Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disorder in which progressive scarring of the lung parenchyma leads to distortion of normal architecture and a continual decline in respiratory performance¹. The disease predominantly arises in older adults—most frequently in individuals over the age of 65—and is characterized by gradually worsening exertional breathlessness, a persistent dry cough, and imaging findings aligned with the usual interstitial pneumonia (UIP) pattern¹. Despite improvements in diagnostic techniques, the overall prognosis for IPF remains poor, with most patients surviving only 3–5 years after diagnosis, a trajectory comparable to certain late-stage malignant conditions².

Forced vital capacity (FVC) serves as a central measure of disease progression and is strongly linked with morbidity and mortality in IPF³. A reduction of 10% or more over a 12-month period consistently signals more aggressive disease behavior and a heightened risk of hospitalization, acute exacerbation, or death³. Because FVC trends over time provide both biological and clinical insight, contemporary therapeutic trials routinely use changes in FVC, percent-predicted FVC, and categorical thresholds (such as ≥10% decline or death) as key endpoints⁴.

Pirfenidone—an oral antifibrotic agent with anti-inflammatory and antioxidant properties—is one of the two approved disease-modifying therapies for IPF⁵. It acts by modulating multiple molecular pathways, including transforming growth factor-β, tumor necrosis factor-α, and platelet-derived growth factor signaling, thereby limiting fibroblast activation and extracellular matrix accumulation⁵. Early trials suggested that pirfenidone may slow functional deterioration, prompting larger randomized studies to rigorously evaluate its effects⁶.

Among these, the CAPACITY trials (Studies 004 and 006) were foundational in defining pirfenidone’s therapeutic role⁷. Study 004 demonstrated a significant reduction in FVC decline, whereas Study 006 observed a more modest response, creating some uncertainty about the consistency of benefit⁷. The subsequent ASCEND trial addressed these discrepancies by showing clear improvements in FVC preservation, physiological outcomes, and progression-free survival in patients treated with pirfenidone⁸. These pivotal results shaped international treatment recommendations and firmly established pirfenidone as a cornerstone of IPF management.

However, differences in trial design, patient cohorts, endpoint definitions, and measurement techniques highlight the need for updated evidence synthesis. Concurrently, biomarker research has expanded understanding of pirfenidone’s biological effects. Serum markers such as surfactant protein-D (SP-D), surfactant protein-A (SP-A), and KL-6—each associated with epithelial injury and fibrosis—may provide earlier indications of treatment response and disease activity⁹. Insights into how pirfenidone modulates these biomarkers have the potential to refine prognostication and therapeutic monitoring.

Several influential studies have contributed to this biomarker-focused evidence base. Ikeda et al. conducted a comprehensive longitudinal assessment of SP-D, SP-A, and KL-6 over 52 weeks of therapy, reporting significant reductions or stabilization in these markers among pirfenidone-treated patients compared with placebo¹⁰. Ronan et al. evaluated bronchoalveolar lavage cytokines and tissue-level mediators before and after treatment, offering mechanistic insights into pirfenidone’s anti-inflammatory and immunomodulatory actions¹¹. Taniguchi et al. provided additional evidence from a Japanese phase III trial examining changes in vital capacity and percent-predicted FVC, further supporting pirfenidone’s effect on functional decline¹².

Taken together, the growing body of randomized trials, biomarker investigations, and mechanistic studies underscores the need for a unified and methodologically rigorous synthesis of pirfenidone’s clinical and biological effects. Existing meta-analyses often focus solely on lung function, combine heterogeneous endpoints, or exclude biomarker data, limiting their applicability to current clinical practice.

The present systematic review and meta-analysis aims to provide an integrated assessment of pirfenidone’s effectiveness across multiple outcome domains. The primary objective is to quantify pirfenidone’s influence on preventing a ≥10% decline in FVC—an outcome that is clinically meaningful and consistently reported in major randomized controlled trials. Secondary objectives include evaluating pirfenidone’s effects on serum biomarkers (SP-D, SP-A, KL-6), bronchoalveolar lavage markers, additional physiological measures (percent-predicted FVC and vital capacity), and mortality where available.

By synthesizing data from six high-quality studies—including three randomized controlled trials, one serum biomarker investigation, one mechanistic BAL study, and one physiological outcomes study—this review offers an updated and cohesive appraisal of pirfenidone’s therapeutic profile. The findings aim to support evidence-based clinical decision-making and identify areas where further work is needed, such as biomarker-driven stratification, personalized treatment approaches, and long-term outcome prediction.

Study Design This systematic review and meta-analysis was developed following the core principles of the PRISMA 2020 reporting framework¹³ and the methodological standards recommended in the Cochrane Handbook for Systematic Reviews of Interventions¹⁴. Before data collection began, a protocol was drafted, but the study was not registered. Although the review protocol was not prospectively registered, all eligibility criteria, outcomes, and analyses were predefined before study selection, and no protocol deviations occurred during the review process. Eligibility Criteria Inclusion Criteria Studies were eligible for inclusion if they met the following conditions: 1. Population: Adults aged 18 or older diagnosed with idiopathic pulmonary fibrosis (IPF) according to established ATS/ERS/JRS/ALAT standards¹. 2. Intervention: Pirfenidone used at any clinically approved dosing regimen. 3. Comparators: Placebo or standard care for randomized trials; comparator groups were not required for biomarker or mechanistic research. 4. Study Designs: o Randomized controlled trials (included in quantitative synthesis) o Biomarker-focused observational studies (serum-based) o Mechanistic investigations using bronchoalveolar lavage (BAL) or tissue samples o Clinical studies examining physiological outcomes such as vital capacity 5. Outcomes of Interest: o Primary: Incidence of ≥10% decline in FVC or death o Secondary: o Changes in FVC (mL or % predicted) o Serum biomarkers (SP-D, SP-A, KL-6) o BAL cytokine profiles o Vital capacity (VC) 6. Publication Features: o Published between 2010 and 2024 o Human studies only o Complete full-text availability Exclusion Criteria Studies were excluded based on the following conditions: • Non-randomized treatment trials (excluded from meta-analysis) • Reviews, commentaries, case reports, and conference abstracts • Animal or in vitro experiments • Insufficient or nonextractable outcome data • Pooled post hoc analyses to prevent duplicate counting • Combination therapy studies unless pirfenidone effects were isolatable • Mechanistic studies without relevant biomarkers The studies by Ikeda et al. (2020)¹⁰, Ronan et al. (2018)¹¹, and Taniguchi et al. (2010)⁶ were retained for qualitative synthesis only, as their data could not be pooled for FVC meta-analysis. Outcomes Primary Outcome • Risk ratio (RR) for ≥10% decline in FVC over a follow-up period of 52–72 weeks. This threshold reflects a clinically meaningful change that correlates strongly with mortality in IPF¹⁵. Secondary Outcomes 1. Serum biomarkers: SP-D, SP-A, KL-6 2. Pulmonary function: Mean FVC change, FVC % predicted, VC 3. BAL and tissue markers: VEGF-A, PlGF, IL-4, IL-10, and BAL SP-D Search Strategy A systematic literature search was conducted in PubMed, Embase, Cochrane Library and Scopus from database inception to the final search date. Searches were performed using combinations of Medical Subject Headings (MeSH) and free-text terms related to pirfenidone, idiopathic pulmonary fibrosis, and relevant clinical and physiological outcomes, with appropriate Boolean operators applied. The search strategy was adapted for each database, and reference lists of included articles were manually screened to identify additional relevant studies. Study Selection Two authors independently screened titles and abstracts and subsequently assessed full-text articles for eligibility. Any disagreements were resolved through discussion, with consultation of a third author when consensus could not be reached. This systematic review and meta-analysis was conducted in accordance with the PRISMA 2020 guidelines. Data Extraction A standardized extraction form was used to obtain: • Study characteristics • FVC outcomes (mean % change or categorical decline ≥10%) • Biomarker levels (SP-D, SP-A, KL-6) • BAL cytokines • Sample sizes • Effect estimates (RR, MD, CIs) Two reviewers cross-checked the extracted data for accuracy. Risk of Bias Assessment Risk of bias was assessed using the Cochrane framework, with no critical methodological concerns identified that would invalidate pooled estimates. Effect Measures Primary Analysis • Effect metric: Risk ratio (RR) • Statistical model: Random-effects model (DerSimonian–Laird) • Precision estimate: 95% confidence intervals • Heterogeneity assessment: I² and χ² (Cochran’s Q) Secondary Analyses • Biomarkers: Narrative synthesis • Physiological variables: Mean differences Synthesis Methods 1. RCTs were synthesized independently to avoid duplication from pooled publications. 2. Biomarker studies were presented descriptively due to heterogeneous reporting formats. 3. Forest plots were generated for the primary outcome. 4. Funnel plots were not produced because fewer than 10 studies were available. Certainty of Evidence The certainty of evidence for the primary outcome was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE)approach, considering risk of bias, consistency of results, directness of evidence, precision of effect estimates, and potential publication bias. 15 Certainty of evidence was rated as high, with no serious inconsistency observed. Sensitivity Analysis Formal sensitivity analyses were not performed due to the limited number of eligible randomized trials.

Study Selection

The database search identified 1124 records. After removal of 362 duplicates, 762 records were screened based on titles and abstracts. Seventy-five full-text articles were assessed for eligibility, of which 69 were excluded for predefined reasons. Six studies fulfilled the inclusion criteria, including threerandomized controlled trials included in the quantitative synthesis and three studies included in the qualitative synthesis. The study selection process is illustrated in Figure 1.

Three randomized controlled trials—ASCEND⁸, CAPACITY 004⁷, and CAPACITY 006⁷—were suitable for quantitative pooling of the primary endpoint (≥10% decline in FVC).

The remaining three studies—Ikeda et al.¹⁰, Ronan et al.¹¹, and Taniguchi et al.⁶—were incorporated into the qualitative component of the review due to their biomarker- or physiology-focused outcomes.

PRISMA 2020 Flow Summary

Characteristics of Included Studies

Table 1. Randomized Controlled Trials (Meta-analysis)

The three RCTs included a total of 1247 participants

The study designs were multicenter, randomized, placebo-controlled trials evaluating pirfenidone 2403 mg/day versus placebo.

Table 2. Secondary Studies (Qualitative Synthesis)

These were not eligible for the meta-analysis, but their biomarker and physiological outcome data strengthen secondary evidence.

Primary Outcome: Effect of Pirfenidone on ≥10% FVC Decline

Table 3. Extracted Event Data

These three trials form the complete quantitative dataset.

Pooled Meta-analysis (Random Effects Model)

• RR = 0.59
• 95% CI = 0.48 – 0.72
• Z = 5.20, p < 0.000001
• Heterogeneity: I² = 12.7% (low)
• Cochrane Q value:χ² = 2.29(df = 2, p = 0.32)

Pirfenidone was associated with a 41% relative reduction in the risk of ≥10% FVC decline compared with placebo.

Formal sensitivity analyses were not performed due to the limited number of eligible randomized trials.

Figure 2:Forest plot showing pooled risk ratios (RR) with 95% confidence intervals for ≥10% decline in forced vital capacity among patients with idiopathic pulmonary fibrosis treated with pirfenidone compared with control, using a random-effects model.

Figure 3: Directional trends in selected serum and bronchoalveolar lavage biomarkers reported across included studies following pirfenidone therapy in idiopathic pulmonary fibrosis. No pooled quantitative analysis was performed.

Forest Plot Interpretation

• Both ASCEND and CAPACITY 004 show statistically significant reductions in FVC progression.
• CAPACITY 006 contributes non-significant but supportive data.
• The pooled effect remains strongly significant.

Table 4.Mean FVC Decline Across Included Randomized Trials

1. Serum Biomarker Findings — Ikeda et al. 2020¹⁰

SP-D

• SP-D levels declined noticeably at weeks 4, 8, 16, 24, 40, and 52,
  indicating a consistent downward trend throughout treatment.
• This pattern suggests that pirfenidone suppresses biomarkers associated with epithelial injury.

SP-A

• SP-A concentrations remained largely stable over time.
• A statistically meaningful difference was observed only at week 8, limiting its usefulness as a responsive biomarker.

KL-6

• KL-6 rose in both treatment and control groups, which is typical in progressing ILD.
• However, the increase was less pronounced in the pirfenidone group.
• Significant group differences occurred at weeks 16 and 28.

Implication

Overall, the biomarker trends—especially the robust decrease in SP-D—indicate that pirfenidone may help stabilize epithelial injury processes, consistent with its observed effects on slowing physiologic decline.

2. Mechanistic Evidence — Ronan et al. 2018¹¹

• Bronchoalveolar lavage analysis showed elevated levels of anti-inflammatory cytokines, including IL-10 and IL-4, in patients treated with pirfenidone.
• Markers related to angiogenic activity—specifically PlGF and VEGF-A—also demonstrated significant increases.
• Measures of structural fibrosis, such as the presence of fibroblastic foci and Ki-67 expression, remained largely unchanged over the study period.

Implication

These findings suggest that pirfenidone primarily influences immune and angiogenic signaling rather than producing rapid alterations in fixed fibrotic architecture, which is consistent with the slow and irreversible nature of IPF fibrosis.

Figure 4:Summary of bronchoalveolar lavage findings reported in selected studies evaluating the effects of pirfenidone therapy in idiopathic pulmonary fibrosis. The figure illustrates reported trends in inflammatory and fibrotic markers as described in individual studies. No pooled quantitative analysis was performed.

3. Functional Outcomes — Taniguchi et al. 2010⁶

• Pirfenidone was associated with a slower reduction in vital capacity over the study period.
• The decline in FVC % predicted was also less pronounced in the pirfenidone group relative to placebo.
• Despite variations in how outcomes were defined across studies, the overall evidence indicates that pirfenidone helps maintain pulmonary function.

Figure 5: Reported changes in selected physiological parameters, including pulmonary function measures, following pirfenidone therapy in patients with idiopathic pulmonary fibrosis, as described in included studies. The figure is intended for descriptive comparison only.

Integrated Interpretation of Secondary Evidence

Across the three supplementary studies:

• Trends in SP-D and KL-6 were consistent with the clinical stability observed in the major randomized trials.
• BAL findings indicated clear anti-inflammatory shifts, reinforcing pirfenidone’s immunomodulatory activity.
• Improvements in FVC % predicted from supportive physiologic studies aligned well with the outcomes reported in the RCTs.

Taken together, these converging lines of evidence strengthen the overall picture of pirfenidone’s benefit, linking biochemical markers, functional measures, and mechanistic profiles into a coherent therapeutic narrative.

This systematic review and meta-analysis integrate data from randomized controlled trials and mechanistic biomarker investigations published between 2010 and 2024 to assess how effectively pirfenidone slows the progression of idiopathic pulmonary fibrosis (IPF). The combined evidence indicates that pirfenidone substantially lowers the likelihood of experiencing a ≥10% decline in FVC—a threshold closely tied to long-term mortality risk¹⁶. These findings align with pirfenidone’s established antifibrotic, anti-inflammatory, and anti-proliferative activity, reinforcing its role as a core therapeutic option in IPF. Summary of Main Findings 1. Reduction in FVC Decline Across three rigorously conducted RCTs, pirfenidone was associated with a meaningful reduction in the incidence of ≥10% FVC decline or death, yielding a pooled relative risk of 0.59—equivalent to a 41% relative risk reduction. This is because an FVC drop of that magnitude is strongly linked to increased mortality³. • ASCEND produced the most robust evidence, demonstrating nearly a 50% improvement in progression outcomes⁸. • CAPACITY 004 showed a comparable benefit⁷. • CAPACITY 006, though not individually significant, still contributed supportive data⁷. The reproducibility of these effects across diverse international cohorts strengthens confidence in the overall conclusion. The certainty of evidence for the primary outcome was rated as high. 2. Serum Biomarkers and Biological Activity The longitudinal serum biomarker evaluation by Ikeda et al. (2020)¹⁰ offered important insight into the biochemical consequences of pirfenidone therapy: • SP-D levels declined steadily throughout the 52-week treatment period, diverging significantly from placebo. • KL-6 levels, though elevated in both groups, showed a less pronounced rise in the pirfenidone arm, indicating reduced epithelial stress. • SP-A exhibited relatively small fluctuations and limited discriminatory value. These patterns are consistent with pirfenidone’s known impact on epithelial injury and profibrotic signaling pathways. 3. BAL and Mechanistic Responses The bronchoalveolar lavage (BAL) study by Ronan et al. (2018)¹¹ reported several notable immunological and angiogenic shifts: • Elevations in anti-inflammatory cytokines such as IL-10 and IL-4 • Increased levels of angiogenic mediators (VEGF-A, PlGF) • No clear changes in markers related to proliferation, apoptosis, or fibroblastic foci These results suggest that pirfenidone may exert immune-modulating effects within the lung microenvironment, even though structural fibrotic changes remain largely stable over shorter treatment periods—consistent with the chronic, irreversible nature of IPF fibrosis. 4. Additional Physiologic Outcomes The findings of Taniguchi et al. (2010)⁶ complement the major RCTs by demonstrating reduced declines in vital capacity (VC) and improved preservation of overall pulmonary function in pirfenidone-treated participants. Comparison with Existing Literature These results mirror earlier pooled analyses, including both manufacturer-sponsored and independent meta-analyses, which similarly noted: • A reliable slowing of lung function decline • An acceptable safety profile • Biomarker trends that correlate with functional improvements¹⁶ A key distinction in the present synthesis is the incorporation of updated biomarker findings, enabling a broader view of pirfenidone’s biological effects beyond physiologic endpoints alone. Strengths of This Review 1. Full compliance with PRISMA 2020 guidelines. 2. Exclusive reliance on independent RCT datasets, avoiding duplicated results. 3. Inclusion of serum biomarker and BAL mechanistic studies, providing a multidimensional evidence base. 4. Data extracted from published figures where numerical values were not explicitly reported, with cross-checking for consistency. 5. Integration of both quantitative and qualitative findings for balanced interpretation. Limitations 1. Only one serum biomarker study was available, restricting the ability to generalize biomarker responses. 2. The small sample size in BAL mechanistic studies limits external validity¹¹. 3. Publication bias could not be assessed due to the limited number of eligible RCTs. 4. Some biomarker values from Ikeda et al.¹⁰ required manual extraction from published figures, although cross-checking ensured accuracy. Clinical Implications 1. Pirfenidone reduces the likelihood of substantial FVC decline by 41%, which is clinically meaningful given the limited treatment landscape. 2. The suppression of epithelial injury markers—particularly SP-D—suggests biological stabilization. 3. Mechanistic evidence indicates that pirfenidone primarily slows ongoing fibrosis rather than reversing established scarring. 4. Unified physiologic, biomarker, and mechanistic findings collectively support the therapeutic role of pirfenidone in modulating disease progression. Future Research Directions • Large-scale randomized trials incorporating comprehensive biomarker panels (SP-D, KL-6, others) • Long-term mechanistic studies examining pirfenidone’s influence on fibroblast signaling and extracellular matrix turnover • Head-to-head comparisons of pirfenidone and nintedanib, integrating biomarker and imaging endpoints • Use of AI-driven HRCT quantification to capture radiologic progression alongside functional markers

Pirfenidone consistently demonstrates a clinically meaningful ability to reduce IPF progression. Across three major RCTs, the therapy lowered the risk of a ≥10% FVC decline by 41%,supporting its role as an effective antifibrotic treatment option.Complementary biomarker studies show stabilization of epithelial injury signals—particularly reductions in SP-D—and mitigation of KL-6 increases, while BAL analyses reveal anti-inflammatory and angiogenic changes even in the absence of rapid structural remodeling.

Collectively, these integrated data reinforce pirfenidone’s multifaceted therapeutic profile and highlight its benefit in preserving functional capacity and slowing disease trajectory. Future investigations should prioritize biomarker validation, therapeutic combination strategies, and personalized treatment approaches to further refine IPF management.

ACKNOWLEDGEMENTS

The authors thank the publicly accessible biomedical databases and journal publishers for providing open access to the literature used in this review.

DECLARATIONS

Funding:
No external funding was received for this work.

Conflict of Interest:
The authors declare no conflict of interest related to this study.

Ethical Approval:
Ethical approval was not required as this study analyzed data from previously published literature.

Data Availability:
All data generated or analyzed during this study are included in the published article (tables, figures, and supplementary files).

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