Diaz-Gallo Lina-Marcela, Oke Vilija, Lundström Emeli, Elvin Kerstin, Ling Wu Yee, Eketjäll Susanna, Zickert Agneta, Gustafsson Johanna T, Jönsen Andreas, Leonard Dag, Birmingham Daniel J, Nordmark Gunnel, Bengtsson Anders A, Rönnblom Lars, Gunnarsson Iva, Yu Chack-Yung, Padyukov Leonid, Svenungsson Elisabet
Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinksa University Hospital, Stockholm, Sweden.
Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
ACR Open Rheumatol. 2022 Jan;4(1):27-39. doi: 10.1002/acr2.11343. Epub 2021 Oct 17.
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 β glycoprotein I [β GPI]-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-DRB103 (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-DRB115 (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-ß GPI-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.
系统性红斑狼疮（SLE）的异质性构成了临床和治疗方面的挑战。因此，我们研究了能否通过自身抗体谱分析结合HLA - DRB1等位基因以及免疫和临床数据来识别未被认识的疾病亚组。
基于对来自两个队列的911例SLE患者中13种与SLE相关的自身抗体（双链DNA、核小体、核糖体P、核糖核蛋白[RNP]68、RNPA、史密斯[Sm]、Sm/RNP、干燥综合征抗原A[SSA]/Ro52、SSA/Ro60、干燥综合征抗原B[SSB]/La、心磷脂[CL] - 免疫球蛋白G[IgG]、CL - 免疫球蛋白M[IgM]和β糖蛋白I[βGPI] - IgG）的检测进行无监督聚类分析。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）以及循环中的细胞因子水平（n = 446）相关。
我们的分析在SLE患者中识别出四个亚组。亚组1（29.3%）以抗SSA/Ro60/Ro52/SSB自身抗体为主，且与HLA - DRB103强烈相关（优势比[OR] = 4.73；95%置信区间[CI] = [4.52 - 4.94]）。盘状红斑在该疾病亚组中更常见（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 - DRB115相关（OR = 1.62，95% CI = [1.41 - 1.84]）。肾炎在该亚组中最为常见（OR = 1.61，95% CI = [1.14 - 2.26]）。亚组3（23.8%）以抗βGPI - IgG/抗CL - IgG/IgM自身抗体为特征，与其他SLE患者相比，HLA - DRB1*04的频率更高。血管事件在亚组3中更常见（OR = 1.74，95% CI = [1.2 - 2.5]）。亚组4（18.2%）在所研究的自身抗体检测中呈阴性，且该亚组与HLA - DRB1无关。此外，八个细胞因子的水平在疾病亚组之间有显著差异。
我们的研究结果表明，基于SLE患者的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等位基因以及免疫和临床特征的关联方面存在差异，提示疾病途径不同。
