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

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 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 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/yr for CYC (P=0.004). Similar results were found for DLCO 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 Rodnan skin scores in the fibroproliferative subset. For the normal-like subset (n=22), superiority of HSCT was less apparent. CONCLUSIONS Longitudinal trends estimated from two 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.