Autoinflammatory bone disorders with special focus on chronic recurrent multifocal osteomyelitis (CRMO)

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Abstract

Sterile bone inflammation is the hallmark of autoinflammatory bone disorders, including chronic nonbacterial osteomyelitis (CNO) with its most severe form chronic recurrent multifocal osteomyelitis (CRMO). Autoinflammatory osteopathies are the result of a dysregulated innate immune system, resulting in immune cell infiltration of the bone and subsequent osteoclast differentiation and activation. Interestingly, autoinflammatory bone disorders are associated with inflammation of the skin and/or the intestine. In several monogenic autoinflammatory bone disorders mutations in disease-causing genes have been reported. However, regardless of recent developments, the molecular pathogenesis of CNO/CRMO remains unclear.

Here, we discuss the clinical presentation and molecular pathophysiology of human autoinflammatory osteopathies and animal models with special focus on CNO/CRMO. Treatment options in monogenic autoinflammatory bone disorders and CRMO will be illustrated.

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Osteomyelitis.

Daniel Lew, Francis A Waldvogel (2004)

Bone and joint infections are painful for patients and frustrating for both them and their doctors. The high success rates of antimicrobial therapy in most infectious diseases have not yet been achieved in bone and joint infections owing to the physiological and anatomical characteristics of bone. The key to successful management is early diagnosis, including bone sampling for microbiological and pathological examination to allow targeted and long-lasting antimicrobial therapy. The various types of osteomyelitis require differing medical and surgical therapeutic strategies. These types include, in order of decreasing frequency: osteomyelitis secondary to a contiguous focus of infection (after trauma, surgery, or insertion of a joint prosthesis); that secondary to vascular insufficiency (in diabetic foot infections); or that of haematogenous origin. Chronic osteomyelitis is associated with avascular necrosis of bone and formation of sequestrum (dead bone), and surgical debridement is necessary for cure in addition to antibiotic therapy. By contrast, acute osteomyelitis can respond to antibiotics alone. Generally, a multidisciplinary approach is required for success, involving expertise in orthopaedic surgery, infectious diseases, and plastic surgery, as well as vascular surgery, particularly for complex cases with soft-tissue loss.

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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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Classification of non-bacterial osteitis: retrospective study of clinical, immunological and genetic aspects in 89 patients.

A Jansson, E D Renner, J Ramser … (2007)

To define non-bacterial osteitis (NBO) as a clinical entity possibly associated with autoimmune manifestations. Patients with sterile osteitis were analysed to develop diagnostic criteria. A total of 89 patients with non-bacterial inflammatory bone lesions were observed for a median of 49 months. History, diagnostic imaging, laboratory and histological data were obtained. Mutation analysis in the genes PSTPIP1 and PSTPIP2 was performed. Patients had an onset of disease at a median age of 10 yrs [interquartile range (IQR) 7.5-12] and suffered a median period of 21 (IQR 9-52) months with a median of three foci per patient. Twenty percent of all the patients demonstrated associated autoimmune disorders, particularly of the skin and bowel. The majority of bone lesions were located in the vertebrae and metaphyses. Slight-to-moderate elevation of inflammation values were found in all the patients and antinuclear antibodies were elevated in 30%. Non-steroidal anti-inflammatory drugs (NSAIDs) were effective in 85% of the patients. HLA-B27 and Human Leukocyte Antigen-DR (HLA-DR)-classification did not differ from the general population. Autoimmune diseases in 40% of all the families, multiply affected family members, linkage to 18q21 and mouse models strongly indicate a genetic basis for NBO. We observed three different courses of disease regarding the duration of complaints, rate of complications and associated autoimmune manifestations leading to a new classification of NBO. Clinical analysis of our cohort leads us to define NBO as a distinct disease entity with three clinical presentations: acute NBO, chronic recurrent multifocal osteomyelitis or persistent chronic NBO. Diagnostic criteria were proposed to differentiate NBO from diseases with similar clinical presentation.

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Journal

Journal ID (nlm-ta): Pediatr Rheumatol Online J

Journal ID (iso-abbrev): Pediatr Rheumatol Online J

Title: Pediatric Rheumatology Online Journal

Publisher: BioMed Central

ISSN (Electronic): 1546-0096

Publication date Collection: 2013

Publication date (Electronic): 23 December 2013

Volume: 11

Page: 47

Affiliations

[1 ]Division of Pediatric Rheumatology and Immunology, Children’s Hospital Dresden, University Medical Center Carl Gustav Carus, TU Dresden, Dresden, Germany

[2 ]Division of Pathology, University Medical Center Carl Gustav Carus, TU Dresden, Dresden, Germany

[3 ]Department of Pediatrics, University of Würzburg, Würzburg, Germany

[4 ]Children’s Hospital, Vivantes Klinikum-Friedrichshain, Berlin, Germany

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Publisher ID: 1546-0096-11-47

DOI: 10.1186/1546-0096-11-47

PMC ID: 3881012

PubMed ID: 24359092

SO-VID: 85049a89-3af8-460e-92f3-fa2ab482e455

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This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Autoinflammatory bone disorders with special focus on chronic recurrent multifocal osteomyelitis (CRMO)

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Most cited references 52

Osteomyelitis.

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

Classification of non-bacterial osteitis: retrospective study of clinical, immunological and genetic aspects in 89 patients.

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