How Organ Manifestations Beyond the Bone May Guide Risk Stratification and Treatment Decisions in Chronic Nonbacterial Osteomyelitis

Chronic nonbacterial osteomyelitis is an autoinflammatory bone disease characterized by pronounced dysregulation of proinflammatory and anti-inflammatory cytokine production and release. Through innate immune dysregulation, patients with chronic nonbacterial osteomyelitis develop bone inflammation, pathological bone remodeling, and associated pain. Notably, secondary activation of adaptive immune mechanisms may contribute to phenotypic variability and the onset of additional tissue and organ involvement (joints, skin, gut). Currently used treatments are empiric, targeting inflammation and/or osteoclasts. While deemed efficacious across clinical cohorts internationally, in the absence of randomized controlled trials, they lack regulatory approval. While chronic nonbacterial osteomyelitis limited to bones frequently responds to anti-inflammatory treatment with naproxen or, in more severe cases, tumor necrosis factor inhibitors and/or osteoclast inhibition with bisphosphonates, patients with additional symptoms may require additional/different treatments targeting effector T cells and associated cytokines (such as interleukin-17 blockers, Janus kinase inhibitors). Thus, changing molecular, cellular, and phenotypic patterns throughout the disease course offer an opportunity for personalized treatment and suggest a ‘window of opportunity’ preventing the onset of additional organ involvement. However, ‘tools’ to guide personalized treatment approaches are currently lacking, and treatment is guided by clinical features, following a trial-and-error approach. This article reviews the available literature, deciphering shared immune mechanisms between chronic nonbacterial osteomyelitis and associated diseases that may guide individualized care. It focuses on shared and disease-specific molecular and cellular patterns of chronic nonbacterial osteomyelitis and associated diseases, delivering arguments for disease stage and phenotype specific treatments, including cytokine blockers and synthetic small-molecule inhibitors.