The Prevalence Of Osteoporosis Is Low in Adult Cutaneous Mastocytosis Patients.

BACKGROUND: Systemic mastocytosis (SM) is a clonal disorder of mast cells (MCs) frequently associated with vertebral osteoporosis (OP) and subsequent vertebral fractures (VFs). The natural history of this OP remains unclear. Importantly, we do not know whether OP represents an early event triggered alongside MC abnormalities, and whether MC clonality is sufficient to trigger osteoporosis. OBJECTIVE: To describe OP in patients with medullar clonality in cutaneous mastocytosis (CM) and monoclonal mast cell activation syndrome (MMAS) and to compare their osteoporosis characteristics with those of nonadvanced SM patients (bone marrow mastocytosis and indolent systemic mastocytosis). METHODS: We retrospectively analyzed clinical, biological, and densitometric data of 27 CM, 13 MMAS, and 135 SM patients from the Mastocytosis Expert Center (CEREMAST) in Toulouse, France. RESULTS: The OP (respectively 3.7, 30.8, and 34.1%) and VFs (0.0%, 15.4%, and 20%) were less frequent in CM than in MMAS and SM, despite the presence of clonal MCs in the bone marrow. Most patients with OP and VFs in the non-SM groups had the usual risk factors for OP. Interestingly, the only non-SM patient with a typical SM-like OP had high bone marrow tryptase, developed bone marrow KIT mutation during follow-up, and had a family history of SM. Our data show that OP is not a common clinical finding in CM but is frequent in MMAS. When OP and VFs occur in CM and MMAS patients, they differ from the usual phenotype of SM bone fragility. CONCLUSIONS: Our findings suggest that, in most CM patients, the meaning and management of OP differs from that of OP in MMAS and nonadvanced SM. Prospective longitudinal studies and the validation of predictors are needed to identify CM and MMAS patients developing SM-related OP.

Characteristics of the (Auto)Reactive T Cells in Rheumatoid Arthritis According to the Immune Epitope Database.

T cells are known to be involved in the pathogenesis of rheumatoid arthritis (RA). Accordingly, and to better understand T cells' contribution to RA, a comprehensive review based on an analysis of the Immune Epitope Database (IEDB) was conducted. An immune CD8+ T cell senescence response is reported in RA and inflammatory diseases, which is driven by active viral antigens from latent viruses and cryptic self-apoptotic peptides. RA-associated pro-inflammatory CD4+ T cells are selected by MHC class II and immunodominant peptides, which are derived from molecular chaperones, host extra-cellular and cellular peptides that could be post-translationally modified (PTM), and bacterial cross-reactive peptides. A large panel of techniques have been used to characterize (auto)reactive T cells and RA-associated peptides with regards to their interaction with the MHC and TCR, capacity to enter the docking site of the shared epitope (DRB1-SE), capacity to induce T cell proliferation, capacity to select T cell subsets (Th1/Th17, Treg), and clinical contribution. Among docking DRB1-SE peptides, those with PTM expand autoreactive and high-affinity CD4+ memory T cells in RA patients with an active disease. Considering original therapeutic options in RA, mutated, or altered peptide ligands (APL) have been developed and are tested in clinical trials.

Sjögren's syndrome associated with erosive rheumatoid arthritis alters its prognosis and long-term therapeutic response: a case-control study.

10% of rheumatoid arthritis (RA) cases are associated to so-called secondary Sjögren's syndrome (SS). These RA cases have higher DAS, fewer remissions. Is this linked to a poor response to DMARDs (disease-modifying anti-rheumatic drugs)? No study has addressed this question to date. Does the association between secondary Sjögren's syndrome (SS) and rheumatoid arthritis (RA) affect the therapeutic response to DMARDs and long-term prognosis? We conducted a retrospective case-control study: 39 RA associated with SS was (anti-SSA antibodies and/or Chisolm stage III or IV) were compared to 39 isolated cases of erosive RA matched by age, duration of progression and gender. The DAS CRP was higher in the RA + SS group in patients with disease progression of 16 years: 2.6 (1.5-4.5) compared to the RA group: 1.6 (1.3-2.8) (p = 0.0001) while fewer patients were in remission: 61 vs. 92% (p = 0.002). A higher number of B DMARDs have been prescribed: RA + SS = 3.04 (1-7); RA = 1.7 (1-5) (p = 0.004). Anti-TNFs are less effective when RA is associated with SS: 30 vs. 70%. Conversely, Rituximab is more effective when RA is associated with SS: 80 vs. 30%. Erosive RA-related SS exacerbates the clinical course of the condition: higher DAS, fewer remissions. This is linked to reduced treatment efficacy: higher number of DMARDs prescribed, reduced efficacy of anti-TNF drugs. RA-related SS could modify sensitivity to biotherapies: lower percentage of remissions and resistance to anti-TNF drugs.

Increased Cardiovascular Risk in Psoriatic Arthritis: Results From a Case-Control Monocentric Study.

Background: Psoriatic arthritis (PsA) is associated with increased cardiovascular morbidity and mortality. The aims of our real-life study were to compare the prevalence of cardiovascular risk factors (CVRFs) and cardiovascular events (CVEs) among patients with PsA with a control population, to evaluate the impact of correcting factors in equations that assess cardiovascular risk (CVR) in PsA, and to determine the percentage of patients who reach the LDLc target as indicated by the European guidelines. Methods: In this observational cross-sectional monocentric case-control study, we used a standardized procedure to systematically assess patients with PsA aged 25-85 years who met the Classification for Psoriatic Arthritis (CASPAR) criteria. Controls were extracted from the MOnitoring NAtionaL du rISque Artériel (MONALISA) study. We compared the prevalence of CVRFs, CVEs, the CVR, and the percentage of patients reaching recommended LDLc target in both populations. The CVR was first assessed using SCORE and QRISK2 equations. Then, the SCORE equation was corrected by applying a 1.5 multiplication factor, as recommended by EULAR for rheumatoid arthritis (SCORE-PsA), and the QRISK2 was corrected using the "rheumatoid arthritis" item (QRISK2-PsA). Results: A total of 207 PsA and 414 controls were included. CVRFs and CVEs were more frequent in the PsA group. After controlling for age and gender, atherothrombotic disease was increased in the PsA population (SCORE p = 0.002, QRISK2 p = 0.001). Using the SCORE-PsA increased the percentage of patients with a high or very high CVR from 39.3 to 45.3% in the PsA group. Similarly, using the QRISK2-PsA increased the percentage of patients with a CVR ≥ 10% from 44.9 to 53.2%. The percentages of patients with PsA with high LDLc in the high and very high CVR groups were not significantly different from controls, despite a trend in favor of patients with PsA. Of the 83 PsA with a QRISK2 ≥ 10%, only 22.9% were treated with statin vs. 35.8% of the 134 controls. The QRISK2-PsA score did not alter these results. Conclusion: In real-life, patients with PsA have a higher prevalence of CVRFs, as well as a higher prevalence of CVEs compared to the general population. The CVR is higher in the PsA population than in the controls either using the SCORE and QRISK2 equations or using the corrected SCORE- PsA and QRISK2-PsA equations.

Factors associated with drug-free remission at 5-year in early onset axial spondyloarthritis patients: Data from the DESIR cohort.

OBJECTIVES: To assess the frequency of patients in drug-free remission at 5 years in a cohort of early axial SpA, and the factors associated with this remission. METHODS: Patients: patients included in the DESIR (DEvenir des Spondyloarthropathies Indifférenciées Récentes) cohort undergoing the 5-year visit were selected for this analysis. Definition of 5-year drug-free remission: (1) all patients in ASAS partial remission and/or ASDAS<1.3 at 5 year visit and (2) taking no disease modifying anti-rheumatic drugs at the 5-year visit and (3) with an ASAS-NSAID score≤25 at the 5-year visit. DATA ANALYSIS: the proportion of patients in drug-free remission was described. The association between demographic, clinical, biological and imaging characteristics and drug-free remission at 5 years was assessed by logistic regression. RESULTS: Of the 412 patients included in this analysis, 73 (18%) were in drug-free remission at the 5-year visit. The baseline clinical factors associated with the chances to be in drug-free remission at the 5-year visit were symptom duration (OR=0.66 [95%CI%: 0.44-0.97]), lower HAQ-AS score (OR=0.32 [0.12-0.78]), lower ASDAS score (OR=0.55 [95%CI: 0.34-0.86]), ASAS-NSAID score (OR=0.91 [95%CI: 0.82-0.99]). Furthermore, anti-TNF use (OR=0.20 [95%CI: 0.08-0.42]) during the follow-up decreased the chances of being in 5-year drug-free remission. CONCLUSION: The probability of being in drug free remission at 5 year when beginning an axial SpA is low and is associated with lower baseline disease activity and functional scores, while starting an anti-TNF is associated with poor chances of later being in drug-free remission. NCT01648907.

Repolarization of Unbalanced Macrophages: Unmet Medical Need in Chronic Inflammation and Cancer.

Monocytes and their tissue counterpart macrophages (MP) constitute the front line of the immune system. Indeed, they are able to rapidly and efficiently detect both external and internal danger signals, thereby activating the immune system to eradicate the disturbing biological, chemical, or physical agents. They are also in charge of the control of the immune response and account for the repair of the damaged tissues, eventually restoring tissue homeostasis. The balance between these dual activities must be thoroughly controlled in space and time. Any sustained unbalanced response of MP leads to pathological disorders, such as chronic inflammation, or favors cancer development and progression. In this review, we take advantage of our expertise in chronic inflammation, especially in rheumatoid arthritis, and in cancer, to highlight the pivotal role of MP in the physiopathology of these disorders and to emphasize the repolarization of unbalanced MP as a promising therapeutic strategy to control these diseases.

Evidence for tmTNF reverse signaling in vivo: Implications for an arginase-1-mediated therapeutic effect of TNF inhibitors during inflammation.

In order to ascertain the significance of transmembrane tumor necrosis factor (tmTNF) reverse signaling in vivo, we generated a triple transgenic mouse model (3TG, TNFR1-/-, TNFR2-/-, and tmTNFKI/KI) in which all canonical tumor necrosis factor (TNF) signaling was abolished. In bone-marrow-derived macrophages harvested from these mice, various anti-TNF biologics induced the expression of genes characteristic of alternative macrophages and also inhibited the expression of pro-inflammatory cytokines mainly through the upregulation of arginase-1. Injections of TNF inhibitors during arthritis increased pro-resolutive markers in bone marrow precursors and joint cells leading to a decrease in arthritis score. These results demonstrate that the binding of anti-TNF biologics to tmTNF results in decreased arthritis severity. Collectively, our data provide evidence for the significance of tmTNF reverse signaling in the modulation of arthritis. They suggest a complementary interpretation of anti-TNF biologics effects in the treatment of inflammatory diseases and pave the way to studies focused on new arginase-1-dependent therapeutic targets.

Apremilast inhibits inflammatory osteoclastogenesis.

OBJECTIVES: Psoriatic arthritis (PsA) is associated with bone erosion and inflammation-induced bone loss, which are mediated by osteoclasts (OC) and modulated by inflammatory cytokines. Apremilast (APR) (a selective phosphodiesterase 4 inhibitor) is efficacious in PsA and acts by inhibiting cytokine production. However, there are no direct data informing whether and how APR affects osteoclast formation in humans. METHODS: Osteoclastogenic cytokine production by activated human peripheral blood mononuclear cells (PBMCs) was measured in the presence and absence of APR. Effects of APR on osteoclast differentiation were tested (i) in co-cultures of activated PBMCs and human CD14+ blood monocytes as well as (ii) in CD14+ blood monocytes stimulated with activated-PBMCs supernatant, TNF or IL-17A. Bone resorption was measured on OsteoAssay plates. Effects of APR on ex vivo osteoclast differentiation were compared in PsA, pre-PsA and psoriasis patients, as well as in healthy controls. RESULTS: APR significantly impaired the expression of key osteoclastogenic cytokines in activated PBMCs. Furthermore, APR dose-dependently and significantly inhibited activated PBMC-driven osteoclast differentiation and ex vivo osteoclast differentiation of PBMCs derived from PsA and pre-PsA patients, but not from psoriasis patients or healthy controls. TNF and IL-17A-enhanced osteoclastogenesis and osteolytic activity of CD14+ blood monocytes from PsA patients was also significantly inhibited by APR. Finally, APR inhibited expression of the key osteoclast fusion protein dendritic cell-specific transmembrane protein. CONCLUSION: Phosphodiesterase 4 targeting by APR not only inhibits osteoclastogenic cytokine production, but also directly suppresses inflammation-driven osteoclastogenesis. These data provide initial evidence that APR has the potential to provide a direct bone protective effect in PsA.

Psychiatric Disorders and Hydroxychloroquine for Coronavirus Disease 2019 (COVID-19): A VigiBase Study.

INTRODUCTION: In the stressful context of the coronavirus disease 2019 (COVID-19) pandemic, some reports have raised concerns regarding psychiatric disorders with the use of hydroxychloroquine. In this study, we reviewed all psychiatric adverse effects with hydroxychloroquine in COVID-19 patients, as well as in other indications, reported in VigiBase, the World Health Organization's (WHO) global database of individual case safety reports. METHODS: First, we analyzed all psychiatric adverse effects, including suicide, of hydroxychloroquine in COVID-19 patients reported to 16 June 2020. We also performed disproportionality analysis to investigate the risk of reporting psychiatric disorders with hydroxychloroquine compared with remdesivir, tocilizumab, or lopinavir/ritonavir prescribed in COVID-19 patients. We used reporting odds ratios (RORs) and their 95% confidence intervals (CIs) to calculate disproportionality. Second, we sought to examine the psychiatric safety profile of hydroxychloroquine in other indications (before 2020). RESULTS: Among the 1754 reports with hydroxychloroquine in COVID-19 patients, we found 56 psychiatric adverse effects. Half of these adverse effects were serious, including four completed suicides, three cases of intentional self-injury, and 12 cases of psychotic disorders with hallucinations. Compared with remdesivir, tocilizumab, or lopinavir/ritonavir, the use of hydroxychloroquine was associated with an increased risk of reporting psychiatric disorders (ROR 6.27, 95% CI 2.74-14.35). Before 2020, suicide was the main cause of death among all adverse drug reactions reported with hydroxychloroquine, followed by cardiac adverse effects (cardiomyopathy) and respiratory failure. CONCLUSIONS: This pharmacovigilance analysis suggests that COVID-19 patients exposed to hydroxychloroquine experienced serious psychiatric disorders, and, among these patients, some committed suicide. Further real-world studies are needed to quantify the psychiatric risk associated with hydroxychloroquine during the COVID-19 pandemic.

Biological DMARD efficacy in psoriatic arthritis: a systematic literature review and meta-analysis on articular, enthesitis, dactylitis, skin and functional outcomes.

OBJECTIVES: There is no hierarchy in the use of biotherapies (bDMARDs) in psoriatic arthritis (PsA) and no published head-to-head comparative studies. Our purpose is to evaluate the respective efficacy of TNF inhibitors, IL12/23 inhibitors (ustekinumab), IL17 inhibitors (secukinumab, ixekizumab) and CTLA4Ig (abatacept) on articular, enthesitis, dactylitis, skin and functional outcomes in PsA. METHODS: Randomised controlled trials assessing bDMARDs in PsA were selected through the MedLine, Cochrane and Embase databases. ACR20/50/70 and PASI75/90 response rates, enthesitis and dactylitis reduction rates and HAQ-DI mean reductions were collected. Pooled meta-analyses were performed to assess relative risks (RR) with their 95% confidence interval (95%CI) for each class of bDMARDs in comparison with placebo. RESULTS: 17 RCTs were analysed. Compared to placebo, all bDMARDs showed higher ACR20 response rates, with RRs ranging from 1.77 (1.31, 2.39) to 3.21 (2.52, 4.08), and a greater HAQ-DI mean reduction. TNF inhibitors, secukinumab and IL17 inhibitors showed higher ACR50/70 and PASI75/90 response rates. TNF inhibitors, secukinumab and IL17 inhibitors showed higher enthesitis resolution rates and only TNF inhibitors and IL17 inhibitors showed higher dactylitis resolution rates, with RRs ranging from 1.41 (1.02, 1.95) to 2.31 (1.60, 3.34) and from 2.07 (1.38, 3.12) to 2.65 (1.79, 3.94), respectively. CONCLUSIONS: All bDMARDs showed higher ACR20 response rates and better HAQ-DI mean reduction compared to placebo. This meta-analysis highlights the variability of bDMARD efficacy on ACR50/70, PASI75/90 and enthesitis or dactylitis response rates. Head-to-head studies are needed to draw definitive conclusions on potential efficacy-related differences between bDMARDs in PsA.

No impact of anti-Rank ligand and PTH analogs on cardiovascular risk in postmenopausal osteoporosis: a systematic literature review and meta-analysis.

The mutual effects of drugs used in osteoporosis and cardiovascular diseases are a point of interest. A literature review and meta-analysis were conducted to address the impact of PTH analogs and anti-Rank ligand on cardiovascular events and overall mortality in individuals with idiopathic osteoporosis; these treatments do not appear to have any effect. INTRODUCTION: Two meta-analyses have been conducted to explore the cardiovascular effects of bisphosphonates. There is no review for other osteoporosis treatments. A literature review and meta-analysis were conducted to address the impact of PTH analogs and anti-Rank ligand on cardiovascular events and overall mortality in individuals with idiopathic osteoporosis. METHODS: A systematic review was conducted in December 2017 in the PubMed, Embase, and Cochrane databases and updated on PubMed in July 2019, selecting trials with a treatment and a control group. We also conducted a search for abstracts of the French Rheumatology Society, American College of Rheumatology, and European League Against Rheumatism's annual meetings over the past 4 years. The main endpoint was the occurrence of cardiovascular events; the secondary was mortality (all causes). RESULTS: Of the 2782 reports initially found, 16 articles were used for the meta-analysis (6 for the anti-Rank ligand and 10 for the PTH analog group). After meta-analysis, there was no significant difference between the placebo group and the anti-Rank ligand group for overall mortality (p = 0.13), the combined endpoint (overall mortality, coronary artery disease, and stroke; p 0.77), and the individual risk of coronary artery disease (p 0.53), arrhythmia (p 0.95), and stroke (p 0.62). After meta-analysis, there was no significant difference between the placebo group and the PTH analogs group for overall mortality (p 0.77), the combined endpoint (p = 0.95), and the individual risk of coronary artery disease (p = 0.74), arrhythmia (p = 0.28), and stroke (p = 0.61). CONCLUSIONS: The anti-Rank ligand and PTH analogs have no impact on cardiovascular risk and overall mortality in idiopathic osteoporosis. To better answer the question whether these treatments can reduce the long-term cardiovascular risk, further comparative studies with longer duration are required.

Inhibition of Osteoclastogenesis by the RNA-Binding Protein QKI5: a Novel Approach to Protect from Bone Resorption.

Increased osteoclastogenesis is a common feature of bone erosion, notably in osteoporosis but also in inflammatory diseases such as rheumatoid arthritis (RA) and osteoarticular infections. Human cytomegalovirus (HCMV) infection has been described to impair monocyte differentiation into macrophages and dendritic cells. However, its effect on monocyte-derived osteoclasts is yet to be determined. We showed here that in vitro HCMV infection is associated with an inhibition of osteoclastogenesis through decreased expression of colony stimulating factor 1 receptor (CSF-1R) and RANK in monocytes, which was mediated by an upregulation of quaking I-5 protein (QKI-5), a cellular RNA-interacting protein. We found that deliberate QKI5 overexpression in the absence of HCMV infection is able to decrease CSF-1R and RANK expression, leading to osteoclastogenesis inhibition. Finally, by using lentiviral vectors in a calvarial bone erosion mouse model, we showed that QKI5 inhibits bone degradation. This work identifies QKI5 as a strong inhibitor of bone resorption. Future research will point out whether QKI5 could be a target for bone pathologies. © 2019 American Society for Bone and Mineral Research.

Rheumatoid Synovial Fluids Regulate the Immunomodulatory Potential of Adipose-Derived Mesenchymal Stem Cells Through a TNF/NF-κB-Dependent Mechanism.

Introduction: Adipose-derived mesenchymal stem cells (ADSC) have been shown to have remarkable immune-modulating effects. However, their efficacy in clinical trials has yet to be fully demonstrated. This could be due to a lack of a proper inflammatory environment in vivo that primes ADSC. Here, we define how the articular microenvironment of rheumatoid arthritis (RA) patients modulates the therapeutic efficiency of ADSC. Methods: Synovial fluids (SF) were collected from 8 RA patients, 2 Spondyloarthritis patients and one control synovial fluid from a patient undergoing traumatic-related surgery. SF inflammatory status was determined by routine analysis and quantification of pro-inflammatory cytokines. ADSC were first treated with SF and ADSC proliferation and gene expression of immunomodulatory factors was evaluated. In order to determine the mechanisms underlying the effect of SF on ADSC, tumor necrosis factor (TNF), interleukin-6 (IL-6), and NF-κB neutralization assays were performed. To evaluate the effect of SF on ADSC functions, ADSC were pre-treated with SF and then co-cultured with either macrophages or T cells. The modulation of their phenotype was assessed by flow cytometry. Results: Pro-inflammatory RASF maintained the proliferative capacity of ADSC and upregulated the gene expression of cyclooxygenase-2 (COX2), indoleamine-1,2-dioxygenase (IDO), interleukin-6 (IL-6), tumor-necrosis factor stimulated gene 6 (TSG6), intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and programmed death-ligand 1 (PD-L1), all factors involved in ADSC immunomodulatory potential. The RASF-induced gene expression was mainly mediated by TNF alone or in combination with IL-6 and signaled through the NF-κB pathway. Conditioning ADSC with pro-inflammatory RASF enhanced their ability to induce CD4+Foxp3+CD25high regulatory T cells (Tregs) and inhibit pro-inflammatory markers CD40 and CD80 in activated macrophages. Conclusions: Inflammatory synovial fluids from RA patients had the capacity to modulate ADSC response, to induce Tregs and modulate the phenotype of macrophages. The clinical use of ADSC in affected joints should take into account the influence of the local articular environment on their potential. Having a sufficient pro-inflammatory microenvironment will determine whether optimal immunoregulatory response should be expected. Direct ADSC intra-articular delivery to patients could be a potential strategy to properly prime their immunomodulatory potential and enhance their clinical benefits.

Short-term risk of major adverse cardiovascular events or congestive heart failure in patients with psoriatic arthritis or psoriasis initiating a biological therapy: a meta-analysis of randomised controlled trials.

Objective: The objective was to investigate the short-term risk of major adverse cardiovascular events (MACEs) or congestive heart failure (CHF) in patients with psoriatic arthritis (PsA) or psoriasis initiating a biological therapy. Methods: Screening for the study was carried out using MEDLINE, Cochrane and Embase, from the inception of the database to December 2017. Randomised controlled trials (RCTs) of anti-tumour necrosis factor (TNF), anti-interleukin (IL)12/23, anti-IL23 and anti-IL17 agents for the treatment of PsA or psoriasis were included. Two investigators independently extracted MACEs or CHF data reported during the placebo-controlled phase. The primary outcome measures were the incidence of MACEs or CHF. Results: Of 753 references screened, 62 articles were selected, and 12 articles were added by manual searches. Accordingly 77 RCTs were included in the meta-analysis (MA) (10 174 patient-years (P-Y)). No significant difference was observed in MACE incidences in patients receiving anti-TNF, anti-IL12/23, anti-IL23 or anti-IL17 agents in comparison to the placebo. However, 10 MACEs were observed in the anti-IL12/23 group (1150 P-Y) compared with 1 in the placebo group (652 P-Y), with 0.01 -0.00 to 0.02 event/P-Y risk difference, which is not statistically significant. This trend was not observed in the anti-IL23 group. No significant difference was observed in CHF incidence in patients receiving biological agents in comparison to placebo. Conclusion: This MA of 77 RCTs did not reveal any significant change in the short-term risk of MACE or CHF in patients with PsA or psoriasis initiating a biological therapy.

Polarization of Rheumatoid Macrophages by TNF Targeting Through an IL-10/STAT3 Mechanism.

Macrophages contribute to the pathogenesis of rheumatoid arthritis (RA). They can display different states of activation or "polarization," notably the so-called inflammatory "M1" and the various alternative "M2" polarizations, characterized by distinct functions. Data regarding the effects of RA anti-cytokine biological disease-modifying anti-rheumatic drugs (bDMARDs) on macrophage polarization are scarce. We aimed to assess in vitro modulation of macrophage polarization by bDMARDs targeting pro-inflammatory cytokines in RA. We generated monocyte derived macrophages using blood samples from 20 RA patients with active RA and 30 healthy controls. We evaluated in vitro the impact on M1 inflammatory macrophages of: etanercept (ETA), adalimumab (ADA), certolizumab (CZP), tocilizumab (TCZ), and rituximab (RTX). We assessed the impact on macrophage polarization using flow cytometry and RTqPCR to study the expression of surface markers and perform functional studies of cytokine production, phagocytosis, and negative feedback control of inflammation. Among evaluated bDMARDs, anti-TNF agents modulated the polarization of inflammatory macrophages by decreasing inflammatory surface markers (CD40, CD80) and favoring alternative markers (CD16, CD163, MerTK). Anti-TNF agents also induced alternative functions in macrophages activated in inflammatory condition with (i) the inhibition of inflammatory cytokines (TNF, IL-6, IL-12), (ii) an increase in phagocytosis. These findings were mechanistically related to an increase in early IL-10 production, responsible for higher negative feedback control of inflammation involving SOCS3 and Gas6. This IL-10 effect was STAT3-dependent. Anti-TNF agents not only inhibit in vitro inflammatory functions of macrophages, but also favor resolution of inflammation through polarization toward alternative features specifically involving the IL-10/STAT3 axis.

A single nucleotide polymorphism of IL6-receptor is associated with response to tocilizumab in rheumatoid arthritis patients.

Biological disease-modifying anti-rheumatic drugs (bDMARDs) have changed care of patients with rheumatoid arthritis (RA). However, bDMARDs are costly, can lead to serious infections, and induce a sustained remission in only 30% of RA patients. In this study, we sought to determine if the clinical response to treatment with Tocilizumab (TCZ), an IL-6 inhibitor, varied with genetic background. The efficacy of TCZ was assessed using the European League Against Rheumatism (EULAR) response criteria, measured after 3 months of treatment in two samples of French RA patients (TOCI and ROC studies). Single nucleotide polymorphisms (SNPs) in 21 candidate genes were genotyped using KasPar method (LGC-genomics, UK) and then analyzed to determine their contribution to variation in the response to treatment. One hundred twenty-three patients in the TOCI group (79.8%) and 48 patients in the ROC group (80%) experienced good or moderate EULAR response. The clinical response to treatment was associated with SNP genotype in the gene IL6R, with patients with the homozygous AA-genotype for rs12083537 (IL6R) showing a significantly better response than homozygous or heterozygous patients with the G allele [TOCI: 87.5% of responders for AA genotype vs. 72.2% for AG or GG genotype (p = 0.018); ROC patients: 89.2% of responders for AA genotype vs. 65.2% for AG or GG genotype, p = 0.044]. A meta-analysis combining data from the two cohorts confirmed the lower response rate in patients carrying a copy of the G allele (OR (95% CI) = 0.35 (0.16-0.61), p = 0.001). No association was found with any of the other SNPs tested.

Modulation of T-cell responses by anti-tumor necrosis factor treatments in rheumatoid arthritis: a review.

Tumor necrosis factor (TNF) is a pleiotropic cytokine involved in many aspects of immune regulation. Anti-TNF biological therapy has been considered a breakthrough in the treatment of chronic autoimmune diseases, such as rheumatoid arthritis (RA). In this review, because of the major involvement of T cells in RA pathogenesis, we discuss the effects of anti-TNF biotherapy on T-cell responses in RA patients. We also outline the potential fields for future research in the area of anti-TNF therapy in RA.This could be useful to better understand the therapeutic efficiency and the side effects that are encountered in RA patients. Better targeting of T cells in RA could help set more specific anti-TNF strategies and develop prediction tools for response.