Four Systemic Lupus Erythematosus Subgroups, Defined by Autoantibodies Status, Differ Regarding HLA-DRB1 Genotype Associations and Immunological and Clinical Manifestations.
Four Systemic Lupus Erythematosus Subgroups, Defined by Autoantibodies Status, Differ Regarding HLA-DRB1 Genotype Associations and Immunological and Clinical Manifestations.
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DOI：
10.1002/acr2.11343
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发表时间：
2022-01
影响因子：
3.4
通讯作者：
Svenungsson E
中科院分区：
文献类型：
--
作者：
Diaz-Gallo LM;Oke V;Lundström E;Elvin K;Ling Wu Y;Eketjäll S;Zickert A;Gustafsson JT;Jönsen A;Leonard D;Birmingham DJ;Nordmark G;Bengtsson AA;Rönnblom L;Gunnarsson I;Yu CY;Padyukov L;Svenungsson E
系统性红斑狼疮（SLE）的异质性构成了临床和治疗的挑战。因此，我们研究了是否可以通过使用自身抗体分析以及 HLA-DRB1 等位基因以及免疫学和临床数据来识别未识别的疾病亚组。基于 13 种 SLE 相关自身抗体（双链 DNA、核小体、核糖体 P、核糖核蛋白 [RNP] 68、RNPA、Smith [Sm]、Sm/RNP、干燥综合征抗原 A [SSA]/Ro52、SSA/Ro60、干燥综合征抗原 B）的检测进行无监督聚类分析[SSB]/La、心磷脂 [CL]-免疫球蛋白 G [IgG]、CL-免疫球蛋白 M [IgM] 和 β2 糖蛋白 I [β2GPI]-IgG），来自两个队列的 911 名 SLE 患者。我们评估了每个 SLE 亚组是否与 HLA-DRB1 等位基因、临床表现 (n = 743) 和循环中细胞因子水平 (n = 446) 相关。我们的分析确定了 SLE 患者的四个亚组。亚组 1 (29.3%) 以抗 SSA/Ro60/Ro52/SSB 自身抗体为主，与 HLA-DRB1*03 密切相关（比值比 [OR] = 4.73；95% 置信区间 [CI] = 4.52‐4.94）。该疾病亚组盘状病变更为常见（OR = 1.71，95% CI = 1.18‐2.47）。亚组 2 (28.7%) 以抗核小体/SmRNP/DNA/RNPA 自身抗体为主，并与 HLA-DRB1*15 相关（OR = 1.62，95% CI = 1.41‐1.84）。肾炎在该亚组中最常见（OR = 1.61，95% CI = 1.14‐2.26）。与其他 SLE 患者相比，亚组 3 (23.8%) 的特点是抗 ß2GPI-IgG/抗 CL-IgG/IgM 自身抗体和 HLA-DRB1*04 出现频率较高。血管事件在亚组 3 中更为常见（OR = 1.74，95% CI = 1.2‐2.5）。亚组 4 (18.2%) 所研究的自身抗体呈阴性，并且该亚组与 HLA-DRB1 无关。此外，八种细胞因子的水平在疾病亚组之间存在显着差异。我们的研究结果表明，根据 SLE 自身抗体谱可以识别出四个相当不同的亚组。这四个 SLE 亚组在与 HLA-DRB1 等位基因的关联以及免疫学和临床特征方面存在差异，表明疾病途径不同。
The heterogeneity of systemic lupus erythematosus (SLE) constitutes clinical and therapeutical challenges. We therefore studied whether unrecognized disease subgroups can be identified by using autoantibody profiling together with HLA‐DRB1 alleles and immunological and clinical data. An unsupervised cluster analysis was performed based on detection of 13 SLE‐associated autoantibodies (double‐stranded DNA, nucleosomes, ribosomal P, ribonucleoprotein [RNP] 68, RNPA, Smith [Sm], Sm/RNP, Sjögren's syndrome antigen A [SSA]/Ro52, SSA/Ro60, Sjögren's syndrome antigen B [SSB]/La, cardiolipin [CL]‐Immunoglobulin G [IgG], CL–Immunoglobulin M [IgM], and β2 glycoprotein I [β2GPI]–IgG) in 911 patients with SLE from two cohorts. We evaluated whether each SLE subgroup is associated with HLA‐DRB1 alleles, clinical manifestations (n = 743), and cytokine levels in circulation (n = 446). Our analysis identified four subgroups among the patients with SLE. Subgroup 1 (29.3%) was dominated by anti‐SSA/Ro60/Ro52/SSB autoantibodies and was strongly associated with HLA‐DRB1*03 (odds ratio [OR] = 4.73; 95% confidence interval [CI] = 4.52‐4.94). Discoid lesions were more common for this disease subgroup (OR = 1.71, 95% CI = 1.18‐2.47). Subgroup 2 (28.7%) was dominated by anti‐nucleosome/SmRNP/DNA/RNPA autoantibodies and associated with HLA‐DRB1*15 (OR = 1.62, 95% CI = 1.41‐1.84). Nephritis was most common in this subgroup (OR = 1.61, 95% CI = 1.14‐2.26). Subgroup 3 (23.8%) was characterized by anti‐ß2GPI‐IgG/anti‐CL–IgG/IgM autoantibodies and a higher frequency of HLA‐DRB1*04 compared with the other patients with SLE. Vascular events were more common in Subgroup 3 (OR = 1.74, 95% CI = 1.2‐2.5). Subgroup 4 (18.2%) was negative for the investigated autoantibodies, and this subgroup was not associated with HLA‐DRB1. Additionally, the levels of eight cytokines significantly differed among the disease subgroups. Our findings suggest that four fairly distinct subgroups can be identified on the basis of the autoantibody profile in SLE. These four SLE subgroups differ regarding associations with HLA‐DRB1 alleles and immunological and clinical features, suggesting dissimilar disease pathways.
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