Seltene autoinflammatorische Knochenerkrankungen

C. Hofmann; F. Jakob; H. J. Girschick; H. Morbach

doi:10.1055/s-0037-1619120

Arthritis und Rheuma, Inhaltsverzeichnis

Arthritis und Rheuma 2014; 34(06): 347-355
DOI: 10.1055/s-0037-1619120

Interdisziplinäre Kinderrheumatologie

Schattauer GmbH

Seltene autoinflammatorische Knochenerkrankungen

Von der Genetik zur InflammationRare autoinflammatory bone disordersFrom genetics to inflammation

C. Hofmann

¹Universitäts-Kinderklinik und Poliklinik Würzburg, Pädiatrische Rheumatologie und Osteologie, Universitätsklinikum Würzburg

,

F. Jakob

²Orthopädisches Zentrum für Muskuloskeletale Forschung, Experimentelle und Klinische Osteologie, Orthopädische Klinik König-Ludwig-Haus Würzburg, Universität Würzburg

,

H. J. Girschick

³Vivantes Klinik für Kinder- und Jugendmedizin, Klinikum im Friedrichshain, Berlin

,

H. Morbach

¹Universitäts-Kinderklinik und Poliklinik Würzburg, Pädiatrische Rheumatologie und Osteologie, Universitätsklinikum Würzburg

› Institutsangaben

Abstract

Zusammenfassung

Autoinflammatorische Knochenerkrankungen sind gekennzeichnet durch eine entzündliche zelluläre Infiltration des Knochens, Osteoklastenaktivierung, Osteolyse und gesteigertes Knochenremodelling infolge einer aberranten Aktivierung des angeborenen Immunsystems. Der Knochenabbau infolge chronischer Osteomyelitis zeigt die enge Verknüpfung zwischen Immun- und Skelett system. Die Identifizierung von definierten molekularen Defekten bei verschiedenen Erkrankungen konnte bereits zu einem besseren Verständnis der komplexen Interaktion zwischen Knochen und Immunsystem beitragen. Die sporadisch auftretende chronische nichtinfektiöse Osteomyelitis stellt die am häufigsten vorkommende Erkrankung dar. Zu den seltenen monogenetischen autoinflammatorischen Erkrankungen zählen: IL-1- Rezeptorantagonist-Mangel, Majeed-Syndrom und Cherubism. Weitere der sogenannten Inflammasom- und auch Stoffwechsel-erkrankungen aufgrund von Enzymdefekten (Hypophosphatasie, hypertrophe Osteoarthropathie) beeinhalten eine signifikante inflammatorisch bedingte Knochenpathologie. Im folgenden Artikel werden diese seltenen Erkrankungen von den molekularen Pathologien bis hin zur klinischen Präsentation diskutiert. Ein besseres Verständnis der pathophysiologischen Grundlagen von autoinflammatorischen Knochenerkrankungen könnte zur Entwicklung weiterer gezielter Therapieansätze beitragen, wovon letztlich auch Patienten mit häufiger vorkommenden Knochenerkrankungen profitieren.

Summary

Autoinflammatory bone disorders are characterized by infiltration of the bone marrow by cells of the (innate?) immune system (chronic osteomyelitis), increased osteoclast activity, osteolysis and accelerated bone remodeling and are caused by an aberrant activation of the innate immune system. Bone resorption due to chronic inflammation highlights the interaction between the immune and the skeletal system. The most common disease subtype is sporadic chronic non-bacterial osteomyelitis (CNO). Several monogenetic and often multisystemic diseases with non-infectious, autoinflammatory bone involvement have been described. In this article we discuss the following osteopathies from their pathophysiology to the clinical phenotype and treatment options: murine CNO, Majeed syndrome, cherubism, hypophosphatasia and primary hypertrophic osteoarthropathy. Some monogenic inflammasomopathies may also present with bone involvement. The analysis of autoinflammatory bone diseases and of CNO mouse models as well as the identification of distinct inflammatory pathways offer still informative insights in the complex interplay between the immune and the skeletal system. Targeting of molecular defects in rare monogenic autoinflammatory disorders may also help to develop new specific treatment strategies for more common diseases with bone inflammation and inflammation-induced bone resorption.

Schlüsselwörter

Seltene Erkrankungen - Inflammation - Genetik - chronische nichtinfektiöse Osteomyelitis

Keywords

Rare diseases - inflammation - genetics - chronic non-bacterial osteomyelitis

Volltext

Referenzen

Literatur
1 Masters SL, Simon A, Aksentijevich I, Kastner DL. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease (*). Annual review of immunology 2009; 27: 621-668.
2 Almeida de Jesus A, Goldbach-Mansky R. Monogenic autoinflammatory diseases: concept and clinical manifestations. Clin Immunol 2013; 147 (03) 155-174.
3 Ferguson PJ, El-Shanti HI. Autoinflammatory bone disorders. Curr Opin Rheumatol 2007; 19 (05) 492-498.
4 Takayanagi H. Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat Rev Immunol 2007; 7 (04) 292-304.
5 Morbach H, Schneider P, Schwarz T. et al. Comparison of magnetic resonance imaging and 99mTechnetium-labelled methylene diphosphonate bone scintigraphy in the initial assessment of chronic non-bacterial osteomyelitis of childhood and adolescents. Clin Exp Rheumatol 2012; 30 (04) 578-582.
6 Jansson A, Renner ED, Ramser J. et al. Classification of non-bacterial osteitis: retrospective study of clinical, immunological and genetic aspects in 89 patients. Rheumatology (Oxford) 2007; 46 (01) 154-160.
7 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 2010; 30 (05) 617-621.
8 Girschick HJ, Raab P, Surbaum S. et al. Chronic non-bacterial osteomyelitis in children. Ann Rheum Dis 2005; 64 (02) 279-285.
9 Schilling F, Kessler S. [Chronic recurrent multifocal osteomyelitis - I. Review]. Klin Padiatr 2001; 213 (05) 271-276.
10 Beck C, Morbach H, Beer M. et al. Chronic nonbacterial osteomyelitis in childhood: prospective follow-up during the first year of anti-inflammatory treatment. Arthritis Res Ther 2010; 12 (02) R74.
11 Jansson AF, Borte M, Hospach A. et al. Diagnostik und Therapie der nichtbakteriellen Osteitis. Monatsschr Kinderheilkd 2014; 162: 539-545.
12 Hurtado-Nedelec M, Chollet-Martin S, Chapeton D. et al. Genetic susceptibility factors in a cohort of 38 patients with SAPHO syndrome: a study of PSTPIP2, NOD2, and LPIN2 genes. J Rheumatol 2010; 37 (02) 401-409.
13 Beck C, Girschick HJ, Morbach H. et al. Mutation screening of the IL-1 receptor antagonist gene in chronic non-bacterial osteomyelitis of childhood and adolescence. Clin Exp Rheumatol 2011; 29 (06) 1040-1043.
14 Hedrich CM, Hofmann SR, Pablik J. et al. Autoinflammatory bone disorders with special focus on chronic recurrent multifocal osteomyelitis (CRMO). Pediatr Rheumatol Online J 2013; 11 (01) 47.
15 Morbach H, Hedrich CM, Beer M, Girschick HJ. Autoinflammatory bone disorders. Clin Immunol 2013; 147 (03) 185-196.
16 Nakashima T, Takayanagi H. Osteoimmunology: crosstalk between the immune and bone systems. Journal of clinical immunology 2009; 29 (05) 555-567.
17 Girschick HJ, Huppertz HI, Harmsen D. et al. Chronic recurrent multifocal osteomyelitis in children: diagnostic value of histopathology and microbial testing. Hum Pathol 1999; 30 (01) 59-65.
18 Neubauer H, Evangelista L, Morbach H. et al. Diffusion-weighted MRI of bone marrow oedema, soft tissue oedema and synovitis in paediatric patients: feasibility and initial experience. Pediatr Rheumatol Online J 2012; 10 (01) 20.
19 Majeed HA, El-Shanti H, Al-Rimawi H, Al-Masri N. On mice and men: An autosomal recessive syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia. J Pediatr 2000; 137 (03) 441-442.
20 Valdearcos M, Esquinas E, Meana C. et al. Lipin-2 reduces proinflammatory signaling induced by saturated fatty acids in macrophages. The Journal of biological chemistry 2012; 287 (14) 10894-10904.
21 Herlin T, Fiirgaard B, Bjerre M. et al. Efficacy of anti-IL-1 treatment in Majeed syndrome. Ann Rheum Dis 2013; 72 (03) 410-413.
22 Beck C, Morbach H, Stenzel M. et al. [Hypophosphatasia]. Klin Padiatr 2009; 221 (04) 219-226.
23 Mornet E, Hofmann C, Bloch-Zupan A. et al. Clinical utility gene card for: hypophosphatasia - update 2013. Eur J Hum Genet. 2014 22. (4).
24 Hofmann C, Girschick H, Mentrup B. et al. Clinical aspects of hypophosphatasia: an update. Clin Rev Bone Miner Metab 2013; 11: 60-70.
25 Girschick HJ, Schneider P, Haubitz I. et al. Effective NSAID treatment indicates that hyperprostaglandinism is affecting the clinical severity of childhood hypophosphatasia. Orphanet journal of rare diseases 2006; 1: 24.
26 Girschick HJ, Mornet E, Beer M. et al. Chronic multifocal non-bacterial osteomyelitis in hypophosphatasia mimicking malignancy. BMC Pediatr 2007; 7: 3.
27 Beck C, Morbach H, Richl P. et al. How can calcium pyrophosphate crystals induce inflammation in hypophosphatasia or chronic inflammatory joint diseases?. Rheumatol Int 2009; 29 (03) 229-238.
28 Yadav MC, Huesa C, Narisawa S. et al. Ablation of Osteopontin Improves the Skeletal Phenotype of Phospho1 Mice. J Bone Miner Res. 2014 May 13
29 Hofmann C, Girschick H, Mornet E. et al. Unexpected high intrafamilial phenotypic variability observed in hypophosphatasia. Eur J Hum Genet 2014; 22: 1160-1164.
30 Girschick HJ, Seyberth HW, Huppertz HI. Treatment of childhood hypophosphatasia with nonsteroidal antiinflammatory drugs. Bone 1999; 25 (05) 603-607.
31 Whyte MP, Greenberg CR, Salman NJ. et al. Enzyme-replacement therapy in life-threatening hypophosphatasia. N Engl J Med 2012; 366 (10) 904-913.
32 Smith EJ, Allantaz F, Bennett L. et al. Clinical, Molecular, and Genetic Characteristics of PAPA Syndrome: A Review. Current genomics 2010; 11 (07) 519-527.
33 Aksentijevich I, Nowak M, Mallah M. et al. De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases. Arthritis Rheum 2002; 46 (12) 3340-3348.
34 Reddy S, Jia S, Geoffrey R. et al. An autoinflammatory disease due to homozygous deletion of the IL1RN locus. N Engl J Med 2009; 360 (23) 2438-2444.
35 Aksentijevich I, Masters SL, Ferguson PJ. et al. An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N Engl J Med 2009; 360 (23) 2426-2437.
36 Castori M, Sinibaldi L, Mingarelli R. et al. Pachydermoperiostosis: an update. Clinical genetics 2005; 68 (06) 477-486.
37 Girschick HJ, Krauspe R, Tschammler A, Huppertz HI. Chronic recurrent osteomyelitis with clavicular involvement in children: diagnostic value of different imaging techniques and therapy with non-steroidal anti-inflammatory drugs. Eur J Pediatr 1998; 157 (01) 28-33.
38 Bergmann C, Wobser M, Morbach H. et al. Primary hypertrophic osteoarthropathy with digital clubbing and palmoplantar hyperhidrosis caused by 15-PGHD/HPGD loss-of-function mutations. Experimental dermatology 2011; 20 (06) 531-533.
39 Papadaki ME, Lietman SA, Levine MA. et al. Cherubism: best clinical practice. Orphanet journal of rare diseases 2012; 7 (Suppl. 01) S6.
40 Ueki Y, Tiziani V, Santanna C. et al. Mutations in the gene encoding c-Abl-binding protein SH3BP2 cause cherubism. Nat Genet 2001; 28 (02) 125-126.