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      Chronic Recurrent Multifocal Osteomyelitis (CRMO): Presentation, Pathogenesis, and Treatment

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          Abstract

          Purpose of Review

          Chronic non-bacterial osteomyelitis (CNO) with its most severe form chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory bone disorder. We summarize the clinical presentation, diagnostic approaches, most recent advances in understanding the pathophysiology, and available treatment options and outcomes in CNO/CRMO.

          Recent Findings

          Though the exact molecular pathophysiology of CNO/CRMO remains somewhat elusive, it appears likely that variable defects in the TLR4/MAPK/inflammasome signaling cascade result in an imbalance between pro- and anti-inflammatory cytokine expressions in monocytes from CNO/CRMO patients. In this context, we present previously unpublished data on cytokine and chemokine expression in monocytes and tissues.

          Summary

          CNO/CRMO is an autoinflammatory bone disorder resulting from imbalanced cytokine expression from innate immune cells. Though the exact molecular pathophysiology remains unclear, variable molecular defects appear to result in inflammasome activation and pro-inflammatory cytokine expression in monocytes from CNO/CRMO patients. Recent advances suggest signaling pathways and single molecules as biomarkers for CNO/CRMO as well as future treatment targets.

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          An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist.

          Ivona Aksentijevich, Seth Masters, Polly J. Ferguson … (2009)
          Autoinflammatory diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the interleukin-1-receptor antagonist, with prominent involvement of skin and bone. We studied nine children from six families who had neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis. Response to empirical treatment with the recombinant interleukin-1-receptor antagonist anakinra in the first patient prompted us to test for the presence of mutations and changes in proteins and their function in interleukin-1-pathway genes including IL1RN. We identified homozygous mutations of IL1RN in nine affected children, from one family from Newfoundland, Canada, three families from The Netherlands, and one consanguineous family from Lebanon. A nonconsanguineous patient from Puerto Rico was homozygous for a genomic deletion that includes IL1RN and five other interleukin-1-family members. At least three of the mutations are founder mutations; heterozygous carriers were asymptomatic, with no cytokine abnormalities in vitro. The IL1RN mutations resulted in a truncated protein that is not secreted, thereby rendering cells hyperresponsive to interleukin-1beta stimulation. Patients treated with anakinra responded rapidly. We propose the term deficiency of the interleukin-1-receptor antagonist, or DIRA, to denote this autosomal recessive autoinflammatory disease caused by mutations affecting IL1RN. The absence of interleukin-1-receptor antagonist allows unopposed action of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone involvement. (ClinicalTrials.gov number, NCT00059748.) 2009 Massachusetts Medical Society
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            Host and Environmental Factors Influencing Individual Human Cytokine Responses.

            Rob ter Horst, Martin Jaeger, Sanne Smeekens … (2016)
            Differences in susceptibility to immune-mediated diseases are determined by variability in immune responses. In three studies within the Human Functional Genomics Project, we assessed the effect of environmental and non-genetic host factors of the genetic make-up of the host and of the intestinal microbiome on the cytokine responses in humans. We analyzed the association of these factors with circulating mediators and with six cytokines after stimulation with 19 bacterial, fungal, viral, and non-microbial metabolic stimuli in 534 healthy subjects. In this first study, we show a strong impact of non-genetic host factors (e.g., age and gender) on cytokine production and circulating mediators. Additionally, annual seasonality is found to be an important environmental factor influencing cytokine production. Alpha-1-antitrypsin concentrations partially mediate the seasonality of cytokine responses, whereas the effect of vitamin D levels is limited. The complete dataset has been made publicly available as a comprehensive resource for future studies. PAPERCLIP.
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              Dietary modulation of the microbiome affects autoinflammatory disease

              John Lukens, Prajwal Gurung, Peter Vogel … (2014)
              The incidences of chronic inflammatory disorders have increased significantly over the past three decades 1 . Recent shifts in dietary consumption are believed to have contributed importantly to this surge, but how dietary consumption modulates inflammatory disease is poorly defined. Pstpip2cmo mice that express a homozygous L98P missense mutation in the Pombe Cdc15 homology (PCH) family proline-serine-threonine phosphatase interacting protein 2 (PSTPIP2) phosphatase spontaneously develop osteomyelitis that resembles chronic recurrent multifocal osteomyelitis (CRMO) in humans 2-4 . Recent reports demonstrated osteomyelitis to critically rely on IL-1β, but deletion of the inflammasome components caspase-1 and NLRP3 failed to rescue Pstpip2cmo mice from inflammatory bone disease 5,6 . Thus, the upstream mechanisms controlling IL-1β production in Pstpip2cmo mice remain to be identified. In addition, the environmental factors driving IL-1β-dependent inflammatory bone erosion are unknown. Here, we show that the intestinal microbiota of diseased Pstpip2cmo mice was characterized by an outgrowth of Prevotella. Notably, Pstpip2cmo mice that were fed a diet rich in fat and cholesterol maintained a normal body weight, but were markedly protected against inflammatory bone disease and bone erosion. Diet-induced protection against osteomyelitis was accompanied by marked reductions in intestinal Prevotella levels and significantly reduced proIL-1β expression in distant neutrophils. Furthermore, proIL-1β expression was also decreased in antibiotics-treated Pstpip2cmo mice, and in wildtype mice that were kept under germfree conditions. We further demonstrated that combined deletion of caspases 1 and 8 was required for protection against IL-1β-dependent inflammatory bone disease, whereas deletion of each caspase alone, elastase or neutrophil proteinase-3 failed to prevent inflammatory disease. Collectively, this work reveals diet-associated changes in the intestinal microbiome as a critical factor regulating inflammasome- and caspase-8-mediated maturation of IL-1β and osteomyelitis in Pstpip2cmo mice.
              Article 0 comments Cited 136 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Christian M. Hedrich: Christian.hedrich@liverpool.ac.uk
                Journal
                Journal ID (nlm-ta): Curr Osteoporos Rep
                Journal ID (iso-abbrev): Curr Osteoporos Rep
                Title: Current Osteoporosis Reports
                Publisher: Springer US (New York )
                ISSN (Print): 1544-1873
                ISSN (Electronic): 1544-2241
                Publication date (Electronic): 27 October 2017
                Publication date PMC-release: 27 October 2017
                Publication date (Print): 2017
                Volume: 15
                Issue: 6
                Pages: 542-554
                Affiliations
                [1 ]ISNI 0000 0001 2111 7257, GRID grid.4488.0, Pediatric Rheumatology and Immunology, Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, , Technische Universität Dresden, ; Dresden, Germany
                [2 ]Vivantes Klinikum Friedrichshain, Children’s Hospital, Berlin, Germany
                [3 ]ISNI 0000 0001 1958 8658, GRID grid.8379.5, Pediatric Rheumatology and Immunology, Children’s Hospital, , University of Würzburg, ; Würzburg, Germany
                [4 ]ISNI 0000 0001 2111 7257, GRID grid.4488.0, Division of Pathology, Medizinische Fakultät Carl Gustav Carus, , Technische Universität Dresden, ; Dresden, Germany
                [5 ]ISNI 0000 0004 1936 8294, GRID grid.214572.7, Department of Pediatrics, , University of Iowa Stead Family Children’s Hospital, ; Iowa City, IA USA
                [6 ]ISNI 0000 0004 1936 8470, GRID grid.10025.36, Department of Women’s and Children’s Health, Institute of Translational Medicine (Child Health), , University of Liverpool, ; East Prescott Road, Liverpool, L14 5AB UK
                [7 ]ISNI 0000 0004 0421 1374, GRID grid.417858.7, Department of Pediatric Rheumatology, , Alder Hey Children’s NHS Foundation Trust Hospital, ; Liverpool, UK
                Article
                Publisher ID: 405
                DOI: 10.1007/s11914-017-0405-9
                PMC ID: 5705736
                PubMed ID: 29080202
                SO-VID: 64705ab3-e980-41c9-a08f-522ec7160c04
                Copyright © © The Author(s) 2017
                License:

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                Funding
                Funded by: University of Liverpool
                Categories
                Subject: Pediatrics (L Ward and E Imel, Section Editors)
                Custom metadata
                issue-copyright-statement © Springer Science+Business Media, LLC, part of Springer Nature 2017

                ScienceOpen disciplines: Orthopedics
                Keywords: chronic non-bacterial osteomyelitis,cno,chronic recurrent multifocal osteomyelitis,crmo,treatment,inflammation,cytokine,bone,biomarkers
                Data availability:
                ScienceOpen disciplines: Orthopedics
                Keywords: chronic non-bacterial osteomyelitis, cno, chronic recurrent multifocal osteomyelitis, crmo, treatment, inflammation, cytokine, bone, biomarkers

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