Background: Macrophage activation syndrome (MAS) is a hyperinflammatory and potentially fatal complication associated with rheumatologic disorders. In Kawasaki disease (KD), MAS is a rare and poorly described condition, making its differentiation from a severe, treatment-resistant presentation of KD particularly challenging. Objective: We aimed to describe MAS in KD by analyzing its epidemiological, clinical, and laboratory characteristics, complications, therapeutic strategies, and outcomes. Methods: A comprehensive literature review of PubMed, Embase, Scopus, and Cochrane Library was conducted to identify English-language studies on KD complicated by MAS, including case reports and case series, until 15 November 2024. Results: A total of 176 pediatric patients (60 females; median age 4 years, range 0.13–17) from 48 articles were included. MAS occurred after or simultaneously with KD diagnosis in 174/176 cases (99%). Common features included fever (100%), splenomegaly (49.4%), and hyperferritinemia (98.2%). Cardiac involvement was reported in 37% of children. The HLH-2004 criteria were met in 63% of cases, while the 2016 Ravelli criteria for MAS complicating systemic juvenile idiopathic arthritis were met in 94%. Treatment included additional doses of IVIG (36.2%), GCs (82.8%), cyclosporine A (28.7%), and biologics (13.8%), with complete MAS resolution in 93% of cases. Conclusions: MAS in KD is a rare but severe complication, with overlapping features that make its differentiation from severe and resistant KD challenging. Persistent fever despite initial IVIG administration, along with splenomegaly and hyperferritinemia, emerge as key warning signs. Ravelli criteria provide stronger diagnostic support compared to the HLH-2004 criteria. Moreover, MAS is associated with increased cardiac involvement.

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.