Johns Hopkins University School of Medicine, Baltimore, MD.
Lilly Research Laboratories, Indianapolis, IN.
Rheumatology (Oxford). 2021 Nov 3;60(11):5390-5396. doi: 10.1093/rheumatology/keab144.
Heterogeneity of SLE patients in clinical trials remains a challenge for developing new therapies. This study used a combinatorial analysis of four molecular biomarkers to define key sources of heterogeneity.
Combinations of IFN (high/low), anti-dsDNA (+/-) and C3 and C4 (low/normal) were used to subset n = 1747 patients from two randomized phase III trials. A dichotomous classification scheme defined SLE (+) as: IFN (high), anti-dsDNA (+), C3 (low) and/or C4 (low). SLE (-) required all of the following: IFN (low), anti-dsDNA (-), C3 (normal) and C4 (normal). Additional analyses subset the data further by IFN, anti-dsDNA and complement.
The trials enrolled n = 2262 patients of which n = 1747 patients had data for IFN, anti-dsDNA, C3 and C4 at baseline. There were n = 247 patients in the SLE (-) population and n = 1500 patients in the SLE (+) population. The SLE (-) population had more mucocutaneous and musculoskeletal disease at baseline, while SLE (+) had more haematological, renal and vascular involvement. There was lower concomitant medication use in the SLE (-) population for corticosteroids and immunosuppressants, except for MTX. Time to severe flare was significantly longer in SLE (-) vs SLE (+) (P < 0.0001) and SRI-4 response rate was significantly lower in SLE (-) vs SLE (+) (P = 0.00016). The USA had more SLE (-) patients (22%) than Mexico/Central America/South America (10%), Europe (7%) and the rest of the world (5%).
Combinatorial analysis of four molecular biomarkers revealed subsets of SLE patients that discriminated by disease manifestations, concomitant medication use, geography, time to severe flare and SRI-4 response. These data may be useful for designing clinical trials and identifying subsets of patients for analysis. Rheumatology key messages SLE patients from a P3 trial were categorized by IFN, anti-dsDNA, C3 and C4 status. Patients lacking molecular markers of SLE distinguished from biomarker positive patients on multiple clinical parameters. Biomarker negative patients have distinct disease characteristics that may impact clinical trial outcomes.
临床试验中 SLE 患者的异质性仍然是开发新疗法的挑战。本研究使用四种分子生物标志物的组合分析来确定主要的异质来源。
从两项随机 III 期试验中，对 n=1747 名患者使用 IFN（高/低）、抗 dsDNA（+/-）和 C3 和 C4（低/正常）的组合进行亚组分析。二分类分类方案将 SLE（+）定义为：IFN（高）、抗 dsDNA（+）、C3（低）和/或 C4（低）。SLE（-）需要以下所有：IFN（低）、抗 dsDNA（-）、C3（正常）和 C4（正常）。进一步的附加分析通过 IFN、抗 dsDNA 和补体对数据进行了亚组分析。
两项试验共纳入 n=2262 名患者，其中 n=1747 名患者在基线时有 IFN、抗 dsDNA、C3 和 C4 的数据。SLE（-）人群中有 n=247 名患者，SLE（+）人群中有 n=1500 名患者。SLE（-）人群的基线时具有更多的粘膜和皮肤肌肉疾病，而 SLE（+）人群具有更多的血液学、肾脏和血管受累。SLE（-）人群中皮质类固醇和免疫抑制剂的合并用药使用率较低，除 MTX 外。SLE（-）与 SLE（+）相比，严重发作的时间明显延长（P<0.0001），SRI-4 反应率明显较低（P=0.00016）。美国 SLE（-）患者（22%）多于墨西哥/中美洲/南美洲（10%）、欧洲（7%）和世界其他地区（5%）。
四种分子生物标志物的组合分析揭示了 SLE 患者的亚组，这些亚组可以通过疾病表现、合并用药、地理位置、严重发作时间和 SRI-4 反应来区分。这些数据可能有助于设计临床试验和确定患者亚组进行分析。风湿病学关键信息：来自 P3 试验的 SLE 患者根据 IFN、抗 dsDNA、C3 和 C4 状态进行分类。缺乏 SLE 分子标志物的患者在多个临床参数上与生物标志物阳性患者区分开来。生物标志物阴性患者具有独特的疾病特征，可能影响临床试验结果。
