title: Serum biomarkers for the diagnosis and monitoring of chronic recurrent multifocal osteomyelitis (CRMO).
abstract: Chronic recurrent multifocal osteomyelitis (CRMO), the most severe form of chronic nonbacterial osteomyelitis, is an autoinflammatory bone disorder. A timely diagnosis and treatment initiation is complicated by the absence of widely accepted diagnostic criteria and an incomplete pathophysiological understanding. The aim of this study was to determine biomarkers for the diagnosis and follow-up of CRMO. Serum of 56 CRMO patients was collected at the time of diagnosis. As controls, sera from treatment-naïve age-matched patients with Crohn's disease (N = 62) or JIA (N = 28) as well as healthy individuals (N = 62) were collected. Multiplex analysis of 25 inflammation markers was performed. Statistical analysis was performed using Kruskal-Wallis and Mann-Whitney U tests, canonical discriminant analysis, and mixed model variance analysis. Mostly monocyte-derived serum proteins were detectable and differed significantly between groups: IL-1RA, IL-2R, IL-6, IL-12, eotaxin, MCP-1, MIP-1b, RANTES. Multicomponent discriminant analysis allowed for the definition of algorithms differentiating between CRMO, Crohn's disease, and healthy controls. Persistently high levels of MCP-1, IL-12, sIL-2R correlated with incomplete remission in follow-up samples from CRMO patients. Discrimination algorithms allow differentiation between patients with CRMO or Crohn's disease, and healthy individuals. IL-12, MCP-1, and sIL-2R can act as markers for treatment response. Though confirmation of our findings in larger multiethnical cohorts is warranted, they may prove valuable to differentiate between otherwise healthy individuals or Crohn's disease patients with "bone pain" and CRMO patients. The elevation of mainly monocyte-derived pro-inflammatory serum proteins supports the hypothesis of pro-inflammatory monocyte/macrophages driving inflammation in CRMO.
authors.affiliation: Pediatric Rheumatology and Immunology, Faculty of Medicine Carl Gustav Carus, University Children's Hospital Dresden, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany.|Children's Hospital, Vivantes Klinikum im Friedrichshain, Berlin, Germany.
authors.forename: Sigrun Renate
authors.initials: SR
authors.lastname: Hofmann
authors.affiliation: Pediatric Rheumatology and Immunology, Faculty of Medicine Carl Gustav Carus, University Children's Hospital Dresden, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany.|Children's Hospital, Vivantes Klinikum im Friedrichshain, Berlin, Germany.
authors.forename: Anne Sophie
authors.initials: AS
authors.lastname: Kubasch
authors.affiliation: Faculty of Medicine Carl Gustav Carus, Institute for Medical Informatics and Biometry, Technische Universität Dresden, Dresden, Germany.|Children's Hospital, Vivantes Klinikum im Friedrichshain, Berlin, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Range
authors.affiliation: Pediatric Rheumatology and Immunology, Faculty of Medicine Carl Gustav Carus, University Children's Hospital Dresden, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany.|Children's Hospital, Vivantes Klinikum im Friedrichshain, Berlin, Germany.
authors.forename: Martin Walther
authors.initials: MW
authors.lastname: Laass
authors.affiliation: University Children's Hospital Würzburg, University of Würzburg, Würzburg, Germany.|Children's Hospital, Vivantes Klinikum im Friedrichshain, Berlin, Germany.
authors.forename: Henner
authors.initials: H
authors.lastname: Morbach
authors.affiliation: University Children's Hospital Würzburg, University of Würzburg, Würzburg, Germany.|Children's Hospital, Vivantes Klinikum im Friedrichshain, Berlin, Germany.
authors.forename: Hermann Joseph
authors.initials: HJ
authors.lastname: Girschick
authors.affiliation: Pediatric Rheumatology and Immunology, Faculty of Medicine Carl Gustav Carus, University Children's Hospital Dresden, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany. Christian.hedrich@uniklinikum-dresden.de.|Children's Hospital, Vivantes Klinikum im Friedrichshain, Berlin, Germany. Christian.hedrich@uniklinikum-dresden.de.
authors.forename: Christian Michael
authors.initials: CM
authors.lastname: Hedrich
mesh_terms: D000293:Adolescent; D000465:Algorithms; D000704:Analysis of Variance; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001171:Arthritis, Juvenile / Q000097:blood / Q000175:diagnosis; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D002648:Child; D003424:Crohn Disease / Q000097:blood / Q000175:diagnosis*; D016207:Cytokines / Q000097:blood*; D003937:Diagnosis, Differential; D016002:Discriminant Analysis; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood*; D008297:Male; D009288:Naproxen / Q000627:therapeutic use; D010019:Osteomyelitis / Q000097:blood / Q000175:diagnosis* / Q000188:drug therapy; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; D016207:Cytokines; D018836:Inflammation Mediators; D009288:Naproxen
keywords: Autoinflammation; Biomarker; Chemokine; Chronic nonbacterial osteomyelitis; Chronic recurrent multifocal osteomyelitis; Cytokine