Detection of hypophosphatasia in hospitalised adults in rheumatology and internal medicine departments: a multicentre study over 10 years.

INTRODUCTION: Hypophosphatasia (HPP) is a rare genetic disease caused by loss-of-function mutations in the ALPL gene encoding the tissue non-specific alkaline phosphatase (ALP). Mild HPP is usually misdiagnosed in adult age. While an elevated serum ALP value draws more attention than a low value, low serum ALP should be better recognised and may lead to HPP detection. METHODS: Patients were selected from the records of the biochemistry department of six University Hospitals in France. Patients were hospitalised in the departments of rheumatology and internal medicine between 2007 and 2017. RESULTS: 56 321 hospitalised patients had at least 2 serum ALP dosages and 664 of these patients had at least 2 low serum ALP≤35 UI/L. Among these 664 patients, 482 (72.6%) had fluctuating low values (mean age 62.9 years; 60% of women) and 182 patients (27.4%) had persistent low values below 35 IU/L (mean age 53.4 years; 67% of women). Among patients with persistent hypophosphatasaemia treated with bisphosphonates, 70.8% never had ALP measurement before treatment and 20.8% were treated despite an abnormal decrease of ALP. Genetic testing was performed in 18 patients and was positive in 11. Genetic diagnosis of HPP was at least 6.0% in persistent hypophosphatasaemia and at least 15.9% in patients with at least three symptoms suggestive of HPP. CONCLUSION: In this 10-year retrospective study, 0.32% of adult patients hospitalised in the rheumatology and internal medicine departments had persistently low serum ALP, and among them, 6% had genetically proven HPP. Reported hypophosphatasaemia represented only 3.6% of hospitalised patients.

Osteoarthritic chondrocytes undergo a glycolysis-related metabolic switch upon exposure to IL-1b or TNF.

BACKGROUND: Osteoarthritis is an age-related disease that currently faces a lack of symptomatic treatment. Inflammation, which is mainly sustained by pro-inflammatory cytokines such as IL-1b, TNF, and IL-6, plays an important role in osteoarthritis progression. In this context, pro-inflammatory cytokines are widely used to mimic the inflammatory component of osteoarthritis in vitro. However, the therapeutic failures of clinical trials evaluating anti-cytokines drugs highlight the lack of overall understanding of the effects of these cytokines on chondrocytes. METHODS: Here, we generated a comprehensive transcriptomic and proteomic dataset of osteoarthritic chondrocytes treated with these cytokines to describe their pro-inflammatory signature and compare it to the transcriptome of non-osteoarthritic chondrocytes. Then, the dysregulations highlighted at the molecular level were functionally confirmed by real-time cellular metabolic assays. RESULTS: We identified dysregulation of metabolic-related genes in osteoarthritic chondrocytes but not in non-osteoarthritic chondrocytes. A metabolic shift, toward increased glycolysis at the expense of mitochondrial respiration, was specifically confirmed in osteoarthritic chondrocytes treated with IL-1b or TNF. CONCLUSION: These data show a strong and specific association between inflammation and metabolism in osteoarthritic chondrocytes, which was not found in non-osteoarthritic chondrocytes. This indicates that the link between inflammation and metabolic dysregulation may be exacerbated during chondrocyte damage in osteoarthritis. Video Abstract.

Harnessing cell-material interactions to control stem cell secretion for osteoarthritis treatment.

Osteoarthritis (OA) is the most common debilitating joint disease, yet there is no curative treatment for OA to date. Delivering mesenchymal stromal cells (MSCs) as therapeutic cells to mitigate the inflammatory symptoms associated with OA is attracting increasing attention. In principle, MSCs could respond to the pro-inflammatory microenvironment of an OA joint by the secretion of anti-inflammatory, anti-apoptotic, immunomodulatory and pro-regenerative factors, therefore limiting pain, as well as the disease development. However, the microenvironment of MSCs is known to greatly affect their survival and bioactivity, and using tailored biomaterial scaffolds could be key to the success of intra-articular MSC-based therapies. The aim of this review is to identify and discuss essential characteristics of biomaterial scaffolds to best promote MSC secretory functions in the context of OA. First, a brief introduction to the OA physiopathology is provided, followed by an overview of the MSC secretory functions, as well as the current limitations of MSC-based therapy. Then, we review the current knowledge on the effects of cell-material interactions on MSC secretion. These considerations allow us to define rational guidelines for next-generation biomaterial design to improve the MSC-based therapy of OA.

Click and bioorthogonal hyaluronic acid hydrogels as an ultra-tunable platform for the investigation of cell-material interactions.

The cellular microenvironment plays a major role in the biological functions of cells. Thus, biomaterials, especially hydrogels, which can be design to mimic the cellular microenvironment, are being increasingly used for cell encapsulation, delivery, and 3D culture, with the hope of controlling cell functions. Yet, much remains to be understood about the effects of cell-material interactions, and advanced synthetic strategies need to be developed to independently control the mechanical and biochemical properties of hydrogels. To address this challenge, we designed a new hyaluronic acid (HA)-based hydrogel platform using a click and bioorthogonal strain-promoted azide-alkyne cycloaddition (SPAAC) reaction. This approach facilitates the synthesis of hydrogels that are easy to synthesize and sterilize, have minimal swelling, are stable long term, and are cytocompatible. It provides bioorthogonal HA gels over an uncommonly large range of stiffness (0.5-45 kPa), all forming within 1-15 min. More importantly, our approach offers a versatile one-pot procedure to independently tune the hydrogel composition (e.g., polymer and adhesive peptides). Using this platform, we investigate the independent effects of polymer type, stiffness, and adhesion on the secretory properties of human adipose-derived stromal cells (hASCs) and demonstrate that HA can enhance the secretion of immunomodulatory factors by hASCs.

Musculoskeletal corticosteroid injections: Recommendations of the French Society for Rheumatology (SFR).

Musculoskeletal corticosteroid injections are widely performed, although the exact practice varies greatly due to advances in knowledge and techniques. This justifies updating and drawing up good practice recommendations. Using a consensus model formalized by the French National Authority for Health (HAS) and based on a literature review that resulted in a "white book", 13 recommendations were developed by a group of experts. These recommendations were then sent online to 48 specialists for evaluation, 27 of whom were rheumatologists and 15 of whom were general practitioners. These recommendations were also presented at the 34th annual meeting of the French Society for Rheumatology (SFR) (Paris, December 2021) at a symposium attended by a hundred or so rheumatologists, who voted on these recommendations in person. The results are presented as an overall score out of 10, a median out of 10 and as tertiles. The agreement was excellent for 10 of these 13 recommendations, with mean values of 8.5 to 9.1 out of 10, median values of 9 or 10 out of 10 and agreement of 91.7% to 97.9%, which corresponds to a consensus. The 3 other recommendations were broadly supported but were the subject of more debate. One relates to patient information (mean 7.3/10, median 8/10, upper tertile 72.9%) with discussion about the waiting period. Another related to the summary report (mean 8.4/10, median 9, upper tertile 91.7%) with discussions about its content and the need to specify the lot number of the injected product. The last one related to periprosthetic injections and the need to consult and get approval from a specialist (mean 8.0/10, median 8, upper tertile 83.3%) with mostly the general practitioners having reservations. In all, there is a very strong consensus among the musculoskeletal corticosteroid injection experts and specialists consulted, which justifies them being taken into consideration to improve our daily practice.

Gait Alteration Due to Haemophilic Arthropathies in Patients with Moderate Haemophilia.

Some patients with moderate haemophilia (PWMH) report joint damage potentially responsible for gait disorders. Three-dimensional gait analysis (3DGA) is a relevant tool for the identification of complex musculoskeletal impairment. We performed an evaluation with 3DGA of 24 PWMH aged 44.3 ± 16.1 according to their joint status [Haemophilia Joint Health Score (HJHS) < 10 or HJHS ≥ 10] and assessed the correlation with the radiological and clinical parameters. Sixteen had HJHS < 10 (group 1) and eight had HJHS ≥ 10 (group 2). They were compared to 30 healthy subjects of a normative dataset. Both knee and ankle gait variable scores were increased in group 2 compared to the controls (p = 0.02 and p = 0.04, respectively). The PWMH of group 2 had a significant increase in their stance phase, double support duration, and stride width compared to the controls and group 1 (p < 0.01). Very low correlations were found for the ankle gait variable score with the ankle Pettersson sub-score (r2 = 0.250; p = 0.004) and ankle HJHS sub-score (r2 = 0.150; p = 0.04). For the knee, very low correlation was also found between the knee gait variable score and its HJHS sub-score (r2 = 0.290; p < 0.0001). Patients with moderate haemophilia presented a gait alteration in the case of poor lower limb joint status.

Efficacy of a nurse-led patient education intervention in promoting safety skills of patients with inflammatory arthritis treated with biologics: a multicentre randomised clinical trial.

OBJECTIVE: To evaluate the effect of a nurse-led patient education on safety skills of patients with inflammatory arthritis treated with biologic disease-modifying antirheumatic drugs (bDMARDs). METHODS: This is a multicentre, open-labelled, randomised controlled trial comparing an intervention group (face-to-face education by a nurse at baseline and 3 months later) with a control group (usual care) at the introduction of a first subcutaneous bDMARD. The primary outcome was score on the BioSecure questionnaire at 6 months (0-100 scale), a validated questionnaire assessing competencies in dealing with fever, infections, vaccination and daily situations. The secondary outcomes were disease activity, coping, psychological well-being, beliefs about medication, self-efficacy and severe infection rate. RESULTS: 129 patients with rheumatoid arthritis and spondyloarthritis were enrolled in nine rheumatology departments; 122 completed the study; 127 were analysed; and 64 received the intervention (mean duration: 65 min at baseline and 44 min at 3 months). The primary outcome was met: the BioSecure score was 81.2±13.1 and 75.6±13.0 in the education and usual care groups (difference: +6.2, 95% CI 1.3 to 11.1, p=0.015), demonstrating higher safety skills in the education group. Exploratory analyses showed better skills regarding infections, greater willingness for vaccinations and greater adherence-related behaviours in the education group. Coping was significantly more improved by education; other secondary outcomes were improved in both groups, with no difference. CONCLUSIONS: Educating patients was effective in promoting patient behaviours for preventing adverse events with bDMARDs. An education session delivered to patients starting a first bDMARD can be useful to help them self-manage safety issues. TRIAL REGISTRATION NUMBER: NCT02855320.

Posttraumatic Osteoarthritis Damage in Mice: From Histological and Micro-Computed Tomodensitometric Changes to Gait Disturbance.

OBJECTIVES: Osteoarthritis is a painful joint disease responsible for walking impairment. Its quantitative assessment by gait analysis in mice may be a relevant and noninvasive strategy to assess the disease severity. In this study, we aimed to determine the severity of osteoarthritis at the tissular and gait levels in unilateral and bilateral posttraumatic murine osteoarthritis. METHODS: Twenty-four C57BL/6 male mice were randomly assigned to 3 groups (n = 8/group): controls, unilateral surgery, and bilateral surgery. Posttraumatic osteoarthritis was induced unilaterally or bilaterally by destabilization of the medial meniscus. Gait analysis was performed weekly with the CatWalkTM XT system until the 16th week after surgery. After animal sacrifices, histological and micro-computed tomographic assessment was performed. RESULTS: Operated knees showed a significant increase in the histological score compared with controls (P < 0.001). Calcified anterior medial meniscal bone volume was higher on the ipsilateral side after unilateral destabilization of the medial meniscus (P < 0.001) and on both sides after bilateral intervention (P < 0.01). One week after surgery, the mice mean speed decreased significantly in both operated groups (P < 0.001 and P < 0.05). In the unilateral group, a significant increase in the contralateral hind print area appeared from week 4 to week 16. CONCLUSIONS: While bilateral destabilization of the medial meniscus induced no detectable gait modification except 1 week after surgery, unilateral model was responsible for a gait disturbance on the contralateral side. Further studies are needed to better define the place of the CatWalkTM in the evaluation of mouse models of osteoarthritis.

Fibromyalgia and Associated Disorders: From Pain to Chronic Suffering, From Subjective Hypersensitivity to Hypersensitivity Syndrome.

The concept of fibromyalgia has progressed to achieve a certain consensus regarding the definition of the condition. We summarize what is known in 2020, be it in terms of diagnosis, with the criteria that have changed over the years, or at the level of the psychological profile, via the notions of "catastrophizing" and "coping" and post-traumatic syndrome. The importance of fatigue and sleep disorders is underlined, with the chronological sequence of post-traumatic syndrome, chronic fatigue, and then amplification of the pain and the onset of multiple associated symptoms. The etiopathogenic debate has been enriched thanks to neuro-imaging data to discover the start of the central neurological signature. The many associated symptoms are reanalyzed in the context of so-called sister conditions which form sometimes more or less separate entities, such as chronic fatigue syndrome or restless legs syndrome for example. What these conditions have in common is hypersensitivity, not just to pain, but also to all exteroceptive stimuli, from deep sensitivity in the neuro-vegetative system, the sense organs and certain functions of the central nervous system, to the psychological aspects and sleep control. In summary, it is possible to define fibromyalgia as a cognitive disorder of cortical integration of chronic pain, with amplification of painful and sensory nociception, decrease in the threshold for the perception of pain, and persistence of a stimulus that maintains the process in chronicity. Fibromyalgia is part of a group of chronic hypersensitivity syndromes of central origin, with a very wide range of means of expression.

Contribution of mycobiota to the pathogenesis of spondyloarthritis.

This review lists current evidences for a contribution of gut mycobiota to the pathogenesis of SpA and related conditions. Gut mycobiota has a small size as compared to bacterial microbiota, but an even greater inter- and intra-individual variability. Although most fungi (brought by food or air) are only transitory present, a core mycobiota of gut resident fungi exists, and interplays with bacteria in a complex manner. A dysbiosis of this gut mycobiota has been observed in Crohn's disease and sclerosing cholangitis, with decreased proportion of Saccharomyces cerevisiae and outgrowth of more pathogenic gut fungi. Fungal-induced lower number of commensal gut bacteria can promote translocation of some bacterial/fungal antigens through mucosae, and live fungi can also cross the epithelial border in Crohn's disease. This dysbiosis also lower the ability of bacteria to metabolize tryptophan into regulatory metabolites, consequently enhancing tryptophan metabolism within human cells, which might contribute to fatigue. Translocation of mycobiotal antigens like curdlan (beta-glucan), which plays a major role in the pathogenesis of SpA in the SGK mice, has been observed in humans. This translocation of fungal antigens in human SpA might account for the anti-Saccharomyces antibodies found in this setting. Contribution of fungal antigens to psoriasis and hidradenitis suppurativa would fit with the preferential homing of fungi in the skin area most involved in those conditions. Fungal antigens also possess autoimmune uveitis-promoting function. As genes associated with SpA (CARD9 and IL23R) strongly regulate the innate immune response against fungi, further studies on fungi contribution to SpA are needed.

Cartilage Biomarkers Coll2-1 and Coll2-1NO2 Are Associated with Knee OA MRI Features and Are Helpful in Identifying Patients at Risk of Disease Worsening.

OBJECTIVE: To assess the cross-sectional association between serum levels of Coll2-1 and Coll2-1NO2, two cartilage degradation biomarkers; the burden of magnetic resonance imaging (MRI) features and clinical outcomes; and to evaluate the predictive value of these biomarkers on progression. DESIGN: A total of 121 subjects with knee osteoarthritis (OA) were followed during 1 year with pain, function, and MRI assessment (PRODIGE study). Type II collagen-specific biomarker Coll2-1 and its nitrated form Coll2-1NO2 were directly measured in serum using immunoassays at baseline and after 3-, 6-, and 12-month follow-up. RESULTS: Serum Coll2-1 and Coll2-1NO2 were correlated with several baseline knee features quantified with Whole-Organ Magnetic Resonance Imaging Score (WORMS). Coll2-1 was significantly correlated with periarticular cysts/bursitis (ρ = 0.29, P < 0.01), subarticular bone attrition (ρ = 0.25, P = 0.01), subarticular cysts (ρ = 0.24, P = 0.02), and articular cartilage integrity (ρ = 0.23, P = 0.03) WORMS subscores for the whole joint as well as with the medial femorotibial joint sum score (ρ = 0.26, P = 0.01) and medial femorotibial joint cartilage (ρ = 0.23, P = 0.02). Coll2-1NO2 correlated with WORMS total score (ρ = 0.23, P = 0.02), WORMS scores in the patellofemoral (ρ = 0.23, P = 0.02) and medial femorotibial compartments (ρ = 0.21, P = 0.03), with osteophytes scores (ρ = 0.27, P < 0.01), subarticular cysts (ρ = 0.24, P = 0.019), and intraarticular loose bodies (ρ = 0.27, P = 0.007). Baseline Coll2-1NO2 was higher in subjects with a pain worsening (426.4 pg/mL [278.04-566.95]) as compared to non-progressors (306.84 pg/mL [200.37-427.84]) over 1 year (AUC = 0.655, P = 0.015). CONCLUSION: Serum cartilage biomarkers Coll2-1 and Coll2-1NO2 are associated with several knee OA features quantified with WORMS. Our study also shows that the baseline value of Coll2-1NO2 is positively associated with pain worsening.

Osteoarthritis: From upcoming treatments to treatments yet to come.

Osteoarthritis affects hundreds of millions of people worldwide, and its prevalence is constantly increasing. While there is currently no treatment that can alter the course of the disease, promising therapeutic strategies and novel targets are being investigated. Innovative cell therapies are already reaching clinical trials, and recent progress in our understanding of the disease is opening new routes for gene therapy. In the long term, the development of new biofabrication tools, such as 3D bioprinting, may pave the way for personalized mini-joint models that could be used to screen drugs and to personalize treatments. This review provides an overview of the most promising therapeutic approaches in the field of osteoarthritis, from upcoming treatments to those that are yet to be discovered.

Isokinetic knee strength deficit in patients with moderate haemophilia.

INTRODUCTION: Knee joint bleedings are responsible for quadriceps atrophy and strength deficit in patients with severe haemophilia. Little is known about patients with moderate haemophilia (PWMH). AIM: To evaluate isokinetic quadriceps and hamstrings strength in PWMH and to assess correlation with radiological and clinical parameter. METHODS: 18 PWMH aged 37.1 ± 11.4 and 18 healthy age-, weight- and height-matched controls performed a knee isokinetic test at 180°/s to assess quadriceps and hamstrings strength. In the PWMH group, knee Pettersson's score was pursued and Haemophilia Joint Health Score 2.1 (HJHS) was performed to determine unaffected knees (knee HJHS = 0) and affected ones (knee HJHS >0). RESULTS: Affected knees had a decrease of quadriceps strength compared to controls, 1.26 ± 0.47 vs 1.64 ± 0.27 Nm/kg and a decrease of hamstring strength, 0.60 ± 0.29 vs 1.03 ± 0.21 Nm/kg, (P < 0.001). Unaffected knees also had a decrease of quadriceps strength compared to controls, 1.36 ± 0.31 vs 1.64 ± 0.27 Nm/kg and a decrease of hamstring strength, 0.69 ± 0.18 vs 1.03 ± 0.21 Nm/kg, (P < 0.001). The conventional hamstring-to-quadriceps ratio was significantly decreased in affected knees compared to controls, 0.46 ± 0.15 vs 0.64 ± 0.13 (P < 0.001) but also in unaffected knees, 0.53 ± 0.16 vs 0.64 ± 0.13 (P = 0.02).No correlation was found between strength and HJHS or Pettersson's score. CONCLUSION: PWMH have a significant knee strength deficit, both on the quadriceps and the hamstrings, which is responsible for an important muscle imbalance.

A Comparison of Two Models Predicting the Presence of Chronic Exertional Compartment Syndrome.

Clinical history and physical examination are usually not sufficient to diagnose leg chronic exertional compartment syndrome (CECS). Two predictive clinical models have been proposed. The first model by De Bruijn et al. is displayed as a nomogram that predicts the probability of CECS according to a risk score. The second model by Fouasson-Chailloux et al. combines two signs (post-effort muscle hardness on palpation or hernia). To evaluate those models, we performed a prospective study on patients who were referred for possible CECS. 201 patients underwent intra-compartmental pressure at 1-min post-exercise (CECS if ≥ 30 mmHg) - 115 had CECS. For the De Bruijn et al. model, the risk score was 7.5±2.2 in the CECS group and 4.6±1.7 in the non-CECS group (p<0.001) with an area under the ROC curve of 0.85. The model accuracy was 80% with a sensitivity of 82% and a specificity of 78%. Concerning Fouasson-Chailloux et al. model, the accuracy was 86%; the sensitivity and the specificity were 75 and 98%, respectively. The De Bruijn et al. model was a good collective model but less efficient in individual application. In patients having both muscle hardness and hernia, we could clinically make the diagnosis of CECS.

Inadequacies of the Lasègue test, and how the Slump and Bowstring tests are useful for the diagnosis of sciatica.

Diagnosis of sciatica mainly relies on pain reproduction by stretching of the lumbar roots since neurological examination and medical history are usually not sufficient to guarantee diagnosis. The Lasègue test is the most popular method, which starts with the straight leg-raising test (SLR). However it is not perfect, and is not always well performed or interpreted. Passive ankle dorsiflexion at the end of the SLR (Bragard test) is more sensitive, but can also remain normal in some cases of sciatica. Other stretching tests can help to recognise lumbar root damage in patients with poorly defined pain in a lower extremity: firstly, the Christodoulides test, i.e. reproduction of L5 sciatic pain by a femoral stretch test; secondly, the Slump test, performed on a patient in a sitting position, by slowly extending their painful leg then passively bending their neck (or the opposite); and thirdly, the Bowstring test, which requires, at the end of the Lasègue test, once the knee has been slightly flexed, pressing on the course of the peroneal and/or tibial nerves in the popliteal fossea to try and reproduce the exact pain felt by the patient. The combination of all these tests takes less than 2minutes, and could improve both the sensitivity and specificity of the physical examination for the diagnosis of sciatica. This article is a review of the limitations of the Lasègue/SLR tests and of the efficacy of these other tests for stretching the lumbar roots.

Lymphocyte Changes in Severe COVID-19: Delayed Over-Activation of STING?

Upon recognition of microbial DNA or self-DNA, the cyclic-GMP-AMP synthase (cGAS) of the host catalyzes the production of the cyclic dinucleotide cGAMP. cGAMP is the main activator of STING, stimulator of interferon genes, leading to interferon synthesis through the STING-TBK1-IRF3 pathway. STING is also a hub for activation of NF-κB and autophagy. The present review details the striking similarities between T and B cell responses in severe coronavirus disease 2019 (COVID-19) and both animal or human models of STING gain of function (SAVI syndromes: STING-associated vasculopathy with onset in infancy). Those similarities may be further clues for a delayed activation of STING in severe COVID-19 patients, due to DNA damages following severe acute respiratory syndrome coronaviruses (SARS-CoV-2) infection and unusual role of STING in SARS-CoV-2 control. In early stages, Th2 differentiation are noticed in both severe COVID-19 and SAVI syndromes; then, CD4+ and CD8+ T cells functional exhaustion/senescent patterns due to TCR hyper-responsiveness are observed. T cell delayed over-responses can contribute to pneumonitis and delayed cytokine secretion with over-production of IL-6. Last, STING over-activation induces progressive CD4+ and CD8+ T lymphopenia in SAVI syndromes, which parallels what is observed in severe COVID-19. ACE2, the main receptor of SARS-CoV-2, is rarely expressed in immune cells, and it has not been yet proven that some human lymphocytes could be infected by SARS-CoV-2 through CD147 or CD26. However, STING, expressed in humans T cells, might be triggered following excessive transfer of cGAMP from infected antigen presenting cells into activated CD4+ and CD8+ T cells lymphocytes. Indeed, those lymphocytes highly express the cGAMP importer SLC19A1. Whereas STING is not expressed in human B cells, B cells counts are much less affected, either in COVID-19 or SAVI syndromes. The recognition of delayed STING over-activation in severe COVID-19 patients could prompt to target STING with specific small molecules inhibitors already designed and/or aspirin, which inhibits cGAS.