Anti-tumor necrosis factor treatment in cherubism — Clinical, radiological and histological findings in two children

• Published in: Bone (New York, N.Y.) Vol. 52; no. 1; pp. 347 - 353
• Main Authors: Hero, M, Suomalainen, A, Hagström, J, Stoor, P, Kontio, R, Alapulli, H, Arte, S, Toiviainen-Salo, S, Lahdenne, P, Mäkitie, O
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.01.2013; Elsevier
• Subjects: Adalimumab; Adaptor Proteins, Signal Transducing - genetics; Animal models; Animals; Biological and medical sciences; Bone resorption; Cherubism; Cherubism - diagnostic imaging; Cherubism - drug therapy; Cherubism - genetics; Cherubism - pathology; Child, Preschool; Children; Computed tomography; Cytokines; Data processing; Disease Models, Animal; Diseases of the osteoarticular system; Female; Fundamental and applied biological sciences. Psychology; Giant cells; Humans; Immunomodulators; Inflammation; Macrophages; Magnetic resonance imaging; Male; Malformations and congenital and or hereditary diseases involving bones. Joint deformations; Mandible; Maxilla; Medical sciences; Medicin och hälsovetenskap; Mice; Monoclonal antibodies; Mutation; Myeloid cells; Orthopedics; Osteoclasts; Osteogenesis; Pharmacology. Drug treatments; Radiography; SH3-binding protein 2; TRANCE protein; Tumor necrosis factor α; Tumor necrosis factor- alpha; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Vertebrates: anatomy and physiology, studies on body, several organs or systems; SH3-binding protein 2; Cherubism; Adalimumab; Tumor necrosis factor α; Human; Stomatology; Diseases of the osteoarticular system; Antipsoriatic agent; Anti-TNF; Tumor necrosis factor a; Immunomodulator; Binding protein; Symptomatology; Treatment; Tumor necrosis factor; Morphology; Osteochondrodysplasia; Child
• ISSN: 8756-3282; 1873-2763; 1873-2763
• DOI: 10.1016/j.bone.2012.10.003

Abstract Cherubism is a rare and disfiguring genetic disorder with excessive bone resorption and multilocular lesions in the mandible and/or maxilla. The disease-causing gain-of-function mutations in the SH3-binding protein 2 (SH3BP2) gene result in increased myeloid cell responses to macrophage colony stimulating factor and RANK ligand, formation of hyperactive osteoclasts (giant cells), and hyper-reactive macrophages that produce excessive amounts of the inflammatory cytokine tumor necrosis factor α (TNF-α). Recent findings in the cherubism mouse model suggest that TNF-α plays a major role in disease pathogenesis and that removal of TNF-α prevents development of the bone phenotype. We treated two children with cherubism with the TNF-α antagonist adalimumab for approximately 2.5 years and collected extensive clinical, radiological and histological follow-up data during the treatment. Histologically the treatment resulted in a significant reduction in the number of multinucleated giant cells and TNF-α staining positivity in both patients. As evaluated by computed tomography and magnetic resonance imaging, the lesions in Patient 1 showed either moderate enlargement (mandibular symphysis) or remained stable (mandibular rami and body, the maxilla). In Patient 2, the lesions in mandibular symphysis showed enlargement during the first 8 months of treatment, and thereafter the lesions remained unchanged. Bone formation and resorption markers remained unaffected. The treatment was well tolerated. Based on our findings, TNF-α antagonist may decrease the formation of pathogenic giant cells, but does not result in lesion regression or prevent lesion expansion in active cherubism. TNF-α modulator treatment thus does not appear to provide sufficient amelioration for patients suffering from cherubism.