Division of Rheumatology, University of Michigan, Ann Arbor, MI, USA.
Research and Development, Pharmaceuticals, Bayer AG, Wuppertal, Germany.
Rheumatology (Oxford). 2024 Nov 1;63(11):3124-3134. doi: 10.1093/rheumatology/keae150.
To examine disease and target engagement biomarkers in the RISE-SSc trial of riociguat in early diffuse cutaneous systemic sclerosis and their potential to predict the response to treatment.
Patients were randomized to riociguat (n = 60) or placebo (n = 61) for 52 weeks. Skin biopsies and plasma/serum samples were obtained at baseline and week 14. Plasma cyclic guanosine monophosphate (cGMP) was assessed using radio-immunoassay. α-Smooth muscle actin (αSMA) and skin thickness were determined by immunohistochemistry, mRNA markers of fibrosis by qRT-PCR in skin biopsies, and serum CXC motif chemokine ligand 4 (CXCL-4) and soluble platelet endothelial cell adhesion molecule-1 (sPECAM-1) by enzyme-linked immunosorbent assay.
By week 14, cGMP increased by 94 (78)% with riociguat and 10 (39)% with placebo (P < 0.001, riociguat vs placebo). Serum sPECAM-1 and CXCL-4 decreased with riociguat vs placebo (P = 0.004 and P = 0.008, respectively). There were no differences in skin collagen markers between the two groups. Higher baseline serum sPECAM-1 or the detection of αSMA-positive cells in baseline skin biopsies was associated with a larger reduction of modified Rodnan skin score from baseline at week 52 with riociguat vs placebo (interaction P-values 0.004 and 0.02, respectively).
Plasma cGMP increased with riociguat, suggesting engagement with the nitric oxide-soluble guanylate cyclase-cGMP pathway. Riociguat was associated with a significant reduction in sPECAM-1 (an angiogenic biomarker) vs placebo. Elevated sPECAM-1 and the presence of αSMA-positive skin cells may help to identify patients who could benefit from riociguat in terms of skin fibrosis.
Clinicaltrials.gov, NCT02283762.
在 riociguat 治疗早期弥漫性皮肤系统性硬皮病的 RISE-SSc 试验中，研究疾病和靶点结合生物标志物及其预测治疗反应的潜力。
将患者随机分为 riociguat 组（n=60）和安慰剂组（n=61），治疗 52 周。在基线和第 14 周时采集皮肤活检和血浆/血清样本。使用放射免疫分析评估血浆环鸟苷酸（cGMP）。通过免疫组化测定α-平滑肌肌动蛋白（αSMA）和皮肤厚度，通过皮肤活检的 qRT-PCR 测定纤维化的 mRNA 标志物，通过酶联免疫吸附测定测定血清趋化因子配体 4（CXCL-4）和可溶性血小板内皮细胞黏附分子-1（sPECAM-1）。
到第 14 周时，riociguat 使 cGMP 增加了 94%（78%），安慰剂增加了 10%（39%）（P<0.001，riociguat 与安慰剂相比）。与安慰剂相比，血清 sPECAM-1 和 CXCL-4 随 riociguat 降低（P=0.004 和 P=0.008）。两组之间皮肤胶原标志物无差异。基线时血清 sPECAM-1 较高或基线皮肤活检中检测到 αSMA 阳性细胞与 riociguat 治疗 52 周后与安慰剂相比，改良罗德南皮肤评分的基线降幅更大（交互 P 值分别为 0.004 和 0.02）。
血浆 cGMP 随 riociguat 升高，提示与一氧化氮-可溶性鸟苷酸环化酶-cGMP 途径结合。与安慰剂相比，riociguat 与 sPECAM-1（血管生成生物标志物）显著降低相关。升高的 sPECAM-1 和存在 αSMA 阳性皮肤细胞可能有助于识别那些在皮肤纤维化方面可能受益于 riociguat 的患者。
Clinicaltrials.gov，NCT02283762。
