Cachexia, chorea, and pain in chronic nonbacterial osteitis and inflammatory bowel disease: a case report.

BACKGROUND: Inflammatory bowel disease is an inflammatory disorder that primarily impacts the gastrointestinal tract, leading to malnutrition and chronic microscopic intestinal blood loss. Uncontrolled systemic inflammation can impact other parts of the body, known as extraintestinal manifestations. Up to 25% of patients with inflammatory bowel disease are reported to have these complications in their skin, joints, bones, eyes, liver, lung, and pancreas (Rogler et al. in Gastroenterology 161(4):1118-1132, 2021). Neurologic involvement as extraintestinal manifestations are less common, reported at 3-19%, including neuropathies, demyelination, and cerebrovascular events (Morís in World J Gastroenterol. 20(5):1228-1237, 2014). CASE PRESENTATION: A 13-year-old Caucasian boy presented with 1 month of progressive lower-extremity pain, weakness, and weight loss. His physical examination was notable for cachexia, lower-extremity weakness, and chorea. Labs revealed normocytic anemia and systemic inflammation. Imaging revealed symmetric abnormal marrow signal in the pelvis and upper femurs. Pathologic examination of the bone revealed chronic inflammation consistent with chronic nonbacterial osteitis. Endoscopy revealed colonic inflammation consistent with inflammatory bowel disease. CONCLUSIONS: Children and adolescents with musculoskeletal pain lasting more than 2 weeks with systemic signs or symptoms like weight loss should prompt evaluation for systemic inflammatory disorders such as chronic nonbacterial osteitis, which can occur in isolation or associated with inflammatory bowel disease. This patient also had a nonspecific neurologic abnormality, chorea, which resolved with treatment of underlying inflammatory disorder. These extraintestinal manifestations may be concurrent with or precede intestinal inflammation, requiring a high index of suspicion when investigating nonspecific systemic inflammation.

Presence of axial spondyloarthritis associated sacroiliitis and structural changes on MR enterography: A direct comparison with sacroiliac joint MRI.

INTRODUCTION: To investigate the acute inflammatory and structural changes of sacroiliitis as auxiliary findings on magnetic resonance enterography (MRE) and their presence on closely timed conventional magnetic resonance imaging of the sacroiliac joint (SI joint MRI). MATERIALS AND METHODS: We screened axial spondyloarthritis patients for the simultaneous presence of MREs and SI joint MRIs. Two blinded radiologists evaluated SI joint MRIs and MREs on two separate occasions. We used the Assessment of SpondyloArthritis International Society (ASAS)/Outcome Measures in Rheumatology Network (OMERACT) definitions for SI joint MRI. We implemented previously published standard definitions for osteitis, erosion, sclerosis, and fatty infiltration of SI joint in MREs that contain T1w and T1w post-gadolinium sequences. RESULTS: SI joint MRI and MRE images were present in 43 patients. The median time between the two modalities was 14 (0-89) days. Twelve patients had ASAS-defined positive SI joint MRI. Radiologist-1 and radiologist-2 detected osteitis on MRE in nine and eight out of these 12 patients, respectively. The two radiologists detected ankylosis and fatty metaplasia with a complete agreement and sclerosis with an almost perfect agreement. Both radiologists agreed on erosions on SI joint MRI in the same 10 cases. Radiologists did not identify acute inflammatory or structural changes on MRE in patients with a negative SI joint MRI for these lesions. CONCLUSION: Along with intestinal findings, additional reporting of acute inflammatory and structural changes of the SI joint on a MRE is valuable and may alert physicians to the presence of previously not diagnosed axial spondyloarthritis.

Synovitis-acne-pustulosis-hyperostosis-osteitis Syndrome with Bilateral Pleural Effusion.

Pleural effusion is a rare manifestation in synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome, which is characterized by the presence of osteoarticular lesions and dermatological involvement. We herein report a 71-year-old man with pleural effusion resulting from SAPHO syndrome. He was successfully treated using corticosteroids and has experienced no recurrence for one year. We should consider SAPHO syndrome when encountering cases of anterior chest pain and pleural fluid.

Molecular Interactions between Dietary Lipids and Bone Tissue during Aging.

Age-related bone disorders such as osteoporosis or osteoarthritis are a major public health problem due to the functional disability for millions of people worldwide. Furthermore, fractures are associated with a higher degree of morbidity and mortality in the long term, which generates greater financial and health costs. As the world population becomes older, the incidence of this type of disease increases and this effect seems notably greater in those countries that present a more westernized lifestyle. Thus, increased efforts are directed toward reducing risks that need to focus not only on the prevention of bone diseases, but also on the treatment of persons already afflicted. Evidence is accumulating that dietary lipids play an important role in bone health which results relevant to develop effective interventions for prevent bone diseases or alterations, especially in the elderly segment of the population. This review focuses on evidence about the effects of dietary lipids on bone health and describes possible mechanisms to explain how lipids act on bone metabolism during aging. Little work, however, has been accomplished in humans, so this is a challenge for future research.

18F-Sodium Fluoride PET/CT Findings in Osteitis Condensans Ilii.

ABSTRACT: Osteitis condensans ilii (OCI) is a benign cause of low back pain for which no clear etiology has been identified. We report cases of 2 women with breast cancer referred for 18F-NaF PET/CT for skeletal staging. Both cases show characteristic findings of OCI on CT images, with 18F-NaF PET uptake in symptomatic patient and no uptake in asymptomatic. 18F-NaF PET CT can be useful in evaluating back pain and may be used as an adjunctive biological maker for assessing OCI as a potential cause of pain.

Dental Apical Inflammation Score (DAIS): Histopathological scoring for the evaluation of the apical inflammatory activity and local bone destruction.

OBJECTIVE: The purpose of this study was to evaluate 210 periapical lesions with a newly created Dental Apical Inflammation Score/DAIS with regard to their inflammatory cell infiltration, bone tissue, epithelium, bacteria and foreign material. STUDY DESIGN: Specimens were obtained from 51 different dental practices over a period of 11 months. These specimens were then sent in for histopathological routine diagnostics. RESULTS: The DAIS classified 81 cases of Type 1 (acute inflammation = low, chronic inflammation = low), 79 cases of Type 2 (acute inflammation = low, chronic inflammation = high), 46 cases of Type 3 (acute inflammation = high, chronic inflammation = low) and 4 cases of Type 4 (acute inflammation = high, chronic inflammation = high). Bone tissue was found in 141 cases, signs for bacterial osteitis in 49 cases, cyst epithelium in 40 cases and foreign material in 27 cases. In 210 cases, cyst epithelium was evident in 27.2 % of Type 1, 15.2 % of Type 2, 8.7 % of Type 3 and in 50 % of Type 4 (p = .019). The 141 cases containing bone tissue showed signs of bacterial osteitis in 16.1 % of Type 1, 29.8 % of Type 2, 77.8 % of Type 3 and in 100 % of Type 4 (p < .001). In 64 cases, Bacteria was evident in 30 % of Type 1, 25 % of Type 2, 55 % of Type 3 and in 100 % of Type 4 (p = .013). CONCLUSION: The DAIS could classify apical lesions with statistically significant differences. Bacterial osteitis in apical lesions was reported for the first time.

Crizotinib-induced osteitis mimicking bone metastasis in a stage IV ALK-rearranged NSCLC patient: a case report.

BACKGROUND: Targeted therapies are a standard of care for first-line treatment of Anaplastic lymphoma kinase (ALK)-rearranged non small cell lung cancer (NSCLC). Giving the rapid pace of drug discovery and development in this area, reporting of adverse effects of ALK inhibitors is crucial. Here, we report a case of osteitis induced by an ALK inhibitor mimicking bone metastasis, a previously undescribed side effect of crizotinib. CASE PRESENTATION: A 31-year-old woman with stage IV ALK-rearranged NSCLC presented with back pain after 3 months of crizotinib treatment. Diagnostic work-up showed osteitis on the 4th and 5th thoracic vertebrae, anterior soft tissue infiltration and epiduritis, without any sign of infection. Spinal cord decompression, histological removal and osteosynthesis were performed. Histologic examination showed necrosis with abundant peripheral neutrophils, no microorganism nor malignant cell. Symptoms and Computarized Tomography-abnormalities rapidly diseappeared after crizotinib withdrawal and did not recur after ceritinib onset. CONCLUSIONS: This is the first report of crizotinib-induced osteitis. Crizotinib differs from other ALK inhibitors as it targets other kinases as well, which may have been responsible for the osteitis. Crizotinib can induce rapidly extensive osteitis, which can mimic tumor progression.

Receptor activator of nuclear factor κB ligand is a biomarker for osteitis of chronic rhinosinusitis.

BACKGROUND: Evidence of osteitis is frequently observed in patients with chronic rhinosinusitis (CRS), especially in recalcitrant cases. However, studies focusing on biological markers of osteitis are limited and it remains unclear whether osteitis is associated with different phenotypes of CRS. This study aimed to analyze the expression and assess the roles of receptor activator of nuclear factor κB ligand (RANKL) in patients with CRS and osteitis. METHODS: CRS patients with nasal polyps (CRSwNP, n = 63), CRS patients without nasal polyps (CRSsNP, n = 8), and control subjects (n = 12) were enrolled. Histologic phenotypes, clinical information, and computed tomography (CT) scores were investigated. The Global Osteitis Scoring Scale (GOSS) and RANKL, a molecular marker of bone remodeling, were analyzed in each type of CRS. CRS mouse models were treated with anti-RANKL. RESULTS: GOSS values were significantly higher in all CRS patients than in the control group. The GOSS value in non-eosinophilic CRSwNP was higher than in eosinophilic CRSwNP. RANKL was upregulated whereas decoy receptor osteoprotegerin (OPG) was downregulated in CRS. RANKL messenger RNA (mRNA) and protein levels were positively correlated with GOSS. RANKL/OPG was increased in recurrent cases compared with primary cases. Multiple inflammatory mediators were positively correlated with the protein level of RANKL in CRS tissues. In the mouse CRSwNP model, anti-RANKL treatment abrogated mucosal inflammation and bone remodeling. CONCLUSION: RANKL expression is associated with clinical osteitis and disease severity in CRSwNP. These findings shed light on the importance of RANKL as a potential biomarker of CRS and a key player in CRS pathogenesis.

Activity of Different Antistaphylococcal Therapies, Alone or Combined, in a Rat Model of Methicillin-Resistant Staphylococcus epidermidis Osteitis without Implant.

We developed a rat model of methicillin-resistant Staphylococcus epidermidis (MRSE) osteitis without implant to compare the efficacy of vancomycin, linezolid, daptomycin, ceftaroline, and rifampin either alone or in association with rifampin. A clinical strain of MRSE was inoculated into the proximal tibia. Following a 1-week infection period, rats received either no treatment or 3, 7, or 14 days of human-equivalent antibiotic regimen. Quantitative bone cultures were performed throughout the 14-day period. The mean ± SD quantity of staphylococci in the bone after a 1-week infection period was 4.5 ± 1.0 log10 CFU/g bone, with this bacterial load remaining stable after 3 weeks of infection (4.9 ± 1.4 log10 CFU/g bone). Vancomycin monotherapy was the most slowly bactericidal treatment, whereas ceftaroline monotherapy was the most rapidly bactericidal treatment. The addition of rifampin significantly increased the bacterial reduction for vancomycin, linezolid, and daptomycin. All tibias were sterilized after 2 weeks of treatment except for animals receiving vancomycin or daptomycin alone (66.6% and 50% of sterilization, respectively). These results show that ceftaroline and linezolid alone remain good options in the treatment of MRSE osteitis without implant. The combination with rifampin increases the antibiotic effect of vancomycin and daptomycin lines.

A Jack of All Trades: Impact of Glucocorticoids on Cellular Cross-Talk in Osteoimmunology.

Glucocorticoids (GCs) are known to have a strong impact on the immune system, metabolism, and bone homeostasis. While these functions have been long investigated separately in immunology, metabolism, or bone biology, the understanding of how GCs regulate the cellular cross-talk between innate immune cells, mesenchymal cells, and other stromal cells has been garnering attention rather recently. Here we review the recent findings of GC action in osteoporosis, inflammatory bone diseases (rheumatoid and osteoarthritis), and bone regeneration during fracture healing. We focus on studies of pre-clinical animal models that enable dissecting the role of GC actions in innate immune cells, stromal cells, and bone cells using conditional and function-selective mutant mice of the GC receptor (GR), or mice with impaired GC signaling. Importantly, GCs do not only directly affect cellular functions, but also influence the cross-talk between mesenchymal and immune cells, contributing to both beneficial and adverse effects of GCs. Given the importance of endogenous GCs as stress hormones and the wide prescription of pharmaceutical GCs, an improved understanding of GC action is decisive for tackling inflammatory bone diseases, osteoporosis, and aging.

Effect of antibiotic infused calcium sulfate/hydroxyapatite (CAS/HA) insets on implant-associated osteitis in a femur fracture model in mice.

Cerament (Bonesupport Holding, Lund, Sweden) is a bioresorbable synthetic bone substitute consisting of calcium sulfate and hydroxyapatite which is successfully used as a bone graft in bone defects or in delayed and non-unions after fractures. Besides, calcium sulfate/ hydroxyapatite (CAS/HA) could have, attributed to its composition and osteoinductive properties, have great importance in the treatment of bone infections with critical size defects (CSD). Aim of the study was to evaluate the effects of antibiotic infused CAS/HA on inflammation and bone healing in an implant-associated osteitis mice model. In a standardized murine model, the left femur of 72 BALB/c mice were osteotomized, generating a CSD (2,5 mm) with stabilization through a 6-hole titanium locking plate. Osteitis has been induced through inoculation of Staphylococcus aureus (SA) into the fracture gap. To analyze the effect of CAS/HA, following groups were generated with either CAS/HA, CAS/HA with gentamycin (CAS/ HA-G) or CAS/HA with vancomycin (CAS/HA-V) insets placed into the osteotomy. Debridément and lavages were progressed on day 7 and 42 to determine the local bacterial growth and the immune reaction. Fracture healing was quantified on day 7 and 42 by x-ray and bone healing markers from blood samples. Progression of infection was assessed by estimation of colony-forming units (CFU) and immune response was analyzed by determination of Interleukin (IL)- 6 and polymorphonuclear neutrophils (PMN) in lavage samples. Osteitis induced higher IL-6 and PMN-levels in the lavage samples on day 7. Both parameters showed a reduction in all groups on day 42. CAS/HA-V revealed a significant reduction of CFU and PMNs in lavage samples on day 42. A positive effect on bone healing could only be shown in non-infected mice. Whereas, application of mere CAS/HA in infected mice did show tendencies of bone destruction and lysis, independent of impregnation with antibiotics or not. Thus, application of CAS/HA in acute implant-associated infections is not recommended. In non-infectious environments or after infect-convalescence CAS/HA could albeit serve as a suggestive tool in trauma and orthopedic surgery.

Osteitis in Chronic Rhinosinusitis.

PURPOSE OF REVIEW: Osteitis is recognized as a common factor in recalcitrant chronic rhinosinusitis (CRS). There is evidence for the association of osteitis with revision surgeries and CRS severity, in terms of higher Lund-Mackay scores. This is a narrative review on the osteitis in CRS patients. RECENT FINDINGS: Evidence to date is inconclusive with regard to the etiology and pathogenesis of this bony thickening. Histopathology of osteitis in primary CRS is likely a process of neo-osteogenesis and bone remodeling. For better understanding, various associating factors have been studied including an inflammatory pattern of rhinosinusitis. Recent studies have associated osteitis with nasal polyps and tissue eosinophilia with the increase in periostin expression and P-glycoprotein mucosal expression. There is no association of osteitis to symptoms or quality of life. Osteitis is an outcome of neo-osteogenesis rather than inflammatory processes in CRS patients without a prior history of surgery. While CT has become a staple in osteitis assessment, the standards for grading osteitic severity remain in an experimental stage. There is no association between the presence or severity of osteitis at the time of surgery and clinical outcomes at 1 year after surgery. This review provides a comprehensive overview of the pathogenesis, epidemiology, and correlation with clinical and biological factors of osteitis in CRS patients.

MR and ultrasound of the hands and wrists in rheumatoid arthritis. Part II. Added clinical value.

Advanced imaging has become just as vital for diagnosing, staging, and monitoring disease in rheumatoid arthritis (RA) patients as it is for cancer patients. Part 1 of this review discussed synovitis, tenosynovitis, erosions, and osteitis-key imaging findings that occur in patients with RA. Part 2 will now show how these features, in combination with clinical and serologic data, can assist clinical decision-making at various stages of a patient's disease course. Specifically, assessing current disease activity and prognosticating future aggressiveness inform treatment decisions at initial presentation, during medical treatment, and at clinical remission. In addition to summarizing the current literature on advanced imaging in RA, clinical examples from different stages throughout the disease course will illustrate practical approaches for applying these research results. Last, this review will describe potential future roles of imaging in RA patients.

MRI and ultrasound of the hands and wrists in rheumatoid arthritis. I. Imaging findings.

The management of patients with rheumatoid arthritis (RA) has rapidly evolved with the development of newer disease-modifying drugs and the recognition that long-term damage can be mitigated by an earlier and more-informed use of these medications. Historically, radiographs were the mainstay of imaging in RA patients, but radiographic joint narrowing and erosions are late and insensitive findings in the disease. MRI (with intravenous contrast agent) and ultrasound (with power Doppler interrogation) of the hands and wrists are able to demonstrate erosions earlier and with greater sensitivity than radiographs. More importantly, these imaging studies also depict synovitis and active soft-tissue inflammation, which represents a precursor to structural damage. Additionally, MRI can show inflammation within the bones (osteitis), which is proving to be the most important prognosticator of an aggressive disease course. Part I of this review discusses the imaging techniques, pitfalls, definitions, and comparative studies of MRI and ultrasound for identifying and quantifying erosions, synovitis, and osteitis. Part II will demonstrate how these imaging findings influence the clinical management of RA patients throughout their disease course, from presentation through clinical remission.

Clinical Characteristics of Japanese Patients with Palmoplantar Pustulosis.

Palmoplantar pustulosis (PPP) is a chronic inflammatory disorder characterized by sterile pustules predominantly involving the palms and soles. The purpose of this review was to describe the characteristics of Japanese PPP patients as PPP is frequently observed within the Japanese population. Most Japanese dermatologists consider PPP a distinct entity, and co-existence of PPP and psoriasis is rare; however, outside Japan, PPP is often considered to be palmoplantar psoriasis, and an extra-palmoplantar lesion associated with PPP is considered to be psoriasis. PPP frequently develops or exacerbates following focal infections such as tonsillitis, odontogenic infection, and sinusitis, either with or without arthralgia. Pustulotic arthro-osteitis (PAO) is a major comorbidity of PPP, most often affecting the anterior chest wall. In Japanese patients, PAO is frequently seen, whereas cases of SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome with symptoms other than PPP and sternocostoclavicular joint pain are extremely rare. A difference in incidence depending on race suggests that different genetic backgrounds may be responsible for susceptibility to these disorders. The treatment of focal infections often results in dramatic effects on cutaneous lesions, as well as joint pain. The characteristics of Japanese patients with PPP are female predominance, mostly smokers, rare co-existence with psoriasis, frequent association with PAO, almost no accompanying celiac disease, and closely associated with focal infection. PPP should be separately considered from palmoplantar psoriasis.

Clinical features and outcomes of Bacille Calmette-Guérin (BCG)-induced diseases following neonatal BCG Tokyo-172 strain immunization.

BACKGROUND: Bacille Calmette-Guérin (BCG) vaccination at birth may cause mild and benign local adverse effects (AE). More serious AE are rarely reported. OBJECTIVE: To describe clinical features and outcomes of BCG (Tokyo-172 strain)-induce diseases (BCG-ID) that required medical attention at a tertiary care center in Bangkok, Thailand. METHOD: We retrospectively reviewed medical records from January 2007 to December 2016 that were selected by ICD-10 codes. The inclusion criteria were the patients under 3 years of age who developed lymphadenitis, osteitis, or disseminated infections of which BCG was a possible pathogen. Cases were classified into suspected (clinically compatible without laboratory confirmation), probable (suspected cases with M. tuberculosis complex identified), and confirmed BCG-ID (probable cases with molecular confirmation of M. bovis BCG strain). RESULTS: 95 children were identified; 57 (60.0%) were male, and the median age at presenting symptom was 3.5 (range: 0.6-28.7) months. Of these, 25 (26.3%) were suspected, 49 (51.6%) were probable, and 21 (22.1%) were confirmed BCG-ID. Overall, 87 (92%) children had regional lymphadenitis corresponding to the BCG site, 5 (5%) had osteitis, and 3 (3%) had disseminated BCG. Of those with lymphadenitis, average size was 2.2 (range 0.7-5) cm. in diameter and 53% (46/87) had pulmonary involvement. Five children with immunodeficiency; three had disseminated BCG and two had lymphadenitis. Eight (9.2%) patients with lymphadenitis underwent needle aspiration; 57 (65.5%) had surgical excision. All children with BCG osteitis underwent surgical intervention in combination with anti-tuberculosis treatment. One patient with osteitis experienced long-term leg length discrepancy. CONCLUSION: Regional lymphadenitis was the most common feature of BCG-ID requiring medical attention. That none of the BCG osteitis were immunocompromised hosts suggested the potential virulence of BCG in neonates. A systematic national surveillance and reporting system is needed to develop accurate estimates of population incidence and support development of effective vaccine policy.

Maxillomandibular giant osteosclerotic lesions.

INTRODUCTION: Giant Osteosclerotic Lesions (GOLs) are a group of rarely reported intraosseous lesions. Their precise diagnosis is important since they can be confused with malignant neoplasms. OBJECTIVE: This retrospective study aimed to record and analyze the clinical and radiographic Giant Osteosclerotic Lesions (GOLs) detected in the maxillomandibular area of patients attending to our institution. Materials and Methods: Informed consent from the patients was obtained and those cases of 2.5 cm or larger lesions with radiopaque or mixed (radiolucid-radiopaque) appearance located in the maxillofacial bones were selected. Assessed parameters were: age, gender, radiographic aspect, shape, borders, size, location and relations to roots. Lesions were classified as radicular, apical, interradicular, interradicular-apical, radicular-apical or located in a previous teeth extraction area. Additionally, several osseous and dental developmental alterations (DDAs) were assessed. RESULTS: Seventeen radiopacities in 14 patients were found and were located almost exclusively in mandible and were two types: idiopathic osteosclerosis and condensing osteitis. GOLs were more frequent in females, and in the anterior and premolar zones. 94.2% of GOLs were qualified as idiopathic osteosclerosis and one case was condensing osteitis. All studied cases showed different osseous and dental developmental alterations (DDAs). The most common were: Microdontia, hypodontia, pulp stones, macrodontia and variations in the mental foramina. CONCLUSIONS: GOLs must be differentiated from other radiopaque benign and malignant tumors. Condensing osteitis, was considered an anomalous osseous response induced by a chronic low-grade inflammatory stimulus. For development of idiopathic osteosclerosis, two possible mechanisms could be related. The first is modification of the normal turnover with excessive osseous deposition. The second mechanism will prevent the normal bone resorption, arresting the osseous breakdown process.

Does the presence of magnetic resonance imaging-detected osteitis at diagnosis with rheumatoid arthritis lower the risk for achieving disease-modifying antirheumatic drug-free sustained remission: results of a longitudinal study.

BACKGROUND: Although infrequent, some rheumatoid arthritis (RA) patients achieve disease-modifying antirheumatic drug (DMARD)-free sustained remission. The absence of RA-specific autoantibodies, such as anticitrullinated protein antibodies (ACPA), is known to be associated with this outcome but further mechanisms underlying the chronic nature of RA are largely unknown. Magnetic resonance imaging (MRI)-detected bone marrow edema (BME), or osteitis, strongly predicts erosive progression and is associated with ACPA positivity. Therefore, we hypothesized that the presence of MRI-detected osteitis is also predictive of not achieving DMARD-free sustained remission and that the presence of osteitis mediates the association between ACPA and DMARD-free sustained remission. METHODS: A 1.5 T unilateral hand and foot MRI was performed at disease presentation in 238 RA patients, evaluating BME, synovitis, and tenosynovitis (summed as MRI inflammation score). DMARD-free sustained remission, defined as the absence of clinical synovitis after DMARD cessation that persisted during the total follow-up, was assessed (median follow-up 3.8 years). Associations between the different MRI-detected inflammatory features and this outcome were studied. A mediation analysis was performed to study whether the presence of BME mediated the association between ACPA and DMARD-free sustained remission. Finally, patterns of MRI-detected inflammation with regard to DMARD-free sustained remission were studied using partial least squares (PLS) regression. RESULTS: Forty-six (19.3%) patients achieved DMARD-free sustained remission. ACPA positivity associated independently with remission (hazard ratio (HR) 0.16, 95% confidence interval (CI) 0.06-0.39). In contrast, no associations were observed between MRI-detected BME (HR 0.99, 95% CI 0.94-1.03), or other MRI inflammatory features, and achieving DMARD-free sustained remission. Thus, the presence of BME did not mediate the association between ACPA and DMARD-free sustained remission. Furthermore, a PLS analysis revealed that patients who did or did not achieve remission could not be distinguished by patterns of MRI-detected inflammation. CONCLUSIONS: At disease presentation, osteitis, as well as other MRI-detected inflammatory features, was not associated with achieving DMARD-free sustained remission over time. Thus, imaging predictors for joint damage and disease persistence differ. The processes mediating RA chronicity remain largely unsolved.

CypD-mPTP axis regulates mitochondrial functions contributing to osteogenic dysfunction of MC3T3-E1 cells in inflammation.

Bone is a dynamic organ, the bone-forming osteoblasts and bone-resorbing osteoclasts form the physiological basis of bone remodeling process. During pathological process of numerous inflammatory diseases, these two aspects are uncoupled and the balance is usually tipped in favor of bone destruction. Evidence suggests that the inflammatory destruction of bone is mainly attributed to oxidative stress and is closely related to mitochondrial dysfunction. The mechanisms underlying osteogenic dysfunction in inflammation still need further investigation. Reactive oxygen species (ROS) is associated with mitochondrial dysfunction and cellular damage. Here, we reported an unexplored role of cyclophilin D (CypD), the major modulator of mitochondrial permeability transition pore (mPTP), and the CypD-mPTP axis in inflammation-induced mitochondrial dysfunction and bone damage. And the protective effects of knocking down CypD by siRNA interference or the addition of cyclosporin A (CsA), an inhibitor of CypD, were evidenced by rescued mitochondrial function and osteogenic function of osteoblast under tumor necrosis factor-α (TNF-α) treatment. These findings provide new insights into the role of CypD-mPTP-dependent mitochondrial pathway in the inflammatory bone injury. The protective effect of CsA or other moleculars affecting the mPTP formation may hold promise as a potential novel therapeutic strategy for inflammation-induced bone damage via mitochondrial pathways.

The polymethoxy flavonoid sudachitin suppresses inflammatory bone destruction by directly inhibiting osteoclastogenesis due to reduced ROS production and MAPK activation in osteoclast precursors.

Inflammatory bone diseases, including rheumatoid arthritis, periodontitis and peri-implantitis, are associated not only with the production of inflammatory cytokines but also with local oxidative status, which is defined by intracellular reactive oxygen species (ROS). Osteoclast differentiation has been reported to be related to increased intracellular ROS levels in osteoclast lineage cells. Sudachitin, which is a polymethoxyflavone derived from Citrus sudachi, possesses antioxidant properties and regulates various functions in mammalian cells. However, the effects of sudachitin on inflammatory bone destruction and osteoclastogenesis remain unknown. In calvaria inflamed by a local lipopolysaccharide (LPS) injection, inflammation-induced bone destruction and the accompanying elevated expression of osteoclastogenesis-related genes were reduced by the co-administration of sudachitin and LPS. Moreover, sudachitin inhibited osteoclast formation in cultures of isolated osteoblasts and osteoclast precursors. However, sudachitin rather increased the expression of receptor activator of NF-κB ligand (RANKL), which is an important molecule triggering osteoclast differentiation, and the mRNA ratio of RANKL/osteoprotegerin that is a decoy receptor for RANKL, in the isolated osteoblasts, suggesting the presence of additional target cells. When osteoclast formation was induced from osteoclast precursors derived from bone marrow cells in the presence of soluble RANKL and macrophage colony-stimulating factor, sudachitin inhibited osteoclastogenesis without influencing cell viability. Consistently, the expression of osteoclast differentiation-related molecules including c-fos, NFATc1, cathepsin K and osteoclast fusion proteins such as DC-STAMP and Atp6v0d2 was reduced by sudachitin. In addition, sudachitin decreased activation of MAPKs such as Erk and JNK and the ROS production evoked by RANKL in osteoclast lineage cells. Our findings suggest that sudachitin is a useful agent for the treatment of anti-inflammatory bone destruction.