Chronic nonbacterial osteitis (CNO) is a rare musculoskeletal disease causing chronic bone pain. It is known that chronic musculoskeletal pain may involve other mechanisms than nociceptive pain only. We investigate the prevalence of neuropathic and nociplastic pain in adult CNO and their association with clinical characteristics and treatment outcomes. Survey study among the Dutch adult CNO cohort (n = 84/195 participated), including PAIN-detect for neuropathic pain, and the Central Sensitization Inventory (CSI), Fibromyalgia Rapid Screening Tool (FiRST), and ACTTION-APS Pain Taxonomy (AAPT) for nociplastic pain. Clinical characteristics and CNO-related bone pain scores were compared between patients with exclusive nociceptive pain and those with nociceptive pain plus neuropathic and/or nociplastic pain (mixed pain). 31% (95% CI 21-41) of patients classified as likely having neuropathic pain according to PAIN-detect. 53% (41-64) of patients displayed central sensitization on CSI, 61% (50-72) screened positive for fibromyalgia on FiRST and 14% (7-23) of patients fulfilled the AAPT criteria, all indicative of nociplastic pain. Mixed pain was associated with longer diagnostic delay (mean difference 2.8 years, 95% CI 0.4-5.2, p = 0.023), lower educational level (72% versus 20%, p < 0.001), and opioid use (37% versus 13%, p = 0.036). Despite comparable disease severity and extent, patients with mixed pain reported significantly higher CNO-related bone pain scores. This study demonstrates the high prevalence of mixed pain in adult CNO, in which neuropathic and nociplastic pain exist alongside nociceptive inflammatory bone pain. Disease burden in CNO may extend beyond inflammatory activity, highlighting the need for a multifaceted management approach.

Chronic nonbacterial osteitis (CNO) is a rare disease spectrum, which lacks biomarkers for disease activity. Sodium fluoride-18 positron emission tomography/computed tomography ([18F]NaF-PET/CT) is a sensitive imaging tool for bone diseases and yields quantitative data on bone turnover. We evaluated the capacities of [18F]NaF-PET/CT to provide structural and functional assessment in adult CNO. A coss-sectional study was performed including 43 adult patients with CNO and 16 controls (patients referred for suspected, but not diagnosed with CNO) who underwent [18F]NaF-PET/CT at our expert clinic. Structural features were compared between patients and controls, and maximal standardized uptake values (SUVmax [g/mL]) were calculated for bone lesions, soft tissue/joint lesions, and reference bone. SUVmax was correlated with clinical disease activity in patients. Structural assessment revealed manubrial and costal sclerosis/hyperostosis and calcification of the costoclavicular ligament as typical features associated with CNO. SUVmax of CNO lesions was higher compared with in-patient reference bone (mean paired difference: 11.4; 95% CI: 9.4-13.5; p < .001) and controls (mean difference: 12.4; 95%CI: 9.1-15.8; p < .001). The highest SUVmax values were found in soft tissue and joint areas such as the costoclavicular ligament and manubriosternal joint, and these correlated with erythrocyte sedimentation rate in patients (correlation coefficient: 0.546; p < .002). Our data suggest that [18F]NaF-PET/CT is a promising imaging tool for adult CNO, allowing for detailed structural evaluation of its typical bone, soft-tissue, and joint features. At the same time, [18F]NaF-PET/CT yields quantitative bone remodeling data that represent the pathologically increased bone turnover and the process of new bone formation. Further studies should investigate the application of quantified [18F]NaF uptake as a novel biomarker for disease activity in CNO, and its utility to steer clinical decision making.

OBJECTIVE: To report a statistical evaluation of symptomatology based on 56 cases of SAPHO syndrome and 352 non-SAPHO involvement cases, to propose a symptomatic scoring system in consideration of early warning for SAPHO syndrome.
METHODS: A cohort comprising 56 subjects diagnosed with SAPHO syndrome was reported, as well as 352 non-SAPHO involvement cases, including their chief complaints, skin manifestations, radiological findings, and laboratory tests. We systematically reviewed previous published five representative huge cohorts from different countries to conclude several specific features of SAPHO by comparing with our case series. The score of each specific index is based on respective incidence and comparison of two cohorts was performed.
RESULTS: In terms of complaint rates, all subjects of two cohorts suffered from osseous pain, which appeared in the anterior chest wall, spine, and limb which were calculated. In respect to dermatological lesions, SAPHO patients suffered from severe acne, and other patients (82.14%) accompanied with palmoplantar pustulosis. Having received radiological examinations, most SAPHO subjects rather than non-SAPHO involvement cases showed abnormal osteoarticular lesions under CT scanning and more detailed information under whole-body bone scintigraphy. Differences also emerged in elevation of inflammation values and rheumatic markers like HLA-B27. Based on our cases and huge cohorts documented, the early warning standard is set to be 5 scores.
CONCLUSIONS: SAPHO syndrome case series with 56 subjects were reported and an accumulative scoring system for the early reminder on SAPHO syndrome was proposed. The threshold of this system is set to be 5 points. Key Points • Fifty-six patients diagnosed by SAPHO syndrome with detailed symptoms and radiological findings were reported. • Comparison was made between the 56 SAPHO patients and 352 non-SAPHO involvement cases. • An accumulative scoring system for the early reminder on SAPHO syndrome was proposed and the threshold of this system is set to be five points.

Chronic nonbacterial osteomyelitis (CNO) is a rare disease spectrum affecting children and adults. Adult CNO may occur as isolated bone inflammation, or with a broad range of extraskeletal features. CNO pathophysiology, including the key drivers of inflammation, remains largely unknown. For pediatric CNO, a role for pro-inflammatory cytokine dysregulation has been proposed, but studies in adults are scarce. We therefore provide immunological characterization of adult CNO. Cross-sectional study in our referral center including adult CNO patients (n = 172) and healthy controls (n = 65). Inflammation parameters and systemic inflammatory based scores(SIBS, including neutrophil/lymphocyte ratio [NLR] and systemic immune inflammation index [SII]) were compared between groups. Cytokine expression was explored with electrochemiluminescent immunoassays in 33 patients, eight healthy controls and 21 osteoporosis patients. Routine inflammation markers were higher in patients than in controls, but generally remained within reference range. Systemic inflammation was more pronounced in patients with additional vertebral involvement as compared to those osteitis in the anterior chest wall alone, in patients with comorbid pustulosis palmoplantaris or psoriasis, and in patients with strongly rather than moderately increased lesional uptake on nuclear imaging. SII was elevated in CNO patients too, but NLR was not. Cytokine expression was generally nondifferential between patients and both control groups, and patients displayed low absolute concentrations of pro-inflammatory cytokines. In this adult CNO cohort, systemic inflammation was generally subtle, but more pronounced in patients with vertebral lesions, associated skin disease, and strongly increased uptake on nuclear imaging. SII was increased in patients compared to healthy controls. Contrasting pediatric studies, we found no increased expression of the pro-inflammatory cytokines that have been proposed to drive the inflammatory cascade, like interleukin-6, -8, and -17 (IL-6, IL-8, and IL-17), and tumor necrosis α (TNF-α). Further studies are needed to evaluate the use of SII in diagnosis and monitoring of CNO, and elucidate the role of cytokine dysregulation in adult disease. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Spinal involvement by chronic non-bacterial osteomyelitis (CNO) has been increasingly reported in recent years, often being presented as a diagnostic dilemma requiring differential diagnosis with bacterial spondylodiscitis and/or neoplasia. This study was aimed at identifying the imaging features of CNO facilitating its differentiation from other spinal diseases. Two radiologists assessed the imaging studies of 45 patients (16 male and 29 female, aged from 6 to 75 years, 15 children) with CNO collected from 5 referential centers. Spinal lesions were found in 17 patients (2 children and 15 adults), most often in the thoracic spine. In children, the lesions involved short segments with a destruction of vertebral bodies. In adults, the main findings were prominent bone marrow edema and osteosclerosis, endplate irregularities, and ankylosing lesions extending over long segments; paraspinal inflammation was mild and abscesses were not observed. In both children and adults, the involvement of posterior elements (costovertebral and facet joints) emerged as an important discriminator between CNO and neoplasia/other inflammatory conditions. In conclusion, a careful inspection of imaging studies may help to reduce the number of biopsies performed in the diagnostic process of CNO.

Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) is a relatively rare and often underdiagnosed disorder characterized by chronic inflammation affecting the bones, joints, and skin. While the precise cause of SAPHO syndrome remains elusive, multiple factors such as genetics, immunological dysregulation, and bacterial influences have been implicated in its pathogenesis. One notable aspect of SAPHO syndrome is the wide variability of symptoms experienced by afflicted individuals. A diverse array of osteoarticular manifestations may be observed, with common sites of involvement including the anterior chest wall, sacroiliac joints, and peripheral joints. Concurrently, patients often present with various skin disorders, such as palmoplantar pustulosis or acne, further adding to the complexity of the syndrome\'s clinical presentation. Treatment strategies for SAPHO syndrome primarily focus on managing symptoms and improving the quality of life for affected individuals. Nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, methotrexate (MTX), and tumor necrosis factor (TNF) inhibitors are considered to modulate the immune response and provide relief. One of the challenges encountered in diagnosing SAPHO syndrome is its potential overlap with other related conditions, leading to diagnostic confusion and difficulties. Distinguishing SAPHO syndrome from similar entities can be complex, requiring a comprehensive evaluation of clinical features, imaging studies, and laboratory investigations. We would like to share an intriguing case involving a 28-year-old woman who arrived with perplexing symptoms of pain in her bilateral hands and feet, her lower back, and acne in the bilateral upper arms and thighs. Through a comprehensive workup, the underlying SAPHO syndrome was uncovered, and it was effectively managed using adalimumab.

Chronic nonbacterial osteomyelitis (CNO) is a rare, and impactful auto-inflammatory bone disease occurring in children and adults. Clinical care for CNO is challenging, as the condition lacks validated classification criteria and evidence-based therapies. This study aimed to map the current diagnostic and therapeutic practices for CNO in adults, as a first step towards a standardized disease definition and future consensus treatment plans.
A primary survey was spread among global rheumatological/bone networks and 57 experts as identified from literature (May 2022), covering terminology, diagnostic tools (clinical, radiological, biochemical) and treatment steps. A secondary survey (sent to primary survey responders in August 2022) further queried key diagnostic features, treatment motivations, disease activity and treatment response monitoring.
36 and 23 physicians completed the primary and secondary survey respectively. Diagnosis was mainly based on individual physician assessment, in which the combination of chronic relapsing-remitting bone pain with radiologically-proven osteitis/osteomyelitis, sclerosis, hyperostosis and increased isotope uptake on bone scintigraphy were reported indicative of CNO. Physicians appeared more likely to refer to the condition as synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome in the presence of joint and skin pathology. MRI was most frequently performed, and the preferred diagnostic test for 47%. X-rays were second-most frequently used, although considered least informative of all available tools. Typical imaging features reported were hyperostosis, osteitis, osteosclerosis, bone marrow edema, while degeneration, soft tissue calcification, and ankylosis were not regarded characteristic. Inflammation markers and bone markers were generally regarded unhelpful for diagnostic and monitoring purposes and physicians infrequently performed bone biopsies. Management strategies diverged, including indications for treatment, response monitoring and declaration of remission. Step-1 treatment consisted of non-steroidal anti-inflammatory drugs/COX-2 inhibitors (83%). Common step 2-3 treatments were pamidronate, methotrexate, and TNF-a-inhibition (anti-TNFα), the latter two regarded especially convenient to co-target extra-skeletal inflammation in SAPHO syndrome. Overall pamidronate and anti-TNFα and were considered the most effective treatments.
Following from our survey data, adult CNO is a broad and insufficiently characterized disease spectrum, including extra-osseous features. MRI is the favoured imaging diagnostic, and management strategies vary significantly. Overall, pamidronate and anti-TNFα are regarded most successful. The results lay out current practices for adult CNO, which may serve as backbone for a future consensus clinical guideline.

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Association of neutrophilic dermatosis (ND), hidradenitis suppurativa (HS) and Behçet\'s disease (BD) and shared efficacy of TNFα axis blockade suggests common physiopathology.
To investigate the clinical features and therapeutic response of ND and HS associated with BD.
We identified 20 patients with ND or HS associated with BD among 1462 patients with BD.
We analysed 20 (1.4%) patients diagnosed with ND or HS associated with BD: 13 HS, 6 pyoderma gangrenosum (PG), and 1 SAPHO. Our 6 PG cases over 1462 BD patients accounts for 400/100 000 prevalence. Thirteen had bipolar aphthosis, 6 vascular, 5 neurologic, and 4 ocular involvements. All PG occurred on limbs and had typical histology with constant dermal neutrophilic infiltrate. All HS had the classical axillary-mammary phenotype. Sixty-nine percent (69%) of HS were Hurley 1 stage. Treatment consisted mainly in colchicine (n = 20), glucocorticoids (n = 12), and anti-TNFα (n = 9). Interesting results with complete or partial responses were obtained with anti-TNFα (9 cases), ustekinumab (3 cases) and tocilizumab (1 case) to treat refractory ND or HS associated with BD.
PG seems overrepresented in patients with BD. Biotherapies such as anti-TNFα, ustekinumab and tocilizumab appear to be promising to treat refractory ND or HS associated with BD.

The present report exemplifies a translational method, which could assist the clinical preevaluation of patients at risk before surgical interventions. In this study, a presurgical implant decision in a case of SAPHO (synovitis, acne, palmoplantar pustulosis, hyperostosis, osteitis) is described. Since the etiology of this syndrome is likely to involve genetic, infectious and immunological components, lipopolysaccharides (LPS) may conceptually trigger cytokine production leading to a specific chronic inflammation and immunological host response. This may hamper proper healing or accentuate the destruction of periodontal host tissues. In our approach, we examined the ex vivo cell viability and immune responses of primary osteoblasts and keratinocytes under sterile inflammation induced by P. gingivalis LPS. Keratinocytes and osteoblasts were obtained from biopsies of the keratinized gingiva and alveolar bone tissues of a SAPHO human subject. Enzymatically dissociated cells were thus cultured and incubated to LPS at different concentrations (50ng/ml, 200ng/ml, 500ng/ml and 1μg/ml) for 24 h in order to test inflammatory cytokine response (quantitative real time PCR) and toxicity (cell viability). Healthy primary keratinocytes and osteoblasts were used as control cells. The highest concentration of LPS (1μg/ml) significantly reduced cell viability (p < 0.05). Meanwhile, all tested LPS concentrations similarly enhanced the mRNA expressions of selected inflammatory cytokines (TNFα, IL-6, IL-8, IL-1β and IL-1𝛼) up to ≈3.5-fold, when compared to the healthy cell controls (p < 0.05). This study demonstrated a valuable inflammatory risk evaluation before implant placement, which was successfully performed based on the presented laboratory diagnostic/prognostic approach.Sapho.