Background/Purpose: In the randomized Scleroderma: Cyclophosphamide Or Transplantation (SCOT trial), normalization of systemic sclerosis (SSc) peripheral blood gene expression signatures at the 26-month visit was observed after myeloablative hematopoietic stem cell transplantation (HSCT) (Assassi, et al., 2019). Herein, we examined long-term molecular changes ensuing after HSCT or 12 months of intravenous cyclophosphamide (CYC) to 54 months after randomization.

Methods: All participants with available peripheral blood total RNA samples at month 38 or month 54 visits were included in the present study. Sixty-two healthy controls of similar age-, gender-, and racial background were also examined. Global transcriptomic studies were performed at pretreatment baseline, 38 months, and 54 months post-randomization, and in healthy controls using Illumina HT-12 arrays. The association of baseline SSc-related transcript module scores (upregulated modules: two interferon modules and neutrophil module; down-regulated module: cytotoxic/NK module) with longitudinal changes in modified Rodnan Skin Score (mRSS) was also examined in each treatment arm using mixed effects regression models (Keyes-Elstein et al., 2021).

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 the baseline visit, a significant down-regulation of interferon and an up-regulation of cytotoxic/NK module were observed at 38 and 54-months in the HSCT arm, indicating a long-term normalization of baseline SSc gene expression signatures (Table 1/Figure 1). No differentially expressed modules were detected in the CYC arm compared to baseline (Table 2).

In comparison to healthy controls, 38-month visit samples in the HSCT showed an upregulation of B cell and plasmablast modules and a downregulation of myeloid and inflammation modules. Importantly, 54-month transplant samples showed no differentially expressed modules compared to healthy controls suggesting completion of immune reconstitution (Table 1/Figure 1). Participants in the CYC arm continued to show an upregulation of interferon and neutrophil modules and a down-regulation of cytotoxic/NK module compared to healthy controls at both time points (Table 2).

Higher baseline interferon transcript modules were associated with a faster rate of decline in mRSS in the HSCT arm (p=0.015 and p=0.005 for M1.2 and M3.4 interferon modules, respectively) but not in the CYC arm (p=0.132 and p=0.202 for M1.2 and M3.4 interferon modules, respectively).

Conclusion: Paralleling the observed clinical benefit, HSCT leads to durable long-term normalization of molecular signature in SSc with completion of immune resetting to 54 months post-HSCT.

« Back to ACR Convergence 2022

ACR Meeting Abstracts - https://acrabstracts.org/abstract/myeloablation-followed-by-hematopoietic-stem-cell-transplantation-leads-to-long-term-normalization-of-systemic-sclerosis-molecular-signatures/