A new boronate ester-based crosslinking strategy allows the design of nonswelling and long-term stable dynamic covalent hydrogels.

Dynamic hydrogels are viscoelastic materials that can be designed to be self-healing, malleable, and injectable, making them particularly interesting for a variety of biomedical applications. To design dynamic hydrogels, dynamic covalent crosslinking reactions are attracting increasing attention. However, dynamic covalent hydrogels tend to swell, and often lack stability. Boronate ester-based hydrogels, which result from the dynamic covalent reaction between a phenylboronic acid (PBA) derivative and a diol, are based on stable precursors, and can therefore address these limitations. Yet, boronate ester formation hardly occurs at physiological pH. To produce dynamic covalent hydrogels at physiological pH, we performed a molecular screening of PBA derivatives in association with a variety of diols, using hyaluronic acid as a polymer of interest. The combination of Wulff-type PBA (wPBA) and glucamine stood out as a unique couple to obtain the desired hydrogels. We showed that optimized wPBA/glucamine hydrogels are minimally- to non-swelling, stable long term (over months), tunable in terms of mechanical properties, and cytocompatible. We further characterized their viscoelastic and self-healing properties, highlighting their potential for biomedical applications.

Development and characterization of a humanized mouse model of osteoarthritis.

OBJECTIVE: In light of the role of immune cells in OA pathogenesis, the development of sophisticated animal models closely mimicking the immune dysregulation during the disease development and progression could be instrumental for the preclinical evaluation of novel treatments. Among these models, immunologically humanized mice may represent a relevant system, particularly for testing immune-interacting DMOADs or cell therapies before their transfer to the clinic. Our objective, therefore, was to develop an experimental model of OA by destabilization of the medial meniscus (DMM) in humanized mice. METHOD: Irradiated 5-week-old NOD/LtSz-scid IL2Rγnull (NSG) mice were humanized by intravenous injection of CD34+ human hematopoietic stem cells. The engraftment efficiency was evaluated by flow cytometry 17 weeks after the humanization procedure. Humanized and non-humanized NSG mice underwent DMM or sham surgery and OA development was assessed 1, 6, and 12 weeks after the surgery. RESULTS: 120 days after the humanization, human T and B lymphocytes, macrophages and NK cells, were present in the blood and spleen of the humanized NSG mice. The DMM surgery induced articular cartilage and meniscal alterations associated with an increase in OA and the meniscal score. Moreover, the surgery triggered an inflammatory response that was sustained at a low grade in the DMM group. CONCLUSIONS: Our study shows for the first time the feasibility of inducing OA by DMM in humanized mice. This novel OA model could constitute a useful tool to bridge the gap between the preclinical and clinical evaluation of immune interacting DMOADs and cell-based therapies.

Clinical relevance of 3D gait analysis in patients with haemophilia.

Haemophilia is characterized by a congenital deficiency of clotting factor VIII or IX. One of the consequences of haemophilia is joint bleedings. Repetitive haemathroses induce cartilage damage and chronic synovitis leading to joint deterioration, and to definitive haemophilic arthropathy which is source of walking disability. Three-dimension gait analysis (3DGA) appears particularly relevant in the case of haemophilia because it allows an evaluation of several joints in weight-bearing situations. The purpose of this study was to review the interest and the contribution of 3DGA in the management of patients with haemophilia. The greatest interest of gait analysis would be to detect early walking changes with a non-invasive and well-tolerated examination, especially in paediatric population. In adulthood, this technic may be also useful to help detect walking worsening in patients known to have already arthropathy. However, it takes time to realize and needs expensive equipment, which limits its possibility of routine use. Although generalizations of these results remain difficult, especially to compare patients with haemophilia to normal population. Indeed, in the studies, patient groups are small and usually heterogeneous in terms of age and target joints. It certainly results of the rarity of the disease. So, it could be interesting to perform a study with a larger cohort in order to allow subgroup analysis, helping to define clearly the place of 3DGA in the strategy of haemophilia evaluation.

Adalimumab in patients with hand osteoarthritis refractory to analgesics and NSAIDs: a randomised, multicentre, double-blind, placebo-controlled trial.

AIM: To test the efficiency of tumour necrosis factor blockers (adalimumab) in patients with painful refractory (non-responders to analgesics and non-steroidal anti-inflammatory drugs (NSAIDs)) hand osteoarthritis (OA). METHODS: We performed a randomised, double-blind, placebo-controlled, parallel group, multicentre study. Patients were randomised to: 1/1 adalimumab 40 mg for two subcutaneous injections at a 15-day interval or placebo and monitored for 6 months. The primary outcome was the percentage of patients with an improvement of more than 50% in global pain (Visual Analogue Scale) between week 0 (W0) and week 6 (W6). Secondary outcomes included the number of painful joints, swollen joints, morning stiffness duration, patient and practitioner global assessments, functional indexes for hand OA, and consumption of analgesics. Analysis on the mean primary outcome measure was done on patients who received at least one injection. RESULTS: 99 patients were recruited and 85 patients were randomised. Among them, 37 patients in the placebo group and 41 in the adalimumab group received at least one injection and were evaluated at W6 (n=78) on the main efficacy outcome. Mean age was 62 years, 85% were women, and mean level of pain was 62 mm at W0. At W6, 35.1% in the adalimumab group versus 27.3% in the placebo group had a pain reduction ≥50% (RR 1.12 (95% CI 0.82 to 1.54; p=0.48). There were no statistical differences for all secondary end points. The rate of adverse events was similar in the two groups. CONCLUSIONS: Adalimumab was not superior to placebo to alleviate pain in patients with hand OA not responding to analgesics and NSAIDs. TRIALS REGISTRATION NUMBER: NCT00597623.

Painful medial knee compartment syndrome in over-45 year-olds: I--medical or surgical management: a series of 174 patients.

INTRODUCTION: There is at present no consensus on the management of degenerative medial meniscus lesions in patients aged over 45 years without proven osteoarthritis, especially given that the causal relation between degenerative meniscal lesion and osteoarthritis remains controversial. A prospective multicenter non randomized study was therefore performed. The principal objective was to assess surgeons' practice in the management of degenerative medial meniscus lesions. The secondary objectives were to identify predictive and prognostic factors and to compare medical versus surgical attitudes so as to draw up an adapted treatment strategy. PATIENTS AND METHOD: One hundred and seventy-four patients were included between September 2008 and February 2010, and distributed between a surgical (n=104) and a medical group (n=70). Minimum follow-up was 6 months. Patient satisfaction and health-related quality of life on the SF-36 questionnaire were assessed at 6 months. RESULTS: No difference emerged between the surgical and medical groups. However, predictive factors for poor results were identified: overweight (p=0.005), cartilage lesions (p=0.035) and meniscus extrusion (p=0.006). DISCUSSION: Results clarified the relation between degenerative meniscus lesions and osteoarthritis, in terms of meniscal incompetence. Meniscal extrusion should be seen as an arthrogenic degenerative meniscus lesion. We recommend a management strategy based on terrain and imaging data (X-ray and MRI), with the aim of providing patient relief while conserving cartilage.

Health economic evaluation of outpatient management of fibromyalgia patients and the costs avoided by diagnosing fibromyalgia in France.

OBJECTIVES: To assess whether the decrease in medical resource use and cost after diagnosing fibromyalgia, observed in a large primary care population in the United Kingdom can be extrapolated to France. METHODS: A questionnaire was created based on medical resource use by 2,260 patients diagnosed with fibromyalgia between 01/01/1998 and 31/03/2003 in the General Practice Research Database in the UK. Sixty French experts (general practitioners, rheumatologists) assessed whether the data from that database are in line with their clinical practice and, if not, were asked to provide data reflecting their own experience. The evaluation period went from 4 years before to 4 years after diagnosis using 1-year cross-sections. Evaluated resources were drug use, diagnostics tests, general practitioners and specialist visits, and also paramedical or alternative treatments. Data regarding inpatient care and productivity loss were not collected. Medical resource use if no diagnosis had been established was estimated, so the impact of diagnosis could be evaluated. RESULTS: Whereas costs gradually increase before diagnosis, stagnation in costs occurs in the year after diagnosis, followed by a moderate decrease afterwards. The same trend was observed whether the panel consisted of general practitioners or rheumatologists. The savings made as a result of fibromyalgia diagnosis add up to 126 euros per patient per year for the health care payer. General practitioner visits, diagnostic tests and drug use represent respectively 57%, 23% and 12% of the savings. CONCLUSIONS: Also in France, early diagnosis of fibromyalgia leads to a decrease in resource use and health care costs.

A comparison between bisphosphonates and other treatments for osteoporosis.

Since their development 30 years ago, bisphosphonates are now one of the standard therapy in the management of osteoporosis. Improvements in terms of anti-resorptive potency have leaded to new molecules available either orally or intravenously, from weekly to yearly administration. Overall tolerance of bisphosphonates is good with regards to the risk of mandibular necrosis, not comparable with those observed in cancer treatment, and with no causal link yet established in osteoporotic patients. Compliance remains poor and should be improved by a better education of the patients about their treatment. Other treatments like teriparatide, raloxifene or strontium ranelate are now also available and give more therapeutic options but also more questions on the best molecule to choose for each patient. There is currently no valid basis for distinguishing in a formal and objective manner the different new-generation bisphosphonates, in terms of efficacy against either vertebral, peripheral or hip fractures. In a same way, comparison between bisphosphonates and the other treatments available for osteoporosis is hard in absence of proper randomised controlled study. This review gives an overview of the recent data on the efficacity and tolerance of bisphosphonates in the different forms of osteoporosis and compares them to the other treatments currently available.

Alternative use of bisphosphonate therapy for rheumatic disease.

Bisphosphonates are widely use for pathologies such as osteoporosis, Paget's disease or bone metastasis. However, their potent antiresorptive properties open new therapeutic opportunities for other conditions associated with an increased focal or systemic bone remodelling. Moreover, apart from their antiresorptive activity, bisphosphonates could also have others properties through a specific analgesic or anti-inflammatory effect. Thus, rheumatic diseases like rheumatoid arthritis, spondylarthritis or SAPHO syndrome (acronym for synovitis, acne, pustulosis, hyperostosis and osteitis) that are associated with systemic and sometimes focal bone loss could be good candidates for bisphosphonate therapy. Other non-inflammatory rheumatic diseases like bone osteonecrosis, algodystrophy, fibrous dysplasia or neuropathic osteoarthropathy are also associated with pain and an increase of focal bone remodelling. Several studies have shown that bisphosphonate could have promising therapeutic potential in these inflammatory or non-inflammatory diseases where therapeutic options are usually few. This review will focus on the new potential alternative indications for bisphosphonate in rheumatic diseases.

[Is training on basic skills and management of critical events responsible of ethical considerations in anaesthesia and intensive care?]. / L'apprentissage des gestes invasifs et de la gestion d'une situation critique pose-t-il des problèmes éthiques en anesthésie-réanimation?

OBJECTIVE: To provide information on morbidity and ethical questions associated with learning of invasive techniques (tracheal intubation, positioning of central venous or epidural catheters) and management of anaphylactic shock. STUDY DESIGN: Retrospective survey. METHODS: Written questionnaire to 54 anaesthesiologists and 55 residents. RESULTS: Training was primarily performed by residents having a 6 months-experience for general anaesthesia and by more experienced residents for epidural analgesia. Residents observed first two or three procedures performed by seniors, but did not have theoretical lectures in 30 to 50% of cases. Dead bodies or manikins were rarely used. Despite the presence of experienced anaesthesiologists during the first attempts, there was a high morbidity rate which was considered by 22 to 37% of the interviewed anaesthesiologists a loss of benefit for the patients. Despite a high level of coaching, a high morbidity rate was associated with the first attempts. However, only few residents explicitly stated to be concerned by ethical questions. Among anaesthesiologists, who had yet to manage anaphylactic shock, 21 and 35% of them reported that diagnostic and treatment could have been performed faster. Virtual learning was misunderstood but 46% of anaesthesiologist described numerous advantages in using simulator of anaesthesia. CONCLUSION: Despite an apparent morbidity with a loss of benefit, informed consent of the patients were rarely obtained.

Possible use of arthrodesis for intractable sacroiliitis in spondylarthropathy: report of two cases.

STUDY DESIGN: Two cases of successful sacroiliac joint arthrodesis for medically intractable aseptic sacroiliitis are reported. SUMMARY OF BACKGROUND DATA: Although successful arthrodesis of the sacroiliac joint had been reported previously for septic sacroiliitis, no report had shown the procedure to be effective for spondylarthropathy. METHODS: Two women with spondylarthropathy involving very painful sacroiliac arthritis for 18 and 24 months had been relieved only transiently by several injections of steroids into the sacroiliac joint under fluoroscopy and by Bermuda casts. Both patients underwent sacroiliac joint arthrodesis. RESULTS: Both patients showed dramatic improvement after sacroiliac joint arthrodesis. Moreover, no relapses had occurred, respectively, after 2 and 3 years of follow-up evaluation despite continuing spondylarthropathy in other joints. CONCLUSIONS: After a careful selection of patients, including positive blocks in the sacroiliac joint, arthrodesis of sacroiliac joint might be considered for so-called "intractable" aseptic sacroiliitis.

[Horton's disease in elderly patients aged over 75: clinical course, complications of corticotherapy. Comparative study of 164 patients. Towards a reduced initial dose]. / Maladie de Horton du sujet âgé de plus de 75 ans: particularites évolutives, complications de la corticothérapie. Etude comparative sur une série de 164 patients. Vers une dose d'attaque réduite.

PURPOSE: Our study compares clinical and therapeutic courses (corticosteroid response, corticosteroid amount, complications) in people with giant cell arteritis before and over 75 years, during the first year of treatment. METHODS: A series of 164 patients was retrospectively analysed (mean age: 73.3 years) among the two subgroups: before 75 and over 75 years. Patient received (monitoring of reduction in the corticosteroid dosage) a 240 mg intravenous bolus of methylprednisolone followed by 0.5 or 0.7 mg/kg/d of prednisone, or 0.7 mg/kg/d of prednisone without the bolus. RESULTS: Corticosteroid response was identical for the two groups, before and over 75 (patients with corticoresistance: 15% vs 11.4%; NS) and giant cell arteritis-related complications were equivalent (n = 2 vs n = 2; NS). Corticosteroid load was slightly lower in the elderly group (cumulative dose of corticosteroids during the first year of treatment 5.2 g vs 5.8 g; P = 0.03). Patients with rheumatic side effects (collapses of vertebral bodies, mainly) were more frequent in the elderly group (15.5% vs 4.3%; P = 0.01), in spite of a limited mean follow-up period (10.7 months). CONCLUSION: Even if steroid response was identical in the therapeutic course of giant cell arteritis, rheumatic side effects appeared more frequent in the elderly group (over 75 years). In order to obtain a corticosteroid-sparing effect, new studies are necessary to evaluate a reduced initial dosage of corticosteroids.

The nosology-taxonomy of recent-onset arthritis: the experience of early-arthritis clinics.

OBJECTIVE: To compare the conclusions of studies addressing the outcome of early-arthritis cohorts. METHODS: The methodologies of previous reports on early-arthritis cohorts were examined, and their results and conclusions were compared. RESULTS: Thirty-four reports on 23 cohorts of early arthritis were found. The methodology was poor in most studies, with numerous inclusion and exclusion biases, frequently short follow-up periods, and a lack of precision about the rationale for diagnosis. However, similar conclusions were reached on several points: a large number of cases of early arthritis remained undifferentiated and/or resolved spontaneously, about 80% of cases initially classified as undifferentiated or rheumatoid arthritis retained this diagnosis during follow-up, and the incidence of psoriatic arthritis in most studies was similar (2% to 4%). Conversely, there were striking discrepancies among studies concerning the frequency of crystal arthropathies (0% to 18%), spondyloarthropathy (1% to 33%) and rheumatoid arthritis (15% to 47%). CONCLUSIONS: There appears to be a lack of agreement among researchers about the nosology and/or taxonomy of many cases of mild arthritis, despite the existence of classification criteria. RELEVANCE: Recognition of cultural bias in the diagnosis of early arthritis could be a prerequisite for the optimization of new sets of criteria for the diagnosis of early rheumatoid arthritis and spondyloarthropathy.

Interindividual variations in beliefs about the placebo effect: a study in 300 rheumatology inpatients and 100 nurses.

PATIENTS AND METHODS: Three hundred patients admitted to a rheumatology department (mean age, 49.2+/-15.5 years) and 100 nurses working in the same teaching hospital (mean age, 36+/-8.6 years) completed a questionnaire on the placebo effect in the treatment of pain. RESULTS: The patients believed that the percentages of subjects who responded occasionally or consistently to a placebo were 32% (+/- 22%) and 21% (+/- 17%), respectively. The figures given by the nurses were only slightly higher: 42% (+/- 23%) and 23% (+/- 17%), respectively. Only 27% of the patients and 58% of the nurses knew that pain could resolve completely under placebo therapy. The mean percentage improvement induced by placebo therapy as compared to the study analgesic was estimated at 21% (+/- 17%) by the patients and 30% (+/- 18%) by the nurses. Only 23% of patients and 24% of nurses knew about nocebo effects. CONCLUSION: These data suggest that during double-blind placebo-controlled trials three-quarters of the placebo arm patients who experience a marked improvement or a nocebo effect may believe they received the active drug. This is likely to reduce the difference between the placebo and active drug groups. Furthermore, most patients and nurses have a negative perception of placebo therapy. It may be useful to include a brief description of placebo and nocebo effects into the patient's information and informed consent documents used in double-blind placebo-controlled trials.

Pseudallescheria boydii knee arthritis in a young immunocompetent adult two years after a compound patellar fracture.

Pseudallescheria boydii arthritis of the knee developed in a 32-year-old immunocompetent man 2 years after a compound patellar fracture contaminated with soil. No other potential portal of entry was identified, suggesting that the fungus remained latent for 2 years. Pseudallescheria arthritis often occurs after a prolonged latency period, causing minimal symptoms that contrast with the frequently severe radiological changes. Although this organism often shows limited sensitivity to most antifungal agents, our patient achieved a full recovery after surgical synovectomy and 6 months of itraconazole therapy (400 mg/ d). This case illustrates the importance of testing for fungi in patients with torpid arthritis, particularly when mild clinical symptoms contrast with severe bone and joint destruction.

Do we use morphine often enough? An opinion survey in 100 rheumatology department patients.

PATIENTS AND METHODS: Shortly before their discharge from a rheumatology department, 100 patients with a mean age of 54 +/- 16 years completed a 20-item questionnaire on morphine therapy. Pain scale scores were 77.1 +/- 19 at admission and 44.2 +/- 24 at questionnaire completion. RESULTS: Thirty-three patients, including 27 with spinal or nerve root disorders, received morphine during their stay. Five of these patients had a malignancy. Among patients who received morphine, 21% (6/29) were disappointed with the drug. Only four of the patients who did not receive morphine (4%) wished they had. Thirty-six percent of patients (30/83) reported previous morphine therapy given by a primary care physician (10/30) or a specialist (14/30) and/or in a hospital (22/30). Only five patients (5/100, 5%) said they regretted not having received morphine for past pain; however, 45% (35/78) of patients agreed with the suggestion that French physicians do not use morphine often enough. Most patients (82%, 65/77) agreed that morphine can be used to treat pain due to rheumatic disorders, although 92% (83/90) felt that morphine should be reserved for "intolerable" pain. Only 37% (34/92) of the patients were apprehensive about using morphine, 57% (45/79) were aware of the risk of dependency, 66% (44/79) of the risk of behavioral or attention disorders, and 53% (41/78) of the risk of tolerance. CONCLUSION: Expectations of French rheumatology department patients about morphine use were roughly satisfactory. The mean pain scale score above which the patients felt morphine should be given was 70.5 +/- 20.

Supralesional and sublesional bone mineral density in spinal cord-injured patients.

This study was performed to evaluate supra- and sublesional bone mineral density (BMD) in spinal cord-injured (SCI) patients after 1 year postinjury, and to correlate the BMD to the neurological level; to correlate the sublesional demineralization to functional parameters (duration postinjury, duration of the initial bedrest); and to assess the role of classic methods of prevention such as walking or standing. Thirty-one SCI patients, all male, were studied vs. 31 controls (age matched). The mean age of the population was 36 years (range 18-60 years). Eleven were tetraplegic and 20 were paraplegic. Twenty-six patients dysplayed a complete motor lesion. The BMD was measured by dual-photon absorptiometry on the lumbar spine and on the femoral neck, and the bone mineral content (BMC) on whole-body scans. Particular attention was paid to the distal femur and proximal tibia upper third. Blood samples and urine samples included phosphocalcic parameters, with determination of urinary hydroxyproline and deoxypyridinoline. SCI patients showed a decrease of sublesional BMD of 41% in comparison with controls. This loss of bone mass is higher at the distal femur (-52%) and proximal tibia (-70%), which are the most common sites of fracture. The degree of demineralization for the lumbar spine, the pelvis, and the lower limbs is independent of the neurological level. The duration of acute posttraumatic immobilization (mean 43.3 days) and the time postinjury increase the loss of bone mass for lower limbs (p = 0.04) and particularly for the proximal tibia (p = 0.02). The study of biomechanical stress (i.e., standing, walking, sitting) does not influence the sublesional BMC. This study underlines the major role of the neurological lesion on the decrease of sublesional BMC in SCI patients and the absence of influence of biomechanical stress.

Chondritis dissecans of concave articular surfaces (acetabulum and glenoid fossa). Two case reports.

We report two patients who had chronic mechanical pain due to substantial cartilage defects documented by arthrography. One of these patients had pain in the hip and declined surgical treatment. The other had pain in the glenohumeral joint; surgery found a fissure in the glenoid fossa cartilage and provided prompt pain relief. These two cases serve as reminders that investigation of the cartilage and subchondral bone in young patients with mechanical pain should not be confined to the convex articular surfaces, although these are more likely to sustain trauma-related damage than concave surfaces. In both our patients, the diagnosis required thin-section computed arthrotomography.

Efficacy of nerve root versus interspinous injections of glucocorticoids in the treatment of disk-related sciatica. A pilot, prospective, randomized, double-blind study.

STUDY OBJECTIVES: Pilot study comparing the short-term efficacy on pain and functional impairment of nerve root sheath versus interspinous glucocorticoid injections in patients admitted to a French rheumatology department for disk-related sciatica or femoral neuralgia. PATIENTS AND METHODS: Thirty patients with refractory nerve root pain (sciatica, n = 29; femoral neuralgia, n = 1) for a mean of four months were randomized to nerve root injection (n = 17) or interspinous injection (n = 13) of the same mixture of 0.10 g of lidocaine hydrochloride and 3.75 mg of cortivazol. Both injection methods were performed under analgesia and benzodiazepine sedation to maintain double blinding. Each patient was evaluated daily during the first seven days of bed rest in the hospital, then after discharge on postinjection day 28. RESULTS: Prompt pain relief was obtained in both groups. On day 1, the mean pain scale score (0-100) fell from 70 +/- 3.9 to 26 +/- 5.6 in the nerve root group and from 63 +/- 4 to 23 +/- 4.7 in the interspinous group. These results were sustained on D7 and D28. CONCLUSIONS: The unusually high level of efficacy of glucocorticoid injection in our study may be ascribable in part to strong placebo and Hawthorne effects and in part to the intrinsic effects of the injections. Whether nerve root injection is superior over interspinous injection remains unproven.