Endothelial and Inflammation Biomarker Profiles at Diagnosis Reflecting Clinical Heterogeneity and Serving as a Prognostic Tool for Treatment Response in Two Independent Cohorts of Patients With Juvenile Dermatomyositis
Wienke, Judith; Pachman, Lauren M; Morgan, Gabrielle A; Yeo, Joo Guan; Amoruso, Maria C; Hans, Victoria; Kamphuis, Sylvia S M; Hoppenreijs, Esther P A H; Armbrust, Wineke; van den Berg, J Merlijn; Hissink Muller, Petra C E; Gelderman, Kyra A; Arkachaisri, Thaschawee; van Wijk, Femke; van Royen-Kerkhof, Annet
(2020) Arthritis & Rheumatology, volume 72, issue 7, pp. 1214 - 1226
(Article)
Abstract
OBJECTIVE: Juvenile dermatomyositis (DM) is a heterogeneous systemic immune-mediated vasculopathy. This study was undertaken to 1) identify inflammation/endothelial dysfunction-related biomarker profiles reflecting disease severity at diagnosis, and 2) establish whether such biomarker profiles could be used for predicting the response to treatment in patients with juvenile DM. METHODS: In total,
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39 biomarkers related to activation of endothelial cells, endothelial dysfunction, and inflammation were measured using multiplex technology in serum samples from treatment-naive patients with juvenile DM from 2 independent cohorts (n = 30 and n = 29). Data were analyzed by unsupervised hierarchical clustering, nonparametric tests with correction for multiple comparisons, and Kaplan-Meier tests with Cox proportional hazards models for analysis of treatment duration. Myositis-specific antibodies (MSAs) were measured in the patients' serum using line blot assays. RESULTS: Severe vasculopathy in patients with juvenile DM was associated with low serum levels of intercellular adhesion molecule 1 (Spearman's rho [r s ] = 0.465, P = 0.0111) and high serum levels of endoglin (r s = -0.67, P < 0.0001). In the discovery cohort, unsupervised hierarchical clustering analysis of the biomarker profiles yielded 2 distinct patient clusters, of which the smaller cluster (cluster 1; n = 8) exhibited high serum levels of CXCL13, CCL19, galectin-9, CXCL10, tumor necrosis factor receptor type II (TNFRII), and galectin-1 (false discovery rate <0.0001), and this cluster had greater severity of muscle disease and global disease activity (each P < 0.05 versus cluster 2). In the validation cohort, correlations between the serum levels of galectin-9, CXCL10, TNFRII, and galectin-1 and the severity of global disease activity were confirmed (r s = 0.40-0.52, P < 0.05). Stratification of patients according to the 4 confirmed biomarkers identified a cluster of patients with severe symptoms (comprising 64.7% of patients) who were considered at high risk of requiring more intensive treatment in the first 3 months after diagnosis (P = 0.0437 versus other cluster). Moreover, high serum levels of galectin-9, CXCL10, and TNFRII were predictive of a longer total treatment duration (P < 0.05). The biomarker-based clusters were not evidently correlated with patients' MSA serotypes. CONCLUSION: Results of this study confirm the heterogeneity of new-onset juvenile DM based on serum biomarker profiles. Patients with high serum levels of galectin-9, CXCL10, TNFRII, and galectin-1 may respond suboptimally to conventional treatment, and may therefore benefit from more intensive monitoring and/or treatment.
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Keywords: Biomarkers, Chemokine CCL19/immunology, Chemokine CXCL10/immunology, Chemokine CXCL13/immunology, Child, Child, Preschool, Cohort Studies, Dermatomyositis/drug therapy, Duration of Therapy, Endoglin/metabolism, Endothelial Cells/metabolism, Endothelium, Vascular/metabolism, Female, Galectin 1/metabolism, Galectins/metabolism, Humans, Immunosuppressive Agents/therapeutic use, Inflammation/immunology, Intercellular Adhesion Molecule-1/metabolism, Male, Prognosis, Proportional Hazards Models, Receptors, Tumor Necrosis Factor, Type II/immunology, Immunology and Allergy, Rheumatology, Immunology, Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural
ISSN: 2326-5191
Publisher: John Wiley and Sons Ltd
Note: Funding Information: We thank the pediatric rheumatology research group at Lurie Children's Hospital, Chicago, which is supported by the CureJM Foundation, and KK Women's and Children's Hospital, Singapore, for kindly providing the samples and the extensive clinical expertise with which to perform this study. We thank the Dutch juvenile DM network, and especially Annette van Dijk‐Hummelman and Ellen Schatorjé, for their help and support in the collection and inclusion of patients and samples. We also thank the Luminex core facility for performing all biomarker measurements. A special thanks goes to the board members of the patient group Myositis of the VSN (Vereniging Spierziekten Nederland), the Stichting KAISZ (Kinderen met Auto‐ImmuunSysteemZiekten), and the Bas Stichting (Dutch juvenile DM patient organization) for their explicit and continuous support for our biomarker research in juvenile DM, as well as the CureJM Foundation, which has enabled the Chicago Center to amass the biobank data for this study. Funding Information: We thank the pediatric rheumatology research group at Lurie Children's Hospital, Chicago, which is supported by the CureJM Foundation, and KK Women's and Children's Hospital, Singapore, for kindly providing the samples and the extensive clinical expertise with which to perform this study. We thank the Dutch juvenile DM network, and especially Annette van Dijk-Hummelman and Ellen Schatorj?, for their help and support in the collection and inclusion of patients and samples. We also thank the Luminex core facility for performing all biomarker measurements. A special thanks goes to the board members of the patient group Myositis of the VSN (Vereniging Spierziekten Nederland), the Stichting KAISZ (Kinderen met Auto-ImmuunSysteemZiekten), and the Bas Stichting (Dutch juvenile DM patient organization) for their explicit and continuous support for our biomarker research in juvenile DM, as well as the CureJM Foundation, which has enabled the Chicago Center to amass the biobank data for this study. Publisher Copyright: © 2020 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.
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