Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA.
Rheumatology (Oxford). 2023 Apr 3;62(4):1543-1551. doi: 10.1093/rheumatology/keac501.
Clinical trials in early diffuse SSc have consistently shown a placebo group response with a declining modified Rodnan skin score (mRSS), with negative outcomes. Our objective was to identify strategies using clinical characteristics or laboratory values to improve trial design.
We identified early diffuse SSc patients first seen at the University of Pittsburgh from 1980-2015. Eligible patients had ≥3 visits, with at least two mRSS scores within the first year of follow-up. We performed Kaplan-Meier analyses, group-based trajectory analysis of mRSS scores, followed by multivariable regression analysis and classification tree analysis. We applied the results to the abatacept in early diffuse systemic sclerosis (ASSET) trial outcome data.
We identified 403 patients with <18 months, and 514 with <36 months disease duration. The median number of mRSS follow-up scores was 14 (interquartile range 8, 25). All methodologic approaches identified skin thickness progression rate, RNA polymerase III (RNAP3) antibody positivity and presence of tendon friction rubs (TFR) as predictors of mRSS trajectory over 5 years of follow-up, and thereby as potential enrichment variables. When applied to the ASSET data, adjustment for both RNAP3 and TFR demonstrated reduction of the placebo mRSS response, particularly at 6 months. A significant difference in the ACR Composite Response Index in Systemic Sclerosis (CRISS) score was found with adjustment by RNAP3 at 6 months, and TFR or RNAP3 at 12 months.
Adjustment for both RNAP3 and TFR predicts mRSS trajectory and diminished the mRSS decline in ASSET placebo group, and identified significant differences in CRISS. RNAP3, particularly, is a stratification or enrichment approach to improve early diffuse SSc trial design.
早期弥漫性硬皮病的临床试验一致显示安慰剂组的改良 Rodnan 皮肤评分（mRSS）下降，结果为阴性。我们的目的是确定使用临床特征或实验室值来改进试验设计的策略。
我们首先在匹兹堡大学确定了 1980-2015 年首次就诊的早期弥漫性硬皮病患者。合格的患者有≥3 次就诊，在随访的前一年至少有两次 mRSS 评分。我们进行了 Kaplan-Meier 分析、mRSS 评分的基于群组的轨迹分析，然后进行多变量回归分析和分类树分析。我们将结果应用于 abatacept 在早期弥漫性系统性硬化症（ASSET）试验的结果数据。
我们确定了 403 名疾病持续时间<18 个月和 514 名疾病持续时间<36 个月的患者。mRSS 随访评分的中位数为 14（四分位距 8，25）。所有方法学方法都确定了皮肤厚度进展率、RNA 聚合酶 III（RNAP3）抗体阳性和肌腱摩擦音（TFR）为 mRSS 轨迹的预测因素，因此也是潜在的富集变量。当应用于 ASSET 数据时，调整 RNAP3 和 TFR 均显示了安慰剂 mRSS 反应的减少，特别是在 6 个月时。在调整了 RNAP3 后，在 6 个月时发现 ACR 系统性硬化症综合反应指数（CRISS）评分有显著差异，而在 12 个月时则是 TFR 或 RNAP3。
调整 RNAP3 和 TFR 可预测 mRSS 轨迹，并减少 ASSET 安慰剂组中 mRSS 的下降，且在 CRISS 中发现了显著差异。特别是，RNAP3 是一种分层或富集方法，可以改进早期弥漫性硬皮病的试验设计。
