolate, and azathioprine. The data in support of these treatments for non-IPF ILD is comparatively lean in contrast to the more robust pirfenidone and nintedanib IPF trials.
One notable exception includes the Scleroderma Lung Studies. In Scleroderma Lung Study II (SLS II), 142 patients with scleroderma-related interstitial lung disease were randomized to oral mycophenolate for 24 months vs oral cyclophosphamide for 12 months plus placebo for 12 months (Tashkin DP, et al. Lancet Respir Med. 2016 Sep;4(9):708-19 ). The 2006 Scleroderma Lung Study established oral cyclophosphamide in scleroderma lung disease as a reasonable standard of care after demonstrating a slowing of disease progression after 12 months of therapy (Tashkin DP, et al. N Engl J Med. 2006 Jun;354[25]:2655-66 ). In SLS II, both cyclophosphamide and mycophenolate improved lung function at 24 months, but mycophenolate was better tolerated with less toxicity.
Other supportive data for immunosuppressive treatments for non-IPF ILD rely heavily on smaller studies, case reports, and retrospective reviews. Choices of who and when to treat are often unclear and typically come from physician preferences and patient values discussions. In the cases of connective tissue disease-associated ILD, patients may already require treatment for the underlying condition. And, while some therapies could be beneficial in a concurrent manner for a patient’s lung disease, many others are not (TNF-alpha antibody therapy, for example).