SAPHO syndrome and pustular skin diseases: shared inflammatory circuits, divergent tissue outcomes, and the limits of a spectrum model.

Both SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome and pustular skin diseases are characterized by neutrophil-dominated inflammatory responses; however, whether they represent manifestations within a shared disease spectrum remains unresolved. The aim of this review was not simply to establish equivalence between these conditions but rather to clarify the extent of their overlap, evaluate the strength of current evidence, and discuss the clinical implications of their potential relationship. In this narrative review, we compare SAPHO syndrome with major pustular skin phenotypes, including palmoplantar pustulosis (PPP), generalized pustular psoriasis (GPP), and acrodermatitis continua of Hallopeau (ACH), focusing on clinical manifestations, genetic susceptibility, immune mechanisms, tissue-specific pathological features, and therapeutic responses. The most stable area of overlap between SAPHO syndrome and pustular skin diseases is observed within the SAPHO-PPP subgroup, whereas direct evidence supporting equivalence between SAPHO syndrome and GPP or ACH remains limited. IL-36 signaling, the IL-23/Th17 axis, keratinocyte activation, myeloid cell responses, and neutrophil recruitment represent potentially shared downstream inflammatory networks. However, although more direct evidence has demonstrated IL-36 pathway dysregulation in a subset of patients with GPP, its contribution to SAPHO-associated osteitis remains unvalidated at the tissue level. The characteristic features of SAPHO syndrome, including aseptic osteitis, hyperostosis, preferential anterior chest wall involvement, and chronic pathological bone remodeling, also differ from the osteoarticular manifestations observed in most pustular skin diseases. Therefore, we propose that SAPHO syndrome and specific pustular phenotypes should be regarded as related but distinct disorders within an overlapping inflammatory network, rather than as different manifestations of a single unified disease entity. This framework may improve interdisciplinary recognition and provide a basis for mechanism-oriented research and stratified therapeutic hypotheses; however, it should not yet be considered a substitute for diagnostic or therapeutic algorithms validated through prospective, tissue-resolved, and mechanism-driven studies.