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Objective: To determine if a lumbar musculature deficiency (paravertebral – PVM – and psoas – PM – muscles) is associated with a higher prevalence of vertebral fractures in osteoporotic patients. Methods: To constitute the fracture group, data were collected retrospectively from patients with one or more recent osteoporotic vertebral fractures between T10 and L5 such as non-injected computerized tomography (CT), dual-energy X-ray absorptiometry (DXA). A control group was made by matching the patients on age, bone mineral density measured by DXA and gender. We analyzed PM and PVM atrophy based on cross-sectional area (CSA) adjusted to the body area as well as fatty infiltration on a 3-level scale and the average muscle density in Hounsfield units (HU). Results: One hundred seventeen patients were included in each group. The fracture group had a lower PVM CSA than the control group (2197.92 ± 460.19 versus 2335.20 ± 394.42 mm2.m−2, respectively p = 0.015), but there was no significant difference in the PM (746.92 ± 197.89 versus 731.74 ± 215.53 mm2.m−2, respectively p = 0.575). The fracture group had a higher grade of fatty infiltration than the control group (PM: 1.3 ± 0.46 versus 1.07 ± 0.25, p < 0.001; PVM: 1.93 ± 0.5 versus 1.74 ± 0.5, p = 0.003) and a lower average muscle density (PM: 26.99 ± 12.83 versus 33.91 ± 8.12 HU, p < 0.001; PVM: 3.42 ± 21.06 versus 12.94 ± 18.88 HU, p < 0.001). Conclusion: This study shows an association between a lack of axial musculature and the occurrence of osteoporotic vertebral fractures. Preventive strengthening exercises could be proposed to osteoporotic patients.

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.

Abstract Background To investigate the association between 12 single nucleotide polymorphisms (SNPs) located on ERAP1 and IL23R with the presence of inflammation on the sacroiliac joint (SIJ) or spinal magnetic resonance imagery (MRI) in an early onset spondyloarthritis (SpA) cohort. Methods All the patients included in the DESIR cohort with an axial SpA and available DNA at baseline were enrolled in this study (n = 645 patients) and underwent a clinical examination, CRP assay, SIJ and spinal MRI scans. Six SNPs located on ERAP1 (rs30187, rs27044, rs27434, rs17482078, rs10050860, rs2287987) and six SNPs located on IL23R (rs1004819, rs10489629, rs1343151, rs2201841, rs10889677, rs11209032) were genotyped. Univariable analyses were performed to test the association between the genotypes and SIJ and spinal MRI inflammation, as well as disease activity based on Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Ankylosing Spondylitis Disease Activity Score-C-Reactive Protein (ASDAS-CRP) and CRP. Results One SNP located on ERAP1 (rs27434) and haplotype CCT of ERAP1 were associated with SIJ inflammation detected by MRI, but these associations were below the Bonferroni corrected threshold of significance. However, one SNP (rs1004819) located on IL23R was associated with SIJ MRI inflammation (rs1004819: TT 42.3%, CT 40.5%, CC 26.5%, p = 0.0005). This locus was also significantly associated with Spondyloarthritis Research Consortium of Canada scores while no association with another inflammatory parameter such as BASDAI, ASDAS-CRP, CRP or Berlin MRI score was identified in this population. Conclusion One locus of the IL23R gene was associated with SIJ MRI inflammation and might be a marker of more active disease in recent onset SpA. Trial registration clinicaltrials.gov, NCTO 164 8907

ABSTRACT Treatment with asfotase alfa has transformed the prognosis of hypophosphatasia in children and improves the bone and muscle signs in adults. The doses used in adults are the same as in children, whereas bone remodeling is different between them. We report on the cases of two patients treated with 1 mg/kg/day of asfotase alfa who developed spinal cord compression from spinal ossifications during treatment. The first patient, 50 years old, presented after 2 years of treatment with quadraparesis secondary to an increase in ossifications of the cervical vertebral ligaments. The neurological damage was resolved after laminectomy, and the patient was then treated for 18 months with doses of 80 mg per week, without recurrence of the bone and muscle signs. The second patient, 26 years old, 78 kg, developed pain and cervical stiffness with pyramidal tract irritation secondary to ossifications of the vertebral ligaments. This improved with a reduction of doses to 80 mg/week, which then, after 6 months of follow‐up, enabled maintained improvement of the bone and muscle pain that was initially obtained. To our knowledge, these are the first reported cases of increased spinal ligamentous ossifications with neurological complications. Biological monitoring in adults does not seem to enable asfotase alfa doses to be adjusted. The levels of serum alkaline phosphatase (ALP) while on the recommended treatment of 1 mg/kg/day are significantly supraphysiological (5000 to 20,000 IU) and the assays of pyrophosphate and pyridoxal phosphate are not correlated with clinical efficacy. In both of our patients, the treatment with 80 mg of asfotase alfa per week, which was proposed after the occurrence of spinal complications, seemed as effective, after a follow‐up of 18 months and 6 months, as the initial treatment for improving the bone and muscle signs, and could be provided as “attack” doses after healing of the pseudoarthroses. © 2021 American Society for Bone and Mineral Research © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Abstract Background To compare the 10-year structural and functional prognosis between patients in sustained remission versus patients in sustained low disease activity (LDA) in early rheumatoid arthritis (RA). Methods We included 256 patients from the ESPOIR cohort who fulfilled the 2010 ACR/EULAR criteria for RA and who were in sustained remission using the Simple Disease Activity Index (SDAI) score (n = 48), in sustained LDA (n = 139) or in sustained moderate to high disease activity (MDA or HDA, n = 69) over 10 years. The mTSSs progression over 10 years and the 10-year HAQ-DI scores were compared between the 3 groups. A longitudinal latent process mixed model was used to assess the independent effect of SDAI status over time on 10-year mTSS progression and HAQ-DI at 10 years. Results Patients in sustained remission group were younger, had lower baseline HAQ-DI and mTSS scores and were less exposed to glucocorticoids, methotrexate or biologic disease-modifying anti-rheumatic drugs over 10 years. Patients in sustained remission had lower 10-year structural progression (variation of mTSS in the remission group: 4.06 (± 4.75) versus 14.59 (± 19.76) in the LDA group and 21.04 (± 24.08), p

ABSTRACT Stopping treatment for osteoporosis with denosumab (Dmab) leads to a major and rapid loss in bone mineral density (BMD) and a risk of vertebral fracture. Subsequent treatment with bisphosphonate (Bp) does not completely prevent this bone loss. We carried out a prospective pilot study to find out whether the gradual dose reduction with denosumab could prevent this bone loss. We proposed a therapeutic protocol consisting in reducing the doses of Dmab to women treated with Dmab for postmenopausal osteoporosis. Six months after the last dose of Dmab 60 mg, the subsequent injection was performed with a reduced dose of 30 mg, and the month‐12 injection was a 15‐mg injection. BMD and serum C‐terminal telopeptide of type I collagen (CTX) were measured at the start of treatment with Dmab (T0), at the last dose with 60 mg (T1), and at 6 months (T2) and 12 months (T3) after the last 15 mg Dmab injection. We included 13 patients aged 68.7 ± 3 years, and treated with Dmab for 45.2 ± 5 months. At the lumbar spine, 39% of the initial gain in BMD was preserved 1 year after the last dose (15 mg). Conversely, at the hip, the bone loss at the end of the treatment reduction protocol was equivalent to the initial gain. The mean CTX level was 166 ± 152 pg/mL 6 months after the last dose (T2; 15 mg), and 549 ± 425 pg/mL 12 months after the last dose (T3; 15 mg). One patient presented two vertebral fractures, 8 months after the last dose of Dmab (15 mg). Gradual dose reduction of denosumab (30 mg then 15 mg) does not prevent bone loss in the hip and partially maintains the initial gain at the spine. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

BackgroundPsoriatic 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.MethodsIn 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).ResultsA 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.ConclusionIn 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.

Summary: 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.

Purpose: The occurrence of multiple vertebral fractures was reported after denosumab discontinuation. The use of bisphosphonates following denosumab has been suggested to prevent this bone loss. The aim of our observational trial was to evaluate the ability of risedronate to prevent the bone loss related to denosumab discontinuation in post-menopausal osteoporosis. Methods: Eighteen female patients, aged 69.8 years (56–79), were followed. All patients were prescribed 35 mg of risedronate per week for 3 months, starting when the next denosumab injection would have been administered. We measured BMD at denosumab initiation (T0), denosumab withdrawal (T1), and nine months after the discontinuation of risedronate (1 year post-denosumab: T2). Results: 1 year after denosumab discontinuation, the mean bone loss at the spine was – 4.6 ± 5.2% for the total population, −0.3 ± 2.3% in patients with prior exposure to bisphosphonates, −6.3 ± 5.7% in patients with prior exposure to teriparatide, and − 7.6 ± 3.5% in naïve patients. Spine BMD loss after the risedronate bridging therapy (T2 vs. T1) was significantly lower in patients who experienced prior exposure to bisphosphonates, when compared to naïve patients (p = .0190) and to patients with prior teriparatide exposure (p = .0176). 1 year after denosumab discontinuation, the mean densitometric loss at the hip was −1.8 ± 3.4% in the total cohort, −0.6 ± 1.8% in the patients previously treated with bisphosphonates, −1.5 ± 4.7% in the patients previously treated with teriparatide, and − 4.2 ± 0.6 in naïve patients. The mean densitometric loss during the off-denosumab period was lower in patients with previous bisphosphonate exposure than in naïve patients (p = .043) and in patients with previous exposure to teriparatide (p = .05). Conclusions: Three months of risedronate treatment does not prevent bone loss in patients who have not been treated with bisphosphonates before denosumab.

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.

Abstract 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.

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.

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.

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.