Study of the Pathophysiological Mechanisms Involved in the SAPHO Syndrome: Genetic Component and Immune Response

Overview

SAPHO syndrome (Synovitis, Acne, Pustulosis, Hyperostosis and Osteitis) is a chronic inflammatory rheumatism associating bone or joint lesions and dermatological manifestations dominated by severe acne and palmar and palmoplantar pustulosis. Prevalence of SAPHO syndrome is estimated at 1/50000 in France, but this figure is probably underestimated due to frequent misdiagnosis. Osteoarticular manifestations form a rheumatic picture very similar to that of other forms of spondyloarthritis (SpA). The latest French recommendations do not distinguish SAPHO syndrome from other forms of SpA. As a result, the management of SAPHO remains fairly heterogeneous, essentially based on the local experience of rheumatologists. Delays in diagnosis and difficulties in finding effective treatment can result in significant disability and reduced quality of life, particularly detrimental in a young population (age at diagnosis is usually between 30 and 40). The wide spectrum of clinical presentations of SAPHO syndrome explains the complexity of managing this condition. Understanding the pathophysiological mechanisms underlying these different forms of the disease is a major challenge for personalized medicine. SAPHO syndrome is a multifactorial disease that is a result of interaction of genetic, environmental, immunological and infectious factors. In the classification of immune-mediated inflammatory diseases, SAPHO syndrome lies midway between autoinflammatory diseases involving the innate immune response and spondyloarthritis associated with abnormalities in the adaptive immune response. Indeed, while the clinical phenotype may resemble spondyloarthritis in certain aspects, the identification of genetic forms of chronic relapsing osteitis, such as DIRA syndrome or Majeed syndrome, argues in favor of an autoinflammatory origin of SAPHO syndrome. Although osteitis is reputed to be sterile, an infectious initiating factor has long been suspected in this disease. Among the bacterial agents, antigens antigens from Cutibacterium acnes were detected in bone biopsies from patients with SAPHO syndrome. It has been suggested that this bacterium may play a role in triggering a systemic inflammatory response systemic inflammatory response mediated in particular by IL-1β.

Although neutrophils (PNN) are the most abundant leukocytes in the circulation and form a first line of innate immune defense, they are difficult to study because they have a short lifespan and, after migrating into tissues, are rapidly eliminated by macrophages. PNN play a central role in the early phase of SpA development, and contribute to the various tissue damage observed. PNN are recruited from the circulation and enter target tissues such as joints, enthesis, digestive tract, skin and eyes, where they produce neutrophil extracellular traps (NETs), cytokines and chemokines that attract other immune cells. In SAPHO syndrome, bone biopsy usually reveals an infiltrate of PNNs, at least in the early stages of the disease. To date, no study has performed extensive phenotyping of circulating blood to identify over- or under-represented cell populations, which could thus be implicated in the disease. Studies showed an increase in the Th17 population in SAPHO patients, elevated low density granulocytes and neutrophil extracellular traps formation, as well as specific protein patterns associated with inflammation. Genetic studies, particularly in Chinese populations, have revealed potential associations with IL-23R and IL-4 genes, as well as SNPs in PEX16 and IQCA1L. However, no large-scale genetic analysis has been conducted in European/Caucasian populations. While certain forms of SAPHO syndrome suggest a genetic predisposition, studies targeting genes associated with monogenic disorders like Majeed, PAPA, and DIRA have yielded negative results. Chinese studies have indicated involvement of genes like CSF2RA, NOD2, MEGF6, and ADAM5. Despite genetic predisposition suspicions, robust associations have not been identified, particularly in Caucasian populations, warranting further research.