Classification of Non-Bacterial Osteitis Retrospective study of clinical, immunological and genetic aspects in 89 patients A. Jansson* ,1 , E. D. Renner* ,1,2 , J. Ramser 3,6 , A. Mayer 1 , M. Haban 3 , A. Meindl 3,6 , V. Grote 1 , J. Diebold 4 , V. Jansson 5 , K. Schneider 1 and B. H. Belohradsky 1 Objective. 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. Methods. 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. Results. 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. Conclusions. Clinical analysis of our cohort leads us to define NBO as a distinct disease entity with three clinical presentations: acute NBO, chronic recurrent multifocal osteomyclitis or persistent chronic NBO. Diagnostic criteria were proposed to differentiate NBO from diseases with similar clinical presentation. KEY WORDS: Non-bacterial osteitis (NBO), Chronic recurrent multifocal osteomyelitis (CRMO), SAPHO syndrome, Complications, Therapy, Classification, Diagnostic criteria, Genetic results. Introduction Non-bacterial bone inflammations with or without associated diseases were described at all ages and at all sites of the skeleton [1–7]. Histological investigations showed non-specific inflamma- tion, fibrotic and/or hyperostotic regeneration [1]. Bacteriological investigations of the bone lesions, however, remained negative [1, 8] and no infectious agent was to be found [1, 7, 9–11]. A number of terms [4, 12, 13] are used to describe diseases with non-bacterial osteitis (NBO) including the SAPHO (synovitis, Acne, Pustulosis, Hyperostosis, Osteitis) syndrome, pustulotic arthro-osteitis, CRMO (Chronic Recurrent Multifocal Osteomyelitis), chronic sclerosing osteomyelitis, lympho- plasmacellular osteomyelitis and others. SAPHO syndrome and CRMO present with osteitis as a common feature. CRMO was regarded to be the paediatric subset of SAPHO syndrome [4, 14]. Recently, however, adults with CRMO [15] and children with SAPHO syndrome [5, 16, 17] were described. In fact, CRMO and SAPHO syndrome share several features: osteitis (sterile bone lesions with non-specific signs of inflammation), unifocal or multifocal presentation, pustulosis, hyperostosis and a good general state of health without spiking fevers, organomegaly, weight loss or fatigue. Several clinicians [3, 4, 18, 19] assume a common pathway for the different diseases associated with osteitis looking at clinical, radiological and histological findings. Supporting the hypothesis of a single pathogenetic pathway for ‘primary’ sterile osteitis, we defined a cohort due to the isolated sterile bone lesions without any other underlying disorders. Clinical, immunological and genetic findings of 89 juvenile and adult patients with osteitis and without arthritis at first presenta- tion were analysed. Diagnostic criteria were established for two main purposes:  Distinguishing NBO from other disease entities with similar clinical presentation.  To diagnose patients with osteitis alone. Subjects and methods Subjects We retrospectively evaluated 89 patients with sterile bone inflammation, who had been diagnosed at or referred to the University Children’s Hospital, Munich between 1977 and 2005. 1 Dr v. Haunersches Kinderspital, Ludwig–Maximilians University, Munich, Germany, 2 Department of Pediatrics, University of Washington, Seattle, WA, USA, 3 Institute of Human Genetics, 4 Institute of Pathology, 5 Department of Orthopaedics, Grosshadern, Ludwig–Maximilians–University and 6 Department of Gynaecology and Obstetrics at the Technical University, Munich, Germany. Submitted 15 December 2005; revised version accepted 25 April 2006. Correspondence to: A. Jansson, MD, Dr v. Haunersches Kinderspital, Ludwig–Maximilians University, Lindwurmstr. 4, D-80337 Munich, Germany. E-mail: Annette.Jansson@med.uni-muenchen.de *Annette Jansson and Ellen D. Renner contributed equally to this work. Rheumatology 2006; 1 of 7 doi:10.1093/rheumatology/kel190 1 of 7 ß The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. 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