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Overview of Idiopathic Pulmonary Fibrosis, Evidence-Based Guidelines, and Recent Developments in the Treatment Landscape
Marilyn K. Glassberg, MD
Participating Faculty

Overview of Idiopathic Pulmonary Fibrosis, Evidence-Based Guidelines, and Recent Developments in the Treatment Landscape

Marilyn K. Glassberg, MD
1 AE, with dyspepsia (36.4%), nausea (27.3%), and rash/photosensitivity (24.2%) being the most common. Notably, 26.7% of patients required a dose adjustment.52 Results of a retrospective observational intent-to-treat study found that pirfenidone was associated with significantly longer survival compared with an IPF cohort from a tertiary referral center (HR, 0.28; 95% CI, 0.16-0.48; P <.0001) after adjusting for age, gender, and FVC, as well as exclusion of severe cases (DLCO <30%).53 The guidelines highlight that the optimal duration of therapy with either antifibrotic treatment is unknown, as is the endurance of treatment effects with ongoing therapy.34,35

New Frontiers for Pirfenidone and Nintedanib

The use of pirfenidone as add-on therapy to nintedanib was compared with the use of nintedanib alone in patients with IPF.54 After 12 weeks of treatment, patients who received pirfenidone plus nintedanib demonstrated significantly less decline in mean FVC from baseline compared with nintedanib alone (–13.3 mL vs –40.9 mL). GI AEs occurred in 69.8% of patients treated with pirfenidone plus nintedanib and in 52.9% of those treated with nintedanib alone, in line with the safety profiles of each drug.54 Although this study supports the potential of combination pirfenidone–nintedanib therapy for patients with IPF, more evidence supporting these outcomes is necessary.

Due to the similarities between IPF and other ILDs, pirfenidone and nintedanib are currently undergoing clinical development targeting other fibrotic lung diseases. Both agents are undergoing phase 3 trials for use in SSc-ILD, an ILD found in patients with SSc with no currently approved treatment.55 Pirfenidone and nintedanib are also being explored in patients with RA-ILD. Despite the availability of drugs with proven articular benefit, none has been demonstrated to affect RA-ILD. Unfortunately, some of the RA-targeted immunotherapies have been implicated in the ex novo occurrence and acceleration of ILDs.56 The benefits demonstrated by pirfenidone and nintedanib may extend to other fibrotic lung diseases, and pharmacists should bear in mind the potential for expanded use of these agents in the coming years.

Antacid Therapy

Because GERD has been implicated as a potential inciting factor in IPF pathogenesis and worsening, antacid therapy (AAT) with proton pump inhibitors (PPIs) or histamine-2 receptor antagonists may provide benefit to patients with IPF; however, the guidelines note a “very low” confidence in effect estimates for the use of these agents.3,34 The guideline recommendations are based on outcomes from observational and retrospective studies in which the use of AAT was shown to decrease the decline in FVC and improve survival in patients with IPF.57,58 More recently, a post hoc analysis of patients with IPF who received pirfenidone in 3 clinical trials evaluated outcomes between those on AAT compared with those not taking AAT (non-AAT). After 52 weeks in the trials, investigators found no significant difference in disease progression, all-cause mortality rate, IPF-related mortality rate, all-cause hospitalization rate, or mean change in percent FVC. Although a relative FVC decline of greater than 10% significantly favored AAT (P = .03), severe GI AEs and pulmonary infections were also more frequent with AAT (P = .015 and P = .035, respectively).40 Similarly, a post hoc analysis of AAT use in patients with IPF who received nintedanib or placebo found that AAT use at baseline did not impact disease course.49 Despite evidence to the contrary, a meta-analysis of 8 observational studies found that pharmacologic treatment of GERD in patients with IPF was associated with a significant reduction in IPF-related mortality compared with no GERD treatment (HR, 0.60; 95% CI, 0.38-0.97; P = .04), but all-cause mortality did not differ between groups.59

AEs associated with long-term use of PPIs include infection, hypomagnesemia, and myocardial infarction.3 Clinicians must weigh the potential AEs associated with long-term use of AAT against the outcomes supported by the literature.27

Combined ILD/PH: Approaches to treatment

A current clinical trial addresses the use of inhaled nitric oxide in the management of patients with IPF and PH.60 The INSTAGE trial studied the efficacy and safety of nintedanib plus sildenafil versus nintedanib monotherapy in patients with more advanced IPF and severe impairment in gas exchange (n = 274) (DLCO ≤35% predicted). Subjects did not show significant improvement in change from baseline in St George’s Respiratory Questionnaire total score at week 12 (primary end point) compared with nintedanib therapy alone. The change in FVC from baseline to 12 and 24 weeks in patients treated with nintedanib alone was –25.5 mL and –58.2 mL, respectively. These results, although not statistically significant, suggest that nintedanib may also have effects on lung function decline in patients with more advanced disease.33

Emerging Therapies

The approvals of pirfenidone and nintedanib substantially altered the treatment landscape of IPF; although these agents slow the decline in lung function, they do not provide a cure for IPF. Several novel agents are currently undergoing clinical development in the hopes that they will provide additional therapeutic options to patients living with this disabling and deadly disease. A multitude of therapeutic targets are currently being explored with hypothesized effects on the clinical course of IPF.61 Although many of these agents are still in the early phases of development, awareness of emerging therapies is an important component of effective patient care. These agents may offer patients hope of improved outcomes through potential enrollment in clinical trials and/or access to alternative therapeutic options once the agents are FDA approved.


Approximately 3 million people worldwide are living with IPF, a chronic, progressive lung disease with substantial morbidity and mortality burdens. The median survival of patients with IPF is 3 to 5 years, and many patients experience unacceptable delays in recognition, diagnosis, and treatment of the disease, which greatly impacts prognosis. Two antifibrotic agents, pirfenidone and

nintedanib, have demonstrated efficacy in slowing the decline of lung function, reducing acute exacerbations, increasing quality of life, and/or improving mortality. The potential for AEs must also be weighed against the benefits of these agents. An in-depth knowledge of the pathogenesis of IPF and outcomes from clinical trials and real-world studies is necessary to understand the role of antifibrotic therapy along with emerging agents in effective IPF management. Ultimately, patient education and counseling are key in the shared decision-making model necessary for the management of a chronic, debilitating disease that has no cure. By applying current guideline recommendations, clinical data, and prescribing information, pharmacists in clinical and managed care positions will be better prepared to improve outcomes for patients with IPF. 

Author affiliation: University of Miami Miller School of Medicine, Miami, FL.
Funding source: This activity is supported by an educational grant from Genentech, Inc.
Author disclosure: Dr Glassberg has the following relevant financial relationships with commercial interests to disclose:
CONSULTANT: Genentech/Roche, Boehringer Ingelheim, Bellerophon, Redx Pharma, Bristol-Myers Squibb
Authorship information: Analysis and interpretation of data; concept and design; critical revision of the manuscript for important intellectual content; drafting of the manuscript; supervision.
Address correspondence to:
Medical writing and editorial support: Rachel Brown, PharmD, MPH.
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