Myeloablation Followed by Hematopoietic Stem Cell Transplantation Leads to 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 normalization of systemic sclerosis (SSc) peripheral blood gene cell (PBC) 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). METHOD:Global PBC transcript studies were performed at pretreatment baseline, 38 months, and 54 months post-randomization, as well as in healthy controls using Illumina HT-12 arrays. RESULTS:Thirty (HSCT=19 and CYC=11) participants had 38-month 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/NK module were observed at 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 the comparison to healthy controls, 38-month visit samples in the HSCT arm showed an upregulation of B cell and plasmablast modules and a downregulation of myeloid and inflammation modules. Importantly, 54-month HSCT samples did not show any differentially expressed modules compared to healthy controls 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 post-HSCT.