Osteoarthritis (OA), one of the most common rheumatic disorders, is characterized by cartilage breakdown and by synovial inflammation that is directly linked to clinical symptoms such as joint swelling, synovitis and inflammatory pain. The gold-standard method for detecting synovitis is histological analysis of samples obtained by biopsy, but the noninvasive imaging techniques MRI and ultrasonography might also perform well. The inflammation of the synovial membrane that occurs in both the early and late phases of OA is associated with alterations in the adjacent cartilage that are similar to those seen in rheumatoid arthritis. Catabolic and proinflammatory mediators such as cytokines, nitric oxide, prostaglandin E(2) and neuropeptides are produced by the inflamed synovium and alter the balance of cartilage matrix degradation and repair, leading to excess production of the proteolytic enzymes responsible for cartilage breakdown. Cartilage alteration in turn amplifies synovial inflammation, creating a vicious circle. As synovitis is associated with clinical symptoms and also reflects joint degradation in OA, synovium-targeted therapy could help alleviate the symptoms of the disease and perhaps also prevent structural progression.

Metabolism is important for cartilage and synovial joint function. Under adverse microenvironmental conditions, mammalian cells undergo a switch in cell metabolism from a resting regulatory state to a highly metabolically activate state to maintain energy homeostasis. This phenomenon also leads to an increase in metabolic intermediates for the biosynthesis of inflammatory and degradative proteins, which in turn activate key transcription factors and inflammatory signalling pathways involved in catabolic processes, and the persistent perpetuation of drivers of pathogenesis. In the past few years, several studies have demonstrated that metabolism has a key role in inflammatory joint diseases. In particular, metabolism is drastically altered in osteoarthritis (OA) and aberrant immunometabolism may be a key feature of many phenotypes of OA. This Review focuses on aberrant metabolism in the pathogenesis of OA, summarizing the current state of knowledge on the role of impaired metabolism in the cells of the osteoarthritic joint. We also highlight areas for future research, such as the potential to target metabolic pathways and mediators therapeutically.

ObjectivesTo investigate the prevalence of osteoarthritis (OA) in patients with diabetes mellitus (DM) and prevalence of DM in patients with OA and whether OA and DM are associated.DesignA systematic literature review and meta-analysis. We included cohort, case–control and cross-sectional studies assessing the number of patients with DM and/or OA. The mean prevalence of OA among patients with DM and DM among patients with OA was calculated. Data from trials assessing an association of diabetes and OA were pooled and results are presented as unadjusted OR and 95% CI.ResultsFrom the 299 publications, we included 49 studies in the analysis, including 28 cross-sectional studies, 11 cohort studies and 10 case–control studies. In all, 21, 5 and 23 articles involved patients with OA exclusively, patients with DM and the general population, respectively. For 5788 patients with DM, the mean OA prevalence was 29.5±1.2%. For 645 089 patients with OA, the prevalence of DM was 14.4±0.1%. The risk of OA was greater in the DM than non-DM population (OR=1.46 (1.08 to 1.96), p=0.01), as was DM in the OA than non-OA population (OR=1.41 (1.21 to 1.65), p<0.00 001). Among the 12 studies reporting an OR adjusted on at least the body mass index, 5 showed no association of DM and OA and 7 identified DM as an independent risk factor.ConclusionsThis meta-analysis highlights a high frequency of OA in patients with DM and an association between both diseases, representing a further step towards the individualisation of DM-related OA within a metabolic OA phenotype.

ObjectiveRegulatory T cells (Tregs) prevent autoimmunity and control inflammation. Consequently, any autoimmune or inflammatory disease reveals a Treg insufficiency. As low-dose interleukin-2 (ld-IL2) expands and activates Tregs, it has a broad therapeutic potential.AimWe aimed to assess this potential and select diseases for further clinical development by cross-investigating the effects of ld-IL2 in a single clinical trial treating patients with 1 of 11 autoimmune diseases.MethodsWe performed a prospective, open-label, phase I–IIa study in 46 patients with a mild to moderate form of either rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Behcet’s disease, granulomatosis with polyangiitis, Takayasu’s disease, Crohn’s disease, ulcerative colitis, autoimmune hepatitis and sclerosing cholangitis. They all received ld-IL2 (1 million IU/day) for 5 days, followed by fortnightly injections for 6 months. Patients were evaluated by deep immunomonitoring and clinical evaluation.Resultsld-IL2 was well tolerated whatever the disease and the concomitant treatments. Thorough supervised and unsupervised immunomonitoring demonstrated specific Treg expansion and activation in all patients, without effector T cell activation. Indication of potential clinical efficacy was observed.ConclusionThe dose of IL-2 and treatment scheme used selectively activate and expand Tregs and are safe across different diseases and concomitant treatments. This and preliminary indications of clinical efficacy should licence the launch of phase II efficacy trial of ld-IL2 in various autoimmune and inflammatory diseases.Trial registration numberNCT01988506.

IntroductionCell stimulation leads to the shedding of phosphatidylserine (PS)-rich microparticles (MPs). Because autoimmune diseases (AIDs) are characterized by cell activation, we investigated level of circulating MPs as a possible biomarker in primary Sjögren's syndrome (pSS), systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).MethodsWe measured plasma levels of total, platelet and leukocyte MPs by prothrombinase capture assay and flow cytometry in 43 patients with pSS, 20 with SLE and 24 with RA and in 44 healthy controls (HCs). Secretory phospholipase A2 (sPLA2) activity was assessed by fluorometry. Soluble CD40 ligand (sCD40L) and soluble P-selectin (sCD62P), reflecting platelet activation, were measured by ELISA.ResultsPatients with pSS showed increased plasma level of total MPs (mean ± SEM 8.49 ± 1.14 nM PS equivalent (Eq), P < 0.0001), as did patients with RA (7.23 ± 1.05 n PS Eq, P = 0.004) and SLE (7.3 ± 1.25 nM PS Eq, P = 0.0004), as compared with HCs (4.13 ± 0.2 nM PS Eq). Patients with AIDs all showed increased level of platelet MPs (P < 0.0001), but only those with pSS showed increased level of leukocyte MPs (P < 0.0001). Results by capture assay and flow cytometry were correlated. In patients with high disease activity according to extra-glandular complications (pSS), DAS28 (RA) or SLEDAI (SLE) compared with low-activity patients, the MP level was only slightly increased in comparison with those having a low disease activity. Platelet MP level was inversely correlated with anti-DNA antibody level in SLE (r = -0.65; P = 0.003) and serum β2 microglobulin level in pSS (r = -0.37; P < 0.03). The levels of total and platelet MPs were inversely correlated with sPLA2 activity (r = -0.37, P = 0.0007; r = -0.36, P = 0.002, respectively). sCD40L and sCD62P concentrations were significantly higher in pSS than in HC (P ≤ 0.006).ConclusionsPlasma MP level is elevated in pSS, as well as in SLE and RA, and could be used as a biomarker reflecting systemic cell activation. Level of leukocyte-derived MPs is increased in pSS only. The MP level is low in case of more severe AID, probably because of high secretory phospholipase A2 (sPLA2) activity, which leads to consumption of MPs. Increase of platelet-derived MPs, sCD40L and sCD62P, highlights platelet activation in pSS.

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Background Various observations have suggested that the course of COVID-19 might be less favourable in patients with inflammatory rheumatic and musculoskeletal diseases receiving rituximab compared with those not receiving rituximab. We aimed to investigate whether treatment with rituximab is associated with severe COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases.Methods In this cohort study, we analysed data from the French RMD COVID-19 cohort, which included patients aged 18 years or older with inflammatory rheumatic and musculoskeletal diseases and highly suspected or confirmed COVID-19. The primary endpoint was the severity of COVID-19 in patients treated with rituximab (rituximab group) compared with patients who did not receive rituximab (no rituximab group). Severe disease was defined as that requiring admission to an intensive care unit or leading to death. Secondary objectives were to analyse deaths and duration of hospital stay. The inverse probability of treatment weighting propensity score method was used to adjust for potential confounding factors (age, sex, arterial hypertension, diabetes, smoking status, body-mass index, interstitial lung disease, cardiovascular diseases, cancer, corticosteroid use, chronic renal failure, and the underlying disease [rheumatoid arthritis vs others]). Odds ratios and hazard ratios and their 95% CIs were calculated as effect size, by dividing the two population mean differences by their SD. This study is registered with ClinicalTrials.gov, NCT04353609.

Osteoarthritis (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 (FFA), reactive oxygen species (ROS)) 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 (AGEs) 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.