Comments
Abstract
Background: The American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Asociación Latinoamericana del Tórax convened to update clinical practice guidelines for interstitial lung disease (ILD).
Objective: To conduct a systematic review to evaluate existing ILD literature to determine whether patients with progressive pulmonary fibrosis (PPF) should be treated with the antifibrotic pirfenidone.
Data Sources: A literature search was conducted across MEDLINE, EMBASE, and Cochrane databases through December 2020 for studies using pirfenidone to treat patients with PPF.
Data Extraction: Mortality, disease progression, lung function, and adverse event data were extracted. Meta-analyses were performed when possible. The Grading of Recommendations, Assessment, Development and Evaluation Working Group approach was used to assess the quality of evidence.
Synthesis: Two studies met inclusion criteria. Meta-analyses revealed that changes in forced vital capacity (FVC) percent predicted (mean difference [MD], 2.3%; 95% confidence interval [CI], 0.5-4.1%), the FVC in milliliters (MD, 100.0 ml; 95% CI, 98.1-101.9 ml), and the 6-minute-walk distance in meters (MD, 25.2 m; 95% CI, 8.3-42.1 m) all favored pirfenidone over placebo. The changes in the diffusing capacity of the lung for carbon monoxide (DLCO) in millimoles per kilopascal per minute (MD, 0.40 mmol/kPa/min; 95%, CI 0.10-0.70 mmol/kPa/min) and risk of DLCO declining more than 15% (relative risk [RR], 0.27; 95% CI, 0.08-0.95) also favored pirfenidone. The risks of gastrointestinal discomfort (RR, 1.83; 95% CI, 1.29-2.60) and photosensitivity (RR, 4.88; 95% CI, 1.09-21.83) were higher with pirfenidone. The quality of the evidence was low or very low according to the Grading of Recommendations, Assessment, Development and Evaluation criteria, depending on the outcome.
Conclusions: Pirfenidone use in patients with PPF is associated with a statistically significant decrease in disease progression and with protection of lung function. However, there is very low certainty in the estimated effects because of limitations in the available evidence.
Primary Source of Funding: Funded by the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Asociación Latinoamericana del Tórax.
The American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS), and Asociación Latinoamericana del Tórax (ALAT) convened an expert committee in 2021 to update the 2015 guidelines on interstitial lung disease (ILD) that recommended the use of antifibrotic therapy for the treatment of idiopathic pulmonary fibrosis (IPF), the prototypical ILD associated with progressive lung fibrosis (1, 2). However, the guideline committee recognized that 1) there is growing interest in non-IPF ILDs that exhibit progressive lung fibrosis, 2) there are similarities in the pathophysiology and clinical characteristics of IPF and non-IPF ILDs (2–8), and 3) there exists an unmet need for guidance on management of such ILDs in patients (9–12). Therefore, the 2021 guideline project expanded to address non-IPF ILDs manifesting progressive pulmonary fibrosis (PPF), also termed “progressive fibrotic ILD” in the literature (1, 3, 5).
PPF is defined as the presence of two or more of the following: 1) physiologic evidence of disease progression (measured by using pulmonary function tests [PFTs]), 2) radiologic evidence of disease progression, or 3) worsening respiratory symptoms, all with no alternative explanations, in patients with ILD who have radiologic evidence of pulmonary fibrosis. A detailed definition of PPF can be found in the official 2022 ILD guideline (13). PPF as a feature of ILD portends a poor prognosis, with patients experiencing early mortality in addition to increased respiratory symptoms and worsened lung function (2, 3, 7, 8, 14, 15). Although treatment for IPF entails the use of antifibrotic therapies to slow the progression of disease, the effect of antifibrotic agents on non-IPF ILDs exhibiting PPF has not been well established (1, 5, 9, 10, 12, 16, 17). As noted by Wells and colleagues (11) in 2018, these “non-IPF patients with inexorably progressive fibrotic disease [are] currently disenfranchised by lack of access to agents that are efficacious in IPF.”
Given the underlying similarities in the pathogenesis of lung fibrosis theorized to exist between IPF and other types of PPF, it is plausible that antifibrotic agents may also have utility in slowing disease progression in other types of PPF (5, 9–12, 15). One such antifibrotic agent, pirfenidone, is an oral agent with antiinflammatory, antioxidative, and antiproliferative effects that received approval for IPF treatment in Japan, Europe, and the United States between 2008 and 2014 (1, 17). To inform the 2022 ATS, ERS, JRS, and ALAT clinical guideline on ILD, this systematic review looks at the existing literature to determine whether patients with non-IPF PPF should be treated with pirfenidone.
This systematic review was conducted to provide evidence for the ATS, ERS, JRS, and ALAT 2022 clinical practice guidelines on ILD. It was registered with the International Prospective Register of Systematic Reviews database (registration number CRD42020205371) and conducted in accordance with the Cochrane Handbook for Systematic Reviews of Interventions (18). The overarching research question asked by the guideline committee was “Should patients with PPF be treated with pirfenidone?”
Given that many specific subtypes of ILDs can exhibit a PPF pattern, for a more comprehensive approach to the topic, the broader research question was broken down to address ILDs on the basis of their radiologic pattern (usual interstitial pneumonia [UIP] vs. non-UIP patterns of pulmonary fibrosis) and ILD subtype. This resulted in eight more specific questions that were addressed in addition to the overarching question: 1) “Should patients with PPF and a radiographic UIP pattern of pulmonary fibrosis be treated with pirfenidone?”, 2) “Should patients with PPF and radiographic non-UIP patterns of pulmonary fibrosis be treated with pirfenidone?”, 3) “Should patients with progressive fibrotic hypersensitivity pneumonitis be treated with pirfenidone?”, 4) “Should patients with progressive fibrotic connective tissue disease–related ILD (CTD-ILD) be treated with pirfenidone?”, 5) “Should patients with progressive fibrotic idiopathic nonspecific interstitial pneumonia (NSIP) be treated with pirfenidone?”, 6) “Should patients with progressive fibrotic sarcoidosis be treated with pirfenidone?”, 7) “Should patients with progressive fibrotic occupational ILD be treated with pirfenidone?”, and 8) “Should patients with progressive unclassified fibrotic ILDs be treated with pirfenidone?”
In these questions, the populations are patients with different subtypes of ILDs that can manifest as PPF. The intervention is pirfenidone, and the comparator is a placebo. Outcomes were selected and prioritized in accordance with the 2015 guideline on the treatment of IPF. Critical outcomes included mortality and disease progression (determined by using changes in the forced vital capacity [FVC] on PFTs). Important outcomes included lung function (determined by using changes in the diffusing capacity of the lung for carbon monoxide [DlCO], forced expiratory volume in 1 second [FEV1], and total lung capacity on PFTs and by using the distance walked during the 6-minute-walk test, or the 6-minute-walk distance [6MWD]), respiratory symptoms (determined by using changes in the St. George’s Respiratory Questionnaire [SGRQ], University of California at San Diego Shortness of Breath Questionnaire [UCSD-SOBQ], Leicester Cough Questionnaire [LCQ], or the cough visual analog scale [VAS] scores), and adverse events (AEs) (1).
The literature search was conducted with assistance of a medical librarian across Medline, Embase, and Cochrane Central Register of Controlled Trials databases with a broad focus on pirfenidone use in fibrotic ILDs through December 2020. In addition, one study (19) meeting our search criteria that was accepted for publication but still in press before the conclusion of this review was included (Figure 1). Two authors independently screened all studies, from title to full-text screens, and disagreements were resolved by consensus. Studies that enrolled patients with PPF and provided treatment with pirfenidone were included. To document PPF at enrollment, studies were required to include documented evidence of disease progression as part of their selection criteria. The reason for this strict criteria is that disease progression is a defining parameter of PPF, as noted in the official 2022 guideline (13), so patients with stable disease needed to be excluded. Randomized controlled trials were prioritized.
Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-analyses flow diagram. IPF = idiopathic pulmonary fibrosis.
[More] [Minimize]Once studies were selected for inclusion, two authors extracted data, which were verified for accuracy by additional authors. Extracted data included key study background characteristics (including the year, location, study type, duration, and funding source), population characteristics (including diagnostic criteria for PPF, subtypes of ILD, and the number of patients in the intervention and control arms), and all relevant outcomes (Table 1). When possible, data from individual studies were pooled to create a meta-analysis by using the generic inverse variance method; RStudio version 4.1.0 was used for all calculations. Individual effect estimates were pooled by using random-effect models. Relative risk (RR) scores were obtained to report the results for binary outcomes, mean differences (MDs) were obtained to report the results for continuous outcomes, and these were accompanied by 95% confidence intervals (CIs). Statistical heterogeneity of treatment effects across subpopulations was assessed by using the I2 test, with an I2 value of 50% or higher indicating significant heterogeneity.
| Study (Reference) | Year | Location | Funding | Duration | PPF Diagnostic Criteria | ILD Subtypes | Study Population | Intervention | Comparator | Study Outcomes | Risk of Bias |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Maher (21) | 2020 | Fourteen countries: Australia, Belgium, Canada, Czech Republic, Denmark, Germany, Greece, Ireland, Israel, Italy, Poland, Portugal, Spain, and UK | F. Hoffmann, La Roche Pharmaceutical Co. | 24 wk | Adults with fibrosing unclassifiable ILD other than IPF and the presence of 1) FVC predicted decline of at least 5% in the 12 mo preceding enrollment or 2) significant symptomatic worsening not due to other causes as determined by the investigator in the 6 mo preceding enrollment | Unclassifiable | Total patients: 253; intervention: 127; placebo: 126 | Pirfenidone, 801 mg three times daily (2,403 mg total daily) | Placebo, three tablets three times daily | Primary: predicted mean change in the FVC as measured by using home spirometry (unable to analyze because of variability). Secondary: 1) Change in the FVC predicted as measured by using site spirometry, 2) 5% FVC decline, 3) 10% FVC decline, 4) DlCO, 5) 6MWD, 6) UCSD-SOBQ score, 7) LCQ score, 8) cough VAS, 9) SGRQ score, 10) hospital admission, 11) acute exacerbation, 12) progression-free survival, and 13) time to death; adverse events | Not serious |
| RELIEF (19) | 2021 | Germany, 17 Sites | German Center for Lung Research and Roche Pharmaceuticals | 48 wk | Adults with diagnosed fibrosing ILD other than IPF and annual FVC decline of at least 5% predicted assessed by at least three FVC measurements in the 6–24 mo preceding enrollment | 1) Chronic (fibrotic) HP; 2) collagen vascular (connective tissue) disease– related RA, SSc, Sjogren syndrome, PM or DM, or MCTD; 3) NSIP; and 4) asbestosis-induced lung fibrosis; results were not reported by subtypes because of small sample sizes | Total patients: 127; intervention: 64; placebo: 63; stopped because of futility triggered by slow recruitment (36.5% of intended 374 enrolled) | Pirfenidone, 534 to 801 mg three times daily (up to 2,403 mg daily) | Placebo, three tablets three times daily | Primary: absolute change in the FVC% predicted from baseline; Secondary: 1) DlCO, 2) exercise capacity as measured by using the 6MWD; 3) time to clinical deterioration; 4) progression-free survival; 5) FVC change of at least 5% predicted; 6) FVC change of at least 10% predicted; and 7) quality of life as measured by using the SGRQ; adverse events | Not Serious* |
The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach was used to assess the certainty of evidence (very low, low, moderate, or high) for each intervention on the outcomes of interest. Study quality was downgraded for a high risk of bias (poor internal validity), inconsistency in data (significant heterogeneity), indirectness in relation to interventions and outcomes of interest, the imprecision of results (wide CIs), and the likelihood of publication bias (20). The effect estimates of the study outcomes with the corresponding assessments of quality are summarized in Table 2, Table 3, and the evidence profile table available in the online supplement (see Table E2 in the online supplement), which was used by the guideline panel to inform their recommendations.
| ILD Subset | FVC% Predicted MD (95% CI); Arm Favored; Evidence Quality | FVC MD (95% CI) (ml); Arm Favored; Evidence Quality | FVC Decline >5% RR (95% CI); Arm Favored; Evidence Quality | FVC Decline >10% RR (95% CI); Arm Favored; Evidence Quality | Mortality RR (95% CI); Arm Favored; Evidence Quality |
|---|---|---|---|---|---|
| All patients with PPF (pirfenidone = 162, control = 158) | 2.3 (0.5–4.1)*; pirfenidone; very low | 100.0 (98.1–101.9)*; pirfenidone; very low | 0.63 (0.48–0.83)*; pirfenidone; low | 0.53 (0.31–0.88)*; pirfenidone; low | 0.20 (0.02–1.64); neither; low |
| Radiographic UIP | N/A | N/A | N/A | N/A | N/A |
| Radiographic non-UIP | N/A | N/A | N/A | N/A | N/A |
| Fibrotic HP | N/A | N/A | N/A | N/A | N/A |
| Fibrotic CTD–related | N/A | N/A | N/A | N/A | N/A |
| Fibrotic idiopathic NSIP | N/A | N/A | N/A | N/A | N/A |
| Fibrotic sarcoidosis | N/A | N/A | N/A | N/A | N/A |
| Fibrotic occupational | N/A | N/A | N/A | N/A | N/A |
| Unclassified fibrotic (pirfenidone = 127, control =124) | 2.10 (0.09–4.11)*; pirfenidone; low | 100.0 (98.1–101.9)*; pirfenidone; low | 0.63 (0.48–0.83)*; pirfenidone; low | 0.53 (0.31–0.88)*; pirfenidone; low | N/A |
| ILD Subset | MD or RR (95% CI) | Arm Favored | Evidence Quality |
|---|---|---|---|
| All patients with PPF (pirfenidone = 162, control = 158) | |||
| PFT result change | |||
| DlCO, MD, mmol/kPa/min | 0.40 (0.10 to 0.70)* | Pirfenidone | Low |
| DlCO decline >15%, RR | 0.27 (0.08 to 0.95)* | Pirfenidone | Low |
| DlCO% predicted, MD | 1.80 (−0.17 to 3.77) | Neither | Low |
| FEV1, MD, ml | 50 (−50 to 140) | Neither | Low |
| TLC, MD, L | 0.20 (0.0 to 0.4) | Neither | Low |
| 6MWD | |||
| Mean change, MD, m | 25.2 (8.3 to 42.1)* | Pirfenidone | Low |
| Patients with >50-m decline, RR | 1.02 (0.69 to 1.51) | Neither | Low |
| Questionnaire scores, MD | |||
| SGRQ | −1.1 (−4.2 to 2.1) | Neither | Low |
| UCSD-SOBQ | −0.09 (−5.95 to 5.77) | Neither | Low |
| LCQ | 0.32 (−0.57 to 1.21) | Neither | Low |
| Cough VAS | −3.30 (−10.91 to 4.31) | Neither | Low |
| AEs, RR | |||
| GI discomfort | 1.83 (1.29 to 2.60)* | Control | Low |
| Photosensitivity | 4.88 (1.09 to 21.8)* | Control | Low |
| Treatment-emergent AE leading to treatment discontinuation | 3.71 (1.43 to 9.63)* | Control | Low |
| Treatment-related, treatment-emergent AE leading to treatment discontinuation | 15.62 (2.10 to 116)* | Control | Low |
| Any treatment-emergent AE | 1.16 (1.06 to 1.27)* | Control | Low |
| Any treatment-related, treatment-emergent AE | 1.54 (1.24 to 1.92)* | Control | Low |
| Other GI and respiratory AEs† | — | Neither | — |
| Unclassified fibrotic subset (pirfenidone = 127, control =124)‡ | |||
| PFT result change | |||
| DlCO decline >15%, RR | 0.27 (0.08 to 0.95)* | Pirfenidone | Low |
| DlCO% predicted, MD | 1.80 (−0.17 to 3.77) | Neither | Low |
| 6MWD | |||
| Mean change, MD, m | 24.7 (6.48 to 42.9)* | Pirfenidone | Low |
| Patients with >50-m decline, RR | 1.02 (0.69 to 1.51) | Neither | Low |
| Questionnaire scores, MD | |||
| SGRQ | −0.80 (−4.31 to 2.71) | Neither | Low |
| UCSD-SOBQ | −0.09 (−5.95 to 5.77) | Neither | Low |
| LCQ | 0.32 (−0.57 to 1.21) | Neither | Low |
| Cough VAS | −3.30 (−10.91 to 4.31) | Neither | Low |
| AEs, RR | |||
| Weight loss | 9.76 (1.27 to 75.14)* | Control | Low |
| GI discomfort | 1.83 (1.29 to 2.60)* | Control | Low |
| Photosensitivity | 4.88 (1.09 to 21.8)* | Control | Low |
| Treatment-emergent AE leading to treatment discontinuation | 3.71 (1.43 to 9.63)* | Control | Low |
| Treatment-related, treatment-emergent AE leading to treatment discontinuation | 15.62 (2.10 to 116)* | Control | Low |
| Any treatment-emergent AE | 1.16 (1.06 to 1.27)* | Control | Low |
| Any treatment-related, treatment-emergent AE | 1.54 (1.24 to 1.92)* | Control | Low |
| Other GI and respiratory AEs† | — | Neither | — |
The literature review resulted in 1,154 total articles, of which 975 were excluded upon the initial title and abstract screen (Figure 1). From the remaining 179, full-text review resulted in the inclusion of two articles for data extraction (Table 1) (19, 21). The primary reason for the exclusion of studies was the lack of documented progression of disease as an a priori criterion within the studies for inclusion. A pilot study evaluating the efficacy and safety of pirfenidone in 34 patients with systemic sclerosis–related ILD and an observational study on 14 patients with fibrotic hypersensitivity pneumonitis are examples of studies that were excluded for this reason (22, 23).
The first study included is a phase II randomized controlled trial by Maher and colleagues published in 2020 (21) that observed 253 patients across 14 countries over a 24-week period to assess the impact of pirfenidone on the change from baseline in the FVC, DlCO, 6MWD, SGRQ score, UCSD-SOBQ score, LCQ score, and cough VAS score as well as in hospital admissions, acute exacerbations, progression-free survival, the time to death, and AEs. The study looked at adults with fibrosing unclassifiable ILDs other than IPF. PPF was confirmed in study participants by documenting the presence of an FVC predicted decline of at least 5% in the 12 months preceding study enrollment or of significant symptomatic worsening not due to other causes, as determined by the study investigator, in the 6 months preceding study enrollment. The primary endpoint was the mean predicted change in the FVC based on home spirometry readings, but variability in the readings precluded prespecified statistical analysis (21).
The second study is the RELIEF (Pirfenidone in Patients with Progressive Fibrotic ILDs Other Than IPF) trial by Behr and colleagues (19). It is a randomized controlled trial that looked at 127 patients across 17 sites in Germany over 48 weeks to assess the impact of pirfenidone on the change from baseline in the FVC, DlCO, 6MWD, and SGRQ score as well as the time to clinical deterioration, progression-free survival, and AEs. This study included patients with chronic (or fibrotic) hypersensitivity pneumonitis, collagen vascular disease–related ILD (or CTD-ILD), idiopathic NSIP, and asbestosis-induced lung fibrosis, but subgroup analyses were not performed because of small sample sizes within each ILD subtype. PPF was confirmed in study participants by documenting a decline of at least 5% in the percent-predicted FVC in the 6 to 24 months preceding study enrollment, assessed over three PFT measurements. The study ended early because of futility triggered by slow recruitment due to the strict enrollment criteria (36.5% of the intended 374 participants were enrolled). The primary endpoint was the change in the percent-predicted FVC over 48 weeks. The authors imputed missing data, ran sensitivity analyses by using prespecified models, and concluded that early stopping did not have a significant impact on the direction of treatment effects or the inferences that can be drawn from the trial (19).
Regarding the research questions, the data in Maher and colleagues’ 2020 study (21) and the RELIEF trial (19) have relevance to and, therefore, help answer the overarching question, “Should patients with PPF be treated with pirfenidone?” In addition, Maher and colleagues (21) enrolled patients with fibrosing unclassifiable ILD in their 2020 study, making their data relevant to the question, “Should patients with progressive unclassified fibrotic ILDs be treated with pirfenidone?” Aside from these two specific questions, the included studies do not have the information that is necessary to address the rest of the questions.
Although the RELIEF trial (19) enrolled patients with fibrotic hypersensitivity pneumonitis, CTD-ILD, and idiopathic NSIP, the data cannot be used to address the current study questions focused on these ILD subtypes because the reported data are not differentiated by ILD subtype. This applies to sarcoidosis and occupational ILD as well, which neither study address. Lastly, these studies do not specifically address or differentiate patients by radiographic UIP or non-UIP patterns of pulmonary fibrosis. Maher and colleagues (2020 study) (21) noted that study participants had at least 10% fibrosis on high-resolution computed tomography images of the lung, but there were no additional specifics on the pattern of fibrosis.
A summary of the critical outcomes for all patients with PPF and for the subset of patients with unclassified fibrotic ILD can be found in Table 2. The key critical outcomes extracted from the available studies were the mean change in FVC% predicted, the mean change in the FVC in milliliters, the risk of an FVC decline >5%, the risk of an FVC decline >10%, and mortality. A total of 320 participants were analyzed for the all-PPF arm, and a total of 251 patients were analyzed for the unclassified fibrotic ILD arm.
For all patients with PPF, a meta-analysis of the mean change in the FVC% predicted (Figure 2) from Maher and colleagues’ 2020 study (21) and the raw, unimputed data from the RELIEF trial (19) revealed the magnitude of the decrease in the FVC% predicted to be significantly smaller for patients receiving pirfenidone than for patients receiving a placebo (MD, 2.3%; 95% CI, 0.5 to 4.1). This parallels findings favoring pirfenidone that the authors of the RELIEF trial found in their primary analysis, in which they supplemented data that were missing because of early study termination with imputed FVC% predicted values by using the Hodges-Lehman estimate (MD, 1.69; 95% CI, −0.65 to 4.03; P = 0.043). However, because of serious risk of bias, indirectness, and imprecision of the data, the results for these outcomes are based on very-low-quality evidence as per GRADE criteria (20).
Figure 2. Meta-analysis of the mean change in the FVC% predicted. CI = confidence interval; DlCO = diffusing capacity of the lung for carbon monoxide; FVC = forced vital capacity; l2 = percentage of variation across studies due to heterogeneity; ILD = interstitial lung disease; MD = mean difference; NA = not applicable; PPF = progressive pulmonary fibrosis; RELIEF = Pirfenidone in Patients with Progressive Fibrotic ILDs Other Than Idiopathic Pulmonary Fibrosis; UIP = usual interstitial pneumonia.
[More] [Minimize]A second meta-analysis looking at the change in the FVC in milliliters (Figure 3) for all patients with PPF found the magnitude and direction of change to be statistically significant and in favor of pirfenidone over a placebo (MD, 100.0 ml; 95% CI, 98.1–101.9 ml) (very low quality of evidence). Maher and colleagues (2020 study) (21) also found that the pirfenidone arm had a lower risk of the FVC declining more than 5% (RR, 0.63; 95% CI, 0.48–0.83) or more than 10% (RR, 0.53; 95% CI, 0.31–0.88) when compared with the placebo arm (low quality of evidence). Likewise, the predicted FVC change from baseline in milliliters as measured by using study-site spirometry (MD, 95.3 ml; 95% CI, 35.9–154.6 ml) and home spirometry (MD, 69.3 ml; 95% CI, 40.11–98.49) favored the pirfenidone arm (low quality of evidence).
Figure 3. Meta-analysis of the mean change in the FVC in milliliters. CI = confidence interval; DLCO = diffusing capacity of the lung for carbon monoxide; FVC = forced vital capacity; l2 = percentage of variation across studies due to heterogeneity; ILD = interstitial lung disease; MD = mean difference; NA = not applicable; PPF = progressive pulmonary fibrosis; RELIEF = Pirfenidone in Patients with Progressive Fibrotic ILDs Other Than Idiopathic Pulmonary Fibrosis; UIP = usual interstitial pneumonia.
[More] [Minimize]There was no significant difference in the risk for mortality at 48 weeks seen in the RELIEF trial (19) between the pirfenidone and placebo arms (RR, 0.20; 95% CI, 0.02–1.64). There was also no statistically significant difference in progression-free survival (with progression including death, an FVC% predicted decline of at least 10%, and a hemoglobin-corrected DlCO% predicted decline of at least 15%) at 400 days (log rank P = 0.20). These were based on low-quality evidence.
The above patterns persisted with the unclassified fibrotic ILD arm of this systematic review, as the majority of data contributing to the all-PPF group was obtained from Maher and colleagues’ 2020 study (21). In comparing patients receiving pirfenidone with those receiving a placebo in the 2020 study by Maher and colleagues (21), the mean change in the FVC% predicted points toward a lower-magnitude decline in the pirfenidone group that reaches statistical significance (MD, 2.10%; 95% CI, 0.09–4.11%). The mean change in the FVC in milliliters similarly points toward a significant difference in favor of pirfenidone over a placebo (MD, 100.0 ml; 95% CI, 98.1–101.9 ml). In addition, the pirfenidone arm had a lower risk of the FVC declining more than 5% (RR, 0.63; 95% CI, 0.48–0.83) or more than 10% (RR, 0.53; 95% CI, 0.31–0.88) when compared with the placebo arm. Lastly, the predicted FVC changes from baseline in milliliters as measured by using study-site spirometry (MD, 95.3 ml; 95% CI, 35.9–154.6 ml) and home spirometry (MD, 69.3 ml; 95% CI, 40.11–98.49 ml) both favored pirfenidone over the placebo. All of these FVC values are based on low-quality evidence. Mortality data are not available for this subtype.
A summary of the important outcomes for all patients with PPF and for the subtype of unclassified fibrotic ILD can be found in Table 3. For the all-PPF group, the RELIEF trial (19) demonstrated a smaller mean decrease in the DlCO in millimoles per kilopascal per minute in the pirfenidone arm than in the placebo arm (MD, 0.40 mmol/kPa/min; 95% CI, 0.10–0.70 mmol/kPa/min). Likewise, Maher and colleagues’ 2020 study (21) found the risk of DlCO declining more than 15% (RR, 0.27; 95% CI, 0.08–0.95) to be lower in the pirfenidone arm. There was no statistically significant difference between the arms in the mean change in the DlCO% predicted, FEV1, or total lung capacity. A third meta-analysis assessed the change in the 6MWD (Figure E1) and found that the pirfenidone arm had significantly less decline in the distance covered in meters than the placebo arm (MD, 25.2 m; 95%, CI, 8.3–42.1 m). The difference in the number of patients with a >50-m decline in the 6MWD was not significant between the arms. A meta-analysis of the mean change in the SGRQ scores (Figure E2) showed no significant differences when comparing the pirfenidone and placebo arms. There were also no significant differences in the change in the scores from baseline for the UCSD-SOBQ, LCQ, or the VAS for cough. All of the above data are based on low-quality evidence.
As it relates to AEs in the all-PPF arm, when compared with placebo, pirfenidone use was found to significantly increase the risk of gastrointestinal discomfort (RR, 1.83; 95% CI, 1.29–2.60) and photosensitivity (RR, 4.88; 95% CI, 1.09–21.83). In addition, Maher and colleagues (2020 study) (21) noted a higher risk of treatment discontinuation in the pirfenidone arm, when compared with the placebo arm, due to development of AEs that were not present before the treatment (RR, 3.71; 95% CI, 1.43–9.63) or that were related directly to the treatment (RR, 15.62; 95% CI, 2.10–116.02). In general, pirfenidone use was associated with an increased risk for any AE not present before treatment (RR, 1.16; 95% CI, 1.06–1.27), including AEs related to the treatment (RR, 1.54; 95% CI, 1.24–1.92). All of the above AE results are based on low quality of evidence (Table 3).
Table 3 also shows that the results for the important outcomes in the unclassified fibrotic ILD subtype parallel the above findings seen with the all-PPF group. The risk of a DlCO decline greater than 15% is lower for the pirfenidone arm (RR, 0.27; 95% CI, 0.08–0.95), the mean change in the 6MWD in meters favors the pirfenidone arm (MD, 24.7 m; 95% CI, 6.48–42.92), and pirfenidone in the unclassified fibrotic ILD group has a similar AE profile to that of the all-PPF group. The remainder of the results showed no significant difference between the pirfenidone and placebo arms. All of the above results are based on low quality of evidence.
This systematic review focused on consolidating findings from the literature on the effects of pirfenidone on patients with documented non-IPF ILDs with PPF to aid expert panelists from the ATS, ERS, JRS, and ALAT in formulating updated clinical guidelines on ILD. Because there is limited research on non-IPF ILDs with a priori confirmation of PPF, only two studies met our inclusion criteria (19, 21). Maher and colleagues (21) could not run the prespecified statistical analyses on their primary endpoint of the mean predicted change in the FVC as based on home spirometry readings because of the variability in readings, so data from the key secondary endpoints were extracted. The RELIEF trial (19) was stopped for futility due to slow enrollment, with only 36.5% of the intended study population enrolled, necessitating imputation of missing data. The imputed data for the primary endpoint of the change in FVC% predicted from baseline favored the pirfenidone arm. Because of these considerations, the quality of evidence for study outcomes based on the GRADE criteria ranges from very low to low. In addition, although the research questions aimed to differentiate ILDs on the basis of their radiographic pattern (UIP vs. non-UIP pattern of pulmonary fibrosis) and subtype of ILD, the available data from the included studies were not used to assess these different diagnostic categories (either due to this not being a focus of the study or due to small sample sizes when analyzing subgroups), limiting the ability to answer all questions.
Regarding pirfenidone use in PPF, the available literature was limited but does offer glimpses into the potential for benefit. From our included studies, pirfenidone decreased disease progression in PPF as measured through the change in the FVC% predicted, the change in the FVC in milliliters, and a risk of FVC decline of greater than 5% or 10% between the pirfenidone and placebo arms. As for lung function, the risk of the DlCO declining by more than 15% and the change in the 6MWD suggests a degree of protection in the pirfenidone arm when compared with the placebo arm. The data did not indicate a mortality benefit or any improvement in respiratory symptom questionnaire scores with pirfenidone use; however, these results should be interpreted with caution, as the relatively short duration of the studies may have contributed to the lack of significant findings in these parameters that are likely to have effects over the long term. The key side effects are gastrointestinal discomfort, photosensitivity, and AEs serious enough to discontinue treatment. It is worth noting that the benefits and side effects largely parallel results seen for pirfenidone use in IPF (24).
These findings suggest that pirfenidone may have a beneficial impact on disease progression and lung function in patients with PPF, specifically in the population with unclassifiable ILDs. Given the limited studies in the literature on this topic, additional research on PPF treatment with pirfenidone is necessary. This is underway (25–31) to further illuminate whether the trends observed in this systematic review persist with larger samples and more studies (Table 4).
| National Clinical Trial Identifier (Reference) | Study Name | ILD Type | Number of Participants | Study Duration | Primary Endpoint | Projected End Date |
|---|---|---|---|---|---|---|
| NCT03385668 (25) | PIRFENIVAS (Pilot Study of Pirfenidone in Pulmonary Fibrosis with Anti-MPO Antibodies) | Anti-MPO–associated | 15 | 52 wk | Absolute change in FVC% predicted | February 2021 |
| NCT03856853 (26) | Efficacy and Safety of Pirfenidone in Patient with Systemic Sclerosis–associated ILD | Systemic sclerosis–associated | 144 | 52 wk | Relative change from baseline of FVC% | May 2021 |
| NCT03857854 (27) | Efficacy and Safety of Pirfenidone in Patient with Dm-ILD | Dermatomyositis-associated | 152 | 52 wk | Relative change from baseline of FVC% | May 2021 |
| NCT02808871 (28) | TRAIL1 (Phase II Study of Pirfenidone in Patients with RAILD) | Rheumatoid arthritis–associated | 270 | 52 wk | Progression (FVC decline of 10% or greater)–free survival | November 2021 |
| NCT02958917 (29) | Study of Efficacy and Safety of Pirfenidone in Patients with Fibrotic Hypersensitivity Pneumonitis | Fibrotic hypersensitivity pneumonitis | 40 | 52 wk | Mean change from baseline in FVC% | December 2021 |
| NCT03221257 (30) | SLSIII (Scleroderma Lung Study III - Combining Pirfenidone with Mycophenolate) | Systemic sclerosis–associated | 150 | 18 mo | Change from baseline in FVC% predicted | June 2022 |
| NCT04193592 (31) | PEARL (Efficacy and Safety of Pirfenidone Treatment in HPS-ILD) | HPS-associated | 50 | 52 wk | Incidence of decline in FVC% predicted >10% | December 2022 |
Pirfenidone use in patients with PPF is associated with a statistically significant decrease in disease progression and with protection of lung function, with key AEs being gastrointestinal discomfort and photosensitivity. However, because of the paucity of published studies, the certainty in these effect estimates is low.
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Author Contributions: All authors contributed to the acquisition, analysis, and interpretation of data along with drafting, revising, and approving the manuscript.
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Author disclosures are available with the text of this article at www.atsjournals.org.
