AdipoRon reduces TGFß1-mediated collagen deposition in vitro and alleviates knee stiffness in vivo.

Arthrofibrosis, which causes joint motion restrictions, is a common complication following total knee arthroplasty (TKA). Key features associated with arthrofibrosis include myofibroblast activation, knee stiffness, and excessive scar tissue formation. We previously demonstrated that adiponectin levels are suppressed within the knee tissues of patients affected by arthrofibrosis and showed that AdipoRon, an adiponectin receptor agonist, exhibited anti-fibrotic properties in human mesenchymal stem cells. In this study, the therapeutic potential of AdipoRon was evaluated on TGFß1-mediated myofibroblast differentiation of primary human knee fibroblasts and in a mouse model of knee stiffness. Picrosirius red staining revealed that AdipoRon reduced TGFß1-induced collagen deposition in primary knee fibroblasts derived from patients undergoing primary TKA and revision TKA for arthrofibrosis. AdipoRon also reduced mRNA and protein levels of ACTA2, a key myofibroblast marker. RNA-seq analysis corroborated the anti-myofibrogenic effects of AdipoRon. In our knee stiffness mouse model, 6 weeks of knee immobilization, to induce a knee contracture, in conjunction with daily vehicle (DMSO) or AdipoRon (1, 5, and 25 mg/kg) via intraperitoneal injections were well tolerated based on animal behavior and weight measurements. Biomechanical testing demonstrated that passive extension angles (PEAs) of experimental knees were similar between vehicle and AdipoRon treatment groups in mice evaluated immediately following immobilization. Interestingly, relative to vehicle-treated mice, 5 mg/kg AdipoRon therapy improved the PEA of the experimental knees in mice that underwent 4 weeks of knee remobilization following the immobilization and therapy. Together, these studies revealed that AdipoRon may be an effective therapeutic modality for arthrofibrosis.

Cost-effectiveness analysis of low-dose prophylaxis versus on-demand treatment for moderate-to-severe hemophilia A in India.

AIM: Hemophilia A (HA) is an inherited bleeding disorder caused by a deficiency of clotting factor VIII in the blood. In resource-limited settings like India, affordability is a significant challenge in managing patients with severe HA. This study aims to assess the cost-effectiveness of intermediate-dose prophylaxis versus on-demand factor therapy in adult and pediatric populations with moderate-to-severe congenital HA without inhibitors in India. METHOD: We conducted a prospective cost-effectiveness analysis from a societal perspective, categorizing patients into a base state and a joint disease state (patients with Hemophilia suffering extensive bleeds leading to chronic joint disease). Using targeted literature search and primary market research, we developed a Markov model measuring the total cost of Hemophilia treatment and health outcomes, including life-years (LYs), quality-adjusted life-years (QALYs), incremental cost-utility ratio (ICUR), and incremental cost-effectiveness ratio (ICER). The model extended over a lifetime horizon of 70 years with a one-year cycle length. Sensitivity analyses assessed study robustness. RESULTS: Low-dose prophylactic therapy was cost-effective for adults (>18 years) and pediatric populations (<18 years), yielding better health outcomes (adults: 0.15 LYs and 2.43 QALYs gained; pediatric: 0.40 LYs and 3.12 QALYs gained). Intermediate-dose prophylaxis showed positive net monetary benefits in terms of Quality-Adjusted Life Years (QALYs) for both adult and pediatric populations, with dominant ICER and ICUR values in both cases. CONCLUSION: Using intermediate-dose prophylactic factor VIII therapy is a cost-effective approach that improves clinical outcomes compared to on-demand therapy in the Indian adult and pediatric HA populations without inhibitors.

The role of intraarticular injections of hyaluronic acid in joint pain relief in hemophilic arthropathy.

INTRODUCTION: Chronic pain in hemophilic patients is due to joint degeneration associated with hemophilic arthropathy. In addition to appropriate hematological treatment (primary prophylaxis), pharmacologic management and Physical Medicine and Rehabilitation should be indicated. When such measures are not sufficient, intraarticular injections (IAIs) of hyaluronic acid (HyA) may be considered. AREAS COVERED: In order to determine whether IAIs of HyA are effective in terms of pain relief in individuals with painful moderate hemophilic arthropathy, a PubMed and Cochrane Library search using 'hemophilia hyaluronic acid' as keywords was performed on 18 July 2023. EXPERT OPINION: In a study of individuals with hemophilic arthropathy (elbows, knees and ankles), 91% of them improved pain after a mean follow-up of 6 years. In another study of individuals with knee arthropathy, after a 7-year follow-up 82% reported an improvement in pain. As for hemophilic ankle arthropathy, in a study 67% of patients showed relief of joint pain at 6-month follow-up. Although the literature on the subject is very heterogeneous and difficult to interpret, it appears that IAIs of HyA can relieve the joint pain of painful moderate hemophilic arthropathy for months. Moreover, the IAIs can be repeated every 6-12 months.

Characterization of a recombinant factor IX molecule fused to coagulation factor XIII-B subunit.

INTRODUCTION AND AIM: Severe haemophilia B (HB) is characterized by spontaneous bleeding episodes, mostly into joints. Recurrent bleeds lead to progressive joint destruction called haemophilic arthropathy. The current concept of prophylaxis aims at maintaining the FIX level >3-5 IU/dL, which is effective at reducing the incidence of haemophilic arthropathy. Extended half-life FIX molecules make it easier to achieve these target trough levels compared to standard FIX concentrates. We previously reported that the fusion of a recombinant FIX (rFIX) to factor XIII-B (FXIIIB) subunit prolonged the half-life of the rFIX-LXa-FXIIIB fusion molecule in mice and rats 3.9- and 2.2-fold, respectively, compared with rFIX-WT. However, the mechanism behind the extended half-life was not known. MATERIALS AND METHODS: Mass spectrometry and ITC were used to study interactions of rFIX-LXa-FXIIIB with albumin. Pharmacokinetic analyses in fibrinogen-KO and FcRn-KO mice were performed to evaluate the effect of albumin and fibrinogen on in-vivo half-life of rFIX-LXa-FXIIIB. Finally saphenous vein bleeding model was used to assess in-vivo haemostatic activity of rFIX-LXa-FXIIIB. RESULTS AND CONCLUSION: We report here the key interactions that rFIX-LXa-FXIIIB may have in plasma are with fibrinogen and albumin which may mediate its prolonged half-life. In addition, using the saphenous vein bleeding model, we demonstrate that rFIX-FXIIIB elicits functional clot formation that is indistinguishable from that of rFIX-WT.

Anti-arthritis Effects of Zingiberaceae Extracts on Models of Inflammatory Joint Disease.

Due to this becoming an aging society, the number of arthritis cases has been increasing. Unfortunately, some currently available medications can cause adverse effects. Using herbal remedies as a form of alternative medicine is becoming increasingly popular. Zingiber officinale (ZO), Curcuma longa (CL), and Kaempferia parviflora (KP) are herbal plants in the Zingiberaceae family that have potent anti-inflammatory effects. This study investigates the anti-inflammatory and chondroprotective effects of ZO, CL, and KP extracts on in vitro and ex vivo inflammatory models. The combinatorial anti-arthritis effect of each extract is also evaluated in an in vivo model. ZO extract preserves cartilaginous proteoglycans in proinflammatory cytokines-induced porcine cartilage explant in a fashion similar to that of CL and KP extracts and suppresses the expression of major inflammatory mediators in SW982 cells, particularly the COX2 gene. CL extract downregulates some inflammatory mediators and genes-associated cartilage degradation. Only KP extract shows a significant reduction in S-GAGs release in a cartilage explant model compared to the positive control, diacerein. In SW982 cells, it strongly suppresses many inflammatory mediators. The active constituents of each extract selectively downregulate inflammatory genes. The combined extracts show a reduction in inflammatory mediators to a similar degree as the combined active constituents. Reductions in paw swelling, synovial vascularity, inflammatory cell infiltration, and synovial hyperplasia are found in the combined extracts-treated arthritic rats. This study demonstrates that a combination of ZO, CL, and KP extracts has an anti-arthritis effect and could potentially be developed into an anti-arthritis cocktail for arthritis treatment.

The role of intra-articular injection of autologous platelet-rich plasma versus corticosteroids in the treatment of synovitis in lumbar facet joint disease.

OBJECTIVES: To compare the efficacy between platelet-rich plasma (PRP) and corticosteroids (CS) in improving magnetic resonance imaging (MRI)-detected synovitis in correlation with clinical complaints among patients with lumbar facet joint (FJ) disease. METHODS: This study was carried out at Eldemerdash Hospital, Cairo, Egypt between September 2019 and January 2021. A prospective, randomized, comparative, single blinded study included 30 patients with lumbar FJ disease, divided into 2 equal groups, received PRP and CS injections. Patients were comparatively assessed before and after the intervention according to number of tender lumbar FJs, maximum active lumbar extension range of motion, LBP visual analogue score, LBP functional disability questionnaires and MRI lumbar FJ detected synovitis and their grading. RESULTS: Both groups showed a significant improvement in all mentioned parameters at follow-up after 3 months. However, PRP injections promoted better performance in terms of MRI synovitis grade in all lumbar FJ levels compared to CS injections. CONCLUSION: Both PRP and CS injections were effective in improving MRI-detected FJ synovitis while concurrently improving all examined parameters at follow-up after 3 months. However, PRP promoted better improvement in MRI-detected synovitis grade, suggesting that it may be a better treatment option for longer duration efficacy.TRN: NCT04860531- 1/3/2021.

Assessing Immunogenicity of Biologic Drugs in Inflammatory Joint Diseases: Progress Towards Personalized Medicine.

Biologic drugs have greatly improved treatment outcomes of inflammatory joint diseases, but a substantial proportion of patients either do not respond to treatment or lose response over time. Drug immunogenicity, manifested as the formation of anti-drug antibodies (ADAb), constitute a significant clinical problem. Anti-drug antibodies influence the pharmacokinetics of the drug, are associated with reduced clinical efficacy, and an increased risk of adverse events such as infusion reactions. The prevalence of ADAb differs among drugs and diseases, and the detection of ADAb also depends on the assay format. Most data exist for the tumor necrosis factor-alpha inhibitors infliximab and adalimumab, with a frequency of ADAb that ranges from 10 to 60% across studies. Measurement of ADAb and serum drug concentrations, therapeutic drug monitoring, has been suggested as a strategy to optimize therapy with biologic drugs. Although the recent randomized clinical Norwegian Drug Monitoring (NOR-DRUM) trials show promise towards a personalized medicine prescribing approach by therapeutic drug monitoring, several challenges remain. A plethora of assay formats, with widely differing properties, is currently used for measuring ADAb. Comparing results between different assays and laboratories is difficult, which complicates the development of cut-offs necessary for guidelines and the implementation of ADAb measurements in clinical practice. With the possible exception of infliximab, limited data on clinical relevance and cost effectiveness exist to support therapeutic drug monitoring as a routine clinical strategy to monitor biologic drugs in inflammatory joint diseases. The aim of this review is to provide an overview of the characteristics and prevalence of ADAb, predisposing factors to ADAb formation, commonly used assessment methods, clinical consequences of ADAb, and the potential implications of ADAb assessments for everyday treatment of inflammatory joint diseases.

A single centre, open label, pilot study evaluating the effect of intra-articular hyaluronic acid injection on pain and functionality when injected into the ankle (tibio-talar and sub-talar) joint in patients with haemophilic arthropathy.

AIMS: Ankle arthropathy commonly affects persons with haemophilia (PWH). Joint damage causes loss of movement, pain and reduced function. Current treatments are limited. Viscosupplementation has been used to treat other patient groups with joint damage. Viscosupplements serve to augment or act as a substitute for synovial fluid and may ameliorate the effects of cartilage loss by cushioning joints and reducing pain. This study evaluated intra-articular Ostenil Plus™ (HA) for ankle arthropathy in PWH. Reduction in pain was the primary outcome. METHODS: A single centre open label pilot study. PWH and significant ankle arthropathy, according to MRI scores, were recruited. Participants received intra-articular HA injections at baseline and 6 months. Follow up assessments were completed three-monthly for 1 year. Pain was assessed by the Visual Analogue Scale (VAS). Participant perceptions of overall changes to pain, function and quality of life were sought. RESULTS: Twenty-four participants were recruited, three withdrew. Twenty-six joints were injected. Twenty participants had severe haemophilia. Mean age 35 years. Participants reported significant reduction in pain over the study. VAS baseline: 5.62; 6 month 3.92; 12-month 3.42, P < .0001. Joint function improved together with ankle HJHS. No change was seen for EQ-5D-5L. Sixteen participants reported reductions in ankle pain and stiffness and greater confidence in undertaking physical activities. No significant adverse reactions were reported. CONCLUSION: Ostenil Plus™ treatment improves pain, function and patient perception of functional ability in PWH and ankle arthropathy. This study supports the use of HA as a safe treatment in PWH.

Arthroscopic tibiotalocalcaneal arthrodesis. Technique, indications and results / Panartrodesis artroscópica de tobillo. Indicaciones, técnica y resultados

Background: Arthroscopic tibiotalocalcaneal arthrodesis with a retrograde nail is performed as a minimally invasive technique in patients without improvement in conservative treatment of osteoarthritis. Complications and hospital stay after surgery are less using this technique when they are compared with open ones. Materials and methods: We review retrospectively from 2016 to 2019 seven patients subjected to a posterior arthroscopic tibiotalocalcaneal arthrodesis with a retrograde intramedullary nail. AOFAS scale was used to assess functional results and we collected other data as complications, time required for bony union, time of nonweight-bearing and scale of satisfaction. We also made a description of the technique we performed. Results: The mean hospital stay was 3.43±0.53 days, patients have well functional results and complications were very low. It was noticed tibiotalar bony union in about 86% of patients 10 weeks after surgery and subtalar bony union in about 71% 20 weeks after surgery. Nonweight-bearing was made using a cast for 4 weeks and later, it was changed for Walker allowing patients partial weight-bearing until 10 weeks after surgery. One patient had wound complications and he needed later surgery and another presented tibiotalar pseudoarthrosis, although without symptoms. Conclusion: Posterior arthroscopic tibiotalocalcaneal arthrodesis offers very good results with a high rate of bony union, few complications, and minimal nonweight-bearing time. This technique could be used in patients without major deformities, especially in those at high risk of complications from the surgical wound.(AU)

Antecedentes: La artrodesis tibiotalocalcánea artroscópica con clavo retrógrado es una técnica mínimamente invasiva que se realiza en pacientes con artrosis que no mejoran con tratamiento conservador. La ventaja de esta técnica es su menor estancia hospitalaria y su menor tasa de complicaciones respecto a técnicas abiertas. Materiales y métodos: Se realiza un estudio retrospectivo descriptivo de los 7 pacientes intervenidos entre 2016-2019 de artrodesis tibiotalocalcánea artroscópica por vía posterior con clavo retrógrado en nuestro hospital. En él se analizan los datos de funcionalidad con la escala AOFAS, grado de satisfacción, tiempo de consolidación, de descarga y complicaciones. Además, se realiza una descripción de la técnica quirúrgica empleada. Resultados: Se observó una estancia hospitalaria de 3,43±0,53 días de media, buena funcionalidad y baja tasa de complicaciones. Obtuvimos consolidación tibiotalar en el 86% de los casos en aproximadamente 10 semanas y una consolidación subtalar en el 71% en 20 semanas. El tiempo de descarga fue de 4 semanas con férula y posteriormente carga parcial con Walker hasta la décima semana postoperatoria. Uno de los casos tuvo que ser reintervenido por complicaciones en la herida quirúrgica y otro presentó seudoartrosis tibiotalar, aunque sin repercusión clínica. Conclusión: La panartrodesis artroscópica por vía posterior ofrece muy buenos resultados, con elevada tasa de consolidación ósea, pocas complicaciones y tiempo de descarga mínimo. Esta técnica podría ser utilizada en pacientes sin grandes deformidades, sobre todo en aquellos con alto riesgo de complicaciones de la herida quirúrgica, al constatarse un descenso de las mismas.(AU)

Panartrodesis artroscópica de tobillo. Indicaciones, técnica y resultados / Arthroscopic tibiotalocalcaneal arthrodesis. Technique, indications and results

Antecedentes: La artrodesis tibiotalocalcánea artroscópica con clavo retrógrado es una técnica mínimamente invasiva que se realiza en pacientes con artrosis que no mejoran con tratamiento conservador. La ventaja de esta técnica es su menor estancia hospitalaria y su menor tasa de complicaciones respecto a técnicas abiertas. Materiales y métodos: Se realiza un estudio retrospectivo descriptivo de los 7 pacientes intervenidos entre 2016-2019 de artrodesis tibiotalocalcánea artroscópica por vía posterior con clavo retrógrado en nuestro hospital. En él se analizan los datos de funcionalidad con la escala AOFAS, grado de satisfacción, tiempo de consolidación, de descarga y complicaciones. Además, se realiza una descripción de la técnica quirúrgica empleada. Resultados: Se observó una estancia hospitalaria de 3,43±0,53 días de media, buena funcionalidad y baja tasa de complicaciones. Obtuvimos consolidación tibiotalar en el 86% de los casos en aproximadamente 10 semanas y una consolidación subtalar en el 71% en 20 semanas. El tiempo de descarga fue de 4 semanas con férula y posteriormente carga parcial con Walker hasta la décima semana postoperatoria. Uno de los casos tuvo que ser reintervenido por complicaciones en la herida quirúrgica y otro presentó seudoartrosis tibiotalar, aunque sin repercusión clínica. Conclusión: La panartrodesis artroscópica por vía posterior ofrece muy buenos resultados, con elevada tasa de consolidación ósea, pocas complicaciones y tiempo de descarga mínimo. Esta técnica podría ser utilizada en pacientes sin grandes deformidades, sobre todo en aquellos con alto riesgo de complicaciones de la herida quirúrgica, al constatarse un descenso de las mismas.(AU)

Background: Arthroscopic tibiotalocalcaneal arthrodesis with a retrograde nail is performed as a minimally invasive technique in patients without improvement in conservative treatment of osteoarthritis. Complications and hospital stay after surgery are less using this technique when they are compared with open ones. Materials and methods: We review retrospectively from 2016 to 2019 seven patients subjected to a posterior arthroscopic tibiotalocalcaneal arthrodesis with a retrograde intramedullary nail. AOFAS scale was used to assess functional results and we collected other data as complications, time required for bony union, time of nonweight-bearing and scale of satisfaction. We also made a description of the technique we performed. Results: The mean hospital stay was 3.43±0.53 days, patients have well functional results and complications were very low. It was noticed tibiotalar bony union in about 86% of patients 10 weeks after surgery and subtalar bony union in about 71% 20 weeks after surgery. Nonweight-bearing was made using a cast for 4 weeks and later, it was changed for Walker allowing patients partial weight-bearing until 10 weeks after surgery. One patient had wound complications and he needed later surgery and another presented tibiotalar pseudoarthrosis, although without symptoms. Conclusion: Posterior arthroscopic tibiotalocalcaneal arthrodesis offers very good results with a high rate of bony union, few complications, and minimal nonweight-bearing time. This technique could be used in patients without major deformities, especially in those at high risk of complications from the surgical wound.(AU)

E8002 Reduces Adhesion Formation and Improves Joint Mobility in a Rat Model of Knee Arthrofibrosis.

Knee arthrofibrosis is a common complication of knee surgery, caused by excessive scar tissue, which results in functional disability. However, no curative treatment has been established. E8002 is an anti-adhesion material that contains L-ascorbic acid, an antioxidant. We aimed to evaluate the efficacy of E8002 for the prevention of knee arthrofibrosis in a rat model, comprising injury to the surface of the femur and quadriceps muscle 1 cm proximal to the patella. Sixteen male, 8-week-old Sprague Dawley rats were studied: in the Adhesion group, haemorrhagic injury was induced to the quadriceps and bone, and in the E8002 group, an adhesion-preventing film was implanted between the quadriceps and femur after injury. Six weeks following injury, the restriction of knee flexion owing to fibrotic scarring had not worsened in the E8002 group but had worsened in the Adhesion group. The area of fibrotic scarring was smaller in the E8002 group than in the Adhesion group (p < 0.05). In addition, the numbers of fibroblasts (p < 0.05) and myofibroblasts (p < 0.01) in the fibrotic scar were lower in the E8002 group. Thus, E8002 reduces myofibroblast proliferation and fibrotic scar formation and improves the range of motion of the joint in a model of knee injury.

Sex-based differences in the severity of radiation-induced arthrofibrosis.

As cancer survivorship increases, so does the number of patients that suffer from the late effects of radiation therapy. This includes arthrofibrosis, the development of stiff joints near the field of radiation. Previous reports have concentrated on skin fibrosis around the joint but largely ignored the deeper tissues of the joint. We hypothesized that fat, muscle, and the joint tissues themselves would play a more significant role in joint contracture after radiation than the skin surrounding the joint. To address this hypothesis, we irradiated the right hind flanks of mice with fractionated and unfractionated dose schedules, then monitored the mice for 3 months postradiotherapy. Mice were euthanized and physiological indications of arthrofibrosis including limb contracture and joint resting position were assessed. Stifle (knee) joints demonstrated significant arthrofibrosis, but none was observed in the hock (ankle) joints. During these studies, we were surprised to find that male and female mice showed a significantly different response to radiation injury. Female mice developed more injuries, had significantly worse contracture, and showed a greater difference in the expression of all markers studied. These results suggest that women undergoing radiation therapy might be at significantly greater risk for developing arthrofibrosis and may require specific adjustments to their care.

Efficacy of Enzyme Replacement Therapy on the range of motion of the upper and lower extremities in 16 Polish patients with mucopolysaccharidosis type II: A long-term follow-up study.

BACKGROUND: Enzyme replacement therapy (ERT) with idursulfase is available for patients with mucopolysaccharidosis (MPS) type II, and improvements in certain somatic signs and symptoms have been reported. The aim of the study was to assess the effectiveness of ERT with idursulfase (Elaprase®) on the passive joint range of motion (JROM) in the upper and lower extremities of patients with MPS II. METHODS: The study included 16 Polish patients diagnosed with MPS II and followed in our Institute in the years 2009-2016. The study group was divided for groups of neuronopathic (group 1, n=12) and non-neuronopathic (group 2, n=4) patients. A passive JROM was measured with a goniometer by one physiotherapist, while in group 1 it was assessed at baseline and after both short-term (52 weeks) and long-term (mean 230 weeks, range: 108-332 weeks) ERT. In group 2, it was assessed at baseline and after short-term ERT (68-85 weeks, no data for long-term ERT). RESULTS: In group 1, after 52 weeks of ERT, we observed some improvement of passive ROM in wrist flexion (5/12 patients), shoulder abduction and wrist extension (3/12 patients), shoulder flexion, elbow and knee extension (2/12 patients). After long-term ERT (mean 230 weeks), the improvement in JROM was observed only in 2 patients. There was no improvement in the shoulder abduction, elbow flexion and extension, hip and knee extension. In group 2, the improvement in passive ROM was observed in several joints: shoulder flexion, wrist flexion and extension improved (2/4 patients) and shoulder abduction (1/4 patients). CONCLUSION: ERT is of low efficacy on correcting the range of motion of joints in MPS II patients.

¿Conlleva la desprescripción de condroprotectores en pacientes con artrosis un incremento del consumo de analgésicos? Estudio observacional retrospectivo / Does the deprescription of chondroprotectors in patients with osteoarthritis lead to an increase in the consumption of analgesics? Observational retrospective study

Objetivo: El objetivo del estudio es evaluar si la desprescripción de medicamentos considerados de bajo valor intrínseco como los condroprotectores o SYSADOA, conlleva un empeoramiento sintomáti-co de la artrosis, incrementándose el consumo de analgésicos.Material y métodos: Siguiendo la práctica clínica habitual se retiró el tratamiento con SYSADOA a pa-cientes de un Centro de Atención Primaria (pobla-ción asignada: 34.382 habitantes, 17% mayores de 65 años) en base a la evidencia científica publicada y a la recomendación de la administración sanitaria de reducir los tratamientos con medicamentos de bajo valor intrínseco. Mediante un estudio obser-vacional post-intervención se analizaron diferen-cias de consumo de analgésicos y AINEs entre un periodo anterior a la retirada y el mismo periodo post-retirada.Resultados: Se analizaron 354 pacientes (68,4% mujeres, media de edad 66,2 años). No se encon-traron diferencias estadísticamente significativas en el consumo de analgesia total en el periodo de 6 meses post-retirada (media de 3,97 envases) com-parado con el periodo de 6 meses previo (media de 4,04 envases). Al estratificar por código ATC, edad y género, únicamente se encontraron diferencias en el consumo de otros analgésicos y antipiréticos teniendo en cuenta el sexo.Conclusión: Se concluye que, considerar con el paciente la desprescripción de SYSADOA a criterio del médico, es seguro y no conlleva un aumento del consumo de analgésicos (otros analgésicos y anti-piréticos, AINE, opioides menores, opioides mayo-res) sugiriendo que no implica un empeoramiento de la enfermedad artrósica. La desprescripción de SYSADOA, además, puede contribuir a reducir la po-limedicación sin alterar la situación clínica y evitar posibles riesgos de efectos adversos o interaccio-nes potenciales (AU)

Objective: The objective of this study is to assess if the deprescription of medications that are consid-ered low intrinsic value medications such as the chondroprotectors or SYSADOA entails a symptom-atic worsening of the arthrosis and consequently an increase of the consumption of analgesics.Material and Methods: Following the usual clinical practise, the SYSADOA treatment was withdrawn to the patients from a Primary Health Care Centre (assigned population: 34,382 inhabitants, 17% up to 65 years old) according to the published scientific proof and the recommendation of the health ad-ministration consisting of reducing the treatments with low intrinsic value medications. Differences in consumption of analgesics and AINEs between a previous period before the withdrawn and the same period post-withdrawn were studied through an observational post-intervention study.Results: 354 patients were analysed (68,4% wom-en, average age 66,2 years). There were not found significant differences from a statistical point of view in the total consumption of analgesia in the 6 months period post-withdrawn (average of 3,97 packagings) compared to the previous period of 6 months (average of 4,04 packagings). When stratifying by ATC code, age and gender, there were only found differences in the consumption of other analgesics and antipyretics taking into account the sex.Conclusion: It is concluded that considering togeth-er with the patient the deprescription of SYSADOA according to doctor’s criteria is safe and does not involve an increase of analgesics consumption (other analgesics, antipyretics, AINEs, major and minor opiods) suggesting that it does not suppose a worsening of the arthrosis disease. Besides, the deprescription of SYSADOA may contribute to re-duce polymedication without disrupting the clinical situation and avoid possible risks of adverse effects or potential interactions

Lysosomal alkalization to potentiate eradication of intra-osteoblastic Staphylococcus aureus in the bone and joint infection setting.

OBJECTIVES: Beyond intracellular penetration, acidic lysosomal pH might affect the intracellular activity of some antimicrobials. This study evaluated the ability of lysosomotropic alkalizing agents to potentiate the antimicrobial eradication of an intra-osteoblastic Staphylococcus aureus reservoir in the setting of bone and joint infection (BJI). METHODS: MICs of 16 anti-staphylococcal molecules active against methicillin-sensitive S. aureus (MSSA) were evaluated at pH 5 and pH 7. Additionally, the lysosomal alkalizing potential (spectrofluorometry) and cytotoxicity (MTT assay) of hydroxychloroquine, amantadine and ammonium chloride were assessed. The results led to further investigation of clindamycin, cotrimoxazole, daptomycin and levofloxacin-alone or in combination with hydroxychloroquine-in an in vitro model of osteoblast infection. The impact of hydroxychloroquine on autophagy was finally investigated using Western blot detection of two autophagic flux indicators, the LC3 membrane protein and the SQSTM1 cargo protein. RESULTS: Daptomycin, cotrimoxazole, clindamycin and levofloxacin alone significantly decreased the intracellular staphylococcal reservoir (5.12 log10 CFU/100 000 cells) by 0.14 (95%CI 0.01-0.34), 0.25 (95%CI 0.12-0.43), 0.16 (95%CI 0.004-0.39) and 1.18 (95%CI 1.04-1.38) log10 CFU/100 000 cells, respectively (p < 10-3). Adding hydroxychloroquine (20 mg/L) increased intralysosomal pH from 4.8 to 7, and concomitantly the inoculum of each antimicrobial was reduced by 0.50 (95%CI 0.30-0.84), 0.73 (95%CI 0.59-0.96), 0.59 (95%CI 0.46-0.78) and 1.8 (95%CI 1.66-2.1) log10 CFU/100 000 cells, respectively (p < 10-4). Cellular levels of LC3II and SQSTM1 showed that hydroxychloroquine has direct activity on the autophagic flux, fostering the eradication of intracellular S. aureus by antimicrobials. CONCLUSION: At high concentrations, hydroxychloroquine used as an adjuvant to antimicrobials improves eradication of an S. aureus intra-osteoblastic reservoir in our in vitro cell infection model. These findings advocate further in vivo evaluation of alkalization efficacy and tolerance in S. aureus BJI.

Magnetic Resonance Imaging-Assessed Subchondral Cysts and Incident Knee Pain and Knee Osteoarthritis: Data From the Multicenter Osteoarthritis Study.

OBJECTIVE: To examine whether knee subchondral cysts, measured on magnetic resonance imaging (MRI), are associated with incident knee osteoarthritis (OA) outcomes. METHODS: We used longitudinal data from the Multicenter Osteoarthritis Study, a community-based cohort of subjects with risk factors for knee OA. Participants without a history of knee surgery and/or inflammatory arthritis (i.e., rheumatoid arthritis and gout) were followed up for 84 months for the following incident outcomes: 1) radiographic knee OA (Kellgren/Lawrence grade ≥2), 2) symptomatic radiographic knee OA (radiographic knee OA and frequent knee pain), and 3) frequent knee pain (with or without radiographic knee OA). In a subset of participants, subchondral cysts were scored on baseline MRIs of 1 knee. Multiple logistic regression, with adjustment for participant characteristics and other baseline knee MRI findings, was used to assess whether subchondral cysts were predictive of incident outcomes. RESULTS: Among the participants with knees eligible for analyses of outcomes over 84 months, incident radiographic knee OA occurred in 22.8% of knees with no baseline radiographic knee OA, symptomatic radiographic knee OA occurred in 17.0% of knees with no baseline symptomatic radiographic knee OA, and frequent knee pain (with or without radiographic knee OA) occurred in 28.8% of knees with no baseline radiographic knee OA and 43.7% of knees with baseline radiographic knee OA. With adjustment for age, sex, and body mass index, the presence of subchondral cysts was not associated with incident radiographic knee OA but was associated with increased odds of incident symptomatic radiographic knee OA (odds ratio 1.92 [95% confidence interval 1.16-3.19]) and increased odds of incident frequent knee pain in those who had radiographic knee OA at baseline (odds ratio 2.11 [95% confidence interval 0.87-5.12]). Stronger and significant associations were observed for outcomes based on consistent reports of frequent knee pain within ~1 month of the study visit. CONCLUSION: Subchondral cysts are likely to be a secondary phenomenon, rather than a primary trigger, of radiographic knee OA, and may predict symptoms in knees with existing disease.

The endothelium-bone axis in development, homeostasis and bone and joint disease.

Blood vessels form a versatile transport network that is best known for its critical roles in processes such as tissue oxygenation, metabolism and immune surveillance. The vasculature also provides local, often organ-specific, molecular signals that control the behaviour of other cell types in their vicinity during development, homeostasis and regeneration, and also in disease processes. In the skeletal system, the local vasculature is actively involved in both bone formation and resorption. In addition, blood vessels participate in inflammatory processes and contribute to the pathogenesis of diseases that affect the joints, such as rheumatoid arthritis and osteoarthritis. This Review summarizes the current understanding of the architecture, angiogenic growth and functional properties of the bone vasculature. The effects of ageing and pathological conditions, including arthritis and osteoporosis, are also discussed.

Desfinanciación de los condroprotectores: ¿Una laguna terapéutica? / Underfunding of chondroprotectors: A therapeutic gap?

Introducción: El empleo de los condroprotectores se presentó como una estrategia mejor encaminada al tratamiento de la artrosis por su efecto modulador y mayor seguridad. Sin embargo, su empleo es discutido y serán retirados de la financiación por el Sistema Nacional de salud (SNS). El objetivo fue revisar y comparar los condroprotectores en términos de eficacia (sobre dolor, función y estrechamiento articular), seguridad y rentabilidad en el manejo de la artrosis. Metodología: Se ha realizado una búsqueda bibliográfica de la literatura. Las bases de datos utilizadas fueron Medline y Scopus. Se revisó guía médica de la ESCEO (European Society for Clinical and Economic Aspects of Osteoarthritis), estudio epidemiológico de la Sociedad Española de Reumatología y fichas técnicas de medicamentos de la Agencia Española del Medicamento. Resultados: Se identificaron un total de 152 artículos con los algoritmos de búsqueda utilizados y los criterios de inclusión/exclusión aplicados. Después de leer títulos y resúmenes, 79 fueron excluidos porque no adecuarse a la calidad metodológica requerida o tratar otras aplicaciones diferentes a la artrosis. Tras la lectura íntegra del resto de artículos, se seleccionaron 36 artículos que se adaptaban al objetivo de este trabajo. Conclusiones: Los ensayos clínicos que evaluaron la diacereína y el condroitín sulfato tuvieron diseños muy variables que podrían justificar la variabilidad de los resultados obtenidos. Con la desfinanciación de estos fármacos por el SNS, el ahorro esperado podría revertirse por el empleo de recursos sanitarios más costosos en el futuro dado el enfoque a corto plazo de las terapias permanentes. (AU)

Introduction: The use of chondroprotectives was presented as a better strategy aimed at the treatment of osteoar-thritis due to its attributed chondromodulatory effect and greater safety. However, their use is disputed.The aim of the present work was to review and compare the chondroprotectives in terms of efficacy (on pain, func-tion and joint narrowing), safety and economic profitability in the management of osteoarthritis. Methodology: A bibliographic search of the literature published has been carried out. The databases used were Medline and Scopus. The medical guide of the ESCEO (European Society for Clinical and Economic Aspects of Osteo-athritis), the epidemiological study of the Spanish Society of Rheumatology and the technical sheets of medicines of the Spanish Agency of Medicines were reviewed. Results: A total of 152 articles were identified with the search algorithms used and the inclusion/exclusion criteria applied. After having read titles and abstracts, 79 were excluded because they did not conform to the required meth-odological quality or to treat other applications other than osteoarthritis. After reading the rest of the articles in their entirety, 36 articles were finally selected that were adapted to the objective of this work. Conclusions: The clinical trials that evaluated diacerein and chondroitin sulfate had highly variable designs that could justify the variability of the results obtained. With the underfunding of these drugs by the SNS, the expected savings could be reversed by the use of more expensive healthcare resources in the future given the short-term focus of permanent therapies. (AU)

Development of a dosing-adjustment tool for fluoroquinolones in osteoarticular infections: The Fluo-pop study.

Fluoroquinolones efficacy depend on both the drug exposure and the level of drug resistance of the bacteria responsible for the infection. Specifically for the Staphylococcus species, which is the microorganism mainly involved in osteoarticular infections (OAI), in-vitro data reported that an AUC/MIC ratio above 115 h maximizes drug efficacy. However, data on OAI patients are lacking and a simple approach to access AUCs is still a clinical issue. We conducted a prospective, single-center study in 30 OAI patients hospitalized in the Rennes University Hospital to model ofloxacin pharmacokinetics and to define a limited sampling strategy (LSS) suitable for ofloxacin and levofloxacin treatments. Modeling was conducted with the Monolix software. The final model was externally validated using levofloxacin data. Monte-Carlo simulations were used to evaluate the probability of target attainment (PTA) of different dosing regimens. Two hundred and ninety-seven (297) ofloxacin concentrations were available for the pharmacokinetic modeling. Ofloxacin pharmacokinetics was best described using a bicompartmental model with a first order elimination, and a transit compartment model absorption. CKD-EPI and sex explained half of ofloxacin pharmacokinetic variability. For LSS, the 0, 1 h and 3 h sampling scheme resulted in the best approach both for BID and TID dosages (R2 adjusted = 91.1% and 95.0%, outliers = 4.8% and 5.0%, respectively). PTA allows choosing the best drug and dosage according to various hypotheses. A simple 3-sample protocol (pre-dose, 1 h after intake and 3 h after intake) to estimate ofloxacin and levofloxacin AUC allows optimal drug dosage for the treatment of osteoarticular infections.