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Short-term progression of interstitial lung disease in systemic sclerosis predicts long-term survival in two independent clinical trial cohorts
  1. Elizabeth R Volkmann1,
  2. Donald P Tashkin1,
  3. Myung Sim1,
  4. Ning Li2,
  5. Ellen Goldmuntz3,
  6. Lynette Keyes-Elstein4,
  7. Ashley Pinckney4,
  8. Daniel E Furst1,
  9. Philip J Clements1,
  10. Dinesh Khanna5,
  11. Virginia Steen6,
  12. Dean E Schraufnagel7,
  13. Shiva Arami7,
  14. Vivien Hsu8,
  15. Michael D Roth1,
  16. Robert M Elashoff2,
  17. Keith M Sullivan9
  18. SLS I and SLS II study groups
    1. 1 Department of Medicine, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, California, USA
    2. 2 Department of Biomathematics, University of California, Los Angeles, California, USA
    3. 3 NIAID, NIH, Bethesda, Maryland, USA
    4. 4 Rho Federal Systems, Inc., Chapel Hill, North Carolina, USA
    5. 5 Department of Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
    6. 6 Department of Medicine, Georgetown University, Washington, District of Columbia, USA
    7. 7 Department of Medicine, University of Illinois Hospital, Chicago, Illinois, USA
    8. 8 Department of Medicine, Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA
    9. 9 Department of Medicine, Duke University, Durham, North Carolina, USA
    1. Correspondence to Dr Elizabeth R Volkmann, Department of Medicine, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA 90095, USA; evolkmann{at}mednet.ucla.edu

    Abstract

    Objective To assess survival and identify predictors of survival in patients with systemic sclerosis-interstitial lung disease (SSc-ILD) who participated in the Scleroderma Lung Studies (SLS) I and II.

    Methods SLS I randomised 158 patients with SSc-ILD to 1  year of oral cyclophosphamide (CYC) vs placebo. SLS II randomised 142 patients to 1 year of oral CYC followed by 1 year of placebo vs 2 years of mycophenolate mofetil. Counting process Cox proportional hazard modelling identified variables associated with long-term mortality in SLS I and II. Internal validation was performed using joint modelling.

    Results After a median follow-up of 8 years, 42% of SLS I patients died, and when known the cause of death was most often attributable to SSc. There was no significant difference in the time to death between treatment arms in SLS I or II. Higher baseline skin score, older age, and a decline in the forced vital capacity (FVC) and the diffusing capacity for carbon monoxide (DLCO) over 2 years were independently associated with an increased risk of mortality in SLS I. The Cox model identified the same mortality predictor variables using the SLS II data.

    Conclusion In addition to identifying traditional mortality risk factors in SSc (skin score, age), this study demonstrated that a decline in FVC and DLCO over 2 years was a better predictor of mortality than baseline FVC and DLCO. These findings suggest that short-term changes in surrogate measures of SSc-ILD progression may have important effects on long-term outcomes.

    • systemic sclerosis
    • interstitial lung disease
    • treatment
    • survival
    • systemic sclerosis
    • interstitial lung disease
    • treatment
    • survival

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    Footnotes

    • Handling editor Josef S Smolen

    • Presented at This manuscript was based on work previously published at the following conferences: Systemic Sclerosis World Congress 2018 (Volkmann ER, Tashkin DP, Sim M, et al, The course of the forced vital capacity during treatment for systemic sclerosis-related interstitial lung disease predicts long-term survival in 2 independent cohorts, Journal of Scleroderma and Related Disorders 2018;3(15):69–101) and the American College of Rheumatology Annual Meeting 2017 (Volkmann ER, Tashkin DP, Sim M, et al, The course of the forced vital capacity during treatment for systemic sclerosis-related interstitial lung disease predicts long-term survival in 2 independent cohorts, Arthritis Rheumatol 2017;69(Suppl 10)).

    • Collaborators The following persons and institutions participated in the Scleroderma Lung Study I: University of California at Los Angeles (UCLA), Los Angeles: PJ Clements, DP Tashkin, R Elashoff, J Goldin, M Roth, D Furst, K Bulpitt, D Khanna, W-LJ Chung, S Viasco, M Sterz, L Woolcock, X Yan, J Ho, S Vasunilashorn, I da Costa; University of Medicine and Dentistry of New Jersey, New Brunswick: JR Seibold, DJ Riley, JK Amorosa, VM Hsu, DA McCloskey, JE Wilson; University of Illinois at Chicago, Chicago: J Varga, D Schraufnagel, A Wilbur, M Lopata, S Arami, P Cole-Saffold; Boston University, Boston: R Simms, A Theodore, P Clarke, J Korn, K Tobin, M Nuite; Medical University of South Carolina, Charleston: R Silver, M Bolster, C Strange, S Schabel, E Smith, J Arnold, K Caldwell, M Bonner; Johns Hopkins School of Medicine, Baltimore: R Wise, F Wigley, B White, L Hummers, M Bohlman, A Polito, G Leatherman, E Forbes, M Daniel; Georgetown University, Washington, DC: V Steen, C Read, C Cooper, S Wheaton, A Carey, A Ortiz; University of Texas at Houston, Houston: M Mayes, E Parsley, S Oldham, T Filemon, S Jordan, M Perry; University of California at San Francisco, San Francisco: K Connolly, J Golden, P Wolters, R Webb, J Davis, C Antolos, C Maynetto; University of Alabama at Birmingham, Birmingham: B Fessler, M Olman, C Sanders, L Heck, T Parkhill; University of Connecticut Health Center, Farmington: N Rothfield, M Metersky, R Cobb, M Aberles, F Ingenito, E Breen; Wayne State University, Detroit: M Mayes, K Mubarak, JL Granda, J Silva, Z Injic, R Alexander; Virginia Mason Research Center, Seattle: D Furst, S Springmeyer, S Kirkland, J Molitor, R Hinke, A Mondt; Data Safety and Monitoring Board: Harvard Medical School, Boston—T Thompson; Veterans Affairs Medical Center, Brown University, Providence, Rhode Island—S Rounds; Cedars Sinai–UCLA, Los Angeles—M Weinstein; Clinical Trials Surveys, Baltimore—B Thompson; Mortality and Morbidity Review Committee: UCLA, Los Angeles—H Paulus, S Levy; Johns Hopkins University, Baltimore—D Martin. The following persons and institutions participated in the Scleroderma Lung Study II: University of Boston, Boston: AC Theodore, RW Simms, E Kissin, FY Cheong; Georgetown University, Washington, DC: VD Steen, CA Read Jr, C Fridley, M Zulmatashvili; Johns Hopkins University, Baltimore: RA Wise, FM Wigley, L Hummers, G Leatherman; Medical University of South Carolina, Charleston: RM Silver, C Strange, FN Hant, J Ham, K Gibson, D Rosson; University of California, Los Angeles (UCLA), Los Angeles: DP Tashkin, RM Elashoff, MD Roth, PJ Clements, D Furst, S Kafaja, E Kleerup, D Elashoff, J Goldin, E Ariola, G Marlis, J Mason-Berry, P Saffold, M Rodriguez, L Guzman, J Brook; University of California, San Francisco (UCSF), San Francisco: J Golden, MK Connolly, A Eller, D Leong, M Lalosh, J Obata; University of Illinois, Chicago: S Volkov, D Schraufnagel, S Arami, D Franklin; Northwestern University, Chicago: J Varga, J Dematte, M Hinchcliff, C DeLuca, H Donnelly, C Marlin; University of Medicine and Dentistry of New Jersey, New Brunswick: DJ Riley, VM Hsu, DA McCloskey; University of Michigan, Ann Arbor: K Phillips, D Khanna, FJ Martinez, E Schiopu, J Konkle; University of Texas, Houston: M Mayes, B Patel, S Assassi, F Tan; National Jewish Health, Denver: A Fischer, J Swigris, R Meehan, K Brown, T Warren, M Morrison; University of Utah, Salt Lake City: MB Scholand, T Frecht, P Carey, M Villegas; University of Minnesota, Minneapolis: J Molitor, P Carlson.

    • Contributors All coauthors met the criteria for authorship.

    • Funding This work was supported in part by the NIH/NIAID: N01-AI05419 (KMS) and HHSN-272201100025C (KMS); the Scleroderma Foundation (ERV); NHI/NIAMS: R01 AR 070470 and K24 AR 063120 (DK); and NHLBI/NIH: R01 HL089758 (DPT), R01 HL089901 (RME), U01 HL 60587 (DPT) and U01 HL 60606 (RME).

    • Competing interests None declared.

    • Patient consent Not required.

    • Ethics approval UCLA IRB and the institutional review board of each site approved the studies.

    • Provenance and peer review Not commissioned; externally peer reviewed.

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