An international, multicentre, double-blind, randomized study (DISSCO): effect of diacerein vs celecoxib on symptoms in knee osteoarthritis.

OBJECTIVE: The objective of this study was to investigate whether diacerein has comparable efficacy with celecoxib in pain reduction for treatment in symptomatic knee OA patients. METHODS: This randomized double-blind multicentre non-inferiority trial evaluated diacerein vs celecoxib treatment in patients with Kellgren-Lawrence grade 2-3 and pain scoring ≥4 (10-cm VAS). Patients were randomized to 6 months of treatment with diacerein 50 mg (n = 187) once daily for 1 month and twice daily thereafter, or celecoxib 200 mg (n = 193) once daily. The primary outcome was the change in WOMAC pain score (0-50 cm) at 6 months, and the secondary outcomes were WOMAC sub-scores, VAS pain score, and the OMERACT-OARSI responder rate. RESULTS: In the per protocol population, the adjusted mean change from baseline in the WOMAC pain score was -11.1 ( 0.9) with diacerein (n = 140) and -11.8 (0.9) with celecoxib (n = 148). The intergroup difference was 0.7 (95% CI: -1.8, 3.2; P = 0.597), meeting the non-inferiority margin. Supportive analysis of the intention-to-treat population gave similar results. Other outcomes showed no significant difference between treatment groups. The incidence of treatment-related adverse events was low and balanced between groups, but a greater incidence of diarrhoea occurred with diacerein (10.2% vs 3.7%). Diarrhoea was considered mild-to-moderate in all but one case with complete resolution. CONCLUSIONS: Diacerein was non-inferior to celecoxib in reducing knee OA pain and improving physical function. Diacerein also demonstrated a good safety profile. TRIAL REGISTRATION: A multicentre study on the effect of DIacerein on Structure and Symptoms vs Celecoxib in Osteoarthritis is a National Institutes of Health (NCT02688400) and European Clinical Trial Database (2015-002933-23) registered phase III (Canada) or IV (Europe) study.

Acute haemodynamic comparison of multisite and biventricular pacing with a quadripolar left ventricular lead.

AIMS: Pacing from multiple sites in the left ventricle (LV) may bring about further resynchronization of the diseased heart compared with biventricular (BiV) pacing. We compared acute haemodynamic response (LV dP/dtmax) of multisite and BiV pacing using a quadripolar LV lead. METHODS AND RESULTS: In 21 patients receiving cardiac resynchronization therapy, a quadripolar LV lead and conventional right atrial and ventricular leads were connected to an external pacing system. A guidewire pressure sensor was placed in the LV for continuous dP/dt measurement. Four multisite pacing configurations were tested three times each and compared with BiV pacing using the distal LV electrode. Nineteen patients had useable haemodynamic data. Median increase in LV dP/dtmax with BiV vs. atrial-only pacing was 8.2% (interquartile range 2.3%, 15.7%). With multisite pacing using distal and proximal LV electrodes, median increase in LV dP/dtmax was 10.2% compared with atrial-only pacing (interquartile range 6.1%, 25.6%). In 16 of 19 patients (84%), two or more of the four multisite pacing configurations increased LV dP/dtmax compared with BiV pacing. Overall, 72% of all tested configurations of multisite pacing produced greater LV dP/dtmax than obtained with BiV pacing. Pacing from most distal and proximal electrodes was the most common optimal configuration, superior to BiV pacing in 74% of patients. CONCLUSION: In the majority of patients, multisite pacing improved acute systolic function further compared with BiV pacing. Pacing with the most distal and proximal electrodes of the quadripolar LV lead most commonly yielded greatest LV dP/dtmax.

Magnetic resonance imaging assessments for knee segmentation and their use in combination with machine/deep learning as predictors of early osteoarthritis diagnosis and prognosis.

Knee osteoarthritis (OA) is a prevalent and disabling disease that can develop over decades. This disease is heterogeneous and involves structural changes in the whole joint, encompassing multiple tissue types. Detecting OA before the onset of irreversible changes is crucial for early management, and this could be achieved by allowing knee tissue visualization and quantifying their changes over time. Although some imaging modalities are available for knee structure assessment, magnetic resonance imaging (MRI) is preferred. This narrative review looks at existing literature, first on MRI-developed approaches for evaluating knee articular tissues, and second on prediction using machine/deep-learning-based methodologies and MRI as input or outcome for early OA diagnosis and prognosis. A substantial number of MRI methodologies have been developed to assess several knee tissues in a semi-quantitative and quantitative fashion using manual, semi-automated and fully automated systems. This dynamic field has grown substantially since the advent of machine/deep learning. Another active area is predictive modelling using machine/deep-learning methodologies enabling robust early OA diagnosis/prognosis. Moreover, incorporating MRI markers as input/outcome in such predictive models is important for a more accurate OA structural diagnosis/prognosis. The main limitation of their usage is the ability to move them in rheumatology practice. In conclusion, MRI knee tissue determination and quantification provide early indicators for individuals at high risk of developing this disease or for patient prognosis. Such assessment of knee tissues, combined with the development of models/tools from machine/deep learning using, in addition to other parameters, MRI markers for early diagnosis/prognosis, will maximize opportunities for individualized risk assessment for use in clinical practice permitting precision medicine. Future efforts should be made to integrate such prediction models into open access, allowing early disease management to prevent or delay the OA outcome.

Risk factors for the long-term incidence and progression of knee osteoarthritis in older adults: role of nonsurgical injury.

Background: For one of the most chronic medical conditions, osteoarthritis, uncertainties remain on the impact of injury chronology, the role of repeat injury on the incidence/progression of this disease and the need for knee arthroplasty. Objectives: To explore, in an older adult population, how nonsurgical knee injuries relate to osteoarthritis incidence/progression and the weight of independent risk factors for arthroplasty. Design: A cohort study design evaluates the long-term impact of injuries on knee osteoarthritis outcomes. Methods: Knees with no prior injury (n = 6358) and with at least one injury (n = 819) ⩽20 years before study inclusion were from the Osteoarthritis Initiative cohort. Sociodemographic, clinical and structural [X-ray, magnetic resonance imaging (MRI)] data at study inclusion and changes within 96 months were analysed. Statistics included a mixed model for repeated measurements, generalized estimating equations and multivariable Cox regression with covariates. Results: At inclusion, knees with prior injury demonstrated greater incidence and severity of osteoarthritis (p ⩽ 0.001). At 96 months, there was a greater increase in symptoms [Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, p = 0.002], joint space width (JSW, p = 0.039) loss, medial cartilage volume loss (CVL, p ⩽ 0.001) and bone marrow lesion size (BML, p ⩽ 0.049). Knees with/without injury at inclusion but with new ones over time had a pronounced increase in symptoms (all WOMAC scores, p ⩽ 0.001), JSW loss, lateral (without) and medial CVL, lateral (without) and medial meniscal extrusion and medial BML (without; all p ⩽ 0.030). Levels of lateral and medial meniscal extrusion (without) and symptoms (with/without; all WOMAC scores, p ⩽ 0.001) were all accentuated with a repeated new injury. Risk factors associated with the highest knee arthroplasty occurrence are new meniscal extrusion and new injury (p ⩽ 0.001). Conclusion: This study highlights the importance of nonsurgical knee injury in older adults as an independent risk factor for knee osteoarthritis and arthroplasty. These data will be beneficial in clinical practice as they will help identify individuals at greater risk of significant disease progression and worst disease outcomes for a customized therapeutic approach.

Risk factors associated with the occurrence of total knee arthroplasty in patients with knee osteoarthritis: a nested case-control study.

Objectives: The aim of this study was to investigate changes over time in osteoarthritis risk factors most closely associated with the occurrence of total knee arthroplasty (TKA). We hypothesize that the robustness of a longitudinal case-control study will provide new information on the association between changes in various clinical and structural parameters in different time frames before TKA. Methods: Cases (195; TKA after cohort entry) and controls (468) matched for age, gender, income, WOMAC pain, Kellgren-Lawrence grade and follow-up duration were from the Osteoarthritis Initiative cohort. Associations between changes in sociodemographic, clinical, imaging and osteoarthritis therapies with the occurrence of TKA were performed using conditional logistic regression analyses. Results: Worsening of WOMAC scores (cOR 1.02-1.20, p ⩽ 0.012), KOOS (1.02-1.04, p ⩽ 0.014), knee injuries sustained in the previous 30-40 years (women 2.70, p = 0.034) and valgus alignment (1.10, p = 0.052) were associated with the occurrence of TKA. Also associated with TKA was cartilage volume loss in the lateral (overall 1.76, p = 0.025; women 1.93, p = 0.047) and medial compartments (⩾10%, overall 1.54, p = 0.027; men 2.34, p = 0.008), occurrence of medial meniscal extrusion (overall 1.77, p = 0.046; men 2.86, p = 0.028), and increase in bone marrow lesions (BMLs) for women (1.09, p = 0.048). The association of risk factors with TKA was reinforced when both an increase in WOMAC pain and cartilage volume loss (1.85, p = 0.001) were combined. Pain medication usage, mainly narcotics and intra-articular steroid injections (IASI), was also associated with TKA, with no impact on changes in cartilage loss or structure. Conclusion: This study provides new information about gender differences in risk factors associated with the occurrence of TKA. Worsening of valgus alignment, cartilage volume loss in the lateral compartment, BMLs and older injuries are important risk factors in women, while medial compartment cartilage loss and meniscal extrusion are in men. The use of pain medication and IASI although associated was found not causal with TKA.

Common Biochemical and Magnetic Resonance Imaging Biomarkers of Early Knee Osteoarthritis and of Exercise/Training in Athletes: A Narrative Review.

Knee osteoarthritis (OA) is the most common joint disease of the world population. Although considered a disease of old age, OA also affects young individuals and, more specifically among them, those practicing knee-joint-loading sports. Predicting OA at an early stage is crucial but remains a challenge. Biomarkers that can predict early OA development will help in the design of specific therapeutic strategies for individuals and, for athletes, to avoid adverse outcomes due to exercising/training regimens. This review summarizes and compares the current knowledge of fluid and magnetic resonance imaging (MRI) biomarkers common to early knee OA and exercise/training in athletes. A variety of fluid biochemical markers have been proposed to detect knee OA at an early stage; however, few have shown similar behavior between the two studied groups. Moreover, in endurance athletes, they are often contingent on the sport involved. MRI has also demonstrated its ability for early detection of joint structural alterations in both groups. It is currently suggested that for optimal forecasting of early knee structural alterations, both fluid and MRI biomarkers should be analyzed as a panel and/or combined, rather than individually.

Pacing electrode selection in a quadripolar left heart lead determines presence or absence of phrenic nerve stimulation.

A 60-year-old ischaemic patient presented for routine cardiac resynchronization therapy (CRT)-D implantation. An investigational quadripolar left ventricular lead was placed in the posterolateral vein. Phrenic nerve stimulation (PNS) was observed, but it occurred during pacing from only one of the four electrodes. A lead with multiple pacing electrodes is a potential alternative to physical adjustment of the lead or discontinuing CRT when PNS occurs.

Intra-articular corticosteroid knee injection induces a reduction in meniscal thickness with no treatment effect on cartilage volume: a case-control study.

Although intra-articular corticosteroid injections (IACI) are commonly used for the treatment of knee osteoarthritis (OA), there is controversy regarding possible deleterious effects on joint structure. In this line, this study investigates the effects of IACI on the evolution of knee OA structural changes and pain. Participants for this nested case-control study were from the Osteoarthritis Initiative. Knees of participants who had received an IACI and had magnetic resonance images (MRI) were named cases (n = 93), and each matched with one control (n = 93). Features assessed at the yearly visits and their changes within the follow-up period were from MRI (cartilage volume, meniscal thickness, bone marrow lesions, bone curvature, and synovial effusion size), X-ray (joint space width), and clinical (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC] pain score) data. Participants who received IACI experienced a transient and significantly greater rate of loss of the meniscal thickness (p = 0.006) and joint space width (p = 0.011) in the knee medial compartment in the year they received the injection, compared to controls. No significant effect of the IACI was found on the rate of cartilage loss nor on any other knee structural changes or WOMAC pain post-treatment. In conclusion, a single IACI in knee OA was shown to be safe with no negative impact on structural changes, but there was a transient meniscal thickness reduction, a phenomenon for which the clinical relevance is at present unknown.

Levels of serum biomarkers from a two-year multicentre trial are associated with treatment response on knee osteoarthritis cartilage loss as assessed by magnetic resonance imaging: an exploratory study.

BACKGROUND: There is an obvious need to identify biomarkers that could predict patient response to an osteoarthritis (OA) treatment. This post hoc study explored in a 2-year randomized controlled trial in patients with knee OA, the likelihood of some serum biomarkers to be associated with a better response to chondroitin sulfate in reducing cartilage volume loss. METHODS: Eight biomarkers were studied: hyaluronic acid (HA), C reactive protein (CRP), adipsin, leptin, N-terminal propeptide of collagen IIα (PIIANP), C-terminal crosslinked telopeptide of type I collagen (CTX-1), matrix metalloproteinase-1 (MMP-1), and MMP-3. Patients were treated with chondroitin sulfate (1200 mg/day; n = 57) or celecoxib (200 mg/day; n = 62). Serum biomarkers were measured at baseline. The cartilage volume at baseline and its loss at 2 years were assessed by quantitative magnetic resonance imaging (MRI). Statistical analysis included analysis of covariance. RESULTS: As data from the original MOSAIC trial showed no differences in cartilage volume and loss in the lateral compartment of the knee joint between the two treatment groups in any comparison, only the medial compartment and its subregions were studied. Stratification according to the median biomarker levels was used to discriminate treatment effect. In patients with levels of biomarkers of inflammation (HA, leptin and adipsin) lower than the median, those treated with chondroitin sulfate demonstrated less cartilage volume loss in the medial compartment, condyle, and plateau (p ≤ 0.047). In contrast, patients treated with chondroitin sulfate with higher levels of MMP-1 and MMP-3, biomarkers of cartilage catabolism, had less cartilage volume loss in the medial compartment, condyle, and plateau (p ≤ 0.050). Patients with higher levels of PIIANP and CTX-1, biomarkers related to collagen anabolism and bone catabolism, respectively, had reduced cartilage volume loss in the medial condyle (p ≤ 0.026) in the chondroitin sulfate group. CONCLUSION: This study is suggestive of a potentially greater response to chondroitin sulfate treatment on cartilage volume loss in patients with knee OA with low level of inflammation and/or greater level of cartilage catabolism. TRIAL REGISTRATION: This is a post hoc study. Original trial registration: ClinicalTrials.gov, NCT01354145 . Registered on 13 May 2011.

Chondroitin sulfate efficacy versus celecoxib on knee osteoarthritis structural changes using magnetic resonance imaging: a 2-year multicentre exploratory study.

BACKGROUND: In osteoarthritis (OA) treatment, although chondroitin sulfate (CS) was found in a number of studies using radiography to have a structure-modifying effect, to date CS use is still under debate. A clinical study using quantitative magnetic resonance imaging (qMRI) is therefore of the utmost importance. Here we report data from a 24-month, randomised, double-blind, double-dummy, controlled, comparative exploratory study of knee OA. The primary endpoint was to determine the effect of CS 1200 mg/day versus celecoxib 200 mg/day on cartilage volume loss (CVL) in the lateral compartment over time as measured by qMRI. Secondary endpoints included assessment of the OA structural changes and signs and symptoms of OA. METHODS: qMRI was performed at baseline and at 12 and 24 months. CVL, bone marrow lesion size, and synovial thickness were evaluated using qMRI. The primary statistical analysis was carried out on the modified intention-to-treat (mITT) population (n = 138) using chi-squared, Fisher's exact, Wilcoxon Mann-Whitney, and Student's t tests and analysis of covariance. Analyses were also conducted on the according-to-protocol (ATP; n = 120) population. RESULTS: In the adjusted mITT analysis, compared with celecoxib treatment, patients treated with CS had a significant reduced CVL at 24 months in the medial compartment (celecoxib -8.1 % ± 4.2, CS -6.3 % ± 3.2; p = 0.018) and medial condyle (-7.7 % ± 4.7, -5.5 % ± 3.9; p = 0.008); no significant effect was seen in the lateral compartment. In the ATP population, CS reduced CVL in the medial compartment at 12 months (celecoxib -5.6 % ± 3.0, CS -4.5 % ± 2.6; p = 0.049) and 24 months (celecoxib -8.4 % ± 4.2, CS -6.6 % ± 3.3; p = 0.021), and in the medial condyle at 24 months (celocoxib -8.1 % ± 4.7, CS -5.7 % ± 4.0; p = 0.010). A trend towards a statistically reduced synovial thickness (celecoxib +17.96 ± 33.73 mm, CS -0.66 ± 22.72 mm; p = 0.076) in the medial suprapatellar bursa was observed in CS patients. Both groups experienced a marked reduction in the incidence of patients with joint swelling/effusion and in symptoms over time. Data showed similar good safety profiles including cardiovascular adverse events for both drugs. CONCLUSION: This study demonstrated, for the first time in a 2-year randomised controlled trial using qMRI, the superiority of CS over celecoxib at reducing CVL in knee OA patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01354145 . Registered 13 May 2011.

Transmyocardial coil implants: a novel approach to transmyocardial revascularization.

BACKGROUND: Transmyocardial laser revascularization (TMLR) has potential benefit for patients with end-stage coronary artery disease and intractable angina not amenable to conventional revascularization techniques. Neovascularization has been proposed to occur around the laser channels. Our aim was to determine the feasibility of a novel nonlaser myocardial revascularization technique and its effect on angiogenesis in a nonischemic porcine model. METHODS: In the first phase, six transmyocardial stainless steel coil implants (TMI) were deployed to the lateral wall of the left ventricle in each of 6 pigs. The animals were sacrificed at 8 and 12 weeks, with a single animal dying prematurely at 4 weeks, and the myocardium was assessed for new vessel growth. In the second phase, 8 implants were deployed in each of 12 pigs with regular fluoroscopic follow-up until sacrifice at 2 weeks to assess implant stability. RESULTS: The deployment procedure was safe and feasible with no complications evident. A significant increase in new vessels at implant sites with 5.43 +/- 3.67, 4.97 +/- 2.44, and 3.57 +/- 2.29 seen per high power field at 12, 8, and 4 weeks, respectively, compared to 1.00 +/- 1.06 (p < 0.0001) in control myocardium. There was no evidence of implant migration in Phase 2. CONCLUSIONS: TMIs can feasibly be deployed in the nonischemic pig model with a high success rate. The presence of angiogenesis at the implant site and the maintenance of this reaction for 3 months implies that TMI may offer an alternative to TMLR while providing a platform for delivery of angiogenic factors.

The presence of meniscal lesions is a strong predictor of neuropathic pain in symptomatic knee osteoarthritis: a cross-sectional pilot study.

INTRODUCTION: Pain in osteoarthritis (OA) has been classically attributed to joint structural damage. Disparity between the degree of radiographic structural damage and the severity of symptoms implies that factors other than the joint pathology itself contribute to the pain. Peripheral and central sensitization have been suggested as two of the underlying mechanisms that contribute to pain in OA. The aim of this study was to explore in symptomatic knee OA patients, the structural changes assessed by magnetic resonance imaging (MRI) that could be used as markers of neuropathic pain (NP). METHODS: This cross-sectional observational pilot study included 50 knee OA patients with moderate to severe pain (VAS ≥40) in the target knee. The presence of NP was determined based on the PainDETECT questionnaire. Among the 50 patients included, 25 had PainDETECT score ≤12 (unlikely NP), 9 had PainDETECT score between 13 and 18 (uncertain NP) and 16 had PainDETECT score ≥19 (likely NP). WOMAC, PainDETECT, and VAS pain scores as well as knee MRI were assessed. RESULTS: Data showed no significant difference in demographic characteristics between the three groups. However, a positive and statistically significant association was found between the WOMAC pain (P <0.001), function (P <0.001), stiffness (P = 0.007) and total (P <0.001) scores as well as higher VAS pain score (P = 0.023), and PainDETECT scores. Although no difference was found in the cartilage volume between groups, the presence of meniscal extrusion in both medial (P = 0.006) and lateral (P = 0.023) compartments, and presence of meniscal tears in the lateral compartment (P = 0.011), were significantly associated with increasing PainDETECT score. Moreover, the presence of bone marrow lesions in the lateral plateau and the extent of the synovial membrane thickness in the lateral recess were associated with increasing PainDETECT scores (P = 0.032, P = 0.027, respectively). CONCLUSIONS: In this study, meniscal lesions, particularly extrusion, were found to be among the strongest risk factors for NP in knee OA patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01733277. Registered 16 November 2012.