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Cited by 36Interstitial Lung Diseases and Idiopathic Pulmonary FibrosisChronic Obstructive Pulmonary Disease (COPD) ResearchOccupational and environmental lung diseases

Serum surfactant protein D as a predictive biomarker for the efficacy of pirfenidone in patients with idiopathic pulmonary fibrosis: a post-hoc analysis of the phase 3 trial in Japan

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Pirfenidone Clinical Study Group in Japan, Ikeda, Kimiyuki, Chiba, Hirofumi, Nishikiori, Hirotaka, Azuma, Arata, Kondoh, Yasuhiro, Ogura, Takashi, Taguchi, Yoshio +8 more·2020·Respiratory Research
DOI 10.1186/s12931-020-01582-yPMC PMC7706186
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Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disorder with a variable disease course. The recent advancement of antifibrotic therapy has increased the need for reliable and specific biomarkers. This study aimed to assess alveolar epithelial biomarkers as predictors for the efficacy of the antifibrotic drug pirfenidone. Methods: We conducted a post-hoc analysis of the prospective, multicenter, randomized, placebo-controlled, phase 3 trial of pirfenidone in Japan (total, n = 267; pirfenidone, n = 163; placebo, n = 104). Logistic regression analysis was performed to extract parameters that predicted disease progression, defined by a ≥ 10% relative decline in vital capacity (VC) from baseline and/or death, at week 52. For assessment of serum surfactant protein (SP)-D, SP-A and Krebs von den Lungen (KL)-6, all patients were dichotomized by the median concentration of each biomarker at baseline to the high and low biomarker subgroups. Associations of these concentrations were examined with changes in VC at each time point from baseline up to week 52, along with progression-free survival (PFS). Additionally, the effect of pirfenidone treatment on serial longitudinal concentrations of these biomarkers were evaluated. Results: In the multivariate logistic regression analysis, body mass index (BMI), %VC and SP-D in the pirfenidone group, and BMI and %VC in the placebo group were indicated as predictors of disease progression. Pirfenidone treatment reduced the decline in VC with statistical significance in the low SP-D and low SP-A subgroups over most of the treatment period, and also prolonged PFS in the low SP-D and low KL-6 subgroups. Furthermore, SP-D levels over time course were reduced in the pirfenidone group from as early as week 8 until the 52-week treatment period compared with the placebo group. Conclusions: Serum SP-D was the most consistent biomarker for the efficacy of pirfenidone in the cohort trial of IPF. Serial measurements of SP-D might have a potential for application as a pharmacodynamic biomarker. Trial registration The clinical trial was registered with the Japan Pharmaceutical Information Center (JAPIC) on September 13, 2005 (registration No. JapicCTI-050121; http://Clinicaltrials.jp)

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  • The 5% drop in SP-D is comparable to decreases described in standard of care IPF drug trials after longer treatment durations, notably the CAPACITY study of pirfenidone (5% at 12 weeks) and the INMARK study of nintedanib (4% at 12 weeks).

    “the 5% drop in SP-D is comparable to decreases described in standard of care IPF drug trials after longer treatment durations, notably the CAPACITY study of pirfenidone (5% at 12 weeks)35 and the INMARK study of nintedanib (4% at 12 weeks)36,37”

    From Inhaled LTI-03 for idiopathic pulmonary fibrosis: a randomized dose escalation study (2026) · cites this paper as [35]

    The Results (Pharmacodynamic property; page unavailable) report that SP-D decreased with pirfenidone from week 8 to week 52, supporting the general comparison. But this paper analyzes a phase 3 trial in Japan, not CAPACITY, and the passages do not report a 5% SP-D decrease at 12 weeks in CAPACITY. The INMARK figure is attached to other citations in the citing sentence. (LLM, conf=0.86)

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Research works printed but not linked: 37

  1. [1]Raghu G Rochwerg B Zhang Y Garcia CAC Azuma A Behr J An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis: an update of the 2011 clinical practice guideline Am J Respir Crit Care Med 2015 192 2 e3 19 10.1164/rccm.201506-1063ST 26177183 · DOI · Paper page
  2. [2]Nathan SD Shlobin OA Weir N Ahmad S Kaldjob JM Battle E Long-term course and prognosis of idiopathic pulmonary fibrosis in the new millennium Chest 2011 140 1 221 229 10.1378/chest.10-2572 21729893 · DOI
  3. [3]Natsuizaka M Chiba H Kuronuma K Otsuka M Kudo K Mori M Epidemiologic survey of Japanese patients with idiopathic pulmonary fibrosis and investigation of ethnic differences Am J Respir Crit Care Med 2014 190 7 773 779 10.1164/rccm.201403-0566OC 25162152 · DOI
  4. [4]Wolters PJ Collard HR Jones KD Pathogenesis of idiopathic pulmonary fibrosis Annu Rev Pathol Mech Dis 2014 9 1 157 179 10.1146/annurev-pathol-012513-104706 PMC4116429 24050627 · DOI
  5. [5]Jenkins RG Simpson JK Saini G Bentley JH Russell AM Braybrooke R Longitudinal change in collagen degradation biomarkers in idiopathic pulmonary fibrosis: an analysis from the prospective, multicentre PROFILE study Lancet Respir Med 2015 3 6 462 472 10.1016/S2213-2600(15)00048-X 25770676 · DOI · Paper page
  6. [7]Organ L Duggan AM Oballa E Taggart S Simpson J Kangombe A Biomarkers of collagen synthesis predict progression in the PROFILE idiopathic pulmonary fibrosis cohort Respir Res. 2018 1 10 PMC6624898 31299951
  7. [8]Noble PW Albera C Bradford WZ Costabel U Glassberg MK Kardatzke D Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): Two randomised trials Lancet 2011 377 9779 1760 1769 10.1016/S0140-6736(11)60405-4 21571362 · DOI · Paper page
  8. [10]Somogyi V Chaudhuri N Torrisi SE Kahn N Müller V Kreuter M The therapy of idiopathic pulmonary fibrosis: What is next? Eur Respir Rev 2019 28 153 1 20 10.1183/16000617.0021-2019 PMC9488691 31484664 · DOI
  9. [11]Neighbors M Cabanski CR Ramalingam TR Sheng XR Tew GW Gu C Prognostic and predictive biomarkers for patients with idiopathic pulmonary fibrosis treated with pirfenidone: post-hoc assessment of the CAPACITY and ASCEND trials Lancet Respir Med 2018 6 8 615 626 10.1016/S2213-2600(18)30185-1 30072107 · DOI
  10. [12]Kreuter M Maher T Gazing into the crystal ball: can treatment response be predicted in IPF? Lancet Respir Med 2018 6 8 570 572 10.1016/S2213-2600(18)30234-0 30072104 · DOI
  11. [13]Walker SR Williams MC Benson B Immunocytochemical localization of the major surfactant apoproteins in type II cells, Clara cells, and alveolar macrophages of rat lung J Histochem Cytochem 1986 34 1137 1148 10.1177/34.9.2426341 2426341 · DOI
  12. [14]Voorhout WF Veenendaal T Kuroki Y Ogasawara Y van Golde LM Geuze HJ Immunocytochemical localization of surfactant protein D (SP-D) in type II cells, Clara cells, and alveolar macrophages of rat lung J Histochem Cytochem 1992 40 1589 1597 10.1177/40.10.1527377 1527377 · DOI
  13. [15]Chiba H Otsuka M Takahashi H Significance of molecular biomarkers in idiopathic pulmonary fibrosis: a mini review Respir Investig 2018 56 5 384 391 10.1016/j.resinv.2018.06.001 30030108 · DOI
  14. [16]Vij R Noth I Peripheral blood biomarkers in idiopathic pulmonary fibrosis Transl Res 2012 159 4 218 227 10.1016/j.trsl.2012.01.012 22424426 PMC3308120 · DOI
  15. [17]Takahashi H Fujishima T Koba H Murakami S Kurokawa K Shibuya Y Serum surfactant proteins A and D as prognostic factors in idiopathic pulmonary fibrosis and their relationship to disease extent Am J Respir Crit Care Med 2000 162 3 1109 1114 10.1164/ajrccm.162.3.9910080 10988138 · DOI
  16. [18]Greene KE King JE Kuroki Y Bucher-Bartelson B Hunninghake GW Newman LS Serum surfactant proteins-A and -D as biomarkers in idiopathic pulmonary fibrosis Eur Respir J 2002 19 3 439 446 10.1183/09031936.02.00081102 11936520 · DOI
  17. [19]Wang K Ju Q Cao J Tang W Zhang J Impact of serum SP-A and SP-D levels on comparison and prognosis of idiopathic pulmonary fibrosis Med (United States) 2017 96 23 PMC5466227 28591049
  18. [21]Raghu G Richeldi L Jagerschmidt A Martin V Subramaniam A Ozoux ML Idiopathic pulmonary fibrosis: prospective, case-controlled study of natural history and circulating biomarkers Chest 2018 154 6 1359 1370 10.1016/j.chest.2018.08.1083 30526970 · DOI
  19. [22]Takahashi H Shiratori M Kanai A Chiba H Kuroki Y Abe S Monitoring markers of disease activity for interstitial lung diseases with serum surfactant proteins A and D Respirology 2006 11 SUPPL. 1 51 54 10.1111/j.1440-1843.2006.00809.x 16423272 · DOI
  20. [23]Kinder BW Brown KK McCormack FX Ix JH Kervitsky A Schwarz MI Serum surfactant protein-A is a strong predictor of early mortality in idiopathic pulmonary fibrosis Chest 2009 135 6 1557 1563 10.1378/chest.08-2209 19255294 PMC2716710 · DOI
  21. [24]Song JW Do KH Jang SJ Colby TV Han S Kim DS Blood biomarkers MMP-7 and SP-A: Predictors of outcome in idiopathic pulmonary fibrosis Chest 2013 143 5 1422 1429 10.1378/chest.11-2735 23715088 · DOI
  22. [25]Yokoyama A Kondo K Nakajima M Matsushima T Takahashi T Nishimura M Prognostic value of circulating KL-6 in idiopathic pulmonary fibrosis Respirology 2006 11 2 164 168 10.1111/j.1440-1843.2006.00834.x 16548901 · DOI
  23. [26]Travis WD Costabel U Hansell DM King TE Lynch DA Nicholson AG An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias Am J Respir Crit Care Med 2013 188 6 733 748 10.1164/rccm.201308-1483ST 24032382 PMC5803655 · DOI
  24. [27]Homma S Bando M Azuma A Sakamoto S Sugino K Ishii Y Japanese guideline for the treatment of idiopathic pulmonary fibrosis Respir Investig 2018 56 4 268 291 10.1016/j.resinv.2018.03.003 29980444 · DOI
  25. [28]Ikeda K Shiratori M Chiba H Nishikiori H Yokoo K Saito A Serum surfactant protein D predicts the outcome of patients with idiopathic pulmonary fibrosis treated with pirfenidone Respir Med 2017 131 184 191 10.1016/j.rmed.2017.08.021 28947028 · DOI
  26. [29]Taniguchi H Ebina M Kondoh Y Ogura T Azuma A Suga M Pirfenidone in idiopathic pulmonary fibrosis Eur Respir J 2010 35 4 821 829 10.1183/09031936.00005209 19996196 · DOI
  27. [30]American Thoracic Society Idiopathic pulmonary fibrosis: diagnosis and treatment: international consensus statement: American Thoracic Society (ATS), and the European Respiratory Society (ERS) Am J Respir Crit Care Med 2000 161 646 664 10.1164/ajrccm.161.2.ats3-00 10673212 · DOI
  28. [32]Taniguchi H Kondoh Y Ebina M Azuma A Ogura T Taguchi Y The clinical significance of 5% change in vital capacity in patients with idiopathic pulmonary fibrosis: Extended analysis of the pirfenidone trial Respir Res 2011 12 1 93 10.1186/1465-9921-12-93 21756364 PMC3160381 · DOI
  29. [33]Azuma A Taguchi Y Ogura T Ebina M Taniguchi H Kondoh Y Exploratory analysis of a phase III trial of pirfenidone identifies a subpopulation of patients with idiopathic pulmonary fibrosis as benefiting from treatment Respir Res 2011 12 1 143 10.1186/1465-9921-12-143 22035508 PMC3216874 · DOI
  30. [34]Taguchi Y Ebina M Hashimoto S Ogura T Azuma A Taniguchi H Efficacy of pirfenidone and disease severity of idiopathic pulmonary fibrosis: Extended analysis of phase III trial in Japan Respir Investig 2015 53 6 279 287 10.1016/j.resinv.2015.06.002 26521105 · DOI
  31. [35]Yoshikawa T Otsuka M Chiba H Ikeda K Mori Y Umeda Y Surfactant protein A as a biomarker of outcomes of anti-fibrotic drug therapy in patients with idiopathic pulmonary fibrosis BMC Pulm Med 2020 20 1 1 11 10.1186/s12890-019-1042-0 32005219 PMC6995128 · DOI
  32. [36]Wakamatsu K Nagata N Kumazoe H Oda K Ishimoto H Yoshimi M Prognostic value of serial serum KL-6 measurements in patients with idiopathic pulmonary fibrosis Respir Investig 2017 55 1 16 23 10.1016/j.resinv.2016.09.003 28012488 · DOI
  33. [37]Okuda R Hagiwara E Baba T Kitamura H Kato T Ogura T Safety and efficacy of pirfenidone in idiopathic pulmonary fibrosis in clinical practice Respir Med 2013 107 9 1431 1437 10.1016/j.rmed.2013.06.011 23849626 · DOI
  34. [38]Nishikiori H Chiba H Ariki S Kuronuma K Otsuka M Shiratori M Distinct compartmentalization of SP-A and SP-D in the vasculature and lungs of patients with idiopathic pulmonary fibrosis BMC Pulm Med 2014 14 1 1 10 10.1186/1471-2466-14-196 25488319 PMC4293112 · DOI
  35. [39]Shigemura M Nasuhara Y Konno S Shimizu C Matsuno K Yamguchi E Effects of molecular structural variants on serum Krebs von den Lungen-6 levels in sarcoidosis J Transl Med 2012 10 1 1 10 10.1186/1479-5876-10-111 22650152 PMC3394217 · DOI
  36. [40]Ronan N Bennett DM Khan KA McCarthy Y Dahly D Bourke L Tissue and bronchoalveolar lavage biomarkers in idiopathic pulmonary fibrosis patients on pirfenidone Lung 2018 196 5 543 552 10.1007/s00408-018-0140-8 30066212 · DOI
  37. [41]Maher TM Stowasser S Nishioka Y White ES Cottin V Noth I Biomarkers of extracellular matrix turnover in patients with idiopathic pulmonary fibrosis given nintedanib (INMARK study): a randomised, placebo-controlled study Lancet Respir Med 2019 7 9 771 779 10.1016/S2213-2600(19)30255-3 31326319 · DOI

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Authors
Pirfenidone Clinical Study Group in Japan, Ikeda, K., Chiba, H., Nishikiori, H., Azuma, A., Kondoh, Y., Ogura, T., Taguchi, Y., Ebina, M., Sakaguchi, H., Miyazawa, S., Suga, M., Sugiyama, Y., Nukiwa, T., Kudoh, S., & Takahashi, H.
Affiliations
  • Sapporo Medical University (JP)
  • Nippon Medical School (JP)
  • Tosei General Hospital (JP)
  • Kanagawa Cardiovascular and Respiratory Center (JP)
  • Tenri Hospital (JP)
  • Tohoku Medical and Pharmaceutical University (JP)
  • Shionogi (Japan) (JP)
  • Saiseikai Kumamoto Hospital (JP)
  • Jichi Medical University (JP)
  • Tohoku University (JP)
  • Japan Anti Tuberculosis Association (JP)
Corresponding author
Chiba, Hirofumi
ORCID
Venue
Respiratory Research
Publisher
Springer Science and Business Media LLC
Published
2020-11-30
Volume
21
Issue
1
Pages
316-316
ISSN
  • 1465-9921 (ISSN-L)
  • 1465-993X
DOI
10.1186/s12931-020-01582-y
PMC
PMC7706186
OpenAlex
W3109328994
Cited by
36
References
3
Citations by year
2026: 7 · 2025: 7 · 2024: 8 · 2023: 9 · 2022: 2 · 2021: 3
FWCI
1.97
Type
journal article
Language
en
Open access
Licence
Locations
  • Respiratory Research (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Grants‐in‐aid for Scientific Research (200500887B)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Chronic Obstructive Pulmonary Disease (COPD) Research
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Occupational and environmental lung diseases
Keywords
idiopathic pulmonary fibrosis, pirfenidone, surfactant protein D, predictive biomarkers, surfactant protein A, KL-6, antifibrotic therapy, disease progression, progression-free survival, pharmacodynamic biomarkers, body mass index, treatment response prediction, post hoc analysis
MeSH terms
Aged, Double-Blind Method, Female, Humans, Lung, Male, Middle Aged, Predictive Value of Tests, Prospective Studies, Pyridones, Time Factors, Vital Capacity, Biomarkers, Body Mass Index, Treatment Outcome, Pulmonary Surfactant-Associated Protein D, Idiopathic Pulmonary Fibrosis

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