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Association of chronic non-bacterial osteomyelitis with Crohn’s disease but not with CARD15 gene variants

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Chronic non-bacterial osteomyelitis (CNO) is an inflammatory, non-infectious disorder of the skeletal system with unknown etiology. Besides bone-inflammation, patients may present with inflammatory involvement of other tissues. Chronic recurrent multifocal osteomyelitis (CRMO) is the most severe form of CNO. We describe the occurrence of Crohn’s disease (CD) in four patients, previously diagnosed with CRMO. Mutations in CARD15, encoding the NOD2 protein, have recently been found in patients with CD. Based on the occurence of CNO and CD in these four and several reported patients, we hypothesized that CD and CRMO might share a common autoinflammatory process. Thus, we searched for CD associated CARD15 gene variants R702W, G908R and 1007fs in 29 CNO patients, 4 of them additionally diagnosed with CD. In the latter one out of the four showed compound heterozygosity for the gene variants R702W and 1007fs. The allele frequency in the 25 patients diagnosed with CNO but not CD was not different from that already reported in healthy people (R702W 4.0%, G908R 2.0%, 1007fs 2.0%). The occurrence of non-bacterial bone inflammation and granulomatous intestinal inflammation seems to represent an extended phenotype of CD, which partly might be explained by potential disease causing mutations in CARD15. However, CNO without intestinal inflammation is not associated with common CARD15 gene variants. Therefore, other variants of genes coding for proteins involved in innate immunity and inflammation might predispose for the occurrence of CNO.

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  1. Girschick HJ, Raab P, Surbaum S et al (2005) Chronic non-bacterial osteomyelitis in children. Ann Rheum Dis 64:279. doi:10.1136/ard.2004.023838

    Article  CAS  PubMed  Google Scholar 

  2. Girschick HJ, Huppertz HI, Harmsen D et al (1999) Chronic recurrent multifocal osteomyelitis in children: diagnostic value of histopathology and microbial testing. Hum Pathol 30:59. doi:10.1016/S0046-8177(99)90301-5

    Article  CAS  PubMed  Google Scholar 

  3. Bognar M, Blake W, Agudelo C (1998) Chronic recurrent multifocal osteomyelitis associated with Crohn’s disease. Am J Med Sci 315:133. doi:10.1097/00000441-199802000-00010

    Article  CAS  PubMed  Google Scholar 

  4. Bousvaros A, Marcon M, Treem W et al (1999) Chronic recurrent multifocal osteomyelitis associated with chronic inflammatory bowel disease in children. Dig Dis Sci 44:2500. doi:10.1023/A:1026695224019

    Article  CAS  PubMed  Google Scholar 

  5. Carpenter E, Jackson MA, Friesen CA et al (2004) Crohn’s-associated chronic recurrent multifocal osteomyelitis responsive to infliximab. J Pediatr 144:541. doi:10.1016/j.jpeds.2003.12.038

    Article  PubMed  Google Scholar 

  6. Dharancy S, Talbodec N, Asselah T et al (1998) The synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome, a rare extra-digestive manifestation of Crohn’s disease. Presentation of 1 case and review of the literature. Gastroenterol Clin Biol 22:240

    CAS  PubMed  Google Scholar 

  7. Jansson A, Renner ED, Ramser J et al (2007) Classification of non-bacterial osteitis: retrospective study of clinical, immunological and genetic aspects in 89 patients. Rheumatology (Oxford) 46:154. doi:10.1093/rheumatology/kel190

    Article  CAS  Google Scholar 

  8. Kotilainen PM, Laxen FO, Manner IK et al (1996) An aseptic inflammation of the clavicle in a patient with Crohn’s disease. A potential manifestation of the SAPHO syndrome. Scand J Rheumatol 25:112. doi:10.3109/03009749609069220

    Article  CAS  PubMed  Google Scholar 

  9. Schilling F, Marker-Hermann E (2003) Chronic recurrent multifocal osteomyelitis in association with chronic inflammatory bowel disease: entheropathic CRMO. Z Rheumatol 62:527. doi:10.1007/s00393-003-0526-7

    Article  CAS  PubMed  Google Scholar 

  10. Vittecoq O, Said LA, Michot C et al (2000) Evolution of chronic recurrent multifocal osteitis toward spondylarthropathy over the long term. Arthritis Rheum 43:109. doi:10.1002/1529-0131(200001)43:1<109::AID-ANR14>3.0.CO;2-3

    Article  CAS  PubMed  Google Scholar 

  11. Golla A, Jansson A, Ramser J et al (2002) Chronic recurrent multifocal osteomyelitis (CRMO): evidence for a susceptibility gene located on chromosome 18q21.3-18q22. Eur J Hum Genet 10:217. doi:10.1038/sj.ejhg.5200789

    Article  PubMed  Google Scholar 

  12. Cho JH (2008) The genetics and immunopathogenesis of inflammatory bowel disease. Nat Rev Immunol 8:458. doi:10.1038/nri2340

    Article  CAS  PubMed  Google Scholar 

  13. Lesage S, Zouali H, Cezard JP et al (2002) CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease. Am J Hum Genet 70:845. doi:10.1086/339432

    Article  CAS  PubMed  Google Scholar 

  14. Girschick HJ, Zimmer C, Klaus G et al (2007) Chronic recurrent multifocal osteomyelitis: what is it and how should it be treated? Nat Clin Pract Rheumatol 3:733. doi:10.1038/ncprheum0653

    Article  PubMed  Google Scholar 

  15. Hugot JP, Zaccaria I, Cavanaugh J et al (2007) Prevalence of CARD15/NOD2 mutations in Caucasian healthy people. Am J Gastroenterol 102:1259. doi:10.1111/j.1572-0241.2007.01149.x

    Article  CAS  PubMed  Google Scholar 

  16. Sun L, Roesler J, Rosen-Wolff A et al (2003) CARD15 genotype and phenotype analysis in 55 pediatric patients with Crohn disease from Saxony, Germany. J Pediatr Gastroenterol Nutr 37:492. doi:10.1097/00005176-200310000-00017

    Article  CAS  PubMed  Google Scholar 

  17. Beck C, Morbach H, Richl P et al (2008) How can calcium pyrophosphate crystals induce inflammation in hypophosphatasia or chronic inflammatory joint diseases? Rheumatol Int 29:229–238

    Article  PubMed  Google Scholar 

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We highly acknowledge the assistance of Sigrun Schneider as study nurse for data acquisition during the study as well as Gertraud Baier and Gabi Haase for excellent technical assistance.

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Correspondence to Henner Morbach.

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Morbach, H., Dick, A., Beck, C. et al. Association of chronic non-bacterial osteomyelitis with Crohn’s disease but not with CARD15 gene variants. Rheumatol Int 30, 617–621 (2010).

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