Assessment of joint health in patients receiving prophylaxis for haemophilia A: a cross-sectional survey in five European countries.

OBJECTIVES: To evaluate joint health, pain and health-related quality of life (HRQoL) in patients with moderate/severe haemophilia A in Europe. DESIGN: Multinational, cross-sectional survey, with retrospective data collection. Data were taken from the Adelphi Real World Haemophilia Disease Specific Programme Wave II, using surveys completed by physicians and patients between February 2020 and May 2021. SETTING: Haematologists/haemato-oncologists and their patients in France, Germany, Italy, Spain and the UK. PARTICIPANTS: Males aged ≥18 years with moderate or severe haemophilia A (baseline clotting factor level ≤5%), without existing inhibitors and currently receiving prophylaxis. Patients were grouped into those with or without haemophilia-affected joints (HAJs) based on bleeding, radiographic, surgical, mobility and joint pain data. PRIMARY OUTCOME MEASURE: Characterisation of humanistic and clinical outcomes in patients with or without HAJs. RESULTS: A total of 120 physicians provided data for 351 eligible patients; 209 (59.5%) patients had HAJs and 142 (40.5%) had no HAJs. Pain/discomfort was significantly different (p=0.01) and reported more frequently in the HAJ (85.7%) vs non-HAJ group (53.3%). Pain medication use was significantly higher in the HAJ versus non-HAJ group (73.2% vs 60.6%; p=0.01). Up to half of the patients with HAJs had synovitis (49.8%) or arthropathy (48.4%), and one-third had undergone joint surgery (35.4%). Overall health status was significantly worse in the HAJ versus non-HAJ group (mean (SD) EuroQol Visual Analogue Scale score: 65.5 (19.3) vs 81.1 (14.6); p=0.01). CONCLUSIONS: In this multinational real-world study, nearly two-thirds of adults with moderate/severe haemophilia A without inhibitors experienced HAJs despite prophylaxis. Individuals with HAJs had higher rates of pain and pain medication use, and lower HRQoL compared with those without HAJs. These data indicate that HAJs represent a clinically relevant burden and early identification/monitoring and management of affected joints should be an important consideration to help prevent long-term joint morbidity.

Connexin 43 Modulation in Human Chondrocytes, Osteoblasts and Cartilage Explants: Implications for Inflammatory Joint Disorders.

Connexin 43 (Cx43) is crucial for the development and homeostasis of the musculoskeletal system, where it plays multifaceted roles, including intercellular communication, transcriptional regulation and influencing osteogenesis and chondrogenesis. Here, we investigated Cx43 modulation mediated by inflammatory stimuli involved in osteoarthritis, i.e., 10 ng/mL Tumor Necrosis Factor alpha (TNFα) and/or 1 ng/mL Interleukin-1 beta (IL-1ß), in primary chondrocytes (CH) and osteoblasts (OB). Additionally, we explored the impact of synovial fluids from osteoarthritis patients in CH and cartilage explants, providing a more physio-pathological context. The effect of TNFα on Cx43 expression in cartilage explants was also assessed. TNFα downregulated Cx43 levels both in CH and OB (-73% and -32%, respectively), while IL-1ß showed inconclusive effects. The reduction in Cx43 levels was associated with a significant downregulation of the coding gene GJA1 expression in OB only (-65%). The engagement of proteasome in TNFα-induced effects, already known in CH, was also observed in OB. TNFα treatment significantly decreased Cx43 expression also in cartilage explants. Of note, Cx43 expression was halved by synovial fluid in both CH and cartilage explants. This study unveils the regulation of Cx43 in diverse musculoskeletal cell types under various stimuli and in different contexts, providing insights into its modulation in inflammatory joint disorders.

Gastric adenocarcinoma with carcinomatosis and degenerative joint disease of the xiphisternum in a Bactrian camel (Camelus bactrianus).

Gastric adenocarcinomas have been sporadically reported in camelids. This report describes a primary gastric adenocarcinoma and subsequent peritoneal carcinomatosis in a 20-year-old female Bactrian camel (Camelus bactrianus). Numerous metastases were present throughout the omentum, liver, abdominal lymph nodes, intestinal serosa, kidneys and lungs. The primary tumour macroscopically resembled an ulcerated crater and originated from the distal four-fifths of the C3 compartment, an anatomical region with naturally prominent gastric rugae and true glands. Moderate numbers of Helicobacter spp colonies were present within gastric pits and necrotic areas of C3. Ménetrier's disease has previously been implicated as a predisposing condition for the development of gastric adenocarcinoma in another camel, but no evidence of this premalignant disorder was found in this case. This camel also suffered from a chronic skin wound of the hump and severe degenerative joint disease of the xiphisternum, the latter of which was presumably associated with excessive pressure on the sternum.

[Advances in the Application of Nanozymes in Joint Disease Therapy]. / çº³ç±³é ¶åœ¨å ³èŠ‚ç–¾ç— ä¸­çš„åº”ç”¨è¿›å±•.

Nanozymes are nanoscale materials with enzyme-mimicking catalytic properties. Nanozymes can mimic the mechanism of natural enzyme molecules. By means of advanced chemical synthesis technology, the size, shape, and surface characteristics of nanozymes can be accurately regulated, and their catalytic properties can be customized according to the specific need. Nanozymes can mimic the function of natural enzymes, including catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx), to scavenge reactive oxygen species (ROS). Reported findings have shown that nanozymes have the advantages of excellent stability, low cost, and adjustable catalytic activity, thereby showing great potential and broad prospects in the application of disease treatment. Herein, we reviewed the advances in the application of nanozymes in the treatment of joint diseases. The common clinical manifestations of joint diseases include joint pain, swelling, stiffness, and limited mobility. In severe cases, joint diseases may lead to joint destruction, deformity, and functional damage, entailing crippling socioeconomic burdens. ROS is a product of oxidative stress. Increased ROS in the joints can induce macrophage M1 type polarization, which in turn induces and aggravates arthritis. Therefore, the key to the treatment of joint diseases lies in ROS scavenging and increasing oxygen (O2) content. Nanozymes have demonstrated promising application potential in the treatment of joint diseases, including rheumatoid arthritis, osteoarthritis, and gouty arthritis. However, how to ensure their biosafety, reduce the toxicity, and increase enzyme activity remains the main challenge in current research. Precise control of the chemical composition, size, shape, and surface modification of nanomaterials is the main development direction for the future.

[Use of osteoarticular ultrasound by emergency physicians]. / Utilisation de l'échographie ostéo-articulaire par le médecin urgentiste.

The use of ultrasound by emergency physicians is now well established. It can be integrated as an extension of the clinical examination, providing diagnostic support during consultation in the emergency department. However, its use in osteoarticular pathologies remains less frequent, despite a growing body of literature demonstrating its value in a variety of pathologies. Ultrasound is operator-dependent, so its proper use requires dedicated training. In Switzerland, training opportunities in osteoarticular ultrasound are still poorly known and not widely used by emergency physicians. This article describes the possibilities of use in the case of osteoarticular pathologies frequently encountered in emergency departments.

L'utilisation de l'échographie par les urgentistes est actuellement bien établie. Elle peut être intégrée comme extension de l'examen clinique et apporte alors une aide au diagnostic lors d'une consultation dans le service des urgences. Son utilisation pour les pathologies ostéoarticulaires reste cependant moins fréquente, malgré une littérature croissante montrant son intérêt dans des pathologies variées. L'échographie est dépendante de l'opérateur et son utilisation adéquate nécessite une formation dédiée. Les possibilités de formation à l'échographie ostéoarticulaire en Suisse restent encore peu connues et peu suivies par les médecins urgentistes. Cet article décrit les possibilités d'utilisation pour des pathologies ostéoarticulaires fréquemment rencontrées aux urgences.

Deciphering the circulating microRNA signature of hemophilic arthropathy.

BACKGROUND: Haemophilic arthropathy (HArt) is a serious complication in patients with hemophilia. Early diagnosis and treatment are essential to minimise the development of HArt. The use of biomarkers may improve early diagnosis of HArt. Circulating microRNAs (miRNAs) are small, non-coding RNAsthat regulate gene expression, and are being investigated as promising biomarkers due to their role in joint and bone metabolism. AIMS: To investigate differential expression of miRNAs and their relationship to arthropathy in patients with hemophilia A. METHODS: miRNA expression was examined in a pilot study followed by a validation study (100 hemophilia A patients with [n = 83] and without HArt [n = 17], 14 controls). Differential miRNA expression was investigated using real-time quantitative PCR. RESULTS: The pilot study identified 2 miRNAs differentially expressed in patients with Hart (Pettersson score ≥ 1), after adjusting for the false discovery rate (FDR). The validation study evaluated these 2 miRNAs. The results demonstrated that two miRNAs (miR- 208a-3p and 524-3p) were significantly underexpressed in plasma of patients with HArt compared to patients without arthropathy, with FDR <0.05 (Fig. 1). In addition, 3 miRNAs (130a-3p, miR- and 506-3p) were significantly underexpressed in patients with moderate HArt (Pettersson score 4 to 7). CONCLUSIONS: In this proof of concept study we identified a signature of 5 circulating miRNAs associated with Hart with potential as diagnosis tools for HArt. These miRNAs are potential negative regulators of gene expression, suggesting their activity in HArt by interfering with osteoblastic (miR- 208a-3p) and osteoclastic (miR-506-3p) differentiation to impair bone mineralization and remodeling processes, or regulating chondrogenesis (miR-335-5p). miRNAs associated with earlier stages of HArt will be further investigated in a sub-study of the prospective clinical trial PROVE, which will investigate the effects of long-term prophylaxis with simoctocog alfa versus emicizumab in adults with hemophilia A.

Efanesoctocog Alfa Prophylaxis for Children with Severe Hemophilia A.

BACKGROUND: Once-weekly efanesoctocog alfa provides high sustained factor VIII activity with superior bleeding prevention as compared with prestudy factor VIII prophylaxis in previously treated patients 12 years of age or older with severe hemophilia A. Data on outcomes of efanesoctocog alfa treatment in children younger than 12 years of age with severe hemophilia A are limited. METHODS: We conducted a phase 3, open-label study involving previously treated patients younger than 12 years of age with severe hemophilia A. Patients received prophylaxis with once-weekly efanesoctocog alfa (50 IU per kilogram of body weight) for 52 weeks. The primary end point was the occurrence of factor VIII inhibitors (neutralizing antibodies against factor VIII). Secondary end points included annualized rates of treated bleeding episodes, bleeding treatment, safety, and pharmacokinetics. RESULTS: A total of 74 male patients were enrolled (38 with an age of <6 years and 36 with an age of 6 to <12 years). No factor VIII inhibitors developed. Most adverse events were nonserious. No serious adverse events that were assessed by the investigator as being related to efanesoctocog alfa were reported. In the 73 patients treated according to the protocol, the median and model-based mean annualized bleeding rates were 0.00 (interquartile range, 0.00 to 1.02) and 0.61 (95% confidence interval, 0.42 to 0.90), respectively. A total of 47 patients (64%) had no treated bleeding episodes, 65 (88%) had no spontaneous bleeding episodes, and 61 (82%) had no episodes of bleeding into joints. A total of 41 of 43 bleeding episodes (95%) resolved with one injection of efanesoctocog alfa. Mean factor VIII activity at steady state was more than 40 IU per deciliter for 3 days and more than 10 IU per deciliter for almost 7 days after dose administration. The geometric mean terminal half-life was 40.0 hours. CONCLUSIONS: In children with severe hemophilia A, once-weekly prophylaxis with efanesoctocog alfa provided high sustained factor VIII activity in the normal to near-normal range (>40 IU per deciliter) for 3 days and more than 10 IU per deciliter for almost 7 days after administration, leading to effective bleeding prevention. Efanesoctocog alfa was associated with mainly nonserious adverse events. (Funded by Sanofi and Sobi; XTEND-Kids ClinicalTrials.gov number, NCT04759131.).

Mesenchymal stem cells and their extracellular vesicles in bone and joint diseases: targeting the NLRP3 inflammasome.

The nucleotide-binding oligomerization domain-like-receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a cytosolic multi-subunit protein complex, and recent studies have demonstrated the vital role of the NLRP3 inflammasome in the pathological and physiological conditions, which cleaves gasdermin D to induce inflammatory cell death called pyroptosis and mediates the release of interleukin-1 beta and interleukin-18 in response to microbial infection or cellular injury. Over-activation of the NLRP3 inflammasome is associated with the pathogenesis of many disorders affecting bone and joints, including gouty arthritis, osteoarthritis, rheumatoid arthritis, osteoporosis, and periodontitis. Moreover, mesenchymal stem cells (MSCs) have been discovered to facilitate the inhibition of NLRP3 and maybe ideal for treating bone and joint diseases. In this review, we implicate the structure and activation of the NLRP3 inflammasome along with the detail on the involvement of NLRP3 inflammasome in bone and joint diseases pathology. In addition, we focused on MSCs and MSC-extracellular vesicles targeting NLRP3 inflammasomes in bone and joint diseases. Finally, the existing problems and future direction are also discussed.

Joint health and pain in the changing hemophilia treatment landscape.

INTRODUCTION: Hemophilia is an inherited bleeding disorder. Bleeding, and in particular joint hemorrhage results in chronic arthropathy and disability. Acute and chronic pain are frequent and limit activity and participation and result in decreased health-related quality of life. Remarkable progress has been made in the diagnosis and treatment of hemophilia but bleeding continues to prove recalcitrant to currently available treatments and joint disease remains problematic. Physiotherapy and pain management are mainstays of current multidisciplinary integrated care of people with hemophilia (PWH). The focus of this review is on preservation of joint health in the era of new and innovative therapies. AREAS COVERED: A search of the PubMed Central was conducted on 1 February 2024 using the MeSH Major Topic terms identified as keywords for the manuscript. This review will highlight what is known and unknown about joint bleeding and arthropathy, including insights on pain as a related complication. EXPERT OPINION: Recent advances in therapeutic interventions aimed at promoting healthy joints in PWH will be discussed, including both the pharmacological treatment landscape and related strategies to promote joint health.

Ultrasound-guided joint procedures in hemophilia: technique, indications and tips.

INTRODUCTION: The therapeutic approach to pain in hemophilia should be multimodal. Intra-articular injections are a good option when joint lesions do not respond to hematological treatment or rehabilitation and orthopedic surgery is not yet indicated. Performing these procedures under ultrasound guidance has been shown to improve their accuracy and efficacy. AREAS COVERED: This article provides a practical overview of the most frequently employed ultrasound-guided intra-articular procedures on the joints of people with hemophilia. The article describes the key elements for performing the technique on the elbow, knee and ankle as the most affected joints. The particularities of the most frequent indications, arthrocentesis, synoviorthesis and analgesic injections with various products are detailed. EXPERT OPINION: Current hematological treatments have made it possible to incorporate new therapeutic tools for pain relief for people with hemophilia, including ultrasound-guided joint procedures, which offer excellent results.

Imaging Assessment of the Pediatric Elbow: Developmental Variants and Common Pathologies.

The pediatric elbow is a complex joint that undergoes rapid growth and development. The normal anatomy of the elbow varies depending on the age of the patient, which can be challenging for imaging interpretation. This article reviews developmental variants and common pathologies of the pediatric elbow, with a focus on their radiologic features. Normal anatomy and development of the pediatric elbow are discussed, including the six ossification centers and elbow alignment. Congenital anomalies such as longitudinal deficiencies of the upper extremity are reviewed. Some common injuries that affect the elbow, such as supracondylar fracture, lateral condyle fracture, medial epicondyle avulsion, and radial head dislocation are also described.

Imaging of Disease and Normal Variant Patterns in Pediatric Hips.

The pediatric hip undergoes significant changes from infancy through adolescence. Proper maturation is crucial for the development of a stable and functional hip joint. Imaging interpretation of the pediatric hip requires distinguishing normal variants and maturation patterns from pathology. We review femoral ossification centers, variants, and conditions that affect the proximal femur, such as Legg-Calvé-Perthes disease; the acetabulum, such as developmental hip dysplasia; the acetabular labrum, such as femoroacetabular impingement; and synovial pathology in children through adolescence. Understanding the spectrum of hip conditions and using advanced imaging techniques are essential for the accurate diagnosis and effective management of pediatric hip disorders.

Imaging of the Pediatric Knee.

During normal development, imaging findings in the immature knee joint may mimic pathology or indicate transient sites of weakness, prone to injury. This article reviews the development of the knee joint, age- and maturation-dependent imaging considerations, and various developmental variants that can be encountered, subdivided into those that involve the tibiofemoral and patellofemoral compartments, soft tissues, and osseous components. The tibiofemoral compartment section reviews the focal periphyseal edema zone (FOPE), ossification variants of the femoral condyles, distal femoral metaphyseal cortical irregularity from periosteal traction, and the metaphyseal subperiosteal stripe, which should be distinguished from pathologic mimickers such as endochondral ossification dysfunction, osteochondritis dissecans (OCD), fibroosseous lesion, periosteal and subcortical pathologies. The patellofemoral compartment section includes a review of partite patella, dorsolateral defect, variant trochlear morphology, and maturation-dependent sites of transient weakness that are prone to injury from repetitive overuse (Sinding-Larsen-Johansson syndrome and Osgood-Schlatter disease) and avulsion fractures (patellar sleeve and tibial tubercle avulsions). Finally, soft tissue (discoid lateral meniscus, meniscal flounce, anterior cruciate ligament variants) and osseous components (meniscal ossicle, fabella, and cyamella) are reviewed.

Imaging of Sacroiliac Joints.

The central role of imaging in diagnosing disorders affecting the sacroiliac joints (SIJs) necessitates a comprehensive understanding of the advantages, limitations, and potential pitfalls of the imaging techniques that can be used. In this article, the anatomy and biomechanics of SIJs are exposed, outlining their unique features, particularly the division into anteroinferior cartilaginous and postero-superior ligamentous parts. Overall, the goal of this article is to offer a comprehensive understanding of imaging techniques, anatomic complexity, and diagnostic considerations relevant to SIJs disorders, facilitating accurate diagnosis and patient management in clinical practice and research.

Intra-articular injection of an extended-release flavopiridol formulation represents a potential alternative to other intra-articular medications for treating equine joint disease.

OBJECTIVE: To establish the pharmacokinetics of the cyclin-dependent kinase-9 inhibitor flavopiridol in equine middle carpal joints, using an extended-release poly lactic-co-glycolic acid (PLGA) microparticle formulation. ANIMALS: 4 healthy horses without evidence of forelimb lameness. METHODS: A 6-week longitudinal pharmacokinetic study was conducted in 2 phases (6 weeks each) in 4 healthy horses. The PLGA microparticles containing 122 µg flavopiridol in 3 mL saline were administered by intra-articular injection into 1 middle carpal joint, with empty PLGA microparticles injected into the contralateral joint as a control. Synovial fluid and plasma were collected at time points out to 6 weeks, and drug concentrations in synovial fluid and plasma were determined using validated protocols. Synovial fluid total protein and total nucleated cell count and differential, CBC, serum biochemistry, and lameness exams were performed at each of the time points. RESULTS: Synovial fluid flavopiridol averaged 19 nM at week 1, gradually reduced to 1.4 nM by 4 weeks, and was generally below the detection limit at 5 and 6 weeks. There was no detectable flavopiridol in the plasma samples, and no adverse effects were observed at any time point. CLINICAL RELEVANCE: Intra-articular injection of PLGA microparticle-encapsulated flavopiridol was well tolerated in horses, with detectable levels of flavopiridol in the synovial fluid out to 4 weeks with negligible systemic exposure. Flavopiridol is a cyclin-dependent kinase-9 inhibitor with potent anti-inflammatory and analgesic activity. The extended-release microparticle formulation promotes intra-articular retention of the drug and it may be an alternative to other intra-articular medications for treatment of equine joint disease.