Stable gene expression of serial skin biopsies defines patient subsets in diffuse cutaneous systemic sclerosis

Systemic sclerosis (SSc) shows complex clinical manifestations including progressive skin and internal organ fibrosis. SSc can be divided into 'intrinsic subsets' by gene expression suggesting patient-specific heterogeneity in pathogenesis or temporal evolution of disease. Here we validate these subsets using an independent patient population, and test whether the genes vary over time with patients changing subsets as disease progresses, or if the genes are a stable feature of the patients within each subset. Skin biopsies were analyzed from 13 dSSc patients enrolled in an open label study of rituximab, 9 dSSc patients not treated with rituximab, and 9 healthy controls. These data recapitulate the patient 'intrinsic subsets' described previously with gene expression associated with cell proliferation, inflammatory processes, and a normal-like group. Serial skin biopsies showed consistent and non-progressing gene expression. We were unable to detect significant differences in gene expression before and after rituximab treatment, consistent with an apparent lack of clinical response. Serial biopsies from each patient stayed within the same gene expression subset regardless of treatment regimen or the time point at which they were taken. This demonstrates the intrinsic subsets are an inherent, reproducible and stable feature of SSc that is independent of disease duration. Skin biopsies were analyzed from 13 dSSc patients enrolled in an open label study of rituximab, 9 dSSc patients not treated with rituximab, and 9 healthy controls.

系统性硬化症（Systemic sclerosis, SSc）具有复杂的临床表现，包括进行性皮肤及内脏纤维化。基于基因表达特征，SSc可被划分为"内在亚型（intrinsic subsets）"，该分类方式反映了发病机制或疾病病程进展中存在的患者特异性异质性。本研究利用独立患者队列对上述亚型进行验证，并检测基因表达是否随时间发生变化：即患者是否会随疾病进展转换亚型，抑或是各亚型内患者的基因特征均为稳定属性。本研究对13名参与利妥昔单抗（rituximab）开放标签研究的弥漫性皮肤型系统性硬化症（diffuse cutaneous systemic sclerosis, dSSc）患者、9名未接受利妥昔单抗治疗的dSSc患者，以及9名健康对照者的皮肤活检样本进行了分析。上述数据重现了此前报道的患者内在亚型，其对应的基因表达分别与细胞增殖、炎症过程相关，另有一类表现为类似正常的基因表达特征。连续皮肤活检结果显示，患者的基因表达始终保持一致且无进展性改变。本研究未检测到利妥昔单抗治疗前后基因表达存在显著差异，这与临床应答不明显的现象相符。每名患者的连续活检样本无论采用何种治疗方案或采样时间点为何，均始终处于同一基因表达亚型中。上述结果表明，内在亚型是系统性硬化症固有、可重复且稳定的特征，与疾病病程无关。本研究对13名参与利妥昔单抗（rituximab）开放标签研究的弥漫性皮肤型系统性硬化症（diffuse cutaneous systemic sclerosis, dSSc）患者、9名未接受利妥昔单抗治疗的dSSc患者，以及9名健康对照者的皮肤活检样本进行了分析。