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Serum biomarkers for the diagnosis and monitoring of chronic recurrent multifocal osteomyelitis (CRMO)

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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.

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Abbreviations

CNO:

Chronic nonbacterial osteomyelitis

CRMO:

Chronic recurrent multifocal osteomyelitis

CRP:

C-reactive protein

Eotaxin:

C-C motif chemokine 11, also known as eosinophil chemotactic protein and eotaxin-1

ESR:

Erythrocyte sedimentation rate

GM-CSF:

Granulocyte macrophage colony stimulating factor

IFN:

Interferon

IL:

Interleukin

IL-1RA:

IL-1 receptor antagonist

JIA:

Juvenile idiopathic arthritis

sIL-2R:

Soluble IL-2 receptor

IP-10:

Interferon gamma-induced protein 10, also known as C-X-C motif chemokine 10 (CXCL10)

MCP-1:

Monocyte chemotactic protein 1

MIG:

Monokine induced by gamma-interferon, also known as Chemokine (C-X-C motif) ligand 9 (CXCL9)

MIP:

Macrophage inflammatory protein

RANTES:

Regulated on activation, normal T cell expressed and secreted protein, also known as Chemokine (C-C motif) ligand 5 (CCL5)

TNF-α:

Tumor necrosis factor α

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Acknowledgments

The authors thank Prof. Dr. Ezio Bonifacio and Carmen Wilhelm for their support during Luminex® analysis and Christine Hedrich for valuable discussion and editing of the manuscript.

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    Authors and Affiliations

    1. Pediatric Rheumatology and Immunology, Faculty of Medicine Carl Gustav Carus, University Children’s Hospital Dresden, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany

      Sigrun Renate Hofmann, Anne Sophie Kubasch, Martin Walther Laass & Christian Michael Hedrich

    2. Faculty of Medicine Carl Gustav Carus, Institute for Medical Informatics and Biometry, Technische Universität Dresden, Dresden, Germany

      Ursula Range

    3. University Children’s Hospital Würzburg, University of Würzburg, Würzburg, Germany

      Henner Morbach & Hermann Joseph Girschick

    4. Children’s Hospital, Vivantes Klinikum im Friedrichshain, Berlin, Germany

      Sigrun Renate Hofmann, Anne Sophie Kubasch, Ursula Range, Martin Walther Laass, Henner Morbach, Hermann Joseph Girschick & Christian Michael Hedrich

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    1. Sigrun Renate Hofmann
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    2. Anne Sophie Kubasch
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    Correspondence to Christian Michael Hedrich.

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    Compliance with ethical standards

    C. M. H. participated in an advisory board meeting by Novartis Pharmaceuticals on the pathophysiology and treatment of systemic JIA. The authors declare that they have no competing interests. The authors declare no relevant financial conflict of interest relevant to this manuscript. The study was supported by the MeDDrive 2014 program, Faculty of Medicine Carl Gustav Carus, TU Dresden (Grant Number: 60.343), and the Novartis Foundation for Therapeutic Research (both grants to C.M.H.). All individuals and/or their parents or legal guardians gave written informed consent. Sample collection and use were approved by the ethics committees of the University of Würzburg (CRMO, JIA patients, and controls) and the University of Technology Dresden/Technische Universität Dresden (Crohn’s disease).

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    Sigrun Renate Hofmann and Anne Sophie Kubasch have contributed equally to this work.

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    Hofmann, S.R., Kubasch, A.S., Range, U. et al. Serum biomarkers for the diagnosis and monitoring of chronic recurrent multifocal osteomyelitis (CRMO). Rheumatol Int 36, 769–779 (2016). https://doi.org/10.1007/s00296-016-3466-7

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    • DOI: https://doi.org/10.1007/s00296-016-3466-7

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