Publications by authors named "Hubert Marotte"

82 Publications

COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases treated with rituximab: a cohort study.

Lancet Rheumatol 2021 Mar 25. Epub 2021 Mar 25.

Service de Rhumatologie, Centre de Référence des Maladies Autoimmunes Systémiques Rares de l'Est et du Sud-Ouest de France, CHU de Bordeaux and UMR-CNRS 5164, Université de Bordeaux, Bordeaux, France.

Background: Various observations have suggested that the course of COVID-19 might be less favourable in patients with inflammatory rheumatic and musculoskeletal diseases receiving rituximab compared with those not receiving rituximab. We aimed to investigate whether treatment with rituximab is associated with severe COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases.

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

Findings: Between April 15, 2020, and Nov 20, 2020, data were collected for 1090 patients (mean age 55·2 years [SD 16·4]); 734 (67%) were female and 356 (33%) were male. Of the 1090 patients, 137 (13%) developed severe COVID-19 and 89 (8%) died. After adjusting for potential confounding factors, severe disease was observed more frequently (effect size 3·26, 95% CI 1·66-6·40, p=0·0006) and the duration of hospital stay was markedly longer (0·62, 0·46-0·85, p=0·0024) in the 63 patients in the rituximab group than in the 1027 patients in the no rituximab group. 13 (21%) of 63 patients in the rituximab group died compared with 76 (7%) of 1027 patients in the no rituximab group, but the adjusted risk of death was not significantly increased in the rituximab group (effect size 1·32, 95% CI 0·55-3·19, p=0·53).

Interpretation: Rituximab therapy is associated with more severe COVID-19. Rituximab will have to be prescribed with particular caution in patients with inflammatory rheumatic and musculoskeletal diseases.

Funding: None.
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http://dx.doi.org/10.1016/S2665-9913(21)00059-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993930PMC
March 2021

Efficacy and safety of rituximab in peripheral ulcerative keratitis associated with rheumatoid arthritis.

RMD Open 2021 Jan;7(1)

Department of Rheumatology, AP-HP, Paris-Sud University Hospitals, Le Kremlin Bicêtre Hospital, Le Kremlin-Bicêtre, France.

Objective: Peripheral ulcerative keratitis (PUK) is a rare but severe ocular complication of rheumatoid arthritis (RA). It can be considered as an ocular manifestation of rheumatoid vasculitis (RV). Our case series aimed to evaluate the efficacy of rituximab (RTX) for PUK occurring in patients with RA.

Methods: Study population were patients with RA-associated PUK treated with RTX 1000 mg on days 1 and 15 at least once after the diagnosis. We identified patients referred to the rheumatology and ophthalmology departments of our hospital between February 2014 and June 2020. We also included patients referred by their specialist after being contacted through the Club Rhumatismes et Inflammation. Demographic data and clinical and biological features were retrospectively collected.

Results: We included seven patients (three men and four women, median age 58 years). All but one had a long-standing RA with a median disease duration of 13.9 years (IQR 0-30.2). RA was erosive in six out of seven patients. All patients had rheumatoid factors and anticitrullinated peptides antibodies were positive in six of them. PUK was complicated by corneal perforation in three patients and required surgery. After a median follow-up of 29.8 months (IQR 5-75), corneal inflammation was controlled in all patients. PUK recurred in one patient, 8 months after a single infusion of RTX. 71% of the patients presented a good articular response. No patient developed other manifestations of RV. No serious adverse event related to RTX was observed.

Conclusion: RTX appears to be an efficient and safe therapeutic option in the treatment of RA-associated PUK.
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http://dx.doi.org/10.1136/rmdopen-2020-001472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845725PMC
January 2021

Factors associated with back complaints among French medical students.

Joint Bone Spine 2021 03 2;88(2):105110. Epub 2020 Dec 2.

Service de santé au travail, CHU de Saint-Étienne, Saint-Étienne, France; Univ Lyon, Univ Lyon 1, Univ St Etienne, IFSTTAR, UMRESTTE, UMR_T9405, 42005 Saint-Étienne, France.

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http://dx.doi.org/10.1016/j.jbspin.2020.105110DOI Listing
March 2021

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

Reliability and Change in Erosion Measurements by High-resolution Peripheral Quantitative Computed Tomography in a Longitudinal Dataset of Rheumatoid Arthritis Patients.

J Rheumatol 2020 Sep 15. Epub 2020 Sep 15.

RELEX-2 was hosted by the University of San Francisco, California, USA. The meeting was sponsored in part by Scanco Medical AG. PGC is supported in part by the UK National Institute for Health Research (NIHR) Leeds Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. S. Finzel, MD, Senior Attending Physician, Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Medical Faculty, University of Freiburg, Freiburg, Germany; S.L. Manske, PhD, Assistant Professor, Department of Radiology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; C.C. Barnabe, MD, MSc, Associate Professor, Departments of Medicine and Community Health Sciences, University of Calgary, and McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, Alberta, Canada; A.J. Burghardt, BS, Research Specialist, Department of Radiology and Biomedical Imaging, University of California San Francisco, California, USA; H. Marotte, MD, PhD, Professor, INSERM 1059, Université de Lyon, and Service de Rhumatologie, CHU de Saint-Etienne, Saint-Etienne, France; A. Scharmga, PhD, Maastricht University, Maastricht, the Netherlands; E.M. Hauge, MD, PhD, Professor, Department of Rheumatology, Aarhus University Hospital and Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; R. Chapurlat, MD, PhD, Professor, INSERM 1033, Hôpital Edouard Herriot, Lyon, France; K. Engelke, PhD, Professor, Department of Medicine 3, FAU University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany; X. Li, PhD, Professor, Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio, USA; B.C. van Teeffelen, Department of Biomedical Engineering, Melbourne School of Engineering, The University of Melbourne, Melbourne, Australia; P.G. Conaghan, MD, PhD, Professor, Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds and NIHR Leeds Biomedical Research Centre, Leeds, UK; K.S. Stok, PhD, Senior Lecturer, Institute for Biomechanics, ETH Zurich, Zurich, Switzerland, and Department of Biomedical Engineering, University of Melbourne, Melbourne, Australia. The authors state that they have no conflicts of interest. Address correspondence to Dr. S. Finzel, Head of Clinical Trials Unit Rheumatology, Department of Rheumatology and Clinical Immunology, University Medical Center, Medical Faculty, University of Freiburg, Hugstetter Strasse 55, 79110 Freiburg, Germany. Email: Accepted for publication September 5, 2020.

Objective: The aim of this multireader exercise was to assess the reliability and change over time of erosion measurements in patients with rheumatoid arthritis (RA) using high-resolution peripheral quantitative computed tomography (HR-pQCT).

Methods: HR-pQCT scans of 23 patients with RA were assessed at baseline and 12 months. Four experienced readers examined the dorsal, palmar, radial, and ulnar surfaces of the metacarpal head (MH) and phalangeal base (PB) of the second and third digits, blinded to time order. In total, 368 surfaces (23 patients´ 16 surfaces) were evaluated per timepoint to characterize cortical breaks as pathological (erosion) or physiological, and to quantify erosion width and depth. Reliability was evaluated by intraclass correlation coefficients (ICC), percentage agreement, and Light k; change over time was defined by means ± SD of erosion numbers and dimensions.

Results: ICC for the mean measurements of width and depth of the pathological breaks ranged between 0.819-0.883, and 0.771-0.907, respectively. Most physiological cortical breaks were found at the palmar PB, whereas most pathological cortical breaks were located at the radial MH. There was a significant increase in both the numbers and the dimensions of erosions between baseline and follow-up ( = 0.0001 for erosion numbers, width, and depth in axial plane; = 0.001 for depth in perpendicular plane).

Conclusion: This exercise confirmed good reliability of HR-pQCT erosion measurements and their ability to detect change over time.
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http://dx.doi.org/10.3899/jrheum.191391DOI Listing
September 2020

Distal phalangeal bone erosions observed by HR-pQCT in patients with psoriatic onycholysis.

Rheumatology (Oxford) 2021 Mar;60(3):1176-1184

Université Claude Bernard Lyon I, Lyon, France.

Objectives: PsA prevalence among skin psoriasis is ∼30%. Nail psoriasis, especially onycholysis, is present in >70% of PsA and the risk of developing PsA is more than doubled in patients with nail involvement. We hypothesized that onycholysis may be associated with early bone erosions of the DIP joint without harbouring PsA symptoms.

Methods: We compared tendon thickness, assessed by US, and bone erosions, assessed by high-resolution peripheral quantitative CT, of the DIP joint in patients with psoriatic onycholysis without PsA (ONY) with those in patients with cutaneous psoriasis only (PSO). We used patients with PsA as reference (PsA group), and healthy age-matched controls (CTRL). Differences between groups were assessed by analysis of variance tests followed by post hoc analysis using the Scheffe method.

Results: Mean (s.e.m.) age of the 87 participants (61% males) was 45.2 (1.3) years. The mean extensor tendon thickness was significantly larger in ONY than in PSO patients. In the PsA group, 68% of patients exhibited erosions of three different shapes: V-, Omega- and U-shape. Association with erosions was greater in the ONY group than in the PSO group (frequency: 57 vs 14%; P < 0.001; mean number of erosions: 1.10 (0.35) vs 0.03 (0.03); P < 0.001).

Conclusion: Onycholysis was associated with significant enthesopathy and bone erosions in our cohort. These data support the pathogenic role of enthesopathy in PsA. Onycholysis may be considered as a surrogate marker of severity in psoriasis.

Trial Registration: ClinicalTrails.gov, https://clinicaltrials.gov, NCT02813720.
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http://dx.doi.org/10.1093/rheumatology/keaa415DOI Listing
March 2021

Tocilizumab in symptomatic calcium pyrophosphate deposition disease: a pilot study.

Ann Rheum Dis 2020 08 25;79(8):1126-1128. Epub 2020 Mar 25.

Service de Rhumatologie, Hopital Lariboisiere, AP-HP, Paris, Île-de-France, France.

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http://dx.doi.org/10.1136/annrheumdis-2020-217188DOI Listing
August 2020

Consensus approach for 3D joint space width of metacarpophalangeal joints of rheumatoid arthritis patients using high-resolution peripheral quantitative computed tomography.

Quant Imaging Med Surg 2020 Feb;10(2):314-325

McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, Canada.

Background: Joint space assessment for rheumatoid arthritis (RA) by ordinal conventional radiographic scales is susceptible to floor and ceiling effects. High-resolution peripheral quantitative computed tomography (HR-pQCT) provides superior resolution, and may detect earlier changes. The goal of this work was to compare existing 3D methods to calculate joint space width (JSW) metrics in human metacarpophalangeal (MCP) joints with HR-pQCT and reach consensus for future studies. Using the consensus method, we established reproducibility with repositioning as well as feasibility for use in second-generation HR-pQCT scanners.

Methods: Three published JSW methods were compared using datasets from individuals with RA from three research centers. A SPECTRA consensus method was developed to take advantage of strengths of the individual methods. Using the SPECTRA method, reproducibility after repositioning was tested and agreement between scanner generations was also established.

Results: When comparing existing JSW methods, excellent agreement was shown for JSW minimum and mean (ICC 0.987-0.996) but not maximum and volume (ICC 0.000-0.897). Differences were identified as variations in volume definitions and algorithmic differences that generated high sensitivity to boundary conditions. The SPECTRA consensus method reduced this sensitivity, demonstrating good scan-rescan reliability (ICC >0.911) except for minimum JSW (ICC 0.656). There was strong agreement between results from first- and second-generation HR-pQCT (ICC >0.833).

Conclusions: The SPECTRA consensus method combines unique strengths of three independently-developed algorithms and leverages underlying software updates to provide a mature analysis to measure 3D JSW. This method is robust with respect to repositioning and scanner generations, suggesting its suitability for detecting change.
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http://dx.doi.org/10.21037/qims.2019.12.11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063288PMC
February 2020

Exposure-Response Relationship of Certolizumab Pegol and Achievement of Low Disease Activity and Remission in Patients With Rheumatoid Arthritis.

Clin Transl Sci 2020 07 1;13(4):743-751. Epub 2020 Apr 1.

Department of Medicine, University of California San Diego, La Jolla, California, USA.

Anti-tumor necrosis factor (anti-TNF) drugs are often prescribed for the treatment of rheumatoid arthritis (RA) and other immune-mediated inflammatory diseases. Although this treatment has been shown to be effective in many patients, up to 40% of patients do not achieve disease control. Drug concentration in plasma may be a factor affecting the observed variability in therapeutic response. In this study, we aimed to identify the plasma concentrations of the anti-TNF certolizumab pegol (CZP), associated with improvement in disease activity in patients with RA. Data were pooled from three randomized, controlled clinical trials with a combined total of 1,935 patients analyzed. Clinical outcomes of low disease activity (LDA) and remission were defined as Disease Activity Score in 28 joints with C-reactive protein (DAS28(CRP)) ≤ 2.7 and < 2.3, respectively. Quartile analysis results indicated that there may be an exposure-response relationship between CZP concentration and LDA/remission outcomes at weeks 12 and 24; the association was strongest for LDA (P < 0.05). Receiver operating characteristic (ROC) analysis showed that CZP concentrations ≥ 28.0 μg/ml at week 12, and ≥ 17.6 μg/ml at week 24, were associated with a greater likelihood of achieving LDA/remission outcomes. Although confirmatory studies are warranted to define the optimal CZP therapeutic range at weeks 12 and 24, these data indicate that CZP concentrations may be associated with improvement of disease activity.
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http://dx.doi.org/10.1111/cts.12760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359948PMC
July 2020

Non-surgical periodontal disease to treat rheumatoid arthritis after selection of the right patients.

Authors:
Hubert Marotte

Rheumatology (Oxford) 2020 05;59(5):928-929

SAINBIOSE, INSERM U1059, Université de Lyon.

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http://dx.doi.org/10.1093/rheumatology/kez624DOI Listing
May 2020

Methotrexate Restores CD73 Expression on Th1.17 in Rheumatoid Arthritis and Psoriatic Arthritis Patients and May Contribute to Its Anti-Inflammatory Effect through Ado Production.

J Clin Med 2019 Nov 3;8(11). Epub 2019 Nov 3.

Immunology Department, University of Lyon, Claude Bernard Lyon 1 University, INSERM 1052, CNRS 5286, Cancer Research Center of Lyon (CRCL), Centre Léon Bérard, 69008 Lyon, France.

Objectives: Th1.17 are highly polyfunctional, potentially harmful CD4 effector T cells (Teff) through IFN-γ and IL-17A coproduction. Th1.17 take part in the pathophysiology of rheumatoid arthritis (RA) and psoriatic arthritis (PsA), in which their hyper activation results in part from defects in negative regulation mechanisms. We recently demonstrated that the ecto-nucleotidase CD73 delineates a Th1.17-enriched Teff population and acts as an endogenous regulatory mechanism. Because Methotrexate (MTX), used as first line treatment of RA and PsA, increases extracellular concentrations of AMP and immunosuppressive adenosine, we investigated the modulation of CD73 by MTX treatment on Teff in RA/PsA patients.

Methods: In a prospective cohort of 26 RA and 15 PsA patients before or under MTX treatment, we evaluated CD73 expression on blood Teff subsets, their cytokine production and AMPase functions.

Results: We showed a decreased CD73 expression on Th1.17 and Th1 in untreated patients compared to healthy donors that was partly restored under MTX. This decrease in untreated patients leads to a halved Ado production by Th1.17 cells. CD73 Teff remained functional under MTX treatment, but their CD73 re-expression may contribute to control their activation.

Conclusion: Our study unveils uncovered mode of action of MTX on Teff subsets modulation and in the adenosine-dependent termination of inflammation in RA and PsA.
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http://dx.doi.org/10.3390/jcm8111859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912794PMC
November 2019

Arthritis associated to cardio-facio-cutaneous syndrome related to a MAP2K1 mutation.

Joint Bone Spine 2020 Mar 27;87(2):169. Epub 2019 Sep 27.

Department of rheumatology, North hospital, university hospital of St-Étienne, avenue Albert-Raimond, 42270 Saint-Priest-en-Jarez, France; SAINBIOSE, Inserm U1059, university of Lyon, Saint-Etienne, 42023 Saint-Étienne, France. Electronic address:

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http://dx.doi.org/10.1016/j.jbspin.2019.09.014DOI Listing
March 2020

Implication of IL-17 in Bone Loss and Structural Damage in Inflammatory Rheumatic Diseases.

Mediators Inflamm 2019 14;2019:8659302. Epub 2019 Aug 14.

Bernard Cortet, EA 4490, Service de Rhumatologie, CHU Lille, Université Lille, 59000 Lille, France.

Proinflammatory cytokines play an important role in the systemic and focal bone loss associated with chronic inflammatory diseases. Targeting these cytokines with biologics and small molecules has led to a major improvement of the bone health of patients with inflammatory arthritis. Cytokines from the IL-17 family have been shown to be involved in the pathogenesis of several diseases such as spondyloarthritis, psoriatic arthritis, or psoriasis. IL-17A has been the first described and the most studied. The recent development of targeted therapies against IL-17A or its receptor and their efficacy has confirmed the importance of this cytokine in the development of inflammatory diseases. The aim of this review was to describe the effects of the IL-17 family and more particularly of IL-17A on bone and cartilage tissues. At the cellular level, IL-17A is proosteoclastogenic whereas its effects on osteoblasts depend on the stage of differentiation of these cells. , IL-17A is not required for normal bone homeostasis but plays an important role in bone loss notably in an ovariectomized mouse model of osteoporosis. Preliminary data from clinical trials showed a stabilisation of bone density in patients treated with anti-IL-17A antibodies. IL-17A plays a central role in the cartilage damage through the induction of collagenases and by decreasing the expression of their inhibitors in synergy with the other proinflammatory cytokines. The prevention of structural damage by anti-IL-17A therapies has been demonstrated in several pivotal clinical trials. Overall, blocking the IL-17A pathway seems to have a positive effect on the bone and cartilage damage observed in inflammatory arthritis. Differences and specificity of these effects compared to those already described with other biologics such as anti-TNF therapies remain to be explored.
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http://dx.doi.org/10.1155/2019/8659302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710740PMC
January 2020

Platelet Inflammatory Response to Stress.

Front Immunol 2019 28;10:1478. Epub 2019 Jun 28.

GIMAP-EA3064, Université de Lyon, Saint-Étienne, France.

Blood platelets play a central hemostatic role, (i) as they repair vascular epithelial damage, and (ii) they play immune defense roles, as they have the capacity to produce and secrete various cytokines, chemokines, and related products. Platelets sense and respond to local dangers (infectious or not). Platelets, therefore, mediate inflammation, express and use receptors to bind infectious pathogen moieties and endogenous ligands, among other components. Platelets contribute to effective pathogen clearance. Damage-associated molecular patterns (DAMPs) are danger signals released during inflammatory stress, such as burns, trauma and infection. Each pathogen is recognized by its specific molecular signature or pathogen-associated molecular pattern (PAMP). Recent data demonstrate that platelets have the capacity to sense external danger signals (DAMPs or PAMPs) differentially through a distinct type of pathogen recognition receptor (such as Toll-like receptors). Platelets regulate the innate immune response to pathogens and/or endogenous molecules, presenting several types of "danger" signals using a complete signalosome. Platelets, therefore, use complex tools to mediate a wide range of functions from danger sensing to tissue repair. Moreover, we noted that the secretory capacity of stored platelets over time and the development of stress lesions by platelets upon collection, processing, and storage are considered stress signals. The key message of this review is the "inflammatory response to stress" function of platelets in an infectious or non-infectious context.
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http://dx.doi.org/10.3389/fimmu.2019.01478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611140PMC
October 2020

Response to: 'Alcohol is not the missing link between related periodontitis and radiologic progression in early Rheumatoid arthritis' by Hillion .

Ann Rheum Dis 2020 09 14;79(9):e108. Epub 2019 Jun 14.

Laboratory of Immunology and Immunomonitoring, Universite Jean Monnet Saint-Etienne Faculte de Medecine Jacques Lisfranc, Saint Priest en Jarez, France.

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http://dx.doi.org/10.1136/annrheumdis-2019-215731DOI Listing
September 2020

Determining the Right Time for the Right Treatment-Application to Preclinical Rheumatoid Arthritis.

Authors:
Hubert Marotte

JAMA Netw Open 2019 06 5;2(6):e195358. Epub 2019 Jun 5.

Santé Ingéniérie Biologie Saint-Etienne, Institute National de la Santé et de la Rechereche Médicale, U1059, Université de Lyon, Saint-Etienne, France.

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http://dx.doi.org/10.1001/jamanetworkopen.2019.5358DOI Listing
June 2019

Osteoclast-Derived Autotaxin, a Distinguishing Factor for Inflammatory Bone Loss.

Arthritis Rheumatol 2019 11 30;71(11):1801-1811. Epub 2019 Sep 30.

INSERM UMR 1033 LYOS and University of Lyon I, Lyon, France, and Lyon Sud Hospital, Pierre-Bénite, France.

Objective: The severity of rheumatoid arthritis (RA) correlates directly with bone erosions arising from osteoclast (OC) hyperactivity. Despite the fact that inflammation may be controlled in patients with RA, those in a state of sustained clinical remission or low disease activity may continue to accrue erosions, which supports the need for treatments that would be suitable for long-lasting inhibition of OC activity without altering the physiologic function of OCs in bone remodeling. Autotaxin (ATX) contributes to inflammation, but its role in bone erosion is unknown.

Methods: ATX was targeted by inhibitory treatment with pharmacologic drugs and also by conditional inactivation of the ATX gene Ennp2 in murine OCs (ΔATX ). Arthritic and erosive diseases were studied in human tumor necrosis factor-transgenic (hTNF ) mice and mice with K/BxN serum transfer-induced arthritis. Systemic bone loss was also analyzed in mice with lipopolysaccharide (LPS)-induced inflammation and estrogen deprivation. Joint inflammation and bone erosion were assessed by histology and micro-computed tomography. The role of ATX in RA was also examined in OC differentiation and activity assays.

Results: OCs present at sites of inflammation overexpressed ATX. Pharmacologic inhibition of ATX in hTNF mice, as compared to vehicle-treated controls, significantly mitigated focal bone erosion (36% decrease; P < 0.05) and systemic bone loss (43% decrease; P < 0.05), without affecting synovial inflammation. OC-derived ATX was revealed to be instrumental in OC bone resorptive activity and was up-regulated by the inflammation elicited in the presence of TNF or LPS. Specific loss of ATX in OCs from mice subjected to ovariectomy significantly protected against the systemic bone loss and erosion that had been induced with LPS and K/BxN serum treatments (30% reversal of systemic bone loss [P < 0.01]; 55% reversal of erosion [P < 0.001]), without conferring bone-protective properties.

Conclusion: Our results identify ATX as a novel OC factor that specifically controls inflammation-induced bone erosions and systemic bone loss. Therefore, ATX inhibition offers a novel therapeutic approach for potentially preventing bone erosion in patients with RA.
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http://dx.doi.org/10.1002/art.41005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817375PMC
November 2019

Non-surgical periodontal disease: A new treatment for rheumatoid arthritis?

Authors:
Hubert Marotte

Joint Bone Spine 2020 01 30;87(1):1-3. Epub 2019 May 30.

Inserm U1059, Sainbiose, Université de Lyon, Saint-Etienne, France; Service de Rhumatologie, CHU de Saint-Etienne, 42055 Saint-Etienne, France. Electronic address:

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http://dx.doi.org/10.1016/j.jbspin.2019.05.002DOI Listing
January 2020

Infliximab Induced a Dissociated Response of Severe Periodontal Biomarkers in Rheumatoid Arthritis Patients.

J Clin Med 2019 May 26;8(5). Epub 2019 May 26.

Department of Rheumatology, Hôpital Nord, CHU Saint-Etienne, 42055 Saint-Etienne, France.

Objective: Rheumatoid arthritis and periodontal disease are associated together, but the effect of therapy provided for one disease to the second one remained under-investigated. This study investigated effect of infliximab therapy used to treat rheumatoid arthritis (RA) on various biomarkers of periodontal disease (PD) severity including serologies of and and matrix metalloproteinase 3.

Methods: Seventy nine RA patients were enrolled at the time to start infliximab therapy and the 28 joint disease activity score (DAS28), anti-cyclic citrullinated petides 2nd generation (anti-CCP2), anti- antibody, and Matrix metalloproteinase 3 (MMP-3) were monitored before and at 6 months of infliximab therapy. Joint damage and severe periodontal disease were assessed at baseline. Anti-CCP2, anti- antibody, and MMP-3 were determined by enzyme-linked immunosorbent assay (ELISA).

Results: At baseline, anti-CCP2 titers were associated with anti- lipopolysaccharide (LPS)-specific antibodies titers ( < 0.05). Anti- antibodies were not significantly correlated with clinical, biological, or destruction parameters of RA disease. At 6 months of infliximab therapy, MMP-3 level decreased (from 119 ± 103 ng/mL to 62.44 ± 52 ng/mL; < 0.0001), whereas antibody levels remained at the same level. DAS28 and inflammation markers C-reactive protein (CRP) and Erythrocyte sedimentation rate (ESR) also decreased significantly during infliximab therapy ( < 0.05) as anti-CCP2 levels ( < 0.001). Only high MMP-3 level at baseline was associated with infliximab efficacy ( < 0.01).

Conclusion: MMP-3 level can be a useful marker of the efficacy of infliximab in RA patients. The treatment did not affect anti- antibodies.
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http://dx.doi.org/10.3390/jcm8050751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6571563PMC
May 2019

Tapering without relapse in rheumatoid arthritis patients with high TNF blocker concentrations: data from STRASS study.

Ann Rheum Dis 2020 07 2;79(7):e81. Epub 2019 May 2.

Laboratory of Immunology and Immunomonitoring, Universite Jean Monnet Saint-Etienne Faculte de Medecine Jacques Lisfranc, Saint Priest en Jarez, France.

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http://dx.doi.org/10.1136/annrheumdis-2019-215546DOI Listing
July 2020

How to Get the Most from Methotrexate (MTX) Treatment for Your Rheumatoid Arthritis Patient?-MTX in the Treat-to-Target Strategy.

J Clin Med 2019 Apr 15;8(4). Epub 2019 Apr 15.

Division of Rheumatology, Medical University Department, Kantonsspital Aarau, 5001 Aarau, Switzerland.

Methotrexate (MTX) is a remarkable drug with a key role in the management of rheumatoid arthritis (RA) at every stage of its evolution. Its attributes include good overall efficacy for signs and symptoms, inhibition of structural damage and preservation of function with acceptable and manageable safety, a large dose-titratable range, options for either an oral or parenteral route of administration, and currently unrivalled cost-effectiveness. It has a place as a monotherapy and also as an anchor drug that can be safely used in combination with other conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or used concomitantly with biological DMARDs or targeted synthetic DMARDs. MTX is not without potential issues regarding toxicity, notably hepatotoxicity and bone marrow toxicity, as well as tolerability problems for some, but not all, patients. But many of these issues can be mitigated or managed. In the face of a welcome expansion in available targeted therapies for the treatment of RA, MTX looks set to remain at the foundation of pharmacotherapy for the majority of people living with RA and other inflammatory rheumatic diseases. In this article, we provide an evidence-based discussion as to how to achieve the best outcomes with this versatile drug in the context of a treat-to-target strategy for the management of RA.
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http://dx.doi.org/10.3390/jcm8040515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518419PMC
April 2019

experimentally induces periodontis and an anti-CCP2-associated arthritis in the rat.

Ann Rheum Dis 2019 05 30;78(5):594-599. Epub 2019 Jan 30.

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

Objectives: Association between periodontal disease (PD) and rheumatoid arthritis (RA) has been extensively described, but direct evidence of causal involvement of PD in RA is missing. We investigated the priming role of oral () in PD and subsequent RA and we assessed biomarkers of bone resorption and arthritis development in rats.

Methods: Lewis rats were orally exposed to either , or control gel for 1 month and then followed for 8 months. The onset and development of PD was assessed by serology, gingivitis severity and micro-CT (µCT). We investigated arthritis development using circulating proinflammatory markers, anticyclic citrullinated peptide (CCP), anticitrullinated protein antibody (ACPA), ankle histology and µCT.

Results: PD was only observed in the treated rats, as early as 1 month postexposure. Joint and systemic inflammation were detected only in the group after 4 and 8 months. At 8 months, inflammatory cell infiltrate was observed in ankle joints and paralleled cortical erosions and overall cortical bone reduction. Furthermore, anti-CCP2 correlated with local and systemic bone loss.

Conclusions: In our long-term study, PD induced by oral exposure to triggered seropositive arthritis, with systemic inflammation and bone erosions. This is the first in vivo demonstration of arthritis induced by oral priming with .
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http://dx.doi.org/10.1136/annrheumdis-2018-213697DOI Listing
May 2019

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

Pharmacogenomics J 2019 08 16;19(4):368-374. Epub 2019 Jan 16.

Clinical Immunology and Osteoarticular Diseases Therapeutic Unit, Lapeyronie University Hospital, Montpellier, France.

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.
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http://dx.doi.org/10.1038/s41397-019-0072-6DOI Listing
August 2019

Cutaneous Mycobacterium chelonae infection in a patient with rheumatoid arthritis treated with glucocorticoids.

Joint Bone Spine 2019 01 30;86(1):105. Epub 2018 Jun 30.

Department of rheumatology, North hospital, university hospital of Saint-Étienne, avenue Albert-Raimond, 42270 Saint-Priest-en-Jarez, France; SAINBIOSE, Inserm U1059, university of Lyon, 42023 Saint-Étienne, France; CIC Inserm U1408, university of Lyon, 42023 Saint-Étienne, France. Electronic address:

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http://dx.doi.org/10.1016/j.jbspin.2018.06.004DOI Listing
January 2019

Prealbumin, platelet factor 4 and S100A12 combination at baseline predicts good response to TNF alpha inhibitors in rheumatoid arthritis.

Joint Bone Spine 2019 03 6;86(2):195-201. Epub 2018 Jun 6.

EA 7408, University Grenoble Alpes, GREPI, 38400 Saint-Martin-d'Hères, France; Rheumatology Department, centre hospitalier universitaire Grenoble Alpes, hôpital Sud Echirolles, 38130 Echirolles, France.

Objectives: Tumour necrosis factor-alpha inhibitors (TNFi) are effective treatments for Rheumatoid Arthritis (RA). Responses to treatment are barely predictable. As these treatments are costly and may induce a number of side effects, we aimed at identifying a panel of protein biomarkers that could be used to predict clinical response to TNFi for RA patients.

Methods: Baseline blood levels of C-reactive protein, platelet factor 4, apolipoprotein A1, prealbumin, α1-antitrypsin, haptoglobin, S100A8/A9 and S100A12 proteins in bDMARD naive patients at the time of TNFi treatment initiation were assessed in a multicentric prospective French cohort. Patients fulfilling good EULAR response at 6 months were considered as responders. Logistic regression was used to determine best biomarker set that could predict good clinical response to TNFi.

Results: A combination of biomarkers (prealbumin, platelet factor 4 and S100A12) was identified and could predict response to TNFi in RA with sensitivity of 78%, specificity of 77%, positive predictive values (PPV) of 72%, negative predictive values (NPV) of 82%, positive likelihood ratio (LR+) of 3.35 and negative likelihood ratio (LR-) of 0.28. Lower levels of prealbumin and S100A12 and higher level of platelet factor 4 than the determined cutoff at baseline in RA patients are good predictors for response to TNFi treatment globally as well as to Infliximab, Etanercept and Adalimumab individually.

Conclusion: A multivariate model combining 3 biomarkers (prealbumin, platelet factor 4 and S100A12) accurately predicted response of RA patients to TNFi and has potential in a daily practice personalized treatment.
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http://dx.doi.org/10.1016/j.jbspin.2018.05.006DOI Listing
March 2019

Evaluation of bone quality with trabecular bone score in active spondyloarthritis.

Joint Bone Spine 2018 12 6;85(6):727-731. Epub 2018 Apr 6.

Rheumatology Department, CHU de St-Etienne, 42055 Saint-Etienne cedex 2, France; INSERM U1059, Laboratoire de Biologie Intégrée du Tissu Osseux, 42055 Saint-Etienne cedex 2, France; Rheumatology Department, Université de Lyon, University Hospital of Saint-Etienne, 42055 Saint-Etienne cedex 2, France. Electronic address:

Objective: Many patients with spondyloarthritis (SpA) are at risk of fracture due to bone fragility, whereas their bone mineral density (BMD) is not significantly diminished. Other tools, such as trabecular bone score (TBS), evaluating other characteristics of bone tissue are therefore necessary in order to evaluate bone changes in these patients. Therefore we evaluated TBS as a bone quality marker, in a cohort of patients with SpA and investigated which clinical and biological factors were correlated with TBS values.

Methods: Patients fulfilling ASAS criteria of SpA with a BMD assessment and visiting our department for initiation or switch of a biologic treatment were selected. The clinical and biological data were collected at the time of BMD measurement.

Results: Ninety-five patients were included in the study, with a mean age of 40.2 and a mean disease duration of 8.2 years. Lumbar BMD T-score was <-1 and <-2.5 in 17% and 3% of patients, respectively. On average, TBS value was 1.34±0.12. Lumbar BMD was positively correlated with TBS (r=0.61), while disease duration, disease activity score and serum PTH levels were negatively correlated with TBS (r=-0.24, r=-0.33, and r=-0.27, respectively). These correlations persisted in a multivariate analysis. Furthermore, more than half of the patients with a BMD level above -2.5 T-score had a low TBS value.

Conclusion: Our results show that TBS provides information additional to BMD on the bone status of patients with SpA. They suggest that TBS may help in identifying those patients at risk of fracture.
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http://dx.doi.org/10.1016/j.jbspin.2018.02.006DOI Listing
December 2018

Early sclerostin expression explains bone formation inhibition before arthritis onset in the rat adjuvant-induced arthritis model.

Sci Rep 2018 02 22;8(1):3492. Epub 2018 Feb 22.

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

Periarticular bone loss in rheumatoid arthritis (RA) is considered to be mainly related to synovial inflammation. However, strong bone loss has also described at the time of arthritis onset. Recently, a paradoxical exacerbation of joint damage was described when blocking sclerostin in various arthritis models. Thus, we aimed to determine kinetics of bone loss and its mechanisms in the adjuvant induced arthritis (AIA) rat model of RA. AIA was induced (n = 35) or not (n = 35) at day 0. In addition to well-known arthritis at day 12, we showed with 3D-imaging and histomorphometry that bone microstructural alterations occurred early from day 8 post-induction, characterized by cortical porosity and trabecular bone loss. Active osteoclastic surfaces were increased from day 8 with RANKL upregulation. More surprisingly SOST and DKK1 were overexpressed from day 6 and followed by a dramatic decrease in bone formation from day 8. At the time of arthritis onset, SOST and DKK1 returned to control values, but frizzled related protein 1 (SFRP1), proinflammatory cytokines, and MMPs started to increase. Bone alterations before arthritis onset reinforce the hypothesis of an early bone involvement in arthritis. Kinetics of osteocyte markers expression should be considered to refine Wnt inhibitor treatment strategies.
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http://dx.doi.org/10.1038/s41598-018-21886-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5823923PMC
February 2018

Remaining local subclinical joint inflammation is associated with deteriorated metacarpeal head bone microarchitecture in rheumatoid arthritis patients low disease activity.

Joint Bone Spine 2018 10 2;85(5):569-572. Epub 2017 Dec 2.

Department of Rheumatology, Hospital Nord, University Hospital, 42023 Saint-Étienne, France; Inserm U1059, Sainbiose, University of Lyon, 42023 Saint-Étienne, France. Electronic address:

Objectives: Bone alterations at the subchondral level during rheumatoid arthritis (RA) remain under investigation. It remains unknown whether subchondral bone damage might still occur in RA patients in clinical remission, which could then infer suggesting that even minor subclinical inflammatory changes in the joint can induce local bone loss.

Methods: Thirty-two RA patients treated with biological disease-modifying anti-rheumatic drugs (bDMARDs) with low disease activity since at least 6 months and having erosion on the second or third metacarpeal head were enrolled in this pilot cross-sectional study. They were divided in two groups according to local inflammation assessed by Doppler-ultrasound exam surrounding the site of erosion. Cortical and trabecular parameters of the metacarpeal head were then assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT) and compared in both groups.

Results: Twenty and twelve RA patients were enrolled in the "Doppler positive erosion" (DE+) group and Doppler negative erosion (DE-) group, respectively. No difference was observed in their clinical or biological RA characteristics. Both cortical density and thickness were similar among groups. Within the trabecular network, while no difference in bone volume was observed, trabecular density as well as trabecular number were decreased (P<0.001 and P<0.05 respectively), whereas trabecular separation and distribution of trabecular separation were increased in DE+ compared to DE- (P<0.05).

Conclusion: In RA patients in low disease activity under bDMARDs, persistence of local inflammation was associated with alteration of the trabecular compartment. Trabecular density was the most strongly altered parameter and could be a candidate to assess drug effect on periarticular bone damage.
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http://dx.doi.org/10.1016/j.jbspin.2017.11.010DOI Listing
October 2018

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

Rheumatoid arthritis treated with tocilizumab in two patients with complicated chronic liver disease with portal hypertension.

Joint Bone Spine 2018 01 27;85(1):115-117. Epub 2017 Jul 27.

Rheumatology Department, University Hospital of Saint-Étienne, avenue Albert-Raimond, 42270 Saint-Priest-en-Jarez, France; Inserm U1059, laboratoire biologie intégrée du tissu osseux, université de Lyon, 42023 Saint-Étienne, France. Electronic address:

Erosive, active rheumatoid arthritis inpatients with portal hypertension combining esophageal varices and ascites complicating chronic liver disease poses serious management problems. Current literature does not provide any valid therapeutic management. We report the case of a woman and a man aged 52 and 66 years respectively having this combination of pathologies. Infusions of 4mg/kg of tocilizumab as monotherapy have produced a weaning from corticosteroids, both clinical and structural remission, with particular liver safety satisfactory at 10 and 18 months.
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http://dx.doi.org/10.1016/j.jbspin.2017.07.004DOI Listing
January 2018