Myeloablation Followed by Hematopoietic Stem Cell Transplantation and Long‐Term Normalization of Systemic Sclerosis Molecular Signatures

Objective In the randomized Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial, myeloablation, followed by hematopoietic stem cell transplantation (HSCT), led to the normalization of systemic sclerosis (SSc) peripheral blood cell (PBC) gene expression signature at the 26‐month visit. Herein, we examined long‐term molecular changes ensuing 54 months after randomization for individuals receiving an HSCT or 12 months of intravenous cyclophosphamide (CYC). Methods Global PBC transcript studies were performed in study participants at pretreatment baseline and at 38 months and 54 months after randomization, as well as in healthy controls using Illumina HT‐12 arrays. Results Thirty (HSCT = 19 and CYC = 11) participants had 38‐month samples available, and 26 (HSCT = 16 and CYC = 11) had 54‐month samples available. In the paired comparison to baseline, a significant down‐regulation of interferon modules and an up‐regulation of cytotoxic/natural killer module were observed at the 38‐month and 54‐month visits in the HSCT arm, indicating a long‐term normalization of baseline SSc gene expression signature. No differentially expressed modules were detected in the CYC arm. In comparison to samples from healthy controls, 38‐month visit samples in the HSCT arm showed an up‐regulation of B cell and plasmablast modules and a down‐regulation of myeloid and inflammation modules. Importantly, 54‐month HSCT samples did not show any differentially expressed modules compared to healthy control samples, suggesting completion of immune reconstitution. Participants in the CYC arm continued to show an SSc transcript signature in comparison to controls at both time points. Conclusion Paralleling the observed clinical benefit, HSCT leads to durable long‐term normalization of the molecular signature in SSc, with completion of immune resetting to 54 months after HSCT.