Clinical and Molecular Findings After Autologous Stem Cell Transplantation or Cyclophosphamide for Scleroderma: Handling Missing Longitudinal Data

• Published in: Arthritis care & research (2010) Vol. 75; no. 2; pp. 307 - 316
• Main Authors: Keyes‐Elstein, Lynette, Pinckney, Ashley, Goldmuntz, Ellen, Welch, Beverly, Franks, Jennifer M., Martyanov, Viktor, Wood, Tammara A., Crofford, Leslie, Mayes, Maureen, McSweeney, Peter, Nash, Richard, Georges, George, Csuka, M. E., Simms, Robert, Furst, Daniel, Khanna, Dinesh, Clair, E. William St, Whitfield, Michael L., Sullivan, Keith M.
• Format: Journal Article
• Language: English
• Published: Boston, USA Wiley Periodicals, Inc 01-02-2023; Wiley Subscription Services, Inc
• Subjects: Autografts; Carbon monoxide; Cyclophosphamide; Cyclophosphamide - therapeutic use; Gene expression; Hematopoietic Stem Cell Transplantation - adverse effects; Hematopoietic Stem Cell Transplantation - methods; Hematopoietic stem cells; Humans; Immunosuppressive Agents - therapeutic use; Inflammation; Mathematical models; Quality of Life; Regression analysis; Respiratory function; Scleroderma; Scleroderma, Localized - drug therapy; Scleroderma, Systemic - diagnosis; Scleroderma, Systemic - drug therapy; Statistical analysis; Stem cell transplantation; Systemic sclerosis; Transplantation, Autologous; Treatment Outcome; Trends
• ISSN: 2151-464X; 2151-4658; 2151-4658
• DOI: 10.1002/acr.24785

Objective
Among individuals with systemic sclerosis (SSc) randomized to cyclophosphamide (CYC) (n = 34) or hematopoietic stem cell transplantation (HSCT) (n = 33), we examined longitudinal trends of clinical, pulmonary function, and quality of life measures while accounting for the influence of early failures on treatment comparisons.
Methods
Assuming that data were missing at random, mixed‐effects regression models were used to estimate longitudinal trends for clinical measures when comparing treatment groups. Results were compared to observed means and to longitudinal trends estimated from shared parameter models, assuming that data were missing not at random. Longitudinal trends for SSc intrinsic molecular subsets defined by baseline gene expression signatures (normal‐like, inflammatory, and fibroproliferative signatures) were also studied.
Results
Available observed means for pulmonary function tests appeared to improve over time in both arms. However, after accounting for participant loss, forced vital capacity in HSCT recipients increased by 0.77 percentage points/year but worsened by –3.70/year for CYC (P = 0.004). Similar results were found for diffusing capacity for carbon monoxide and quality of life indicators. Results for both analytic models were consistent. HSCT recipients in the inflammatory (n = 20) and fibroproliferative (n = 20) subsets had superior long‐term trends compared to CYC for pulmonary and quality of life measures. HSCT was also superior for modified Rodnan skin thickness scores in the fibroproliferative subset. For the normal‐like subset (n = 22), superiority of HSCT was less apparent.
Conclusion
Longitudinal trends estimated from 2 statistical models affirm the efficacy of HSCT over CYC in severe SSc. Failure to account for early loss of participants may distort estimated clinical trends over the long term.