Background/Purpose: The Scleroderma:Cyclophosphamide or Transplantation Trial (SCOT) study compared stem cell transplant to monthly cyclophosphamide (CYC) in patients with scleroderma (SSc). We studied baseline lymphocyte subsets comparing age and gender matched controls with SCOT participants who were previously treated in the prior 12 months and those who received no treatment during this period.

Methods: Lymphocytes from 123 controls and 72 SCOT participants at baseline were analyzed by flow cytometry. For each lymphocyte subset count, the significance of difference was determined using the Mann-Whitney-Wilcoxon rank sum test.

Results: Compared to controls, those with SSc showed significant reductions in central memory CD8 T cells, memory B cells, myeloid and plamacytoid dendritic cells, and in FOXP3+CD25+ T regulatory (Treg) cells (Table 1). Conversely, participants had increases in naïve CD4 cells and effector CD8 T cells. No significant differences in any lymphocyte subset were observed between those previously treated (n=57) and untreated (n=15). Additionally, no differences were observed between participants previously treated with CYC (n=23) and those that were not (n=49) All participants had an increased Th2/Th1 CD4 cell ratio compared to controls.

Conclusion: We found a number of differences between healthy controls and participants in terms of T cell subsets (including Tregs) and B cells attesting to the profound immune dysregulation in severe early diffuse SSc. Increased numbers of induced Th2 CD4 T cells supports the theory that Th2 (rather than Th1) cell play a role in the pathogenesis. Furthermore, the decreased numbers of Tregs may transformation to pathogenic effector T cells of Th17 or Th2 lineages with respective pro-inflammatory or pro-fibrotic activity. The role of memory B cells is unclear, although reduced numbers may represent trafficking to sites of inflammation or disease activity. The counts of abnormal cell subsets were similar in the treated and untreated patients suggesting that even in the treated patients the subset counts were abnormal primarily due to scleroderma itself rather than immune modulatory treatment. Even treatment with cyclophosphamide resulted in a baseline lymphocyte profile that was not significantly different from those patients treated with other agents In other words, our data suggests severe disease was more influential than drug immunosuppression in producing the immunophenotype abnormalities. The hypothesis that correction of lymphocyte aberration will affect clinical disease progression needs to be studied in a prospective trial.

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Table 1: Lymphocyte subset counts (per microliter of blood) in patients with SSc and healthy controls.