Duke Health Referring Physicians


Myeloablative HSCT Corrects Molecular Signatures in Systemic Sclerosis

No significant changes in these signatures were observed among study participants who received conventional therapy with cyclophosphamide

Individuals with severe systemic sclerosis (SSc) who undergo hematopoietic stem cell transplant (HSCT) as treatment experience significant corrections in the SSc-related molecular signatures at both the RNA and serum protein levels, a novel multilevel global molecular study found. Moreover, changes in the SSc-related molecular signatures are associated with clinical improvements in lung and skin manifestations of the disease. Conventional treatment with cyclophosphamide has no effect on these genomic signatures, the study authors concluded.

Shervin Assassi, MD, a rheumatologist from the University of Texas McGovern School of Medicine in Houston presented these findings at the 2018 American College of Rheumatology and Association of Rheumatology Healthcare Professionals Annual Meeting held October 19 to 24 in Chicago, IL.  Keith M. Sullivan, MD, from the Duke Cancer Institute and Duke School of Medicine in Durham, NC, participated in the study.

The goal of the study was to assess global molecular changes ensuing from myeloablative HSCT in individuals with SSc and compare those changes in patients treated with cyclophosphamide, Assassi told attendees.

“An interferon signature is the most prominent gene expression profile in whole blood samples of SSc patients,” Assassi said. “The presence of an interferon signature has also been reported…in the peripheral blood mononuclear cells and purified lymphocytes and monocytes of SSc patients.”

The study utilized samples collected from the Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial. SCOT participants were characterized by early severe systemic scleroderma with organ involvement—mean disease duration ranged from 2.0 to 2.4 years, and more than 90% of participants had radiologic evidence of interstitial lung disease. The SCOT trial found that myeloablative autologous HSCT offered long-term benefits for individuals with SSc, including improved survival.

Researchers were able to analyze whole blood RNA samples from SCOT trial participants before randomization to myeloablative HSCT or treatment with cyclophosphamide, at 8 months and at 26 months after treatment. In HSCT, immune recovery is assumed to be complete at 26 months. Patients in the cyclophosphamide group would have completed treatment 14 months earlier, Assassi explained. In the HSCT group, there were 27 samples at baseline, 23 at month 8 during immune recovery, and 17 at month 26. In the cyclophosphamide group, there were 35 baseline samples, 23 at month 8 during active treatment, and 18 at month 26. The study included age-, sex-, and race-matched controls; Assassi noted that this was a unique aspect of this study.

Compared with control group participants, those with SSc had 3,168 differentially expressed genes, suggesting that there is a distinct genetic profile for patients with the disease. Researchers utilized whole blood modular analysis, a method that groups genes into co-expressed modules across human diseases and then assigns biologically functional relevance to the modules. Analysis found that three modules were upregulated and one module was downregulated in patients with SSc. Two of the upregulated modules were interferon related and the third was neutrophil related. The single downregulated module was related to cytotoxic natural killer (NK) cells.

After completion of immune recovery at 26 months, those who had undergone HSCT had significant decreases in the two most prominently upregulated transcript signatures (IFN and neutrophil modules) and significant increases in the downregulated cytotoxic NK module. Cyclophosphamide-treated participants had no significant changes in these genomic signatures.

Assassi and colleagues also analyzed concomitantly collected serum samples for more than 100 inflammatory and immunologic proteins at baseline and at month 26. Serum protein composite scores correlating with the transcript modules showed changes that mirrored the RNA data. Specifically, interferon and neutrophil serum protein composite scores decreased significantly 26 months after HSCT. As expected, no significant changes in serum proteins were observed in the cyclophosphamide arm.

Finally, the percent change in each of the SSc-related transcript signatures (IFN, neutrophil, and cytotoxic NK modules) at 26 months was compared with the percent change in the modified Rodnan Skin Score (mRSS) and lung volume assessed by forced vital capacity (FVC%). Declines in the interferon and neutrophil modules were significantly associated with an improvement in FVC%. Moreover, an increase in the cytotoxic NK module correlated with improvement in the mRSS at 26 months. Further study is needed to assess the durability of these findings over time, the authors concluded.

Source: Assassi S, Wang X, Ying J, et al. Changes in the systemic sclerosis molecular signatures after myeloablation followed by autologous hematopoietic stem cell transplantation and their clinical correlates. Presented at: 2018 ACR/ARHP Annual Meeting; October 19-24, 2018; Chicago, IL. Abstract 899.