The complex pathophysiology of chronic nonbacterial osteitis (CNO) and how it informs treatment

Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disease characterized by pathological inflammasome activation and a pronounced dysregulation of cytokine expression. Recent advances have linked pathological activation of mitogen-activated protein kinases with altered expression of immune-regulatory interleukin-10, resulting in impaired inhibition of inflammasomes. Moreover, rare variants in the P2RX7 gene, encoding for the ATP-dependent P2X7 surface receptor, have been linked with pathological activation of inflammasomes in up to 40% of people with CNO. These observations explain clinical response to currently used off-label treatments targeting inflammation and/or osteoclasts. An expanded clinical phenotype with skin, joint, and/or gut involvement may be the result of a secondary activation of adaptive immune mechanisms. In patients with synovitis, acne, pustulosis hyperostotic and osteitis, lymphocyte activation may be responsible for the development of additional organ involvement. This manuscript summarizes recent advances in the understanding of CNO, discussing the possibility of future disease stage and phenotype-specific treatment.