An integrated transcriptomics and network pharmacology approach to explore the mechanism of Wang-Bi tablet against SAPHO syndrome.

BACKGROUND: SAPHO syndrome is recognized as a rare entity with damage to skin and bones due to inflammation. Currently, the treatment for SAPHO syndrome is still a challenge in clinical practice. In this study, an integrated transcriptomics and network pharmacology approach was applied to explore the therapeutic effect and mechanism of Wang-Bi tablet (WBT) on SAPHO syndrome. METHODS: The main components of WBT and their targets, as well as the targets of SAPHO syndrome, were collected from databases. Network visualization was performed using Cytoscape software. The GO and KEGG enrichment analysis was executed by David dataset. Then, the molecular mechanism of WBT improving SAPHO syndrome was validated by transcriptomics of peripheral blood neutrophils in SAPHO syndrome. Finally, the above results were validated by molecular docking. RESULTS: The Network Pharmacology results showed there are 152 core targets for WBT treatment on SAPHO syndrome. RNA-seq data showed 442 differentially expressed genes (DEGs) in peripheral blood neutrophils of SAPHO patients. Intriguingly, NIK/NF-kappaB-, MyD88-dependent toll-like receptor-, and MAPK pathway were included in the enrichment results of network pharmacology and RNA-seq. Moreover, we verified that the core components of WBT have good affinity with the core targets of NIK/NF-kappaB-, MyD88-dependent toll-like receptor-, and MAPK pathway by molecular docking. CONCLUSIONS: This study illustrated that the possible mechanisms of WBT against SAPHO syndrome may be related to NIK/NF-kappaB-, MyD88-dependent toll-like receptor-, and MAPK pathway, and further experiments are needed to prove these predictions.

Genetic variants in FBLIM1 gene do not contribute to SAPHO syndrome and chronic recurrent multifocal osteomyelitis in typical patient groups.

BACKGROUND: Syndrome of synovitis acne pustulosis hyperostosis osteitis (SAPHO) and chronic recurrent multifocal osteomyelitis (CRMO) present two diseases of a dermatologic and rheumatologic spectrum that are variable in manifestation und therapeutic response. Genetic risk factors have long been assumed in both diseases, but no single reliable factor has been identified yet. Therefore, we aimed to clinically characterize a patient group with syndrome of synovitis acne pustulosis hyperostosis osteitis (SAPHO) (n = 47) and chronic recurrent multifocal osteomyelitis (CRMO)/ chronic non-bacterial osteomyelitis (CNO) (n = 9) and analyze a CRMO candidate gene. METHODS: Clinical data of all patients were collected and assessed for different combinations of clinical symptoms. SAPHO patients were grouped into categories according to the acronym; disease-contribution by pathogens was evaluated. We sequenced coding exons of FBLIM1. RESULTS: Palmoplantar pustular psoriasis (PPP) was the most common skin manifestation in CRMO/CNO and SAPHO patients; most SAPHO patients had sterno-costo-clavicular hyperostosis. The most common clinical category of the acronym was S_PHO (n = 26). Lack of pathogen detection from bone biopsies was more common than microbial isolation. We did not identify autosomal-recessive FBLIM1 variants. CONCLUSIONS: S_PHO is the most common combination of symptoms of its acronym. Genetic analyses of FBLIM1 did not provide evidence that this gene is relevant in our patient group. Our study indicates the need to elucidate SAPHO's and CRMO/CNO's pathogenesis.

Copy Number Variation of Multiple Genes in SAPHO Syndrome.

OBJECTIVE: SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome is a type of rare chronic aseptic inflammation of unknown etiology. To date, no research to our knowledge has reported copy number variation (CNV) of genes that could affect predisposition to SAPHO syndrome. We investigated the association between CNV profile and SAPHO syndrome. METHODS: We used array comparative genomic hybridization (CGH) to screen for CNV in a nuclear family including 2 patients and a healthy control. We then validated the copy numbers of candidate genes found in the array CGH assay and other candidate genes by TaqMan real-time PCR in 360 case and control samples. RESULTS: Ten regions from 8 chromosomes were found to have abnormal gene copies in the nuclear family, so the CNV of candidate genes (ADAM5, CSF2RA, IL3RA, and 9 other genes) were tested by TaqMan PCR. Significant copy number loss of CSF2RA (p = 0.000) and NOD2 (p = 0.005), and significant copy number gain of MEGF6 (p = 0.002) and ADAM5 (p = 0.000) were seen in patients with SAPHO compared with controls at the a = 0.05 level. There were no differences in the other 8 candidate genes between patient and control samples (p > 0.05). CONCLUSION: Our study established the first association between CNV in CSF2RA, NOD2, MEGF6, and ADAM5 and SAPHO syndrome. These findings may offer insight into the pathogenesis of SAPHO and provide the basis for improved diagnosis and treatment.

Association analysis of interleukin-23 receptor SNPs and SAPHO syndrome in Chinese people.

OBJECTIVE: SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis) is an autoimmune disease of unknown etiology that seriously affects patients' daily lives. Family-based investigations support genetic contributions toward disease susceptibility. The present study evaluated whether the previously reported autoimmune disease-associated single nucleotide polymorphisms (SNPs) have any genetic overlap with SAPHO syndrome. METHOD: Genomic DNA was obtained from 71 SAPHO patients and 104 healthy controls. The SNP genotypes of each patient were determined with polymerase chain reaction and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Genotype, allele, and haplotype frequencies were analyzed with SPSS software. RESULTS: Three SNP sites (rs10889677 and rs2201841 of interleukin [IL]-23R, and rs2243248 of IL-4) showed significant correlation with the occurrence of SAPHO syndrome in additive and dominant genetic models, while rs7517847 of IL-23R showed substantial correlation with SAPHO in the dominant genetic model. The G allele of rs2243248 (IL-4) was a high risk factor for SAPHO (P = 2.41e-5, odds ratio [OR] =7.79, 95% CI: 2.59-23.3). The haplotype (A-G-C-G-T), comprising 5 SNPs of the IL-23R gene, had a significantly higher frequency in the SAPHO cohort than in the controls (P = .011, OR = 2.05, 95% CI: 1.12-3.60). CONCLUSION: Variants rs10889677, rs2201841, and rs7517847 of IL-23R, and variant rs2243248 of IL-4, showed strong associations with SAPHO syndrome. Patients carrying the A-G-C-G-T haplotype of IL-23 are significantly more likely to develop SAPHO syndrome.

IL-23/Th17 targeted therapies in SAPHO syndrome. A case series.

SAPHO syndrome is a rare entity with skin and rheumatologic inflammatory presentation. The treatment is not standardized, and in case of inadequate response to anti-inflammatory drugs, the use of anti-TNF or anti-IL-1 biologic treatments has been reported. The IL-23/Th17 axis may be involved in SAPHO syndrome. We report the results of six courses of IL-23 and IL-17 targeted therapies (3 ustekinumab and 3 secukinumab) in patients with SAPHO syndrome unresponsive to previous treatments (csDMARDs and bDMARDs). With a mean treatment duration of 5.5 months, improvement of skin symptoms was noticed in three cases, one improvement with secukinumab and two remissions (one with secukinumab, one with ustekinumab). Regarding the rheumatic symptoms, no major improvement was obvious under any of the six treatment courses. No particular safety concerns were reported, except cases of paradoxical psoriasis flare in one under ustekinumab and the other case under secukinumab.

Different Contributions of CDKAL1, KIF21B, and LRRK2/MUC19 Polymorphisms to SAPHO Syndrome, Rheumatoid Arthritis, Ankylosing Spondylitis, and Seronegative Spondyloarthropathy.

OBJECTIVES: Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome, rheumatoid arthritis (RA), ankylosing spondylitis (AS), and seronegative spondyloarthropathy (SPA) are autoimmune diseases of unknown etiology, which share some clinical manifestations in common. Previous family-based investigations support genetic contributions to the susceptibility of these diseases. The current study evaluated whether three previously reported AS-associated single-nucleotide polymorphisms (SNPs), rs6908425 T>C in CDKAL1, rs11584383 T>C near KIF21B, and rs11175593 C>T near LRRK2/MUC19, have any genetic overlap across multiple autoimmune diseases including SAPHO syndrome, RA, AS, and SPA. MATERIALS AND METHODS: Genomic DNA was obtained from 71 SAPHO, 125 RA, 67 AS, and 35 SPA Han Chinese patients, as well as 104 healthy controls. SNPs were genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Genotype and allele frequencies were analyzed using chi-square test. RESULTS: rs6908425 T>C in CDKAL1 was significantly different between SAPHO cases and healthy controls (odds ratios = 2.056, 95% confidence intervals: 1.211-3.490; p = 0.007), but no SNPs were associated with the risk of developing RA, AS, or SPA (p > 0.05). Analysis of genotype distributions showed similar results. A significant difference was only found in the genotype frequency of rs6908425 in SAPHO cases (p = 0.004); no significant differences were detected among patients with RA, AS, and SPA (p > 0.05). CONCLUSIONS: Our results suggest that rs6908425 in CDKAL1 is associated with the risk of developing SAPHO in Han Chinese populations. People who carry the risk allele T of rs6908425 might be more prone to developing SAPHO syndrome.

The inflammasomes in autoinflammatory diseases with skin involvement.

During the past years, significant progress in the understanding of the complexity, regulation, and relevance of innate immune responses underlying several inflammatory conditions with neutrophilic skin involvement has been made. These diseases belong to the novel class of autoinflammatory diseases, and several are caused by mutations in genes regulating the function of innate immune complexes, termed inflammasomes, leading to enhanced secretion of the proinflammatory cytokine IL-1ß. Consequently, targeting of IL-1ß has proven successful in the treatment of these diseases, and the identification of related pathogenic mechanisms in other more common skin diseases characterized by autoinflammation and neutrophilic tissue damage also provides extended opportunities for therapy by interfering with IL-1 signaling.

The SAPHO syndrome.

OBJECTIVE: To review the epidemiology, presentation, diagnosis, treatment, pathogenesis, and genetics of the syndrome known under the acronym of SAPHO for Synovitis, Acne, Pustulosis, Hyperostosis, and Osteitis to heighten awareness of this entity. METHODS: We conducted a Medline search using SAPHO syndrome, chronic recurrent multifocal osteitis/osteomyelitis, and related terms as keywords and extracted further relevant articles from the retrieved references. RESULTS: The SAHPO acronym identifies a syndrome encompassing a variety of osteoarticular disorders that are frequently accompanied by dermatoses characterized by neutrophilic pseudoabscesses, but can also occur in isolation. SAPHO syndrome is rare, although probably underrecognized because its diagnosis may be challenging because of the wide variability in its musculoskeletal and cutaneous manifestations. This is especially true when atypical sites are involved and when specific skin lesions are absent. There are no standardized treatment protocols available. Current treatments are empirical and have the objective of providing relief from the at times debilitating pain associated with SAPHO syndrome. They include nonsteroidal anti-inflammatory drugs and analgesics as first-line agents. Systemic corticosteroids, disease-modifying anti-rheumatic drugs, biologicals targeting tumor necrosis factor alpha and interleukin-1, and bisphosphonates have all been beneficial in some patients, but ineffective in others. This suggests that the pathogenesis of SAPHO syndrome is multifactorial, but this aspect remains poorly explored, although bacteria and immunological dysfunction are hypothesized to play a role. CONCLUSIONS: The early recognition, diagnosis, and prompt treatment of SAPHO syndrome can prevent the unnecessary use of long-term antibiotics or invasive procedures, while rapidly alleviating pain in a majority of affected patients.

Single-nucleotide polymorphisms p53 G72C and Mdm2 T309G in patients with psoriasis, psoriatic arthritis, and SAPHO syndrome.

Psoriasis (Ps), psoriatic arthritis (PsA), and SAPHO syndrome are diseases of unknown etiology that share common clinical features; however, family studies support the hypothesis of a genetic background for each of these diseases. To study the two common single-nucleotide polymorphisms (SNP) in the murine-double-minute-2-(Mdm2) and p53 genes in patients with Ps, PsA, and SAPHO syndrome. Genomic DNA was obtained from 187 patients with Ps, 50 with PsA, and 36 with SAPHO as well as 478 healthy controls. Mdm2-gene SNP T309G and p53-gene SNP G72C genotypes were determined by the polymerase chain reaction. Genotype and allele frequencies were analyzed with chi(2)-tests. Among the patients with Ps and PsA, no differences in allele or genotype frequencies of the p53-gene SNP G72C and Mdm2-gene SNP T309G were detected. However, in the SAPHO patients group, the frequencies of the Mdm2 SNP309 G allele and the genotype SNP 309 GG were significantly increased compared with the controls (G allele: 51.4 vs. 38.7%, P = 0.034; genotype GG: 36.1 vs. 14.2%, P = 0.002). In addition, the frequencies of the p53 SNP72 C allele and the genotype SNP 72 CC were also increased in the SAPHO patients cohort (C allele: 36.1 vs. 25.6%, P = 0.05; genotype CC: 16.7 vs. 6.3%, P = 0.05). SAPHO syndrome may be linked to an imbalance between MDM2 and p53 regulation with a "weak" p53-response associated with the Mdm2 SNP 309 G allele. In contrast, the p53 network does not seem to play a major role in pathogenesis of Ps or PsA.

Genetic susceptibility factors in a cohort of 38 patients with SAPHO syndrome: a study of PSTPIP2, NOD2, and LPIN2 genes.

OBJECTIVE: The SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis) is a rare disorder that mainly affects bone and skin. Chronic multifocal osteitis is the main diagnostic feature. Genetic studies of HLA genes have shown no role for these class II antigens, whereas studies of 2 mouse models (cmo and Lupo) point to a role of the PSTPIP2 gene. We analyzed the PSTPIP2 gene in patients with SAPHO syndrome. METHODS: In a cohort of 38 patients with SAPHO we analyzed PSTPIP2 and 2 other candidate genes, NOD2/CARD15 (Crohn's disease occurs in about 10% of SAPHO patients), and LPIN2 (clinical similarities of SAPHO with Majeed syndrome). RESULTS: Rare variants of the 3 genes observed in patients with SAPHO were not specific or were not found more frequently compared to controls, suggesting no major pathogenetic role of these genes in the SAPHO syndrome. CONCLUSION: We found no association between PSTPIP2, NOD2, and LPIN2 variants and the SAPHO syndrome.

Neutrophil dysfunction in a family with a SAPHO syndrome-like phenotype.

SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis) is an inflammatory disorder of the bone, skin, and joints. We describe a family with multiple affected members who segregate a SAPHO syndrome-like phenotype, and we report the results of neutrophil studies and candidate gene analysis. We obtained written informed consent and a family history and reviewed medical records. We collected DNA and sequenced candidate genes, and we performed functional studies on neutrophils isolated from the proband and her mother. The pedigree segregated chronic osteomyelitis and cutaneous inflammation in a pattern that suggested an autosomal-dominant disorder. No coding sequence mutations were detected in PSTPIP1, PSTPIP2, LPIN2, SH3BP2, or NCF4. Analysis of neutrophil function in the proband, including nitroblue tetrazolium tests, myeloperoxidase assays, neutrophil chemotaxis, and neutrophil chemotaxis assays, revealed no identifiable abnormalities. However, an abnormality in the luminol, but not the isoluminol, respiratory burst assays following stimulation with phorbol myristate acetate (PMA) was detected in neutrophils isolated from the affected proband. Internal oxidant production was also reduced in the proband and her mother when neutrophils were treated with fMLP with or without platelet-activating factor, PMA alone, or tumor necrosis factor alpha alone. This family segregates a disorder characterized by chronic inflammation of the skin and bone. Functional differences in neutrophils exist between affected individuals and controls. The biologic significance of this defect remains unknown. Identification of the gene defect will help identify an immunologic pathway that, when dysregulated, causes inflammation of the skin and bone.

Diffuse chronic sclerosing osteomyelitis and the synovitis, acne, pustolosis, hyperostosis, osteitis (SAPHO) syndrome in two sisters.

Two sisters with diffuse chronic sclerosing osteomyelitis of the mandible and the humerus and the synovitis, acne, pustolosis, hyperostosis and osteitis syndrome (SAPHO syndrome) are presented. The diagnoses of diffuse chronic sclerosing osteomyelitis at the age of 12 years and 27 years, respectively, were based on typical medical history, clinical symptoms and radiographic, histologic and scintigraphic findings. Because skin lesions and scintigraphic enhancement of the sternoclavicular joints with hyperostosis were present, a SAPHO syndrome was diagnosed in both sisters. Microbiological cultures of biopsy specimens revealed coagulase-negative Staphylococcus aureus at the humerus and Haemophilus parainfluenzae, Streptococcus, Actinomyces and Veilonella species at the mandible. Repeated operative procedures, including decortications, resection and reconstruction, and multiple histologic and microbiologic studies were performed over a period of up to 20 years. Since HLA typing yielded identical gene loci, we suggest that hereditary and autoimmune factors may play a role in the pathogenesis of these cases.

Psoriatic arthritis and the spectrum of syndromes related to the SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome.

During the past year, the increasing use of nuclear magnetic resonance imaging techniques, with their ability to delineate cartilage and ligamentous structures and to identify edema, are providing a radical improvement in ascertainment of musculoskeletal abnormalities, although their significance remains incompletely delineated. A second theme has come from the study of spondyloarthropathies in different ethnic groups and societal environments, revealing that the Northern European and North American form of the disease, with its powerful association with HLA-B27, is little evident in the rest of the world's population and that different susceptibility genes and environmental factors operate in other regions and peoples. Related to this theme is the compelling evidence of the marked influence of HIV infection on the development of spondyloarthropathies in Africa. Two areas of immune recognition are discussed as examples of emerging fields that may provide useful paradigms for the experimental approach to mechanisms in psoriatic arthritis. One of these is the three-cell model of CD8 T-cell interaction, in which a dendritic cell presents a peptide from an immunogenic protein to both a CD4 and CD8 T-cell clone, providing a cognitive interaction that disrupts tolerance and results in the expansion of the cytotoxic T-cell clone. In this respect, the combination of an activated dendritic cell, together with enhanced availability of arthritogenic microbial antigens caused by microbial persistence, are interesting candidates to explore as the basis of the HIV-associated rheumatic diseases. The second area of immune recognition is the growing understanding of the outline of the solution to the problem of the association of a spondyloarthropathy with several

SAPHO syndrome or psoriatic arthritis? A familial case study.

OBJECTIVE: To discuss the relationships between SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) syndrome and the group of spondylarthropathies. METHODS: Few reports of familial SAPHO have been published. We describe three children, two sisters and one brother, whose clinical and radiological presentation was in accordance with SAPHO syndrome. RESULTS: Two children developed psoriasis, and one child palmoplantar pustulosis. Both sacroiliac and sternoclavicular joints were involved in these three cases. Some features in our observations are also common to psoriatic arthritis. No association was found with HLA antigens, but a history of trauma preceding the onset of symptoms was present in all three children. CONCLUSIONS: We can consider that SAPHO is nosologically related to spondylarthropathies. Psoriatic arthritis could be the missing link between SAPHO and spondylarthropathies. It is likely that both genetic and environmental factors are involved.