Abundance alteration of nondominant species in fecal-associated microbiome of patients with SAPHO syndrome.

BACKGROUND: SAPHO syndrome is a group of symptoms consisting of synovitis, acne, pustulosis, hyperostosis and osteosis. There is no specific laboratory index assist in the diagnosis of SAPHO because of its highly heterogeneous clinical manifestations. Pathogenic microorganisms had been identified in biopsies of some SAPHO cases and particular gene mutations were also linked to the occurrence of SAPHO. It is largely unknown whether intestinal microbiome plays a role in pathogenesis of SAPHO. To explore the intestinal microbiome structure of SAPHO syndrome, fecal samples from 17 SAPHO patients and 14 healthy controls (HC) were collected for 16S rDNA sequencing. RESULTS: Our results showed that there was no significant difference in alpha indexes and beta diversity between SAPHO and HC samples, while there were 14 operational taxonomic units (OTUs) in the Wilcoxon rank-sum test and 42 OTUs in the MetagenomeSeq analysis showed significant difference in distribution between the SAPHO and HC groups, 3 of which in Firmicutes were also observed in the random forest analysis and used to construct a receiver operating characteristic curve to evaluate the diagnostic value, the area under the curve was 0.86. CONCLUSION: Fecal-associated microbiome in the SAPHO samples was characterized by the alteration in abundance of some nondominant species, and the 3 selected OTUs in Firmicutes could serve as candidate biomarkers for SAPHO syndrome diagnosis.

The role of Cutibacterium acnes in auto-inflammatory bone disorders.

Chronic nonbacterial osteomyelitis (CNO) and SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) syndrome are auto-inflammatory disorders manifesting as chronic inflammation of bones and joints, which in SAPHO is often accompanying by skin changes. The aetiology of these diseases is unknown, but includes genetic, infectious and immunological components. It has been proposed that Cutibacterium (formerly Propionibacterium) acnes plays a role in the pathogenesis. In this review, we summarise reported cases of CNO or SAPHO syndrome in which C. acnes has been isolated from bones. To identify cases, a search was done in May 2018 using the MEDLINE Ovid interface (1946 to present). We found 14 publications reporting 98 patients with auto-inflammatory bone disorders, of whom 48 (49%) had positive bone biopsies for C. acnes. This bacterium was more frequently isolated from open biopsies than percutaneous ones (43/69 (62%) vs 1/7 (14%); p = 0.04) and biopsies were more frequently positive in patients who presented with simultaneous skin manifestations (19/36 (53%) vs 4/12 (33%); p = 0.03).Conclusion: In patients with CNO or SAPHO, C. acnes can be isolated from open biopsies suggesting that in these patients, C. acnes might be a pathogen rather than a contaminant. The fact that biopsies are more frequently positive in patients who present with simultaneous skin manifestations suggests that these individuals might have a genetic predisposition for impaired clearance of C. acnes. What is known • Chronic nonbacterial osteomyelitis (CNO) and SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) syndrome are auto-inflammatory disorders manifesting as inflammation of bones. Both diseases are an important differential diagnosis in children who present with symptoms of (multifocal) osteomyelitis. • The pathogenesis of CNO and SAPHO is multifactorial emcompassing genetic, infectious and immunological components, including interleukin (IL)-1 dysregulation. There is a controversy as to whether Cutibacterium (formerly Propionibacterium) acnes plays a role in the aetiology of CNO and SAPHO. It has been postulated that the presence of C. acnes might trigger auto-inflammatory chronic inflammation in genetically predisposed individuals. What is new • In patients with CNO or SAPHO, C. acnes can be isolated more frequently from open biopsies, than from percutaneous ones, suggesting that C. acnes might be a pathogen rather than a contaminant. • Biopsies are more frequently positive in patients who present with simultaneous skin manifestations suggesting that these individuals might have a genetic predisposition for impaired clearance of C. acnes. Impaired C. acnes clearance likely leads to increased IL-1 beta (ß) production by skin cells, bone cells and phagocytes, which is one of the main cytokines underlying chronic inflammatory bone disorders.

SAPHO, autophagy, IL-1, FoxO1, and Propionibacterium (Cutibacterium) acnes.

Overt infection by Propionibacterium acnes is lacking in many SAPHO syndromes, and antibiotics have only a transient and incomplete effect, either in SAPHO syndrome or acne. As several auto-inflammatory bone disorders sharing overproduction of IL-1ß can mimic SAPHO, this syndrome could partly depend on genetically encoded overproduction of IL-1ß. However, cyclic intracellular infections, mostly by P. acnes, can contribute to the enhanced IL-1ß release by some skin cells, and probably by bone cells. P. acnes is indeed a powerful trigger of NLRP3-inflammasome activation and IL-1ß, leading to osteitis and enhanced mesenchymal cells differentiation in osteoblasts. Recent advances in the understanding of acne suggest that first steps of this disorder are not driven by P. acnes, but by a relative deficiency of FoxO1 within the nucleus of sebaceous cells. A similar defect of FoXO1 in bone cells should also be sought in SAPHO, since repression of FoxO1 gene is found in lesional psoriasis skin, and is associated with an increased number of osteoblasts and high bone mass in mice. FoxO1 selectively promotes IL-1ß production, so that its downregulation could help some P. acnes t escape innate immunity and persist in a latent state in bone cells, including mesenchymal stem cells. However, P. acnes itself possibly contributes to FoxO1 downregulation, like H. pylori infection which induces nuclear inactivation of FoxO1 in human gastric cells to slow down autophagic clearance. As bisphosphonates, which often improve SAPHO syndromes, enhance autophagy, it may be worth testing whether their combination with antibiotics is synergistic in SAPHO syndromes.

Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome - A challenging diagnosis not to be missed.

SAPHO syndrome manifests as chronic inflammation of bones and joints, which may or may not be accompanied by skin changes. The term SAPHO is an acronym that stands for synovitis, acne, pustulosis (usually palmoplantar), hyperostosis and osteitis. The bones most commonly affected are those in the anterior chest wall (mainly the sternum, clavicles and sternocostoclavicular joints), the vertebrae and the sacroiliac joints, but peripheral and flat bones may also be involved, especially in children. There are no validated diagnostic criteria for SAPHO, and diagnosis is based on clinical and radiological findings. One of the main challenges in diagnosis is that the clinical features may occur many years apart. Additionally, patients may not develop all manifestations. Delayed diagnosis, as a result of a lack of awareness of SAPHO, can lead to patients suffering ongoing pain and disfiguring skin manifestations. One theory is that Propionibacterium acnes (isolated from bone biopsies in many SAPHO patients) triggers an auto-immune mediated chronic inflammation in genetically predisposed individuals. Treatment involves the use of nonsteroidal anti-inflammatory drugs, intra-articular steroids, bisphosphonates and biologicals. The course of SAPHO is often prolonged but, despite the challenges in diagnosis and treatment, the long-term prognosis is good.

Autoinflammatory bone disorders: update on immunologic abnormalities and clues about possible triggers.

PURPOSE OF REVIEW: To provide an update on the genetics and immunologic basis of autoinflammatory bone disorders including chronic recurrent multifocal osteomyelitis including the monogenic forms of the disease. RECENT FINDINGS: Ongoing research in murine, canine and human models of sterile bone inflammation has solidified the hypothesis that sterile bone inflammation can be genetically driven. Mutations in Pstpip2, LPIN2 and IL1RN have been identified in monogenic autoinflammatory bone disorders that have allowed more detailed dissection of the immunologic defects that can produce sterile osteomyelitis. Recent studies in murine chronic multifocal osteomyelitis, deficiency of the interleukin-1 receptor antagonist (DIRA), Majeed syndrome and SAPHO syndrome reveal abnormalities in innate immune system function. IL-1 pathway dysregulation is present in several of these disorders and blocking IL-1 therapeutically has resulted in control of disease in DIRA, Majeed syndrome and in some cases of SAPHO and CRMO. Basic research demonstrates the importance of the innate immune system in disease pathogenesis and offers clues about potential disease triggers. SUMMARY: Research and clinical data produced over the last several years support the important role of innate immunity in sterile osteomyelitis. Based on what has been learned in the monogenic autoinflammatory bone disorders, IL-1 is emerging as an important pathway in the development of sterile bone inflammation.

Propionibacterium acnes: infection beyond the skin.

Propionibacterium acnes is a Gram-positive bacterium that forms part of the normal flora of the skin, oral cavity, large intestine, the conjunctiva and the external ear canal. Although primarily recognized for its role in acne, P. acnes is an opportunistic pathogen, causing a range of postoperative and device-related infections. These include infections of the bones and joints, mouth, eye and brain. Device-related infections include those of joint prostheses, shunts and prosthetic heart valves. P. acnes may play a role in other conditions, including inflammation of the prostate leading to cancer, SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome, sarcoidosis and sciatica. If an active role in these conditions is established there are major implications for diagnosis, treatment and protection. Genome sequencing of the organism has provided an insight into the pathogenic potential and virulence of P. acnes.

The SAPHO syndrome--are microbes involved?

The syndrome of synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) includes a rare group of chronic, relapsing, inflammatory osteoarticular disorders that is conventionally associated with manifestations in the skin. Diagnostic dilemmas can arise due to incomplete manifestations or confusion generated through mimicking of other conditions, such as osteomyelitis. The aetiology of this syndrome remains unclear, but probably involves genetic, immunological and infectious mechanisms. The possible pathogenetic role of infectious agents in genetically predisposed individuals, resulting in a 'reactive osteitis', has been suggested because microbes such as Propionibacterium acnes have been recovered from bone biopsy samples. However, this hypothesis has not been demonstrated as yet. Current knowledge with regard to treatment of this syndrome is based on results reported from small case studies and, thus, is still empiric. The use of antibiotics, instituted based on the isolation of Propionibacterium acnes, has been reported to show conflicting results. Promising results for potential future application have recently been reported for treatment of SAPHO with bisphosphonates and antagonists of tumour necrosis factor-α. This review aims to evaluate the existing knowledge on the SAPHO syndrome and to provide information on symptoms, diagnosis and treatment options for this disease.

SAPHO syndrome: is a range of pathogen-associated rheumatic diseases extended?

SAPHO syndrome, representing a constellation of synovitis, acne, palmo-plantar pustulosis, hyperostosis, and osteitis, is now recognized as a distinct medical entity: a reactive infectious osteitis. Genetic, immunological, and bacterial mechanisms are implicated in the development of the disease. Diagnostic problems may arise due to non-complete manifestations of SAPHO: either acne and arthritis or acne and anterior wall osteitis with an unclear pustulosis history. The interventional study of Assmann et al. is a significant addition to a long range of publications showing an association of SAPHO with Propionibacterium acnes. Randomized control studies are needed to confirm the effects of antibiotic therapy.

Efficacy of antibiotic therapy for SAPHO syndrome is lost after its discontinuation: an interventional study.

INTRODUCTION: The acronym SAPHO was introduced in 1987 to unify the various descriptions of a seronegative arthritis associated with skin manifestations and to show synovitis, acne, pustulosis, hyperostosis, and osteitis with and without sterile multifocal osteomyelitis. The etiology of SAPHO syndrome is unknown, but an association with infection by semipathogenic bacteria like Propionibacterium acnes has been suggested. We conducted an interventional study of SAPHO patients receiving antibiotics. METHODS: Thirty-seven patients met the clinical criteria of SAPHO syndrome, 21 of them underwent a needle biopsy of the osteitis lesion, and 14 of them showed positive bacteriological cultures for P. acnes. Thirty patients (14 bacteriological positive and 16 without biopsy) were treated with antibiotics for 16 weeks. The activity of skin disease and osteitis were assessed by a physician using a scoring model (from 0 to 6). In addition, patients completed a Health Assessment Score (HAS, from 0 to 6). The erythrocyte sedimentation rate was determined and a MRI (of the osteitis lesion, radiologic activity score from 0 to 2) was performed in week 1 (W1), week 16 (W16), and week 28 (W28, 12 weeks after antibiotics). RESULTS: Twenty-seven patients continued the medication (azithromycin, n = 25, 500 mg twice a week; clindamycin, n = 1, 300 mg daily; or doxycycline, n = 1, 100 mg daily) for 16 weeks. After W16 the scores for MRI (1.5 to 1.1, P = 0.01), skin activity (3.2 to 1.2, P = 0.01), osteitis activity (4.0 to 2.1, P = 0.02), and HAS (3.3 to 2.1, P = 0.01) decreased significantly. However, this was followed by increasing values for MRI scores (1.2 to 1.4, P = 0.08), skin activity (1.2 to 1.7, P = 0.11), osteitis activity (1.9 to 2.7, P = 0.01), and HAS (2.2 to 3.3, P = 0.02) from W16 to W28. The comparison of the scores in W1 and W28 in these 12 patients showed no significant differences. CONCLUSIONS: For the period of application, the antibiotic therapy seems to have controlled the disease. After antibiotic discontinuation, however, disease relapse was observed. SAPHO syndrome thus groups with other chronic inflammatory arthropathies with a need for permanent therapy.

Secondary syphilis presenting as SAPHO syndrome features.

The SAPHO syndrome may evolve following low virulent infections. This report describes a patient who developed a clinical syndrome that complied with the formal diagnostic criteria of the SAPHO following an infection with syphilis. His clinical manifestations gradually resolved following antibiotic therapy. This interesting association underlines the pathogenic circumstances linking infections and various rheumatic conditions. It is less evident whether resolution of the symptoms was ascribed to the eradication of the bacteria or perhaps due to cessation of the auto-inflammatory reaction to the infection induced. In our description we suggest a correlation between infection with Treponema pallidum and the induction of SAPHO syndrome.

Propionibacterium acnes and SAPHO syndrome: a case report and literature review.

OBJECTIVE: To describe the presence of Propionibacterium acnes (P. acnes) in a series of patients with SAPHO syndrome in which a bone biopsy has been carried out and to discuss the results comparing them to the data described in the literature. METHODS: In 6 out of 56 patients with SAPHO syndrome, a bone biopsy from osteitic lesion was carried out. This invasive investigation was performed only in those cases in which it was necessary to clarify the diagnosis. RESULTS: Of the 6 biopsies processed, P. acnes was isolated in only one case. No other infectious agents were identified. CONCLUSION: P. acnes is not often found in bone lesions of SAPHO syndrome. A bone biopsy may represent a procedure useful for corroborating the diagnosis or for excluding other diseases only in specific cases.

Is SAPHO syndrome a target for antibiotic therapy?

The etiology of the synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome remains unclear. Infectious factors are proposed to be relevant in the etiopathogenesis of the disease. To our knowledge, this is the first reported case of a proposed relationship between Staphylococcus aureus cultured from plantar pustule and SAPHO syndrome, which was successfully treated with co-trimoxazole (CTM) (sulfamethoxazole/trimetoprim). CTM might be the drug of choice for therapy for SAPHO syndrome because of combined antibiotic and immunomodulatory properties. Hypersensitivity testing of the medication in vitro was performed to identify, in the preclinical stage, the hypersensitivity reaction to CTM, which may have been severe.

[A case of SAPHO syndrome with paraplegia due to a thoracic kyphosis].

A 63-year-old man visited our hospital in January 1993 because of back pain, which had been present for a year and persisted. The patient was diagnosed compression fracture of thoracic spine by another hospital. Thoracic plain radiographs revealed destructive and sclerotic changes with reduction of height of T 8, T 9 vertebral body. He had kyphosis on this level. Radiographs of the chest revealed hyperostosis of bilateral proximal clavicle. We diagnosed SAPHO syndrome (synovitis, acne, pustlosis, hyperostosis, and osteomyelitis: SAPHO) with T 8, T 9 spondylodiscitis, however without any skin manifestations. Oral indomethacin was effective, however thoracic kyphosis progressed gradually. Spastic gait and paraplegia appeared from February 1998, at last on July he was unable to walk independently. MRI showed the compression of spinal cord on T 8, T 9 level. We performed circumferential decompression and fusion with instrumentation. His paraplegia improved after surgery. We describe a rare case of SAPHO syndrome with paraplegia due to a thoracic kyphosis.

Chronic recurrent multifocal osteomyelitis in children: diagnostic value of histopathology and microbial testing.

Chronic recurrent, unifocal or multifocal osteomyelitis (CRMO), an inflammatory disorder of unknown origin, involves different osseous sites and may be associated with palmoplantar pustulosis. Bacterial cultures of affected tissue were reported negative in nearly all cases. Radiological and magnetic resonance imaging features of CRMO have been described, but differential diagnosis remains difficult, including rheumatic diseases, bacterial osteomyelitis, and malignancy. Although definite diagnosis relies on histopathologic confirmation by biopsy, histopathologic criteria have not been defined. Because CRMO may be treated with nonsteroidal antiinflammatory drugs, but not antibiotics, distinguishing CRMO from bacterial osteomyelitis is of major importance. Histopathologic analysis of 12 patients with CRMO indicated a wide variation of reparative changes of bone, but chronic inflammation could not be found at all sites in the same biopsy. The inflammatory infiltrate was mostly scattered, consisting mainly of lymphocytes, plasma cells, histiocytes, and also few neutrophil granulocytes. Immunohistochemistry showed a predominance of CD3(+), CD45RO(+) T-cells, which were mainly CD8(+). In addition, CD20(+) B cells and CD68(+) macrophages were abundant in each biopsy specimen. Mild lymphocytic and granulocytic infiltrates were also detected in three synovial biopsy specimens obtained from adjacent joints. All bacterial and fungal cultures from native biopsy tissues were negative. Amplification of partial-length 16S ribosomal DNA by polymerase chain reaction (PCR) using broad-range eubacterial primers was below the detection limit in all patients. Because histopathologic features alone may not provide conclusive evidence, CRMO should be included in the differential diagnosis of chronic inflammatory bone lesions in children, and the definite diagnosis should be made by the clinical picture, x-ray studies, bone scan, bacterial culture, and histopathologic analysis in a multidisciplinary approach.