Serum IL-33, a new marker predicting response to rituximab in rheumatoid arthritis

Background. Recent works have suggested a possible link between IL-33 and B-cell biology. We aimed to study in different cohorts and with an accurate ELISA assay the possible association between serum IL-33 detection and response to rituximab (RTX) in rheumatoid arthritis (RA) patients. Method. Serum IL-33, rheumatoid factor (RF), anti-citrullinated cyclic peptide antibodies (anti-CCP), high serum IgG level were assessed in 111 RA patients receiving a first course of 2 grams RTX (cohort 1) in an observational study and in 74 RA patients treated with the same schedule in routine care (cohort 2). Uni and multivariate analyzes identified factors associated with a European League Against Rheumatism response at 24 weeks. Results. At week 24, 84/111 (76%) and 54/74 (73%) patients reached EULAR response in the cohorts 1 and 2, respectively. Serum IL-33 was detectable in only 33,5% of the patients. In the combined cohorts, presence of RF or anti-CCP (OR 3.27, 95%CI [1.13-9.46]; p=0.03), high serum IgG (OR 2.32, 95%CI [1.01-5.33]; p=0.048) and detectable serum IL-33 (OR 2.40, 95%CI [1.01-5.72]; p=0.047) were all associated with RTX response in multivariate analysis. Combination of these 3 factors increased the likelihood to response to RTX. When serum IL-33 detection was added to seropositivity and serum IgG level, 100% of the patients with the 3 risk factors (corresponding to 9% of the population) responded to RTX (OR versus patients with none of the 3 risk factors = 29.61; 95% CI [1.30-674.79] p=0.034) Conclusion. Detectable serum IL-33 may predict clinical response to RTX, independently of and synergistically with autoantibodies and serum IgG level

Expression and involvement of the cholinergic system in osteoarthritis

L’acétylcholine peut être produite par des fibres nerveuses cholinergiques, ou par des cellules non neuronales. Outre son rôle de neuromédiateur, elle a une action anti-inflammatoire. Nous avons étudié l’expression et l’implication du système cholinergique neuronal et non neuronal dans le cartilage articulaire et l’os sous-chondral. Des fibres nerveuses cholinergiques sont présentes dans l’os sous-chondral humain arthrosique. Les chondrocytes et ostéoblastes murins et humains peuvent aussi produire, transporter, dégrader et répondre à l’acétylcholine. L’activation in vitro de ce système, par la nicotine, se fixant sur les récepteurs nicotiniques, limite la production chondrocytaire et ostéoblastique d’IL6, de MMP3 et 13 induite par l’IL1β. La nicotine n’a plus d’effet sur les chondrocytes et ostéoblastes issus de souris invalidées génétiquement pour le récepteur nicotinique α7 (α7nAchR) est impliqué dans l’activation du chondrocyte et de l’ostéoblaste. Chez l’Homme, un duplicat du gène CHRNA7 codant pour le α7nAchR est responsable d’une protéine non fonctionnelle, appelée CHRFAM7A. L’expression de ce duplicat par les chondrocytes humains est corrélée au niveau d’expression de MMP. Bien que considéré comme un agoniste spécifique du α7nAchR, sur les chondrocytes le GTS-21 a une action semblant dépendre des récepteurs sérotoninergiques. Enfin, les lésions d’arthrose post-traumatique sont plus sévères chez les souris invalidées pour le α7nAchR que chez les souris sauvages. L’ensemble de ces données atteste d’un rôle important du système cholinergique dans l’arthrose via le α7nAchR qui pourrait constituer une nouvelle cible thérapeutique dans l’arthrose.Acetylcholine can be produced by cholinergic nerve fibres, or by non-neural cells. In addition to its role as a neurotransmitter, it has an anti-inflammatory action. We studied the expression and involvement of the neuronal and non-neuronal cholinergic system in joint cartilage and subchondral bone. Cholinergic nerve fibres are present in human osteoarthritic subchondral bone. Murine and human chondrocytes and osteoblasts can also produce, transport, degrade and respond to acetylcholine. In vitro activation of the cholinergic system by nicotine, binding to nicotine receptors, limits the IL6, MMP3 and 13 chondrocyte and osteoblast production induced by IL1β. Nicotine has no longer effect on chondrocytes and osteoblasts from mice genetically invalidated for the nicotinic receptor alpha-7 (α7nAchR), meaning α7nAchR is involved in the activation of chondrocyte and osteoblast. In humans, a duplicate of the CHRNA7 gene encoding α7nAchR is responsible for a non-functional protein, called CHRFAM7A. The expression of this duplicate by human chondrocytes is correlated with the expression level of MMP. Although considered a specific α7nAchR agonist, on chondrocytes GTS-21 has an action that appears to be dependent on serotonin receptors. Finally, post-traumatic osteoarthritic lesions are more severe in mice invalidated for α7nAchR than in wild type mice. All these data attest to an important role of the cholinergic system in osteoarthritis via α7nAchR, which could constitute a new therapeutic target in osteoarthriti

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Role of the autonomic nervous system in osteoarthritis

International audienceJoint homeostasis is affected by local and systemic processes. Catecholaminergic and cholinergic fibers innervate the synovium, trabecular bone, and periosteum. Several studies have investigated the involvement of the autonomic nervous system (ANS) in joint homeostasis and the pathophysiology of osteoarthritis (OA). Various resident cells of osteoarticular tissues express receptors for sympathetic and parasympathetic neurotransmitters (norepinephrine/epinephrine and acetylcholine, respectively), which enables them to respond to autonomic stimuli. Furthermore, some of these cells are also able to synthesize neurotransmitters locally and secrete them, which may then act locally regardless of autonomic innervation. The sympathetic nervous system (SNS) is known for promoting bone loss, which has also been demonstrated in the subchondral bone during OA. However, it could interfere with other mechanisms in joint homeostasis. Indeed, intake of beta-blockers decreases pain sensation in individuals with OA; hence, the SNS could be one of the systemic links between hypertension and OA. Parasympathetic fibers may also be implicated in joint homeostasis and local control of inflammation. The vagus nerve has been found to have a strong anti-inflammatory action in other rheumatic diseases through the nicotinic alpha-7 receptor, which is locally expressed by most joint resident cells. Altogether, these data suggest that the ANS is involved in joint homeostasis and OA pathogenesis

Vagus nerve stimulation in musculoskeletal diseases

International audienceThe vagus nerve is the main nerve of the parasympathetic autonomic nervous system. Beyond its vegetative functions, the vagus nerve possesses anti-inflammatory and analgesic properties. Initially developed in the treatment of refractory epilepsy, vagus nerve stimulation (VNS) is currently being evaluated in several musculoskeletal diseases. VNS can be invasive by placing an electrode around the cervical vagus nerve and connected to a generator implanted subcutaneously or non-invasive stimulating the cervical vagus nerve branch percutaneously (auricular or cervical). In rheumatoid arthritis (RA) patients, VNS has been shown to dampen the inflammatory response of circulatory peripheral cells. Several open-labeled small pilot studies have demonstrated that VNS, either invasive or transcutaneous, is associated with a significant decrease of RA disease activity. As well, other studies have shown that VNS could limit fatigue in Sjogren's syndrome and systemic lupus, or decrease pain in fibromyalgia as well as in erosive hand osteoarthritis. However, some questions remain, such as the settings of stimulation, the duration of treatment, or the optimal stimulation route. Finally, randomized controlled trials versus sham stimulation with large samples of patients are mandatory to definitively conclude about the efficacy of VNS

Approche phénotypique de l’arthrose : le cas de l’arthrose associée au syndrome métabolique

International audienceL’arthrose associée au syndrome métabolique est un phénotype clinique défini par ses facteurs de risque (obésité et syndrome métabolique) et qui se caractérise par une inflammation de bas grade chronique. L’obésité est un facteur de risque reconnu de gonarthrose, mais aussi d’arthrose digitale. Le syndrome métabolique augmente le risque d’arthrose avec à la fois un effet cumulatif des maladies métaboliques mais aussi un rôle indépendant et propre de chaque maladie métabolique (diabète, dyslipidémie ou hypertension artérielle). Plusieurs mécanismes expliquent l’augmentation des cas incidents d’arthrose chez le sujet obèse. Tout d’abord, l’excès de masse grasse est responsable d’une augmentation des contraintes mécaniques. Le tissu adipeux est aussi responsable de la production endocrine de médiateurs pro-inflammatoires (cytokines, adipokines, acides gras, radicaux libres oxygénés) ayant un rôle néfaste sur les tissus articulaires. Plus récemment, la dysbiose et la sarcopénie du sujet obèse ont été impliquées dans cette association. L’arthrose, qu’elle soit métabolique ou pas, est associée à une surmortalité cardiovasculaire qui peut s’expliquer par la sédentarité mais aussi par les facteurs de risques communs ainsi que par l’inflammation de bas grade, présente en cas de maladie métabolique. Enfin, la prévention primaire et la prise en charge de l’obésité et du syndrome métabolique pourraient permettre de ralentir la survenue et la progression de l’arthrose

Metabolic stress-induced joint inflammation and osteoarthritis

International audienceOsteoarthritis (OA) is a heterogeneous disorder with several risk factors. Among them, obesity has a major impact on both loading and non-loading joints. Mechanical overload and activity of systemic inflammatory mediators derived from adipose tissue (adipokines, free fatty acids, reactive oxygen species) provide clues to the increased incidence and prevalence of OA in obesity. Recently, research found greater OA prevalence and incidence in obese patients with cardiometabolic disturbances than “healthy” obese patients, which led to the description of a new OA phenotype - metabolic syndrome (MetS)-associated OA. Indeed, individual metabolic factors (diabetes, dyslipidemia, and hypertension) may increase the risk of obesity-induced OA. This review discusses hypotheses based on pathways specific to a metabolic factor in MetS-associated OA, such as the role of advanced glycation end products and glucose toxicity. A better understanding of these phenotypes based on risk factors will be critical for designing trials of this specific subset of OA

Coronary heart disease is associated with a worse clinical outcome of hand osteoarthritis: a cross-sectional and longitudinal study

International audienceObjective To determine whether cardiometabolic factors are associated with hand osteoarthritis (HOA) symptoms, radiographic severity and progression in a post hoc analysis of the phase III Strontium ranelate Efficacy in Knee OsteoarthrItis triAl (SEKOIA) trial, designed to determine the effect of strontium ranelate on knee osteoarthritis (OA).Methods Among the 1683 patients randomised in the SEKOIA study, 869 with radiographic HOA at baseline (rHOA≥2 joints with Kellgren-Lawrence grade ≥2) were included in a cross-sectional analysis. For longitudinal study, we included only the 307 patients with rHOA at baseline from the placebo group. We evaluated whether baseline symptomatic HOA, radiographic severity and clinical and rHOA progression were associated with coronary heart disease and/or metabolic diseases (obesity, diabetes and hypertension, dyslipidaemia) by multivariate regression analysis.Results At baseline, 869 patients (72% women) were included in the cross-sectional analysis; 26% were symptomatic. On multivariate analysis, symptomatic HOA was associated with coronary heart disease (OR 3.59, 95% CI (1.78 to 7.26)) but not metabolic diseases. After a mean follow-up of 2.6 years, for the 307 participants in the placebo group, on multivariate analysis, worse clinical HOA outcome was associated with coronary heart disease (OR 2.91, 95% CI (1.02 to 8.26)). The slow radiographic progression did not allow for revealing any associated factors.Conclusions Symptomatic HOA and worse HOA clinical course are associated with coronary heart disease. These results strengthen the systemic component of HOA and the association between OA pain and cardiac events

Time to Total Knee Arthroplasty after Intra-Articular Hyaluronic Acid or Platelet-Rich Plasma Injections: A Systematic Literature Review and Meta-Analysis

Intra-articular (IA) hyaluronic acid (HA) and platelet-rich plasma (PRP) injections are increasingly being prescribed for knee osteoarthritis (KOA). However, failure of the medical treatment may result in total knee arthroplasty (TKA). We wondered if IA HA or PRP injections (intervention) may delay the time to TKA (outcome) among KOA patients (population), compared to KOA patients not receiving these injections (comparator). For this systematic literature review (SLR) and meta-analysis, we selected observational studies with at least one group of patients receiving IA HA or PRP and with TKA data available. The main outcome was time from the diagnosis of KOA to TKA. We included 25 articles in the SLR (2,824,401 patients) and four in the meta-analysis. The mean strengthening the reporting of observational studies in epidemiology (STROBE) score was 63%. For patients receiving versus not receiving HA injections, the delay between a declared diagnosis of KOA to TKA was increased by 9.8 months (95% CI (8.2–11.4)). As compared with standard of care, the effect size of HA injections for this outcome was 0.57 (95% CI (0.36–0.76)). Only one study described a median time from PRP injections to TKA of 4.1 years (range 0.3–14.7). IA HA injections were associated with increased time to TKA. Causality cannot be concluded because of missing confounder factors as comorbidities. Data were insufficient to conclude any effect of PRP injections on TKA delay