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Rheumatoid synovitis is infiltrated by immune cells that interact with synoviocytes, leading to the pannus formation. Inflammation or cell interaction effects are mainly evaluated with cytokine production, cell proliferation or migration. Few studies interest on cell morphology. Here, the purpose was to deepen some morphological changes of synoviocytes or immune cells under inflammatory conditions. Inflammatory cytokines, IL-17 and TNF that are largely involved in RA pathogenesis, induced a change in synoviocyte morphology, inducing a retracted cell with higher number of pseudopodia. Several morphological parameters decreased in inflammatory conditions: cell confluence, area and motility speed. The same impact on cell morphology was observed in co-culture of synoviocytes and immune cells in inflammatory/non-inflammatory conditions or with cell activation (miming the in vivo situation), affecting both cell types: synoviocytes were retracted and inversely immune cells proliferated, indicating that cell activation induced a morphological change of cells. In contrast, with RA but not control synoviocytes, cell interactions were not sufficient to affect PBMC and synoviocyte morphology. The morphological effect came only from the inflammatory environment. These findings reveal that the inflammatory environment or cell interactions induced massive changes in control synoviocytes, with cell retraction and increase of pseudopodia number, leading to better interactions with other cells. Except in the case of RA, the inflammatory environment was absolutely required for such changes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.)

The morphology of fibroblast-like synoviocytes (FLS) issued from the synovial fluid (SF) of patients suffering from osteoarthritis (OA), rheumatoid arthritis (RA), or from healthy subjects (H), as well as the ultrastructure and mechanical properties of the FLS-secreted extracellular vesicles (EV), were analyzed by confocal microscopy, transmission electron microscopy, atomic force microscopy, and tribological tests. EV released under healthy conditions were constituted of several lipid bilayers surrounding a viscous inner core. This "gel-in" vesicular structure ensured high mechanical resistance of single vesicles and good tribological properties of the lubricant. RA, and to a lesser extent OA, synovial vesicles had altered morphology, corresponding to a "gel-out" situation with vesicles surrounded by a viscous gel, poor mechanical resistance, and poor lubricating qualities. When subjected to inflammatory conditions, healthy cells developed phenotypes similar to that of RA samples, which reinforces the importance of inflammatory processes in the loss of lubricating properties of SF.

Background: The IL-23/IL-17 axis is involved in inflammatory diseases including arthritis and psoriasis. However, the response to IL-23 or IL-17 inhibitors is different depending on the disease. The aim was to compare the effects of interactions between immune and stromal cells on the IL-23 axis to understand these differences., Methods: Peripheral blood mononuclear cells were co-cultured with RA synoviocytes or Pso skin fibroblasts, with or without phytohemagglutinin, IL-23, or anti-IL-23 antibody. Production of IL-6, IL-1β, IL-23, IL-17, IL-12, and IFNγ was measured by ELISA. IL-23 and cytokine receptor gene expression (IL-17RA, IL-17RC, IL-12Rβ1, IL-12Rβ2, and IL-23R) was analyzed by RT-qPCR. IL-12Rβ1 and IL-23R subunits were analyzed by flow cytometry., Results: The production of IL-6, IL-1β, IL-17, IL-12, and IFNγ with synoviocytes or skin fibroblasts was rather similar, and cell interactions with immune cells increased their production, specifically that of IL-17. A major difference was observed for IL-23. Interactions with synoviocytes but not with skin fibroblasts decreased IL-23 secretion while mRNA level was increased, mainly with synoviocytes, reflecting a major consumption difference. IL-23 addition had only one effect, the increase of IL-17 secretion. Cell activation induced similar effects on cytokine receptor gene expression in co-cultures with synoviocytes or skin fibroblasts. The key difference was the cell interaction effects depending on the stromal cell origin. Interactions with synoviocytes increased the expression of both IL-23 receptor subunits at mRNA levels and IL-23R at the surface expression level while interactions with skin fibroblasts decreased their expression at the mRNA level and had no effect at the surface expression level., Conclusion: Interactions between immune and stromal cells are crucial in cytokine production and their receptor expression. The origin of stromal cells had a major influence on the production of IL-23 and its receptor expression. Such differences may explain part of the heterogeneity in treatment response., (© 2022. The Author(s).)

Interactions between B cells and stromal cells have essential functions in immune cell development and responses. During chronic inflammation, the pro-inflammatory microenvironment leads to changes in stromal cells, which acquire a pathogenic phenotype specific to each organ and disease. B cells are recruited to the site of inflammation and interact with these pathogenic stromal cells contributing to the disease's severity. In addition to producing autoantibodies, B cells contribute to the pathogenesis of autoimmune inflammatory diseases by serving as professional antigen-presenting cells, producing cytokines, and through additional mechanisms. This review describes the role of B cells and their interactions with stromal cells in chronic inflammation, with a focus on human disease, using three selected autoimmune inflammatory diseases: rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis. Understanding B cells roles and their interaction with stromal cells will help develop new therapeutic options for the treatment of autoimmune diseases., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Pigmented villonodular synovitis (PVNS) is a rare inflammatory articular disease sharing common characteristics with rheumatoid arthritis (RA), notably hyperplasia of the synovium due to a hyperproliferation of synoviocytes, and with cancer owing to mutations of the CSF1/M-CCSF gene. Targeting synovium hyperplasia by the local delivery of Cadmium (Cd) has been already tested in vitro and in vivo models of RA and could be applied to PVNS. PVNS and RA synoviocytes were exposed to low doses of Cd. After different culture time points, a qualitative analysis was done by microscopy and quantitative measurements of apoptosis, cell viability and IL-6 production were carried. IL-6 production by PVNS synovial tissue was also quantified after Cd treatment with or without the presence of pro-inflammatory cytokines (IL-17 + TNF). Addition of Cd induced cell death in both PVNS (1 ppm) and RA (0.1 ppm) synoviocytes, which increased with time and Cd concentrations. Cd increased the percentage of apoptotic cells and decreased cell viability and IL-6 production. In all these experiments, PVNS synoviocytes were tenfold less sensitive to Cd than RA synoviocytes. Cd decreased IL-6 production by PVNS synovial tissue and its effect was enhanced with pro-inflammatory cytokines. In summary, PVNS synoviocytes show resistance to Cd-induced cell death and decreased inflammation. Intra-articular use of Cd could represent a potential therapeutic tool in PVNS., (© 2022. The Author(s).)

Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to joint destruction and bone erosion. Even if many treatments were developed with success in the last decades, some patients fail to respond, and disease chronicity is still a burden. Mechanisms involved in such resistance may include molecular changes in stromal cells. Other explanations can come from observations of tenosynovial giant cell tumor (TGCT), first considered as an inflammatory arthritis, but with unusual neoplastic features. TGCT leads to synovium hypertrophy and hyperplasia with hemosiderin deposition. It affects young adults, resulting in secondary osteoarthritis and increased morbidity. TGCT shows clinical, histological and genetic similarities with RA but affecting a single joint. However, the monoclonality of some synoviocytes, the presence of translocations and rare metastases also suggest a neoplastic disease, with some features common with sarcoma. TGCT is more probably in an intermediate situation between an inflammatory and a neoplastic process, with a main involvement of the proinflammatory cytokine CSF-1/CSF1R signaling axis. The key treatment option is surgery. New treatments, derived from the RA and sarcoma fields, are emerging. The tyrosine kinase inhibitor pexidartinib was recently FDA-approved as the first drug for severe TGCT where surgery is not an option. Options directly targeting the excessive proliferation of synoviocytes are at a preclinical stage., Competing Interests: PM has a patent for the use of PUMA gene therapy in arthritis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Robert, Farese and Miossec.)

Objectives: This study aims to investigate if addition of fibroblast-stromal cell markers to a classification of synovial pathotypes improves their predictive value on clinical outcomes in rheumatoid arthritis (RA)., Methods: Active RA patients with a knee needle synovial biopsy at baseline and finished 1-year follow-up were recruited from a real-world prospective cohort. Positive staining for CD20, CD38, CD3, CD68, CD31, and CD90 were scored semiquantitatively (0-4). The primary outcome was radiographic progression defined as a minimum increase of 0.5 units of the modified total Sharp score from baseline to 1 year., Results: Among 150 recruited RA patients, 123 (82%) had qualified synovial tissue. Higher scores of CD20+ B cells, sublining CD68+ macrophages, CD31+ endothelial cells, and CD90+ fibroblasts were associated with less decrease in disease activity and greater increase in radiographic progression. A new fibroblast-based classification of synovial pathotypes giving more priority to myeloid and stromal cells classified samples as myeloid-stromal (57.7%, 71/123), lymphoid (31.7%, 39/123), and paucicellular pathotypes (10.6%, 13/123). RA patients with myeloid-stromal pathotype showed the highest rate of radiographic progression (43.7% vs. 23.1% vs. 7.7%, p = 0.011), together with the lowest rate of Boolean remission at 3, 6, and 12 months. Baseline synovial myeloid-stromal pathotype independently predicted radiographic progression at 1 year (adjusted OR: 3.199, 95% confidence interval (95% CI): 1.278, 8.010). Similar results were obtained in a subgroup analysis of treatment-naive RA., Conclusions: This novel fibroblast-based myeloid-stromal pathotype could predict radiographic progression at 1 year in active RA patients which may contribute to the shift of therapeutic decision in RA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhang, Ma, Mo, Jing, Zheng, Chen, Wu, Chen, Zhang, Zou, Lin, Xu, Zou, Yang, Ling, Miossec and Dai.)

Inflammatory monocyte-derived dendritic cells (Mo-DCs) have been described in several chronic inflammatory disorders, such as rheumatoid arthritis (RA), and are suspected to play a detrimental role by fueling inflammation and skewing adaptive immune responses. However, the characterization of their phenotype is still limited, as well as the comprehension of the factors that govern their differentiation. Here, we show that inflammatory Mo-DCs generated in vitro expressed a large and atypical panel of C-type lectin receptors, including isoforms of CD209 and CD206, CD303 and CD207, as well as intracellular proteins at their surfaces such as the lysosomal protein CD208. Combination of these markers allowed us to identify cells in the synovial fluid of RA patients with a close phenotype of inflammatory Mo-DCs generated in vitro. Finally, we found in coculture experiments that RA synoviocytes critically affected the phenotypic differentiation of monocytes into Mo-DCs, suggesting that the crosstalk between infiltrating monocytes and local mesenchymal cells is decisive for Mo-DCs generation.

The role of IL-17 in many inflammatory and autoimmune diseases is now well established, with three currently registered anti-IL-17-targeted therapies. This story has taken place over a period of 20 years and led to the demonstration that a T cell product could regulate, and often amplify, the inflammatory response. The first results described the contribution of IL-17 to local features in arthritis. Then, understanding was extended to its systemic effects, with a focus on cardiovascular aspects. This review provides a historical perspective of these discoveries focused on arthritis, which started in 1995, followed 10 years later by the description of Th17 cells. Today, IL-17 inhibitors for three chronic inflammatory diseases have been registered. More options are now being tested in ongoing and future clinical trials. Inhibitors of IL-17 family members and Th17 cells ranging from antibodies to small molecules are under active development. The identification of patients with IL-17-driven disease is a key target for the improved selection of patients expected to have a strongly positive response.

Rheumatoid arthritis (RA) remains a cause of morbidity and mortality in many patients while new treatments have changed the face of the disease. Despite the emergence of these new drugs, cardiovascular (CV) diseases remain more frequent in RA patients compared with the general population. However, predictive biomarkers of RA severity and precise guidelines to manage the CV risk in these patients are still lacking. Pro-inflammatory cytokines contribute both to RA and CV pathogenesis. Focusing on IL-17A, high levels of bioactive IL-17A were associated with destruction in RA but also during myocardial infarction. The study aimed to assess the relationship between bioactive IL-17A, destruction and the occurrence of CV events (CVE) in RA patients with a very long follow-up. Thirty-six RA patients were followed between 1970 and 2012 in Lyon, France. They were tested for bioactive IL-17A and clinical and biological characteristics were recorded at baseline. Then, the occurrence of CVE was registered during the follow-up. To study the bioactive fraction of IL-17A, the bioassay used the ability of human umbilical vein endothelial cells to produce IL-8 in presence of RA plasma samples with or without an anti-IL-17A antibody. Bioactive IL-17A level at baseline was higher in RA patients who later experienced a CVE compared to those without (0.77 vs 0.21 ng/ml, p -value = 0.0095, Mann-Whitney test) and synergized with joint destruction ( p -value = 0.020, Kruskal-Wallis test). Through its effects on vessels and thrombosis, high levels of bioactive IL-17A could represent a long-term marker of CV risk., (Copyright © 2020 Robert, Hot, Mifsud, Ndongo-Thiam and Miossec.)

Purpose of Review: To provide an overview of recently published work covering key mechanisms involved in the pathogenesis of rheumatoid arthritis (RA), with focus on the early and late stages., Recent Findings: Present understanding of RA pathogenesis has been mainly focused on the inflammatory process at the established phase of the disease, but recent work has shed light on important molecular and cellular mechanisms involved both at the early and late/refractory stages. In early RA, the involvement of anticitrullinated protein antibodies in RA induction has been identified with a critical role of the IL-23/Th17 axis in the control of their pathogenicity. At the late stage, RA may be viewed as a cell-autonomous genetic and epigenetic disease, characterized by altered cell death pathways in synoviocytes after long-term exposure to inflammation. An improved knowledge of these cell-intrinsic altered pathways is the basis for the targeting of pathogenic synoviocytes, as a new therapeutic alternative against resistance to current treatment targeting the immune system., Summary: We summarize these pathological pathways, and their understanding will facilitate the design of new diagnostic tools and therapeutic strategies combining the targeting of pathogenic synoviocytes with current immune-targeted therapies.

Background: Methotrexate (MTX) at low dose is a key drug for rheumatoid arthritis (RA). MTX is widely used alone or combined with biologics or steroids. The aim was to study its effects on cytokine production using an in vitro model with synoviocytes interacting with peripheral blood mononuclear cells (PBMC) to reproduce the interactions in RA synovium. Methods: Activated-PBMC were co-cultured with RA synoviocytes during 48 h. A dose-response of MTX was tested and different biotherapies (Infliximab, Tocilizumab, Abatacept and Rituximab) were added alone or in combination with MTX. Cytokine production (IL-17, IL-6, IL-1β, IFN-γ, and IL-10) was measured by ELISA. These results were compared with those obtained with steroids. Results: MTX alone had a modest inhibitory effect on cytokine production compared to steroids. The most effective concentration was one of the lowest, 0.01 μg/ml, as for steroids. Infliximab was the most active biotherapy ( p ≤ 0.05 for all cytokines) followed by Tocilizumab ( p ≤ 0.05 for all cytokines except IL-6). Abatacept and Rituximab had a more restricted effect on cytokines ( p ≤ 0.05 for IL-1β and IFN-γ). The combination MTX/biotherapies did not increase significantly the inhibition of cytokine production but some specific inhibitory effects were observed with Infliximab on IL-17 and IL-6, and with Abatacept and Rituximab on IL-1β. Conclusion: Low dose of MTX was at least as effective as high dose. The effects of the combination with biotherapies showed an important level of heterogeneity between the levels of some specific cytokines and the degree of inhibition with drugs., (Copyright © 2019 Noack and Miossec.)

Objective: Activation of osteoclastogenesis at the bone site in rheumatoid arthritis (RA) is well established. The mechanisms by which circulating osteoclast precursors contribute are still unclear. Peroxisome proliferator-activated receptor γ coactivator 1β (PGC-1β) is implicated in transcriptional regulation of osteoclastogenesis in mouse models. This study was undertaken to investigate the contribution of PGC-1β to circulating osteoclast precursors and its link to bone destruction in RA., Methods: PGC-1β expression in RA peripheral blood CD14+ monocytes was increased and showed correlation with joint destruction shown on radiographs. Cells from RA patients or healthy controls were transfected with a lentivirus vector for PGC-1β gene silencing or overexpression and cultured with macrophage colony-stimulating factor and RANKL. Bone resorption activity, bone-degrading enzymes, and signaling molecules were measured in these mature osteoclasts., Results: Increased nuclear accumulation of PGC-1β was observed in RA peripheral blood CD14+ monocytes, and these cells had stronger osteoclastogenesis than in healthy controls. PGC-1β protein expression was positively correlated with radiographic joint destruction (r = 0.396-0.413; all P < 0.05). PGC-1β knockdown suppressed (51-82% reduction) the expression of cathepsin K, tartrate-resistant acid phosphatase (TRAP), and matrix metalloproteinase 9 (MMP-9), as well as osteoclast differentiation and bone resorption activity. Conversely, PGC-1β overexpression increased these markers (by 1.5-1.8-fold) and osteoclastogenesis. VIVIT, an inhibitor of NFATc1 activation, inhibited the effect of overexpressed PGC-1β by reducing cathepsin K, TRAP, and MMP-9 expression. Chromatin immunoprecipitation assay and dual-luciferase reporter gene assay showed PGC-1β bound to NFATc1 promoter, leading to transcriptional activation., Conclusion: Activation of the PGC-1β/NFATc1 pathway in circulating osteoclast precursors was associated with bone destruction in RA. This may represent a new treatment target., (© 2019 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

Objectives: Tumour necrosis factor-alpha inhibitors (TNFi) are effective treatments for Rheumatoid Arthritis (RA). Responses to treatment are barely predictable. As these treatments are costly and may induce a number of side effects, we aimed at identifying a panel of protein biomarkers that could be used to predict clinical response to TNFi for RA patients., Methods: Baseline blood levels of C-reactive protein, platelet factor 4, apolipoprotein A1, prealbumin, α1-antitrypsin, haptoglobin, S100A8/A9 and S100A12 proteins in bDMARD naive patients at the time of TNFi treatment initiation were assessed in a multicentric prospective French cohort. Patients fulfilling good EULAR response at 6 months were considered as responders. Logistic regression was used to determine best biomarker set that could predict good clinical response to TNFi., Results: A combination of biomarkers (prealbumin, platelet factor 4 and S100A12) was identified and could predict response to TNFi in RA with sensitivity of 78%, specificity of 77%, positive predictive values (PPV) of 72%, negative predictive values (NPV) of 82%, positive likelihood ratio (LR+) of 3.35 and negative likelihood ratio (LR-) of 0.28. Lower levels of prealbumin and S100A12 and higher level of platelet factor 4 than the determined cutoff at baseline in RA patients are good predictors for response to TNFi treatment globally as well as to Infliximab, Etanercept and Adalimumab individually., Conclusion: A multivariate model combining 3 biomarkers (prealbumin, platelet factor 4 and S100A12) accurately predicted response of RA patients to TNFi and has potential in a daily practice personalized treatment., (Copyright © 2018 Société française de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.)

Rheumatoid and psoriatic arthritis are chronic inflammatory diseases, with massive increase of cardiovascular events (CVE), and contribution of the cytokines TNF-α and IL-17. Chronic inflammation inside the joint membrane or synovium results from the activation of fibroblasts/synoviocytes, and leads to the release of cytokines from monocytes (Tumor Necrosis Factor or TNF) and from T lymphocytes (Interleukin-17 or IL-17). At the systemic level, the very same cytokines affect endothelial cells and vessel wall. We have previously shown [1,2] that IL-17 and TNF-α, specifically when combined, increase procoagulation, decrease anticoagulation and increase platelet aggregation, leading to thrombosis. These results are the basis for the models of interactions between IL-17 and TNF, and genes expressed by activated endothelial cells. This work is devoted to mathematical modeling and numerical simulations of blood coagulation and clot growth under the influence of IL-17 and TNF-α. We show that they can provoke thrombosis, leading to the complete or partial occlusion of blood vessels. The regimes of blood coagulation and conditions of occlusion are investigated in numerical simulations and in approximate analytical models. The results of mathematical modeling allow us to predict thrombosis development for an individual patient., (Copyright © 2017 Académie des sciences. Published by Elsevier Masson SAS. All rights reserved.)

In rheumatoid arthritis (RA), the proliferation of fibroblast-like synoviocytes (FLS) is the cause of chronic inflammation in joints and of joint damage. Delivery of the pro-apoptotic gene PUMA to FLS via human adenovirus type 5 (HAdV5) vectors has been tested as a therapeutic approach, but efficiency is hampered by low transduction, as FLS do not express HAdV5 receptors on the cell surface. Here we show that efficient transduction of PUMA in FLS can be achieved by conjugating HAdV5 to a baculovirus, which binds to the cell surface via the envelope glycoprotein Gp64. Intra-articular injection in an adjuvant-induced rat model of RA induces apoptosis of FLS, leading to significant decrease in joint inflammation, joint damage, and bone loss with improvement in joint function and mobility. Our results demonstrate the therapeutic potential of PUMA gene therapy as a local treatment in various forms of arthritis in which abnormal FLS proliferation is implicated.Proliferation of synoviocytes contributes to joint damage in rheumatoid arthritis. Here the authors show that targeting of these cells by a vector, consisting of a baculovirus conjugated to an adenovirus carrying the pro-apoptotic gene PUMA, has therapeutic efficacy in a rat arthritis model.

Objectives: Zinc (Zn) has major effects on immune system activation while Cadmium (Cd) has anti-inflammatory and anti-proliferative effects in several chronic inflammatory contexts. The aim of this work was to investigate by which mechanisms Zn could compete with Cd and eventually counteract its deleterious effects. Rheumatoid arthritis (RA) synoviocytes exposed to cytokines were used as a model of chronic inflammation; osteoarthritis (OA) synoviocytes were used as control., Methods: Cell/medium fractionation constants were analyzed for different metals by inductively-coupled-plasma mass-spectrometry by comparison to the 70Zn spike. Interleukin-17 (IL-17) and tumor necrosis factor-alpha (TNF-α) were used to mimic inflammation. Gene expression of ZIP-8 importer, metallothioneins-1 (MT-1s) and the ratio between metalloprotease-3 and the tissue inhibitor of metalloproteinases (MMP-3)/TIMP-1) were evaluated after pre-exposure to cytokines and Cd, with or without the addition of exogenous Zn (0.9 ppm). Cell viability was measured by neutral red assay and IL-6 production by ELISA., Results: Synoviocytes selectively absorbed and retained Cd in comparison to Zn. Metal import increased with IL-17/TNF-α exposure, through the enhanced ZIP-8 expression. Zn did not modify ZIP-8 expression, while Cd reduced it (p<0.05). Zn induced a reduction of Cd-induced MT-1s expression, in particular of MT-1X (3-fold), and subsequently the final intra-cellular content of Cd. By reducing Cd accumulation in cells, Zn reversed Cd anti-proliferative and anti-inflammatory effects but preserved the low MMP-3/TIMP-1 ratio induced by Cd, which was enhanced by inflammatory conditions., Conclusion: Zinc counteracts the deleterious effect of Cd by reducing its import and accumulation in the cell, without the reactivation of destructive pathways such as MMPs.

Rheumatoid arthritis (RA) is a chronic inflammatory disease leading to joint destruction. Cytokines play a key role in its pathogenesis. They contribute to the induction and maintenance of inflammation and thus provide therapeutic targets. Many cytokines are involved in RA, and this review focuses on a few critical ones: tumor necrosis factor (TNF), interleukin (IL)-6, IL-1, IL-17, and GM-CSF. TNF and IL-6 are both well-established targets in RA treatment, and new biologic agents are reaching the market. IL-1 represents a more complex cytokine as results in humans do not reach those in animal models. IL-17 and GM-CSF are cytokines representing new targets either as early treatment or in non-responders to other biologics. The interaction between cytokines and their signaling pathways are the basis for the development of new strategies with small molecules or bispecific antibodies. Clearly, the targeting of cytokines has been a major progress in RA treatment, but many issues remain open. Although remission can be better achieved, reactivation of the disease too often occurs upon treatment discontinuation. Better understanding and targeting of chronicity remains a goal to achieve in the future.

Dendritic cells (DCs) are central regulators of the balance between immunity and tolerance, and alteration of the specialized DC system is a common feature of both systemic and tissue-specific autoimmune diseases. Increasing evidence indicates that the heterogeneity and the remarkable functional diversity of DC subsets might be differentially affected in autoimmune disorders, which accounts for different pathologies. This Review discusses recent findings that support this concept and provides a new conceptual overview of the altered function and distribution of DCs in autoimmune disorders. The discussion will focus on systemic lupus erythematosus - a prototype of a multi-organ disease - as well as rheumatoid arthritis and idiopathic inflammatory myopathies, pathologies characterized by tissue-specific lesions. Studies on these diseases have revealed common and disease-specific changes in DC distribution and in critical DC functions, such as phagocytosis, cytokine secretion and migration. An improved understanding of the roles of altered DC distribution and/or disturbed key functions in these autoimmune diseases will pave the way for the development of new therapies aiming at reducing immunogenicity and at enhancing the tolerogenic capacity of DCs. Although some tolerogenic DCs have already been introduced in the clinic, the successful translation of other DC-based therapies will require considerable research efforts.

The European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases convened a task force of experts in rheumatoid arthritis (RA) and clinical trial methodology to comment on the new draft 'Guideline on clinical investigation of medicinal products for the treatment of RA' released by the European Medicines Agency (EMA). Special emphasis was placed by the group on the development of new drugs for the treatment of early RA. In the absence of a clear definition of early RA, it was suggested that clinical investigations in this condition were conducted in disease-modifying antirheumatic drugs naïve patients with no more than 1 year disease duration. The expert group recommended using an appropriate improvement in disease activity (American College of Rheumatology (ACR) or Simplified/Clinical Disease Activity Index (SDAI/CDAI) response criteria) or low disease activity (by any score) as primary endpoints, with ACR/European League Against Rheumatism remission as a secondary endpoint. Finally, as compelling evidence showed that the Disease Acrivity Score using 28-joint counts (DAS28) might not provide a reliable definition of remission, or sometimes even low disease activity, the group suggested replacing DAS28 as a measurement instrument to evaluate disease activity in RA clinical trials. Proposed alternatives included SDAI, CDAI and Boolean criteria., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: During chronic inflammation, immune cells, notably Th17 cells, infiltrate the inflammatory site and interact with local mesenchymal cells. Applied to rheumatoid arthritis (RA), the aim is to study the interactions between synoviocytes and peripheral blood mononuclear cells (PBMC) with a focus on the Th17 pathway and to identify a mechanism which leads to high IL-17 secretion with an interest on podoplanin., Methods: PBMC from healthy donors and RA patients were co-cultured with RA synoviocytes during 48 h, in the presence or not of phytohemagglutinin. An antibody against podoplanin was used in co-culture. Cytokine production (IL-6, IL-1β and IL-17) was measured by ELISA and cell staining (CD3, CD4, IL-17 and podoplanin) by flow cytometry., Results: In control conditions, IL-6 and IL-1β production was increased in PBMC-synoviocyte co-culture compared to PBMC alone (p = 0.02). No additional effect was observed with PBMC activation. Flow cytometry analysis showed no difference in the percentage of Th17 cells in activated PBMC alone or with synoviocytes (p = 0.4), indicating that Th17 differentiation requires only T cell activation. Conversely, IL-17 production was highly increased in co-cultures with activated PBMC vs. activated PBMC alone (p = 0.002). Transwell experiments confirm that cell-cell contact was critical for IL-17 secretion. The incubation of either PBMC or synoviocytes with an anti-podoplanin antibody decreased IL-17 secretion by 60 % (p = 0.008)., Conclusions: Interactions between resting PBMC and synoviocytes are sufficient to induce IL-6 and IL-1β production. Both PBMC activation and cell interactions are needed to induce a high IL-17 secretion. Podoplanin contributes at the level of both lymphocytes and synoviocytes.

Objective: To compare the effects of TNF-α and IL-17A on osteogenic differentiation of isolated fibroblast-like synoviocytes (FLS) from healthy donors, osteoarthritis (OA) and rheumatoid arthritis (RA) patients., Methods: FLS were cultured in osteogenic medium, with and without TNF-α and/or IL-17A. Extracellular matrix mineralization was evaluated by alizarin red staining and alkaline phosphatase activity (ALP) measurement. mRNA expression was analyzed by qRT-PCR for Wnt5a, BMP2 and Runx2, genes associated with osteogenesis, for DKK1 and RANKL, genes associated with osteogenesis inhibition and Schnurri-3, a new critical gene in the cross talk with osteoclasts. IL-6 and IL-8 production was measured by ELISA., Results: In osteogenic medium, matrix mineralization and increased ALP activity indicated that FLS can undergo osteogenic differentiation, which was increased with TNF-α and IL-17A. The expression of osteogenesis activators (BMP2 and Wnt5a) was increased with cytokines and that of the osteogenesis inhibitor DKK1 was decreased. There was no difference between all three cell types. In contrast, RA FLS were particularly sensitive to the synergistic increase of Shn3 with TNF-α and IL-17A. Levels of IL-6 and IL-8 were also higher for RA-FLS, compared to healthy and OA FLS., Conclusion: IL-17A and/or TNF-α treatment favor an osteogenesis induction in isolated FLS, independent of their origin. RA-FLS were more sensitive to the synergistic increase of Schnurri-3 expression. Combined with the higher levels of inflammation, this may in turn activate osteoclastogenesis, leading to increased bone destruction seen in destructive arthritis., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: Bone morphogenetic proteins (BMPs) are multifunctional secreted growth factors regulating a broad spectrum of functions in numerous systems. An increased expression and production of specific BMPs have been described in the rheumatoid arthritis (RA) synovium. The aim of this study was to analyze the involvement of the BMP signaling pathway in RA synoviocytes in response to interleukin-17 (IL-17) and tumor necrosis factor-alpha (TNF-α)., Methods: The expression of components of the BMP signaling pathway (BMP receptors, BMP ligands, BMP signal transducers, and BMP antagonists) was analyzed by quantitative polymerase chain reaction before and after treatment of RA synoviocytes with TNF-α or IL-17 or both. Regulation was studied in the presence of the specific BMP inhibitor DMH1 (dorsomorphin homologue 1) or an exogenous BMP ligand, BMP6. Expression and production of pro-inflammatory cytokines (IL-6 and granulocyte-macrophage colony-stimulating factor), chemokines (IL-8, CCL2, CCL5, and CXCL10), and matrix metalloproteinases (MMP-1, -2, -3, -9, and -13) were analyzed., Results: RA synoviocytes express BMP receptors (mainly BMPRIA, ACTRIA, and BMPRII), signal transducers of the Smad family (Smad1 and 5 and co-Smad4), and different BMP antagonists. The modulation of the expression of the BMP target genes-Id (inhibitor of DNA-binding/differentiation) proteins and Runx (Runt-related transcription factor) transcription factors-after the addition of exogenous BMP shows that the BMP signaling pathway is active. RA synoviocytes also express BMP ligands (BMP2, BMP6, and BMP7) which are highly upregulated after activation with TNF-α and IL-17. Autocrine BMP signaling pathway can be blocked by treatment with the inhibitor DMH1, leading to an increase in the upregulated expression of pro-inflammatory cytokines, chemokines, and MMPs induced by the activation of RA synoviocytes with TNF-α and IL-17. Conversely, the additional stimulation of the BMP pathway with the exogenous addition of the BMP6 ligand decreases the expression of those pro-inflammatory and pro-destructive factors., Conclusion: The results indicate that the canonical BMP pathway is functionally active in human RA synoviocytes and that the inhibition of autocrine BMP signaling exacerbates the pro-inflammatory phenotype induced in RA synoviocytes by the stimulation with IL-17 and TNF-α.

Objectives: Anticitrullinated protein antibodies (ACPA) are specifically associated with rheumatoid arthritis (RA) and produced in inflamed synovial membranes where citrullinated fibrin, their antigenic target, is abundant. We showed that immune complexes containing IgG ACPA (ACPA-IC) induce FcγR-mediated tumour necrosis factor (TNF)-α secretion in macrophages. Since IgM rheumatoid factor (RF), an autoantibody directed to the Fc fragment of IgG, is also produced and concentrated in the rheumatoid synovial tissue, we evaluated its influence on macrophage stimulation by ACPA-IC., Methods: With monocyte-derived macrophages from more than 40 healthy individuals and different human IgM cryoglobulins with RF activity, using a previously developed human in vitro model, we evaluated the effect of the incorporation of IgM RF into ACPA-IC., Results: IgM RF induced an important amplification of the TNF-α secretion. This effect was not observed in monocytes and depended on an increase in the number of IgG-engaged FcγR. It extended to the secretion of interleukin (IL)-1β and IL-6, was paralleled by IL-8 secretion and was not associated with overwhelming secretion of IL-10 or IL-1Ra. Moreover, the RF-induced increased proinflammatory bioactivity of the cytokine response to ACPA-IC was confirmed by an enhanced, not entirely TNF-dependent, capacity of the secreted cytokine cocktail to prompt IL-6 secretion by RA synoviocytes., Conclusions: By showing that it can greatly enhance the proinflammatory cytokine response induced in macrophages by the RA-specific ACPA-IC, these results highlight a previously undescribed, FcγR-dependent strong proinflammatory potential of IgM RF. They clarify the pathophysiological link between the presence of ACPA and IgM RF, and RA severity., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Rheumatoid arthritis (RA) is a chronic inflammatory disease leading to joint destruction and bone resorption. The proinflammatory cytokine interleukin 17 (IL-17), primarily produced by Th17 cells, has been shown to be involved in all stages of the disease and to be an important contributor of RA chronicity. Three major processes drive the IL-17-mediated chronicity. Several epigenetic events, enhanced in RA patients, lead to the increased production of IL-17 by Th17 cells. IL-17 then induces the production of several inflammatory mediators in the diseased synovium, which are further synergistically enhanced via combinations of IL-17 with other cytokines. IL-17 also promotes the survival of both the synoviocytes and inflammatory cells and promotes the maturation of these immune cells. This leads to an increased number of synoviocytes and inflammatory cells in the synovial fluid and in the synovium leading to the hyperplasia and exacerbated inflammation observed in joints of RA patients. Furthermore, these IL-17-driven events initiate several feedback-loop mechanisms leading to increased expansion of Th17 cells and thereby increased production of IL-17. In this review, we aim to depict a complete picture of the IL-17-driven vicious circle leading to RA chronicity and to pinpoint the key aspects that require further exploration., (© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Introduction: The goal of this study is to investigate whether the -308G > A promoter polymorphism in the tumor necrosis factor alpha (TNFA) gene is associated with disease severity and radiologic joint damage in a large cohort of patients with rheumatoid arthritis (RA)., Methods: A long-term observational early RA inception cohort (n = 208) with detailed information about disease activity and radiologic damage after 3, 6 and 9 years of disease was genotyped for the TNFA -308G > A promoter polymorphism (rs1800629). A longitudinal regression analysis was performed to assess the effect of genotype on RA disease severity and joint damage. Subsequently, a meta-analysis, including all publically available data, was performed to further test the association between joint erosions and the TNFA polymorphism. To learn more about the mechanism behind the effect of the polymorphism, RNA isolated from peripheral blood from RA patients (n = 66) was used for TNFA gene expression analysis by quantitative PCR., Results: Longitudinal regression analysis with correction for gender and disease activity showed a significant difference in total joint damage between GG and GA+AA genotype groups (P = 0.002), which was stable over time. The meta-analysis, which included 2,053 patients, confirmed an association of the genetic variant with the development of erosions (odds ratio 0.78, 95% CI 0.62, 0.98). No significant differences in TNFA gene expression were observed for the different genotypes, confirming earlier findings in healthy individuals., Conclusions: Our data confirm that the TNFA -308G > A promoter polymorphism is associated with joint damage in patients with RA. This is not mediated by differences in TNFA gene expression between genotypes.

Objectives: To examine the effect of interleukin-17 (IL-17) on rheumatoid arthritis (RA) synoviocyte migration and invasiveness., Methods: IL-17A and tumour necrosis factor α (TNFα)-induced messenger RNA expression in RA synoviocytes was analysed using Affymetrix U133A microarrays. The capacity of IL-17 alone or in combination with TNFα to induce synoviocyte migration and invasion was tested using Boyden and transwell Matrigel invasion chambers. A functional DNA binding assay was used to evaluate the regulation of the key hypoxia-related gene hypoxia-inducible factor 1 (HIF-1α) expression and activation. The role of metalloproteinase 2 (MMP2) in IL-17-induced invasiveness was assessed using small interfering RNA. Hypoxia pathway gene expression was measured in the blood of RA patients and healthy volunteers using Affymetrix microarrays., Results: Among the genes induced by IL-17A in RA synoviocytes, a molecular pattern of inflammation hypoxia-related genes, including CXC chemokine receptor 4 (CXCR4) and MMP2 was identified. Using immunofluorescence microscopy, the expression of CXCR4 was confirmed on synoviocytes. IL-17A and TNFα induced synoviocyte migration and invasion through a CXCR4-dependent mechanism with a synergistic effect. Their combination activated HIF-1α through the nuclear factor κB pathway. IL-17 enhanced invasion through MMP2 induction as demonstrated using siRNA. Finally, hypoxia genes were overexpressed in the blood of RA patients., Conclusion: IL-17A, specifically when combined with TNFα may contribute to the progression of RA, notably through their effect on synoviocyte aggressiveness. Part of this effect results from activation of the CXCR4/stromal cell-derived factor 1 and hypoxia-mediated pathways.

Objective: From an immunologic standpoint, the mechanisms by which treatment with tocilizumab (TCZ), a humanized anti-interleukin-6 (anti-IL-6) receptor antibody, results in improvement in rheumatoid arthritis (RA) patients are still not fully understood. In vitro studies and studies in mouse models have demonstrated the critical role of IL-6 in Th17 cell differentiation. Th17 lymphocytes have been shown to be strongly involved in RA pathogenesis, and the purpose of this study was to investigate the effect of IL-6 blockade on the balance between Th17 cells and Treg cells in patients with active RA., Methods: Patients with active RA for whom TCZ had been prescribed by a rheumatologist were enrolled in this study. Phenotypic analyses of T cell populations were performed, and the Disease Activity Score in 28 joints (DAS28) was assessed. Serum cytokine levels and other parameters of inflammation were measured before the first infusion and after the third infusion of TCZ (8 mg/kg)., Results: Compared to controls, levels of Th17 cells (CD4+IL-17+) were increased and Treg cells (CD4+CD25(high) FoxP3+) were decreased in the peripheral blood of patients with active RA. The suppressive function of circulating Treg cells was not impaired in patients with active RA. TCZ treatment induced a significant decrease in the DAS28 associated with a significant decrease in the percentage of Th17 cells (from a median of 0.9% to 0.45%; P = 0.009) and an increase in the percentage of Treg cells (from a median of 3.05% to 3.94%; P = 0.0039) in all patients., Conclusion: This study demonstrates for the first time that inhibition of IL-6 function by TCZ corrects the imbalance between Th17 cells and Treg cells in patients with RA., (Copyright © 2012 by the American College of Rheumatology.)

Objectives: Rheumatoid arthritis is characterized by an early inflammatory related periarticular osteopenia. A new high resolution direct digital X-ray device has been recently developed to provide bone texture analysis which is designed to assess changes in trabecular bone architecture. For the first time, we have evaluated trabecular bone texture impairment in rheumatoid arthritis patients compared to healthy controls., Methods: In this cross-sectional study, the reproducibility was assessed by three separate digital X-rays of the right hand, with repositioning in 14 late rheumatoid arthritis patients and 14 healthy subjects. Then, trabecular bone texture of the MCP2 and MCP3 from patients enrolled in a prospective cohort of 78 rheumatoid arthritis patients was compared with that of 50 healthy subjects, using three texture parameters: Hmean, co-occurrence and run-length., Results: The coefficients of variation of the high resolution direct digital X-ray measurements ranged from 0.5 to 1.8%. Only the Hmean parameter was significantly decreased in rheumatoid arthritis patients compared to healthy subjects at MCP2 (0.637±0.040 vs. 0.654±0.032, P<0.05) and at MCP3 (0.646±0.044 vs. 0.665±0.037, P<0.05). This reduction was significantly correlated to disease activity., Conclusions: This study demonstrated both the good reproducibility of the high resolution digital X-ray measurements and the trabecular bone texture impairment at MCP joints in rheumatoid arthritis patients. In addition to provide a high resolution hand radiograph, this technique may represent an interesting tool to easily quantify periarticular osteopenia with a low radiation dose., (Copyright © 2011. Published by Elsevier SAS.)

Objective: Th17 cells have been implicated in rheumatoid arthritis (RA). We hypothesized that the interaction of T cells with bone marrow-derived mesenchymal stem cells (BM-MSCs) or with fibroblast- like synoviocytes (FLS) might, with the help of T cell-secreted inflammatory cytokines (i.e., interleukin-17A [IL-17A], tumor necrosis factor α [TNFα], and/or interferon-γ [IFNγ]), promote Th17 cell expansion and activation., Methods: Peripheral blood mononuclear cells (PBMCs) from healthy blood donors were cocultured with BM-MSCs or FLS from RA patients or osteoarthritis (OA) patients. Cocultures were exposed to phytohemagglutinin with or without IL-17A, TNFα, or IFNγ. Quantitative reverse transcription-polymerase chain reaction analysis, enzyme-linked immunosorbent assay, and cytofluorometry were used to measure IL-17A production., Results: Interaction of PBMCs with BM-MSCs inhibited Th1 and Th2 responses, but promoted Th17 cell expansion, as early as 24 hours, as demonstrated by increases in retinoic acid receptor-related orphan nuclear receptor γ or IL-17A messenger RNA (mRNA) levels, IL-17A secretion levels, and IL-17A-secreting cell frequency, as well as by T cell switching to the Th17 pathway after 2 rounds of stimulation with MSCs. IL-17A production was also increased in PBMCs stimulated with anti-CD3 plus anti-CD28 or in isolated CD3+ or CD45RO+ T cells, thus demonstrating the role of T cell activation. Levels of mRNA for IL-6, IL-8, and IL-1β were further amplified when T cell-secreted inflammatory cytokines were added. Interestingly, OA FLS or RA FLS also enhanced IL-17A and IL-6 production, but only RA FLS enhanced IFNγ and IL-1β production. We further demonstrated that MSC-mediated Th17 promotion requires caspase 1 activation by using an inhibitory peptide and measuring its activity., Conclusion: We found that the interaction of MSCs or FLS with T cells promotes the activation and expansion of Th17 cells through caspase 1 activation. Since proinflammatory and T cell-secreted inflammatory cytokines are also amplified, this mechanism may participate in the chronicity of RA., (Copyright © 2012 by the American College of Rheumatology.)

Rheumatoid arthritis (RA) is one of the most appropriate conditions for the application of personalised medicine as a high degree of heterogeneity has been recognised, which remains to be explained. Such heterogeneity is also reflected in the large number of treatment targets and options. A growing number of biologics as well as small molecules are already in use and there are promising new drugs in development. In order to make the best use of treatment options, both targeted and non-targeted biomarkers have to be identified and validated. To this aim, new rules are needed for the interaction between academia and industry under regulatory control. Setting up multi-centre biosample collections with clear definition of access, organising early, possibly non-committing discussions with regulatory authorities, and defining a clear route for the validation, qualification and registration of the biomarker-drug combination are some of the more critical areas where effective collaboration between the drug industry, academia and regulators is needed.

Rheumatoid arthritis (RA) is a chronic inflammatory disease where the contribution of T cells is now supported by clinical results. Among the cytokines produced by T cells, interleukin (IL)-17A (previously known as IL-17) and IL-17F constitute the signature cytokines of the newly described Th17 T helper cell subset. While the effects of IL-17A on RA synoviocytes been well described, those of IL-17F remain less studied. The present review describes the effects of IL-17A and IL-17F on synoviocytes and their contribution to RA pathogenesis. Although IL-17F is less active than IL-17A when used alone, IL-17A and IL-17F induce in synoviocytes a rather similar expression pattern in the presence of tumour necrosis factor α. They enhance their response by stabilising mRNA of cytokines and enhancing receptor expression. They increase the migration, chemokine gene expression and invasiveness of synoviocytes. They contribute to disease chronicity by inhibiting synoviocyte apoptosis. Finally, they enhance metalloprotease secretion leading to cartilage damage. These properties support the combined inhibition of IL-17A and -F to control RA inflammation and joint destruction.

Objective: The aim of this study was to compare the effects of interleukin (IL)-17A and IL-17F on gene expression and signalling in human rheumatoid arthritis (RA) synoviocytes., Methods: IL-17A- and IL-17F-induced mRNA expression was analysed using Affymetrix microarrays. IL-6 and IL-8 secretion was evaluated by ELISA. Inhibition of two receptors (IL-17RA and IL-17RC) was achieved by small interfering RNA (saran). The effects on mitogen-activated protein kinase (MAPK), activator protein 1 (AP-1) and nuclear factor κB (NF-κB) expression and activation were evaluated by western blotting, qRT-PCR and DNA binding assay., Results: IL-17A and IL-17F induced a molecular pattern characterised by 27 inflammation-related genes for IL-17F and 165 for IL-17A. Virtually all IL-17A and IL-17F inducible genes were dependent on NF-κB activation, whereas a small number were modulated by p38. IL-17A induced activation of all three MAPKs (ERK, p38 and JNK) and downstream transcription factors AP-1 and p65 NF-κB. IL-17F was less potent but induced activation of p50 NF-κB. IL-17A was more potent at inducing IL-6 secretion than IL-17F, which was inactive alone. IL-17A and, to a lesser extent, IL-17F induced TRAF6 but not MyD88. Inhibition of either IL-17RA or IL-17RC expression via siRNA led to near complete abrogation of IL-6 expression mediated by IL-17A and the combination of IL-17F and tumour necrosis factor α., Conclusion: Like IL-17A, IL-17F regulates proinflammatory gene expression by a very similar but not identical signalling pathway involving IL-17RA and IL-17RC.

Background: The analysis of gene expression data shows that many genes display similarity in their expression profiles suggesting some co-regulation. Here, we investigated the co-expression patterns in gene expression data and proposed a correlation-based research method to stratify individuals., Methodology/principal Findings: Using blood from rheumatoid arthritis (RA) patients, we investigated the gene expression profiles from whole blood using Affymetrix microarray technology. Co-expressed genes were analyzed by a biclustering method, followed by gene ontology analysis of the relevant biclusters. Taking the type I interferon (IFN) pathway as an example, a classification algorithm was developed from the 102 RA patients and extended to 10 systemic lupus erythematosus (SLE) patients and 100 healthy volunteers to further characterize individuals. We developed a correlation-based algorithm referred to as Classification Algorithm Based on a Biological Signature (CABS), an alternative to other approaches focused specifically on the expression levels. This algorithm applied to the expression of 35 IFN-related genes showed that the IFN signature presented a heterogeneous expression between RA, SLE and healthy controls which could reflect the level of global IFN signature activation. Moreover, the monitoring of the IFN-related genes during the anti-TNF treatment identified changes in type I IFN gene activity induced in RA patients., Conclusions: In conclusion, we have proposed an original method to analyze genes sharing an expression pattern and a biological function showing that the activation levels of a biological signature could be characterized by its overall state of correlation.

Background: The use of TNF inhibitors has been a major progress in the treatment of chronic inflammation. However, not all patients respond. In addition, response will be often lost when treatment is stopped. These clinical aspects indicate that other cytokines might be involved and we focus here on the role of IL-17. In addition, the chronic nature of joint inflammation may contribute to reduced response and enhanced chronicity. Therefore we studied the capacity of IL-17 to regulate synoviolin, an E3 ubiquitin ligase implicated in synovial hyperplasia in human rheumatoid arthritis (RA) FLS and in chronic reactivated streptococcal cell wall (SCW)-induced arthritis., Methodology/principal Findings: Chronic reactivated SCW-induced arthritis was examined in IL-17R deficient and wild-type mice. Synoviolin expression was analysed by real-time RT-PCR, Western Blot or immunostaining in RA FLS and tissue, and p53 assessed by Western Blot. Apoptosis was detected by annexin V/propidium iodide staining, SS DNA apoptosis ELISA kit or TUNEL staining and proliferation by PCNA staining. IL-17 receptor A (IL-17RA), IL-17 receptor C (IL-17-RC) or synoviolin inhibition were achieved by small interfering RNA (siRNA) or neutralizing antibodies. IL-17 induced sustained synoviolin expression in RA FLS. Sodium nitroprusside (SNP)-induced RA FLS apoptosis was associated with reduced synoviolin expression and was rescued by IL-17 treatment with a corresponding increase in synoviolin expression. IL-17RC or IL-17RA RNA interference increased SNP-induced apoptosis, and decreased IL-17-induced synoviolin. IL-17 rescued RA FLS from apoptosis induced by synoviolin knockdown. IL-17 and TNF had additive effects on synoviolin expression and protection against apoptosis induced by synoviolin knowndown. In IL-17R deficient mice, a decrease in arthritis severity was characterized by increased synovial apoptosis, reduced proliferation and a marked reduction in synoviolin expression. A distinct absence of synoviolin expressing germinal centres in IL-17R deficient mice contrasted with synoviolin positive B cells and Th17 cells in synovial germinal centre-like structures., Conclusion/significance: IL-17 induction of synoviolin may contribute at least in part to RA chronicity by prolonging the survival of RA FLS and immune cells in germinal centre reactions. These results extend the role of IL-17 to synovial hyperplasia.

Objectives: A new high-resolution peripheral quantitative CT (HR-pQCT) system allows for in vivo assessment of bone microarchitecture and volumetric bone mineral density (vBMD) with an 82 microm isotropic resolution. With this device, the microarchitecture impairment was evaluated in patients with rheumatoid arthritis (RA) in comparison with healthy controls and measured the erosion volume at metacarpal heads (MCPs)., Methods: In this cross-sectional study, the reproducibility was first assessed by 3 HR-pQCT exams with repositioning in 14 patients with late RA and 14 healthy subjects. Then, HR-pQCT parameters were measured in a group of 93 patients with RA and 31 healthy controls. Two RA subgroups were distinguished: early RA (disease duration < or =2 years) (n=36) and late RA (n=57) and compared them to healthy controls., Results: The precision of the HR-pQCT volumetric measurements as assessed with coefficient of variation ranged from 0.7% to 1.8% in patients with late RA and from 0.6% to 1.4% in healthy subjects at MCPs. Total and trabecular vBMD and trabecular thickness were significantly decreased in patients with RA compared to healthy subjects and were significantly correlated to disease activity. The erosion volume was highly correlated to a semiquantitative assessment using the Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) scoring system applied to the HR-pQCT slices., Conclusions: This study demonstrated the good reproducibility of the HR-pQCT volumetric measurements at MCPs and confirmed the involvement of trabecular compartment in periarticular osteopoenia. Thus, HR-pQCT appears interesting to simultaneously assess differences in bone volumetric density, microarchitecture and erosions.

Background: Patients with rheumatoid arthritis (RA) have a systemic Th1 defect associated with inflammation., Objective: To examine the hypothesis that interleukin 17 (IL-17) contributes to this defect., Methods: IL-17 effects on Th1 markers were examined on T-bet and interferon gamma (IFNgamma) expression in peripheral blood mononuclear cells (PBMCs) from patients with RA or healthy controls (HC). Receptor specificities were determined by analysis of the Th1-specific IL-12 receptor beta2 (IL-12Rbeta2), Th17-specific IL-23R and the common IL-12Rbeta1 chain expression. Effects of IL-17 or IFNgamma on IL-6, IL-1, IL-8, matrix metalloproteinase-8 (MMP-8) were measured by real-time RT-PCR in RA synovial cells., Results: RA PBMCs were less responsive to IL-12-induced IFNgamma than HC PBMCs. IL-12 hyporesponsiveness was increased by IL-17 treatment associated with a selective reduction in IL-12Rbeta2, but not IL-23R, IL-12Rbeta1 or T-bet, which was reversed with IL-17R inhibition. IL-17 inhibited IL-12Rbeta2 expression in developing Th1 cells. In RA synovial cells, IL-17 induced IL-6, IL-1, IL-8 and MMP-8, whereas IFNgamma had minimal or inhibitory effects., Conclusion: In RA, IL-12 hyporesponsiveness is associated with IL-17R-mediated downregulation of IL-12Rbeta2 expression. IL-17 may reinforce Th17 lineage commitment and proinflammatory and destructive effects through Th1 inhibition and positive feedback effects in RA synovial cells. Anti-inflammatory effects of IL-17/IL-17R antagonism may include the restoration of protective Th1 responses.

Tumor necrosis factor alpha (TNFalpha) is a pro-inflammatory cytokine that plays pivotal roles in regulating the inflammatory response in rheumatoid arthritis (RA). Intensive studies on TNFalpha-driven inflammation processes have led to the development of TNFalpha blockers for RA treatment. However, response to these therapies is heterogeneous with roughly two-thirds of patient response and one-third non-response. Given the destructive nature of RA, the risk of adverse effects, and considerable costs for TNFalpha blocker therapy, there is a strong need to identify predictors of response prior to start the TNFalpha blocker therapy. Here we review several studies focused on predicting the response to TNFalpha blockers. Demographic, clinical, radiological, blood, genetic or synovial tissue biomarkers were studied to find some predictive biomarkers of TNFalpha blocker response. Unfortunately, results from these studies are heterogeneous. Discrepancy between these studies can be explained in part to the heterogeneity between the studies. As difference in the response criteria used, the delay of efficacy for the primary endpoint, and the genetic background of each population were all observed. Nevertheless, a high local and systemic level of TNFalpha prior to TNFalpha blocker therapy seems to be associated with a good clinical response. However, to validate these results, additional studies using independent and large cohorts are needed., (Copyright 2010 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)

Inflammatory related hand bone damage in rheumatoid arthritis is characterized by erosions and periarticular osteoporosis and can lead to substantial clinical disability. So far, conventional radiograph has been considered to be the gold standard for detecting bone damage and monitoring disease progression, but it lacks sensitivity. So other techniques have been recently developed to identify erosions earlier, to be able to change therapy; if necessary. This report reviews, in its first part, the different ways of detecting erosions such as conventional radiograph, magnetic resonance imaging or imaging ultrasonography and, in its second part, the techniques used for the assessment of hand periarticular osteoporosis like dual-X-ray absorptiometry, digital-X-ray radiogrammetry or quantitative ultrasonography., (Copyright 2010 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)