{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T02:34:45Z","timestamp":1787020485049,"version":"build-2736575974"},"reference-count":18,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T00:00:00Z","timestamp":1764288000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T00:00:00Z","timestamp":1764288000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["K23 HL150237"],"award-info":[{"award-number":["K23 HL150237"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Respir Res"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The forced vital capacity (FVC) is the most commonly used endpoint in registrational trials for systemic sclerosis-associated interstitial lung disease (SSc-ILD). However, the FVC has known methodological pitfalls, is affected by extra-pulmonary SSc manifestations and may not be clinically meaningful to patients. Combining individual outcomes into a composite endpoint is an attractive alternative for measuring treatment response and augmenting statistical efficiency in SSc-ILD trials.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We previously developed a composite endpoint for SSc-ILD using data from the Scleroderma Lung Study (SLS) I (comparing cyclophosphamide versus placebo for SSc-ILD), which included physiological (FVC), radiological (quantitative extent of fibrosis in the zone of maximum involvement) and patient-reported outcomes (transitional dyspnea index and health assessment disability questionnaire), which demonstrated a more robust treatment effect of cyclophosphamide than the FVC alone. The purpose of this post-hoc analysis was to validate this composite endpoint in an external clinical trial cohort (SLS II [cyclophosphamide versus mycophenolate for SSc-ILD). A secondary goal was to determine whether the composite endpoint predicted long-term mortality in SLS I and II.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Seventy-two of the 142 randomized participants in SLS II had all composite endpoint components at 24 months and were included in this analysis. In both SLS I and II, the standardized effect size (Cohen\u2019s d) was greater when the composite endpoint model was applied than when the FVC alone model was applied. In SLS I and II, the composite endpoint was a better predictor of long-term survival (HR 0.76 vs. 0.98 and 0.59 vs. 0.98, for the composite index vs. FVC Cox proportional hazards models in SLS I and II, respectively). Patients with high composite outcomes scores in both SLS I and II had significantly worse long-term survival than patients with low scores (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.039 for log-rank test).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The results of this post-hoc analysis provide further evidence that a composite endpoint comprised of physiological, radiological and patient-reported outcomes is a promising endpoint for SSc-ILD trials. Future validation studies are needed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>SLS II: NCT00883129 (Date of registration April 17, 2009); SLS I: NCT00004563 (Date of registration: February 10, 2000).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12931-025-03401-8","type":"journal-article","created":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T11:26:51Z","timestamp":1764329211000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A composite endpoint for systemic sclerosis-associated interstitial lung disease: association with mortality in two clinical trial cohorts"],"prefix":"10.1186","volume":"26","author":[{"given":"Elizabeth R.","family":"Volkmann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly","family":"Wilhalme","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sam","family":"Good","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace Hyun J.","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Goldin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D.","family":"Roth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald P.","family":"Tashkin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,28]]},"reference":[{"key":"3401_CR1","doi-asserted-by":"crossref","unstructured":"Hoffmann-Vold AM, Allanore Y, Alves M, Brunborg C, Air\u00f3 P, Ananieva LP, et al. Progressive interstitial lung disease in patients with systemic sclerosis-associated interstitial lung disease in the EUSTAR database. Ann Rheum Dis. 2021;80:219\u201327.","DOI":"10.1136\/annrheumdis-2020-217455"},{"key":"3401_CR2","doi-asserted-by":"publisher","first-page":"e18","DOI":"10.1164\/rccm.202202-0399ST","volume":"205","author":"G Raghu","year":"2022","unstructured":"Raghu G, Remy-Jardin M, Richeldi L, Thomson CC, Inoue Y, Johkoh T, et al. Idiopathic pulmonary fibrosis (an Update) and progressive pulmonary fibrosis in adults: an official ATS\/ERS\/JRS\/ALAT clinical practice guideline. Am J Respir Crit Care Med. 2022;205:e18\u201347.","journal-title":"Am J Respir Crit Care Med"},{"key":"3401_CR3","doi-asserted-by":"crossref","unstructured":"Tashkin DP, Elashoff R, Clements PJ, Goldin J, Roth MD, Furst DE, et al. Cyclophosphamide versus placebo in scleroderma lung disease. 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Volkmann reports the following financial relationships outside of the submitted work on SLSI and II outcomes: Consulting fees from Boehringer Ingelheim, BMS, GSK; Speaking fees (unbranded disease state lectures) from Boehringer Ingelheim; Grant support from Kadmon, Horizon Therapeutics, Prometheus, Boehringer Ingelheim, GSK, AstraZeneca. Holly Wilhalme reports no competing interests. Sam Good reports no competing interests. Grace Hyun J. Kim reports being a research consultant for MedQIA and has an issue patent UC-2015-0324982-A1. Jonathan Goldin reports no relevant financial disclosures. He reports being the founder of MedQIA and has an issue patent UC-2015-0324982-A1. Donald P. Tashkin reports receiving modest financial support from Genentech for participation in an investigator-initiated trial outside of the submitted work. Michael D. Roth reports receiving institution support from Genentech for leading an investigator-initiated clinical trial in SSc-ILD outside of the SLS I and II study reported here.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"337"}}