Publications by authors named "Eric Toussirot"

140 Publications

Mini-Review: The Administration of Apoptotic Cells for Treating Rheumatoid Arthritis: Current Knowledge and Clinical Perspectives.

Front Immunol 2021 25;12:630170. Epub 2021 Feb 25.

INSERM CIC-1431, Centre d'Investigation Clinique Biothérapie, Pôle Recherche, CHU de Besançon, Besançon, France.

Rheumatoid arthritis (RA) is a chronic immune-mediated disease managed by conventional synthetic drugs, such as methotrexate (MTX), and targeted drugs including biological agents. Cell-based therapeutic approaches are currently developed in RA, mainly mesenchymal stroma cell-based approaches. Early-stage apoptotic cells possess direct and indirect anti-inflammatory properties. During the elimination of dying cells (a process called efferocytosis), specific mechanisms operate to control immune responses. There are compelling evidences in experimental models of arthritis indicating that apoptotic cell administration may benefit joint inflammation, and may even have therapeutic effects on arthritis. Additionally, it has been demonstrated that apoptotic cells could be administered with standard treatments of RA, such as MTX or TNF inhibitors (TNFi), given even a synergistic response with TNFi. Interestingly, apoptotic cell infusion has been successfully experienced to prevent acute graft-vs.-host disease after hematopoietic cell transplantation in patients with hematologic malignancies, with a good safety profile. In this mini-review, the apoptotic cell-based therapy development in arthritis is discussed, as well as its transfer in the short-term to an innovative treatment for patients with RA. The use of apoptotic cell-derived factors, including secretome or phosphatidylserine-containing liposomes, in RA are also discussed.
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http://dx.doi.org/10.3389/fimmu.2021.630170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7950318PMC
February 2021

A pragmatic non-invasive assessment of liver fibrosis in patients with psoriasis, rheumatoid arthritis or Crohn's disease receiving methotrexate therapy.

Clin Res Hepatol Gastroenterol 2020 Jan-Jun;44S:100003. Epub 2020 Feb 8.

Service d'hépatologie et de soins intensifs digestifs, CHRU Jean-Minjoz, 25030 Besançon cedex, France.

Background And Aims: The reported hepatotoxicity of methotrexate underlines the need for a repeated non-invasive and reliable evaluation of liver fibrosis. We estimated, using a non-invasive strategy, the prevalence of significant liver fibrosis in patients treated by methotrexate and the predictors of significant fibrosis (fibrosis≥F2).

Methods: Fibrosis was prospectively evaluated using 9 non-invasive tests in consecutive patients with psoriasis, rheumatoid arthritis, or Crohn's disease. Significant fibrosis was assessed without liver biopsy by defining a "specific method" (result given by the majority of the tests) and a "sensitive method" (at least one test indicating a stage≥F2).

Results: One hundred and thirty-one patients (66 Psoriasis, 40 rheumatoid arthritis, and 25 Crohn's disease) were enrolled, including 83 receiving methotrexate. Seven tests were performed on average per patient, with a complete concordance in 75% of cases. Fibroscan® was interpretable in only 61% of patients. The best performances (AUROC>0.9) for predicting significant fibrosis were obtained by tests dedicated to steatohepatitis (FibroMeter NAFLD, NFS and FPI). The prevalence of fibrosis≥F2 according to the "specific" or the "sensitive" assessment of fibrosis was 10% and 28%, respectively. Methotrexate exposure did not influence the fibrosis stage. Factors independently associated with significant fibrosis according our "sensitive method" were age, male gender, and metabolic syndrome.

Conclusion: We provided a non-invasive approach for identifying liver fibrosis≥F2 by using 8 biochemical tests and Fibroscan®. In this population, the risk of significant fibrosis was related to age, male gender, and presence of metabolic syndrome, but was not influenced by methotrexate.
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http://dx.doi.org/10.1016/j.clirex.2020.100003DOI Listing
February 2020

Mini-Review: The Contribution of Adipokines to Joint Inflammation in Inflammatory Rheumatic Diseases.

Authors:
Eric Toussirot

Front Endocrinol (Lausanne) 2020 23;11:606560. Epub 2020 Dec 23.

INSERM CIC-1431, Centre d'Investigation Clinique Biothérapie, Pôle Recherche, CHU de Besançon, Besançon, France.

Inflammatory rheumatic diseases (IRD) are complex disorders characterized by chronic inflammation of the joints and related skeletal structures. The most common forms of IRD are rheumatoid arthritis (RA) and spondyloarthritis (SpA), including axial SpA (axSpA) and psoriatic arthritis (PsA). Obesity is a frequent comorbidity in RA and PsA, and to a lesser extend in axial SpA. The association between obesity and IRD may be explained by the release from fat tissue of several bioactive proteins, namely adipokines. Adipokines are involved in the regulation of various processes such as lipid or glucose metabolism, but also inflammation. Adipokines are interrelated with the immune system, with both innate and adaptive immune cell connections. Several adipokines with pro-inflammatory effects have been identified such as leptin, visfatin or resistin. Conversely, adiponectin and more specifically its low molecular weight isoform, is considered to have antiinflammatory properties. In this review, we discuss the contribution of adipokines to the joint inflammation of IRD, the relation they have with immune pathways of these diseases, their links with the structural impact on peripheral joints and/or axial skeleton, and also the influence they may have on the cardiometabolic risk of IRD.
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http://dx.doi.org/10.3389/fendo.2020.606560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786430PMC
December 2020

Sustained remission of ankylosing spondylitis following intravesical Bacillus Calmette et Guérin immunotherapy for bladder cancer.

Clin Exp Rheumatol 2020 Nov 22. Epub 2020 Nov 22.

INSERM CIC-1431, CHU de Besançon, Centre d' Investigation Clinique Biothérapie, Pôle Recherche, Besançon;Fédération Hospitalo-Universitaire INCREASE, CHU de Besançon; and Université Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France.

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November 2020

Visceral adiposity in patients with psoriatic arthritis and psoriasis alone and its relationship with metabolic and cardiovascular risk.

Rheumatology (Oxford) 2020 Nov 24. Epub 2020 Nov 24.

Laboratoire de Biochimie Médicale, UF de Biochimie Endocrinienne et Métabolique, CHU de Besançon et EA 3920 Marqueurs pronostiques et facteurs de régulation des pathologies cardiaques et vasculaires, Université de Bourgogne Franche Comté, Besançon, France.

Background: Fat mass distribution, especially in the abdominal visceral region, has been rarely evaluated in patients with PsA or psoriasis (PsO).

Methods: Patients with PsA and patients with PsO alone were evaluated and compared with control subjects (1:1 ratio in each patient group) matched for age, sex and BMI category. Body composition and fat distribution (android and visceral fat) were evaluated by DXA. Anthropometric measurements, disease activity and the systematic coronary risk evaluation (SCORE) cardiovascular risk were assessed. Metabolic parameters (insulin, homeostasis model assessment for insulin resistance), serum adipokines [total and high-molecular-weight adiponectin, leptin, resistin and retinol-binding protein-4 (RBP4)] were measured.

Results: Data for 52 patients with PsA and 52 patients with PsO and their respective paired controls were analysed. Android fat and visceral fat were found to be significantly higher in patients with PsO compared with their controls, while these measurements did not differ between patients with PsA and their controls. By multivariate analysis, after adjusting for age, sex and BMI, visceral fat was higher in PsO patients compared with PsA patients (P = 0.0004) and the whole group of controls (P = 0.0013). Insulin levels and HOMA-IR were increased in both PsA and PsO groups. High-molecular-weight/total adiponectin ratio was decreased in patients with PsO. RBP4 was significantly higher in both PsA and PsO patients. In patients with PsO, visceral fat strongly correlated with SCORE (r = 0.61).

Conclusion: Visceral fat accumulates more in PsO alone than in PsA. Visceral adiposity may be a more pressing concern in PsO relative to PsA.

Trial Registration: The ADIPSO study (Évaluation du tissu ADIpeux et des adipokines dans le PSOriasis et le rhumatisme psoriasique et analyse de ses relations avec le risque cardiovasculaire) is a case-control study conducted in Besançon, France, and is registered on ClinicalTrials.gov under the number NCT02849795.
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http://dx.doi.org/10.1093/rheumatology/keaa720DOI Listing
November 2020

Increased high molecular weight adiponectin and lean mass during tocilizumab treatment in patients with rheumatoid arthritis: a 12-month multicentre study.

Arthritis Res Ther 2020 09 29;22(1):224. Epub 2020 Sep 29.

Laboratoire de Biochimie Médicale, UF de Biochimie Endocrinienne et Métabolique, CHU de Besançon; EA 3920 Marqueurs pronostiques et facteurs de régulation des pathologies cardiaques et vasculaires, Université de Bourgogne Franche Comté, Besançon, France.

Background: Patients with rheumatoid arthritis (RA) have an increased risk of cardiovascular (CV) disease. Adiponectin is involved in the metabolism of glucose and lipids with favourable effects on CV disease, especially its high molecular weight (HMW) isoform. Body composition changes are described in RA with various phenotypes including obesity. The effects of tocilizumab on serum adiponectin and body composition, especially fat mass, in patients with RA are not well determined.

Methods: Patients with active RA despite previous csDMARDs and/or bDMARDs and who were tocilizumab naïve were enrolled in a multicentre open-label study. They were evaluated at baseline, 1, 3, 6 and 12 months. Clinical assessment included body mass index (BMI) and anthropometric measurements. Lipid and metabolic parameters, serum adiponectin (total and HMW), leptin, resistin and ghrelin were measured at each time point. Body composition (lean mass, fat mass, % fat, fat in the android and gynoid regions) was evaluated at baseline, 6 and 12 months.

Results: One hundred seven patients were included. Both total and HMW adiponectin significantly increased from baseline to month 3, peaking respectively at month 3 (p = 0.0105) and month 1 (p < 0.0001), then declining progressively until month 6 to 12 and returning to baseline values. Significant elevation in HMW adiponectin persisted at month 6 (p = 0.001). BMI and waist circumference significantly increased at month 6 and 12, as well as lean mass at month 6 (p = 0.0097). Fat mass, percentage fat and android fat did not change over the study period. Lipid parameters (total cholesterol and LDL cholesterol) increased while glycaemia, insulin and HOMA-IR remained stable. Serum leptin, resistin and ghrelin did not change during follow-up.

Conclusions: Tocilizumab treatment in RA patients was associated with a significant increase in total and HMW adiponectin, especially at the onset of the treatment. Tocilizumab also induced a significant gain in lean mass, while fat mass did not change. These variations in adiponectin levels during tocilizumab treatment could have positive effects on the CV risk of RA patients. In addition, tocilizumab may have an anabolic impact on lean mass/skeletal muscle.

Trial Registration: The ADIPRAT study was a phase IV open-label multicentre study retrospectively registered on ClinicalTrials.gov under the number NCT02843789 (date of registration: July 26, 2016).
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http://dx.doi.org/10.1186/s13075-020-02297-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523335PMC
September 2020

Rituximab for rheumatoid arthritis-associated large granular lymphocytic leukemia, a retrospective case series.

Semin Arthritis Rheum 2020 10 16;50(5):1109-1113. Epub 2020 Jun 16.

Rheumatology Department, University Hospital, 58 Rue Montalembert, Clermont-Ferrand, France.

Objectives: To assess the efficacy and tolerance profile of rituximab in rheumatoid arthritis (RA)-associated large granular lymphocyte leukemia (LGLL).

Methods: Multicenter retrospective case series. Inclusion criteria were RA defined by the ACR/EULAR 2010 criteria and LGLL defined by absolute LGL count ≥ 0.3 × 10/L with evidence of an expanded clonal LGL population (flow cytometry, TCR-γ polymerase chain reaction, or Stat3 mutation).

Results: Fourteen patients (10 women, mean age 55.2 ± 14.2 years) included; 13 were seropositive for anti-cyclic citrullinated peptides (n = 11) or rheumatoid factor (n = 10). LGLL diagnosis was made 9.5 [IQR: 3.25;15.5] years after RA diagnosis. Thirteen patients had T-LGLL. Rituximab was the first-line therapy for LGLL for 4 patients. Previous treatment lines included methotrexate (n = 7), cyclophosphamide (n = 2), cyclosporin A (n = 1), or granulocyte colony-stimulating factor (n = 4). Rituximab was used in monotherapy (n = 8) or associated to methotrexate (n = 3), granulocyte colony-stimulating factor (n = 2), or alkylating agents (n = 1). The number of rituximab cycles ranged from 1 to 11 (median 6), with high heterogeneity in dosing regimens. Median duration response after rituximab initiation was 35 [IQR: 23.5;41] months. The overall response rate was 100%: 8 patients experienced complete response (normalization of blood count and LGL ≤ 0.3 × 10/L) and 6 experienced partial responses (improvement in blood counts without complete normalization). The tolerance profile was good, with no infectious complications.

Conclusion: rituximab appears as a valuable therapeutic option for RA-associated LGLL.
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http://dx.doi.org/10.1016/j.semarthrit.2020.05.020DOI Listing
October 2020

Spondyloarthritis-Associated IgA Nephropathy.

Kidney Int Rep 2020 Jun 16;5(6):813-820. Epub 2020 Mar 16.

Department of Nephrology, Hôpital Européen Georges-Pompidou, Assistance Publique-Hopitaux de Paris, Paris, France.

Introduction: IgA nephropathy (IgAN) can be associated with spondyloarthritis (SpA). The course of SpA-associated IgAN remains largely unknown due to the absence of large cohorts.

Methods: This retrospective study included patients with biopsy-proven IgAN and definite SpA. Kidney biopsies were centrally examined and scored according to the IgAN Oxford Classification. Thirty-two patients fulfilled the inclusion criteria, with a male:female ratio of 9:1 and median age of 27 and 37 years at SpA and IgAN diagnosis, respectively. HLA-B27 was positive in 90% of cases, and most patients (60%) presented with ankylosing spondylitis. The mean baseline estimated glomerular filtration rate (eGFR) was 84 ± 26 ml/min per 1.73 m, and the urine protein-to-creatinine ratio was 0.19 g/mmol.

Results: Renal biopsy revealed frequent presence of crescents (33%) and interstitial inflammation (18%). Despite almost constant use of renin-angiotensin system inhibitors, combined with steroids in 13 of 32 patients, renal outcome was particularly poor. After a median follow-up of 5.9 years, 4 patients (12.5%) reached end-stage renal disease and 41% of patients experienced a >50% decrease of eGFR. The mean annual eGFR decline rate was -4.3 ± 6.7 ml/min per 1.73 m. The risk of reaching class IV or V chronic kidney disease (CKD) stage during follow-up was associated with the presence of hypertension, level of proteinuria, and baseline S- and T-scores of the Oxford.

Conclusion: SpA-associated IgAN is associated with a poor renal outcome, despite frequent use of steroids. Tumor necrosis factor (TNF)-α blockade did not appear to influence the rate of eGFR decline in this setting.
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http://dx.doi.org/10.1016/j.ekir.2020.03.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271945PMC
June 2020

L5 Radiculopathy with Neurological Deficit Due To Sacral Insufficiency Fracture.

J Rheumatol 2020 06;47(6):939-940

Service de radiologie, Centre Hospitalier Universitaire de Besançon, and Laboratoire Nanomédecine Imagerie et Thérapeutique EA4662, Université de Franche Comté, Besançon, France.

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http://dx.doi.org/10.3899/jrheum.190517DOI Listing
June 2020

The Interrelations between Biological and Targeted Synthetic Agents Used in Inflammatory Joint Diseases, and Obesity or Body Composition.

Authors:
Eric Toussirot

Metabolites 2020 Mar 13;10(3). Epub 2020 Mar 13.

INSERM CIC-1431, CHU de Besançon, Centre d'Investigation Clinique Biothérapie, Pôle Recherche, 25000 Besançon, France.

Obesity is a comorbidity that plays a role in the development and severity of inflammatory joint diseases, including rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis. The relationships between obesity and adipose tissue and the treatments given for inflammatory joint diseases are bidirectional. In fact, biological agents (bDMARDs) and targeted synthetic agents (tsDMARDs) may influence body weight and body composition of treated patients, while obesity in turn may influence clinical response to these agents. Obesity is a prevalent comorbidity mainly affecting patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) with specific phenotypes. Tumour necrosis factor alpha (TNFα) inhibitors have been associated with changes in body composition by improving lean mass, but also by significantly increasing fat mass, which localized toward the abdominal/visceral region. The IL-6 inhibitor tocilizumab is associated with an increase in lean mass without change in fat mass. The clinical response to TNFα inhibitors is attenuated by obesity, an effect that is less pronounced with IL-6 inhibitors and the B-cell depletion agent rituximab. Conversely, body weight has no influence on the response to the costimulation inhibitor abatacept. These effects may be of help to the physician in personalized medicine, and may guide the therapeutic choice in obese/overweight patients.
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http://dx.doi.org/10.3390/metabo10030107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175105PMC
March 2020

Tocilizumab failure in malignancy-related polymyalgia rheumatica.

Joint Bone Spine 2020 07 13;87(4):366-368. Epub 2019 Dec 13.

AP-HP Hôpital St Antoine, Service de Médecine Interne et Inflammation (DHUi2B), Sorbonne Université, 75012 Paris, France.

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http://dx.doi.org/10.1016/j.jbspin.2019.12.001DOI Listing
July 2020

An unusual association of CANOMAD and rheumatoid arthritis with a long-term follow-up.

Joint Bone Spine 2020 05 23;87(3):263-264. Epub 2019 Sep 23.

University Hospital of Besançon, Department of Neuromuscular Diseases, Besançon, 25000, France.

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http://dx.doi.org/10.1016/j.jbspin.2019.09.009DOI Listing
May 2020

Pharmacological management of axial spondyloarthritis in adults.

Authors:
Eric Toussirot

Expert Opin Pharmacother 2019 Aug 16;20(12):1483-1491. Epub 2019 May 16.

INSERM CIC-1431, Clinical Investigation Center in Biotherapy, University Hospital of Besançon , Besançon , France.

: Spondyloarthritis (SpA) refers to a group of disorders sharing common clinical, genetic and imaging characteristics. Axial (ax) SpA corresponds to a subgroup that mainly affects the axial skeleton, leading to inflammatory back pain and progressive radiographic changes of the sacroiliac joints and the spine. axSpA are currently subdivided into two forms, namely the radiographic and nonradiographic form, and are associated with musculoskeletal pain, restriction of spinal mobility, specific extra-articular features and overall, altered quality of life. The therapeutic management of axSpA has considerably progressed and is now well standardized. : Herein, the author reviews the pharmacological treatments that may be used in axSpA, including radiographic and nonradiographic forms in addition to the role of nonsteroidal anti-inflammatory drugs (NSAIDs), TNF alpha (TNFi), and IL-17A (IL-17Ai) inhibitors. : NSAIDs remain the mainstay of initial therapy and biological agents may be then envisaged. TNFi and IL-17Ai may be used in axSpA, but physicians have more experience with TNFi. Only TNFi are licensed for the treatment of nonradiographic axSpA. IL-17Ai may be used as first or second line biologic disease modifying antirheumatic drugs (bDMARDs) and further results are needed to better define their position in the therapeutic management of axSpA.
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http://dx.doi.org/10.1080/14656566.2019.1617853DOI Listing
August 2019

Safety of the use of anti-IL17A treatment in a patient with certolizumab-induced sarcoidosis.

Clin Exp Rheumatol 2019 Mar-Apr;37(2):344-345. Epub 2019 Mar 7.

Department of Rheumatology, Hôpital Nord Franche-Comté, Trevenans, France.

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May 2019

MAIT cells: potent major cellular players in the IL-17 pathway of spondyloarthritis?

RMD Open 2018 28;4(2):e000821. Epub 2018 Dec 28.

INSERM CIC-1431, University Hospital of Besançon, Clinical Investigation Center in Biotherapy, Besançon, France.

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http://dx.doi.org/10.1136/rmdopen-2018-000821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326357PMC
December 2018

Anti-neutrophil cytoplasmic antibody-associated chronic inflammatory arthritis without vasculitis. Data from a French nationwide survey.

Autoimmun Rev 2018 12 12;17(12):1268-1269. Epub 2018 Oct 12.

UMR1227, Lymphocytes B et Autoimmunité, Université de Brest, Inserm, LabEx IGO, Brest, France; Service de rhumatologie, Centre National de Référence des Maladies Auto-immunes Rares de l'Adulte CERAINO, CHU de Brest, Brest, France. Electronic address:

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http://dx.doi.org/10.1016/j.autrev.2018.07.005DOI Listing
December 2018

Unilateral Accessory Sacroiliac Joint with Bone Marrow Edema Mimicking Sacroiliitis.

J Rheumatol 2018 08;45(9):1327-1328

University Hospital of Besançon, Department of Radiology, Besançon, France.

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http://dx.doi.org/10.3899/jrheum.180030DOI Listing
August 2018

Increased IL-22- and IL-17A-Producing Mucosal-Associated Invariant T Cells in the Peripheral Blood of Patients With Ankylosing Spondylitis.

Front Immunol 2018 13;9:1610. Epub 2018 Jul 13.

INSERM CIC-1431, University Hospital of Besançon, Clinical Investigation Center in Biotherapy, Besançon, France.

The IL-23/T helper 17 (Th17) axis plays an important role in joint inflammation in ankylosing spondylitis (AS). Conventional CD4 Th17 cells are a major source of IL-17A. IL-22 is another cytokine implicated in AS pathophysiology and is produced by Th17 and Th22 cells. In this study, we aimed to analyze conventional and non-conventional T cell subsets producing IL-17A and IL-22 in patients with AS. We thus evaluated the intracellular staining for IL-17A, IL-22, and IFN-γ in peripheral blood mononuclear cells of 36 patients with AS and 55 age- and sex-matched healthy controls (HC). Conventional CD4 and CD8 T cells, γδ T cells, and mucosal-associated invariant T (MAIT) cells were evaluated. In patients with AS, we found a decreased frequency and number of γδ T cells, of MAIT cells and of IFN-γ CD4 and CD8 T cells. Th17-related IL-17A/IFN-γ CD4 T cells were decreased in AS. The number of IL-22 MAIT cells was higher in AS compared with HC, as well as the number of IFN-γ/IL-17A MAIT cells. The number of IFN-γ/IL-17A MAIT cells was higher only in female patients with AS compared with female HC. The cellular source of IL-17A was thus not restricted to conventional Th17 CD4 T cells and might involve innate-like T cells, such as MAIT cells. Circulating MAIT cells producing IL-22 were increased in AS. These results strengthen the importance of innate and innate-like sources of IL-17A and/or IL-22.
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http://dx.doi.org/10.3389/fimmu.2018.01610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053500PMC
July 2018

Could Sodium Chloride be an Environmental Trigger for Immune-Mediated Diseases? An Overview of the Experimental and Clinical Evidence.

Front Physiol 2018 24;9:440. Epub 2018 Apr 24.

Institut National de la Santé et de la Recherche Médicale CIC-1431, Centre d'Investigation Clinique Biothérapie, University Hospital Besançon, Besançon, France.

Immune mediated diseases (IMDs) are complex chronic inflammatory diseases involving genetic and environmental factors. Salt intake has been proposed as a diet factor that can influence the immune response. Indeed, experimental data report the influence of sodium chloride on the differentiation of naive CD4 T cells into IL-17 secreting T helper (Th) cells (Th17 cells), by a mechanism involving the serum glucocorticoid kinase-1 (SGK1) that promotes the expression of the IL-23 receptor (IL-23R). The IL-23/IL-23R is critical for pathogenic inflammatory Th17 cell differentiation. Experimental data in murine models of arthritis, colitis and encephalomyelitis corroborate these findings. This manuscript reviews the current knowledge on the effects of sodium chloride on innate and adaptive immunity. We also performed a systematic literature review for clinical studies examining the relationships between salt consumption and the development or the activity/severity of the most common IMDs mediated by the IL-23/Th17 pathway, i.e., rheumatoid arthritis (RA), multiple sclerosis (MS), and Crohn's disease (CD). Nine studies were found, 4 in RA, 4 in MS and 1 in CD. An association was found between developments of anti-citrullinated protein antibody (ACPA) positive RA in smokers and salt intake, but these results were not confirmed in another study. For MS, no association was observed in pediatric subjects while in adult patients, a link was found between salt intake and disease activity. However, this result was not confirmed in another study. These conflicting results highlight the fact that further evaluation in human IMDs is required. Moreover, physicians need to develop clinical trials with diet interventions to evaluate the impact of low salt intake on disease activity/severity of IMDs.
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http://dx.doi.org/10.3389/fphys.2018.00440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5928237PMC
April 2018

Ixekizumab: an anti- IL-17A monoclonal antibody for the treatment of psoriatic arthritis.

Authors:
Eric Toussirot

Expert Opin Biol Ther 2018 01 29;18(1):101-107. Epub 2017 Nov 29.

a INSERM CIC-1431 , University Hospital of Besançon, Clinical Investigation Center in Biotherapy , Besançon , France.

Introduction: Psoriatic arthritis (PsA) is an inflammatory rheumatic disease that manifests itself with synovitis, dactylitis, enthesitis and also axial involvement. Interleukin-17A has been identified as a master cytokine in the inflammatory response and pathogenesis of PsA and spondyloarthritis in general. Ixekizumab is a new humanized monoclonal antibody that blocks the biological activity of IL-17A. This biological agent has previously demonstrated a high level of efficacy in psoriasis. Areas covered: This review discusses the basic immunology of the IL-17 cytokine family, the contribution of IL-17A to the immunopathogenesis of PsA, the clinical trials that evaluated ixekizumab in patients with PsA (SPIRIT program) and the safety of this agent. Expert opinion: Ixekizumab demonstrated its efficacy in different aspects of PsA including peripheral joint involvement, dactylitis, skin symptoms and patient reported outcomes in the 2 phase III trials from the SPIRIT program. Its safety profile was consistent with previous observations in patients with psoriasis. The role of IL-17A in the management of patients with PsA needs further clarification. According to EULAR recommendations for the management of PsA, IL-17A inhibitors may be used as second line biological DMARDs after TNF inhibitors.
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http://dx.doi.org/10.1080/14712598.2018.1410133DOI Listing
January 2018

Paradoxical elevation of serum TRACP5b levels despite increase in lumbar spine bone mineral density during anti-TNFα therapy in patients with inflammatory rheumatic disease: a 2-year prospective assessment of bone mass, bone metabolism, and the trabecular bone score.

Eur J Rheumatol 2017 Sep 1;4(3):189-193. Epub 2017 Sep 1.

Department of Endocrine and Metabolic Biochemistry, University Hospital of Besançon, Besançon, France.

Objective: To examine the impact of long-term anti-TNFα therapy on bone mass, bone metabolism, and the trabecular bone score (TBS) in patients with rheumatoid arthritis (RA) or ankylosing spondylitis (AS).

Material And Methods: In eight patients with RA and 12 with AS, bone mineral densities (BMDs) of the lumbar spine (LS), left and right femoral neck, and total skeleton were measured using dual X-ray absorptiometry at baseline and then at 6, 12, and 24 months after anti TNFα therapy. The TBS was also calculated. At baseline and at 1, 3, 6, 12, 18, and 24 months, bone metabolism was assessed by measurements of pro-collagen-I carboxyterminal propeptide (PICP), osteocalcin, and bone alkaline phosphatase levels in the serum, which are indicative of bone formation and β-isomerized carboxy-terminal telopeptide of type-I collagen (β-CTX-I) and serum isoform 5b of tartrate-resistant acid phosphatase (TRACP5b) levels in the serum, which are indicative of bone resorption.

Results: In patients with RA, the LS T-score increased (3.2%, p<0.001) and the TBS progressively decreased (-3.9%, p=0.03). In patients with AS, the LS BMD and T-score increased (4.3% and 6.2%, respectively; p<0.001) with no significant change in the TBS. Serum TRACP5b levels dramatically increased in both groups (227% in patients with RA and 150% in those with AS, p<0.001), while β-CTX-I levels did not change. Serum osteocalcin and PICP levels showed a transitory increase in patients with AS.

Conclusion: Long-term anti-TNFα therapy increased LS bone mass and affected bone quality (TBS) with little impact on bone remodeling. Conversely, TRACP5b levels dramatically increased during anti-TNFα therapy but without any detrimental effect on bone mass.
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http://dx.doi.org/10.5152/eurjrheum.2017.17006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5685278PMC
September 2017

Harnessing Apoptotic Cell Clearance to Treat Autoimmune Arthritis.

Front Immunol 2017 9;8:1191. Epub 2017 Oct 9.

INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Fédération Hospitalo-Universitaire INCREASE, LabEx LipSTIC, Université Bourgogne Franche-Comté, Besançon, France.

Early-stage apoptotic cells possess immunomodulatory properties. Proper apoptotic cell clearance during homeostasis has been shown to limit subsequent immune responses. Based on these observations, early-stage apoptotic cell infusion has been used to prevent unwanted inflammatory responses in different experimental models of autoimmune diseases or transplantation. Moreover, this approach has been shown to be feasible without any toxicity in patients undergoing allogeneic hematopoietic cell transplantation to prevent graft--host disease. However, whether early-stage apoptotic cell infusion can be used to treat ongoing inflammatory disorders has not been reported extensively. Recently, we have provided evidence that early-stage apoptotic cell infusion is able to control, at least transiently, ongoing collagen-induced arthritis. This beneficial therapeutic effect is associated with the modulation of antigen-presenting cell functions mainly of macrophages and plasmacytoid dendritic cells, as well as the induction of collagen-specific regulatory CD4 T cells (Treg). Furthermore, the efficacy of this approach is not altered by the association with two standard treatments of rheumatoid arthritis (RA), methotrexate and tumor necrosis factor (TNF) inhibition. Here, in the light of these observations and recent data of the literature, we discuss the mechanisms of early-stage apoptotic cell infusion and how this therapeutic approach can be transposed to patients with RA.
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http://dx.doi.org/10.3389/fimmu.2017.01191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5640883PMC
October 2017

Switching from originator biological agents to biosimilars: what is the evidence and what are the issues?

RMD Open 2017 12;3(2):e000492. Epub 2017 Sep 12.

SAINBIOSE INSERM U1059, University of Lyon, Saint-Etienne, France.

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http://dx.doi.org/10.1136/rmdopen-2017-000492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5604708PMC
September 2017

Serum adipokines, adipose tissue measurements and metabolic parameters in patients with advanced radiographic knee osteoarthritis.

Clin Rheumatol 2017 Nov 22;36(11):2531-2539. Epub 2017 Aug 22.

Endocrine and Metabolic Biochemistry, University Hospital of Besançon, F-, 25000, Besançon, France.

We conducted the present study to evaluate the serum levels of adipokines (leptin, total and high molecular adiponectin, resistin), a marker of cartilage breakdown (C2C), and ghrelin together with body composition in patients with knee osteoarthritis (OA). Fifty patients and 50 sex-matched healthy subjects (HS) were evaluated. Knee OA was scored according to the Kellgren-Lawrence (KL) grade. Body composition parameters including lean mass and measurements of fat mass (total fat, adiposity, fat in the android and gynoid regions, visceral fat and trunk/legs fat ratio) were obtained using dual energy X-ray absorptiometry. Most of the recruited patients (88%) had advanced knee OA with KL grade 3 or 4. The patients had higher body mass index than HS (p < 0.0001). Serum leptin, high molecular adiponectin, resistin and ghrelin levels did not differ between patients and HS. Total adiponectin was higher in women with OA compared to women from the HS group (p = 0.004). Total fat mass, adiposity and measurements of central adiposity (fat in the android region, trunk/lower limbs fat ratio and visceral fat) were increased in patients with knee OA (all p < 0.05). Total adiponectin was borderline associated with the severity of OA. Our results show that total adiponectin is significantly increased in women with advanced knee OA. Independently of gender, patients with severe knee OA were characterized by a significant excess of fat with a distribution toward the visceral region. This abnormal body composition may contribute to the cardiometabolic profile that is described in patients with knee OA.
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http://dx.doi.org/10.1007/s10067-017-3789-0DOI Listing
November 2017

Biologics in myelodysplastic syndrome-related systemic inflammatory and autoimmune diseases: French multicenter retrospective study of 29 patients.

Autoimmun Rev 2017 Sep 10;16(9):903-910. Epub 2017 Jul 10.

Service de Médecine Interne, Hôpital Saint Antoine, APHP, Université Paris 6, 75012 Paris, France; Service de médecine interne, CHU Bretagnes Atlantique, Vannes, France.

Background: Systemic inflammatory and autoimmune diseases (SIADs) associated with myelodysplastic syndromes are often difficult to treat. Corticosteroids are efficient but only usually at high doses. The use of biologics needs to be specified.

Methods: In a French multicenter retrospective study, we analyzed the efficacy and safety of biologics (tumor necrosis factor-α [TNF-α] antagonists, tocilizumab, rituximab and anakinra) for SIADs associated with myelodysplastic syndromes (MDSs). Clinical, biological and overall treatment responses were evaluated. When several lines of treatment were used, data were analyzed before and at the end of each treatment line and were pooled to compare overall response among steroids, disease-modifying anti-rheumatic drugs (DMARDs) and biologics.

Results: We included 29 patients (median age 67years [interquartile range 62-76], 83% males) with MDS-related SIADs treated with at least one biologic. The MDSs were predominantly refractory anemia with excess blasts 1 (38%) and refractory cytopenia with multilineage dysplasia (21%). The SIADs were mainly arthritis (n=6; 20%), relapsing polychondritis (n=8; 30%) and vasculitis (n=10; 34%). During a 3-year median follow-up (IQR 1.3-4.5), a total of 114 lines of treatments were used for all patients: steroids alone (22%), DMARDs (23%), TNF-α antagonists (14%), anakinra (10%), rituximab (10%), tocilizumab (7%) and azacytidine (9%). Considering all 114 lines, overall response (complete and partial) was shown in 54% cases. Overall response was more frequent with steroids (78%) and rituximab (66%) than DMARDs (45%) and other biologics (33%) (p<0.05). Rituximab had better response in vasculitis and TNF-α antagonists in arthritis. During follow-up, 20 patients (71%) presented at least one severe infection.

Conclusion: This nationwide study demonstrates the efficacy of steroids for SIAD-associated MDSs but a high frequency of steroid dependence. The response to biologics seems low, but rituximab and azacytidine seem promising.
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http://dx.doi.org/10.1016/j.autrev.2017.07.003DOI Listing
September 2017

New treatment options and emerging drugs for axial spondyloarthritis: biological and targeted synthetic agents.

Authors:
Eric Toussirot

Expert Opin Pharmacother 2017 Feb 27;18(3):275-282. Epub 2017 Jan 27.

a INSERM CIC-1431 , University Hospital of Besançon, Clinical Investigation Center in Biotherapy , Besançon , France.

Introduction: Ankylosing spondylitis (AS) and axial spondyloarthritis (ax SpA) are chronic inflammatory diseases mainly involving the axial skeleton. Pharmacological treatments for AS and ax SpA usually include local glucocorticoid injections, NSAIDs and anti-TNFα agents. Since around 30% to 40% of patients are non responders or intolerant to anti-TNFα agents, we need new therapeutic options for AS and ax SpA. Areas covered: This review describes the new biological agents that can be used or are in development for AS or ax SpA as well as emerging synthetic targeted drugs. Expert opinion: Based on the rationale of the involvement of the IL-23/Th17 axis in AS, novel biological agents have been developed and include secukinumab, an anti-IL-17A agent and ustekinumab, an anti-IL-23 antibody. New compounds in the class of synthetic drugs are apremilast, a PDE4 inhibitor, and inhibitors of kinase pathways. Secukinumab gave positive results in the treatment of AS. Ustekinumab yielded promising results in AS in an open labeled study. Apremilast is not effective in AS while results with kinase inhibitors are preliminary. Future studies will clarify the place of secukinumab in the therapeutic management of AS, its influence on radiographic progression and its effects on the non radiographic form of the disease.
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http://dx.doi.org/10.1080/14656566.2017.1284793DOI Listing
February 2017

Interleukin-6: a promising target for the treatment of polymyalgia rheumatica or giant cell arteritis?

RMD Open 2016 31;2(2):e000305. Epub 2016 Aug 31.

Department of Internal Medicine , Centre de référence maladies auto-immunes et systémiques rares, Hôpital Cochin, AP-HP , Paris , France.

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http://dx.doi.org/10.1136/rmdopen-2016-000305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5013443PMC
August 2016

Apoptotic cell infusion treats ongoing collagen-induced arthritis, even in the presence of methotrexate, and is synergic with anti-TNF therapy.

Arthritis Res Ther 2016 08 11;18(1):184. Epub 2016 Aug 11.

INSERM UMR1098, F-25000, Besançon, France.

Background: Apoptotic cell-based therapies have been proposed to treat chronic inflammatory diseases. The aim of this study was to investigate the effect of intravenous (i.v.) apoptotic cell infusion in ongoing collagen-induced arthritis (CIA) and the interaction of this therapy with other treatments used in rheumatoid arthritis (RA), including methotrexate (MTX) or anti-TNF therapy.

Methods: The effects of i.v. apoptotic cell infusion were evaluated in a CIA mouse model in DBA/1 mice immunized with bovine type II collagen. The number and functions of antigen-presenting cells (APC), regulatory CD4(+) T cells (Treg), and circulating anti-collagen auto-antibodies were analyzed in CIA mice.

Results: Treatment of arthritic mice with i.v. apoptotic cell infusion significantly reduced the arthritis clinical score. This therapeutic approach modified T cell responses against the collagen auto-antigen with selective induction of collagen-specific Treg. In addition, we observed that APC from apoptotic-cell-treated animals were resistant to toll-like receptor ligand activation and favored ex vivo Treg induction, indicating APC reprogramming. Apoptotic cell injection-induced arthritis modulation was dependent on transforming growth factor (TGF)-β, as neutralizing anti-TGF-β antibody prevented the effects of apoptotic cells. Methotrexate did not interfere, while anti-TNF therapy was synergic with apoptotic-cell-based therapy.

Conclusion: Overall, our data demonstrate that apoptotic-cell-based therapy is efficient in treating ongoing CIA, compatible with current RA treatments, and needs to be evaluated in humans in the treatment of RA.
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http://dx.doi.org/10.1186/s13075-016-1084-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4982016PMC
August 2016

Paradoxical reactions under TNF-α blocking agents and other biological agents given for chronic immune-mediated diseases: an analytical and comprehensive overview.

RMD Open 2016 15;2(2):e000239. Epub 2016 Jul 15.

Department of Dermatology, University Hospital of Besançon, Besançon, France; University of Franche-Comté, Besançon, France.

Paradoxical adverse events (PAEs) have been reported during biological treatment for chronic immune-mediated diseases. PAEs are defined as the occurrence during biological agent therapy of a pathological condition that usually responds to this class of drug. A wide range of PAEs have been reported including dermatological, intestinal and ophthalmic conditions, mainly with antitumour necrosis factor α (TNF-α) agents. True PAEs include psoriasis, Crohn's disease and hidradenitis suppurativa. Other PAEs may be qualified as borderline and include uveitis, scleritis, sarcoidosis and other granulomatous diseases (granuloma annulare, interstitial granulomatous dermatitis), vasculitis, vitiligo and alopecia areata. Proposed hypotheses to explain these PAEs include an imbalance in cytokine production, the differential immunological properties between the monoclonal antibodies and TNF-α soluble receptor, an unopposed type I interferon production and a shift towards a Th1/Th2 profile. Data from registries suggest that the risk for paradoxical psoriasis is low and non-significant. We discuss management of these PAEs, which depends on the type and severity of the adverse events, pre-existing treated conditions and the possibility of alternative therapeutic options for the underlying disease. Paradoxical adverse events are not restricted to anti-TNF-α agents and close surveillance of new available biological drugs (anti-interleukin-17/23, anti-integrin) is warranted in order to detect the occurrence of new or as yet undescribed events.
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http://dx.doi.org/10.1136/rmdopen-2015-000239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4964220PMC
August 2016

Golimumab in radiographic and nonradiographic axial spondyloarthritis: a review of clinical trials.

Drug Des Devel Ther 2016 1;10:2087-94. Epub 2016 Jul 1.

Department of Neuromuscular Examinations and Diseases, University Hospital of Besançon, Besançon, France.

Axial spondyloarthritis (Ax SpA) refers to chronic inflammatory rheumatic diseases that mainly affect the axial skeleton, leading to erosions and new bone formation in the sacroiliac joints and/or the spine. Ax SpA includes the radiographic form of the disease, ie, ankylosing spondylitis (AS), and the nonradiographic Ax SpA (non-Rx Ax SpA) forms. Anti-tumor necrosis factor alpha (TNFα) agents are used in the treatment of Ax SpA in patients who do not respond to or are intolerant to nonsteroidal anti-inflammatory drugs. In these patients, anti-TNFα agents show promising results by targeting the inflammatory process and providing symptomatic relief. Golimumab is a fully human anti-TNFα agent that is currently approved for the treatment of both AS and non-Rx Ax SpA in Europe. This review focuses on the results of clinical trials with golimumab for the treatment of AS (GO-RAISE studies) and non-Rx Ax SpA (GO-AHEAD study) and on the effects of this agent on imaging findings (radiographic progression, magnetic resonance imaging inflammation) as well as on biological parameters. Overall, golimumab is a valid therapeutic option in patients with AS and non-Rx Ax SpA in Europe.
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http://dx.doi.org/10.2147/DDDT.S107587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4936813PMC
April 2017