Publications by authors named "Philippe Gaudin"

104 Publications

Cut-off value to identify a flare using the Flare Assessment in Rheumatoid Arthritis (FLARE-RA) questionnaire: analysis of the TOSCA study.

Rheumatology (Oxford) 2021 Mar 31. Epub 2021 Mar 31.

Rheumatology Department, Pitié Salpêtrière hospital, Sorbonne Université - Assistance Publique Hôpitaux de Paris, Paris, France.

Objective: The Flare Assessment in Rheumatoid Arthritis (FLARE-RA) self-administered questionnaire aims to identify patients who had flare in the interval between 2 consultations. This study aimed to establish a threshold for FLARE-RA score to identify RA flare.

Methods: The Tocilizumab SubCutAneous (TOSCA) study evaluated the efficacy and safety of subcutaneous Tocilizumab (TCZ) to patients with active RA. Disease activity was assessed with the DAS28ESR at baseline and at week 2 (W2), W4, W12, and W24. The FLARE-RA questionnaire was administered at W12 and W24. Patient satisfaction, assessed at baseline and W24 with the Patient Acceptable Symptom State (PASS), was used as a surrogate marker of no flare. A correlation was sought between the FLARE-RA score at W12 and W24 and the area under the receiver operating characteristic (ROC) curve (AUC) for monthly DAS28ESR. The optimal FLARE-RA cut-off below which patient satisfaction reached the PASS was explored with an ROC curve.

Results: 139 patients were included (mean age 57.3 ± 13.8 years, 74.1% women, mean RA duration 10.8 ± 9.2 years, mean DAS28ESR 5.8 ± 1.1). The correlation between the FLARE-RA score and DAS28ESR AUC was moderate at all times: rho = 0.41 at W12 (p<0.0001) and 0.51 at W24 (p<0.0001). The optimal cut-off for the FLARE-RA score to identify absence of flare (i.e. an acceptable situation based on the PASS) was 2.3 with an AUC of 0.81.

Conclusion: FLARE-RA and DAS28ESR assessment differ; we propose a FLARE-RA cut-off of 2.3, below which the situation (i.e. without flare) is acceptable for patients.
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http://dx.doi.org/10.1093/rheumatology/keab261DOI Listing
March 2021

Chlamydia-infected Macrophages mediate Interleukin-23 and Tumor Necrosis Factor-driven Reactive Arthritis in SKG Mice.

Arthritis Rheumatol 2021 Jan 16. Epub 2021 Jan 16.

Univ. Grenoble Alpes, GREPI TIMC-IMAG, UMR 5525, 38000, Grenoble, France.

Objective: ZAP-70 BALB/c (SKG) mice develop reactive arthritis (ReA) after Chlamydia muridarum (Cmu) infection. Since intracellular pathogens enhance their replicative fitness in stressed host cells, we examined how myeloid cells taking up Cmu drive arthritis.

Methods: Female SKG, Il17a-deficient SKG and BALB/c mice were genitally infected with Cmu or Cmu Luciferase. Cmu dissemination was assessed by in vivo imaging or genomic DNA amplification. Macrophages were depleted using clodronate liposomes. Anti-TNF, anti-IL-23p19 were administered after infection or arthritis onset. Hspa5, Tgtp1, Il23a, Il17a, Il12b and Tnf expression was compared in SKG and BALB/c mice.

Results: One-week post infection, macrophages and neutrophils infiltrated the uterus; both carried Cmu DNA to the spleen. Cmu load was higher in SKG than BALB/c. Macrophage depletion reduced Cmu load and prevented arthritis. Compared with BALB/c, expression of Il23a and Il17a was increased in SKG uterine and splenic neutrophils. Anti-IL-23p19 during infection or Il17a deficiency suppressed arthritis. Tnf was over-expressed in SKG joints within one-week post infection and persisted. TNF inhibition during infection or at arthritis onset suppressed arthritis. Endoplasmic reticulum stress was constitutively increased in SKG joints but was induced, with immunity-related GTPase, by Cmu infection in uterus.

Conclusion: The load of Cmu is higher in SKG than BALB/c mice. While proinflammatory IL-23 produced by neutrophils contributes to the initiation of Cmu-mediated ReA, macrophage depletion reduces Cmu dissemination to other tissues, tissue burden, and arthritis. TNF inhibition suppresses arthritis. Our data suggest that enhanced bacterial dissemination in SKG macrophages drives TNF production required for persistent arthritis.
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http://dx.doi.org/10.1002/art.41653DOI Listing
January 2021

GlutenSpA trial: protocol for a randomised double-blind placebo-controlled trial of the impact of a gluten-free diet on quality of life in patients with axial spondyloarthritis.

BMJ Open 2020 11 20;10(11):e038715. Epub 2020 Nov 20.

Rheumatology, CHU Clermont-Ferrand, Clermont-Ferrand, France.

Introduction: Subclinical intestinal inflammation and gut dysbiosis have been reported in patients with spondyloarthritis (SpA). In common practice, rheumatologists are increasingly confronted with patients with inflammatory rheumatism who are on gluten-free diets (GFDs), despite the lack of reliable data from controlled studies. This study aims to determine the impact of a GFD on the quality of life of patients with axial SpA.

Methods And Analysis: The GlutenSpA study is a 24-week, randomised, double-blinded, placebo-controlled, multicentre trial. Patients with axial SpA (n=200) will follow a 16-week GFD and be randomly assigned (1:1) to an experimental or control arm. In the experimental arm with receive at least 6 gluten-free breads per day + 200 g of gluten-free penne pasta per week + 6 rice flavour capsules per day. The control arm will receive at least 6 gluten-containing breads per day + 200 g of gluten-containing penne pasta per week + 6 vital gluten-containing capsules per day. The primary end-point is the variation in Assessment of SpondyloArthritis International Society-Health Index (ASAS-HI) questionnaire between week 16 and baseline. A second open-label period of 8 weeks will follow the intervention period, during which the patient will be free to decide whether they will follow the GFD. The secondary outcomes comprise several patient-reported outcomes (SpA activity (Bath Ankylosing Spondylitis Disease Activity Index)), fatigue (Functional Assessment of Chronic Illness Therapy), depression (Hospital Anxiety and Depression Scale), functional disability index (Bath Ankylosing Spondylitis Functional Index)), variations in body mass index and Homeostasis Model Assessment Index and variations in the abundance and type of bacterial species found in the gut microbiota for a subgroup of patients (n=40). The data will be analysed using the intention-to-treat principle.The regional ethics committee (CPP Nord-ouest IV) has approved the study (IDRCB 2018-A00309-46). The results of the trial will be submitted for publication in peer-reviewed journals. The authors have no relationship that may have influenced the submitted work.

Trial Registration Number: NCT04274374.
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http://dx.doi.org/10.1136/bmjopen-2020-038715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682451PMC
November 2020

Foot-Worn Inertial Sensors Are Reliable to Assess Spatiotemporal Gait Parameters in Axial Spondyloarthritis under Single and Dual Task Walking in Axial Spondyloarthritis.

Sensors (Basel) 2020 Nov 12;20(22). Epub 2020 Nov 12.

University Grenoble Alpes, AGEIS, 38000 Grenoble, France.

The aim of this study was (1) to evaluate the relative and absolute reliability of gait parameters during walking in single- and dual-task conditions in patients with axial spondyloarthritis (axSpA), (2) to evaluate the absolute and relative reliability of dual task effects (DTE) parameters, and (3) to determine the number of trials required to ensure reliable gait assessment, in patients with axSpA. Twenty patients with axSpa performed a 10-m walk test in single- and dual-task conditions, three times for each condition. Spatiotemporal, symmetry, and DTE gait parameters were calculated from foot-worn inertial sensors. The relative reliability (intraclass correlation coefficients-ICC) and absolute reliability (standard error of measurement-SEM and minimum detectable change-MDC) were calculated for these parameters in each condition. Spatiotemporal gait parameters showed good to excellent reliability in both conditions (0.59 < ICC < 0.90). The reliability of symmetry and DTE parameters was low. ICC, SEM, and MDC were better when using the mean of the second and the third trials. Spatiotemporal gait parameters obtained from foot-worn inertial sensors assessed in patients with axSpA in single- and dual-task conditions are reliable. However, symmetry and DTE parameters seem less reliable and need to be interpreted with caution. Finally, better reliability of gait parameters was found when using the mean of the 2nd and the 3rd trials.
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http://dx.doi.org/10.3390/s20226453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697708PMC
November 2020

Impact of disease activity and treatments on ovarian reserve in patients with rheumatoid arthritis in the ESPOIR cohort.

Rheumatology (Oxford) 2021 Apr;60(4):1863-1870

Assistance Medicale à la Procréation, CECOS, CHU Estaing, Clermont-Ferrand University, France.

Objectives: Patients with RA have a higher prevalence of infertility than the general population. This study sought to examine the impact of RA disease activity and treatments on ovarian reserve measured by serum anti-Müllerian hormone (AMH) levels in the ESPOIR cohort. We sought to better define the indications for fertility preservation.

Methods: Patients and serum analysis data were derived from the French national cohort ESPOIR. Enrolled patients (n = 102; 18-37-year-olds) fulfilled ACR/EULAR 2010 criteria for RA. Serum AMH levels were measured at T0, T6, T12, T24 and T36 months post-diagnosis. The impacts of RA activity (DAS28 and CRP level) and treatments (MTX only or with other medications) were evaluated at each study visit.

Results: A gradual decrease in patients' serum AMH levels was observed over time, in line with the descending curve described for healthy women. Serum AMH levels of RA patients in comparison with the values considered normal for age did not reveal any significant differences (P > 0.05). We did not observe any impact of RA treatments. We demonstrated an inverse correlation between AMH variation and disease activity (DAS28: r = -0.27, P = 0.003; CRP: r = -0.16, P = 0.06).

Conclusion: This is the first study to determine serum AMH levels of a large cohort of RA patients over 36 months. Rapid disease activity control appears to be required to limit changes in the ovarian reserve. Fertility preservation is not likely to be necessary if inflammation is promptly controlled.

Clinicaltrials.gov Identifier: NCT03666091.
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http://dx.doi.org/10.1093/rheumatology/keaa535DOI Listing
April 2021

Evaluation of the impact of a nurse-led program of patient self-assessment and self-management in axial spondyloarthritis: results of a prospective, multicentre, randomized, controlled trial (COMEDSPA).

Rheumatology (Oxford) 2021 02;60(2):888-895

Rheumatology Department, Cochin Hospital, Assistance Publique Hôpitaux de Paris, France.

Objective: To evaluate the impact of a nurse-led program of self-management and self-assessment of disease activity in axial spondyloarthritis.

Methods: Prospective, randomized, controlled, open, 12-month trial (NCT02374749). Participants were consecutive axial spondyloarthritis patients (according to the rheumatologist) and nurses having participated in a 1-day training meeting. The program included self-management: educational video and specific video of graduated, home-based exercises for patients; and self-assessment: video presenting the rationale of tight monitoring of disease activity with composite scores (Ankylosing Spondylitis Disease activity Score, ASDAS/Bath Ankyslosing Spondylitis Disease Activity Index, BASDAI). The nurse trained patients to collect, calculate and report (monthly) ASDAS/BASDAI. Treatment allocation was by random allocation to this program or a comorbidities assessment (not presented here and considered here as the control group).

Results: A total of 502 patients (250 and 252 in the active and control groups, respectively) were enrolled (age: 46.7 (12.2) years, male gender: 62.7%, disease duration: 13.7 (11.0) years). After the one-year follow-up period, the adherence to the self-assessment program was considered good (i.e. 79% reported scores >6 times). Despite a lack of statistical significance in the primary outcome (e.g. coping) there was a statistically significant difference in favor of this program for the following variables: change in BASDAI, number and duration of the home exercises in the active group, and physical activity (international physical activity score, IPAQ).

Conclusion: This study suggests a short-term benefit of a nurse-led program on self-management and self-assessment for disease activity in a young axial spondyloarthritis population in terms of disease activity, exercises and physical activity.
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http://dx.doi.org/10.1093/rheumatology/keaa480DOI Listing
February 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

Serum calprotectin is increased in early axial spondyloarthritis with sacroiliitis and objective signs of inflammation: Results from the DESIR cohort.

Joint Bone Spine 2021 01 5;88(1):105068. Epub 2020 Sep 5.

Department of Rheumatology, CHU Grenoble Alpes, Echirolles, France; University Grenoble Alpes, GREPI TIMC, CNRS UMR 5525, Grenoble, France.

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http://dx.doi.org/10.1016/j.jbspin.2020.08.003DOI Listing
January 2021

Efficacy, safety and cost-effectiveness of a web-based platform delivering the results of a biomarker-based predictive model of biotherapy response for rheumatoid arthritis patients: a protocol for a randomized multicenter single-blind active controlled clinical trial (PREDIRA).

Trials 2020 Aug 31;21(1):755. Epub 2020 Aug 31.

Rheumatology Department and Health Research Institute, Hospital Clinico San Carlos, Madrid, Spain.

Background: Rheumatoid arthritis (RA) is one of the leading chronic inflammatory rheumatism. First-line therapy with synthetic disease-modifying antirheumatic drugs (sDMARD) is insufficiently effective in 40% of cases and these patients are treated with biotherapies. The increased use of these drugs each year is becoming a public health issue with considerable economic burden. This cost is 20 times higher than that of sDMARD. However, among patients treated with biotherapies, clinical practice shows that about one third will not respond to the selected drug. In nonresponse cases, practitioners currently have no choice but to perform an empirical switching between different treatments, because no tool capable of predicting the response or nonresponse to these molecules is currently available.

Methods: The study is a prospective, phase III, controlled, multicenter, and randomized, single-blind (patient) clinical trial, including RA patients with a previous failure to anti-TNF therapies. The main objective is the analysis of the clinical and pharmacoeconomic impact after 6 months of treatment. Intervention arm: prescription of biotherapy (rituximab, adalimumab, abatacept) using SinnoTest® software, a prediction software based on proteomic biomarkers. Control arm: prescription of biotherapy based on current practice, without the SinnoTest® software (any biotherapy). In addition, a substudy will be carried out within this trial to generate a biobank and further analyze the proteomic profile of the patients and their modification throughout the study.

Discussion: This clinical trial study will be the first validation study of a biotherapy response prediction software, bringing personalized medicine into the management of RA. We expect that the findings from this study will bring several benefits for the patient and the Health Care System.

Trial Registration: ClincalTrials.gov NCT04147026 . Registered on 31 October, 2019.
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http://dx.doi.org/10.1186/s13063-020-04683-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456748PMC
August 2020

Evaluation of the impact of a nurse-led program of systematic screening of comorbidities in patients with axial spondyloarthritis: The results of the COMEDSPA prospective, controlled, one year randomized trial.

Semin Arthritis Rheum 2020 08 27;50(4):701-708. Epub 2020 May 27.

Rheumatology Department, Cochin Hospital, Assistance Publique Hôpitaux de Paris, Paris, France; Université de Paris, INSERM U-1153, CRESS, Paris, France.

Objective: To evaluate the impact of a nurse-led program of systematic screening for the management (detection/prevention) of comorbidities.

Methods: Prospective, randomized, controlled, open, 12-month trial (NCT02374749).

Participants: consecutive patients with axial Spondyloarthritis (axSpA) (according to the rheumatologist) THE PROGRAM: A nurse collected data on comorbidities during a specific outpatient visit. In the event of non-agreement with recommendations, the patient was informed and a specific recommendation was given to the patient (orally and in a with a detailed written report). Patients were seen after one year in a nurse-led visit. TREATMENT ALLOCATION: random allocation (i.e. either this program or an educational program not presented here and considered here as the control group).

Main Outcome: change after one year of a weighted comorbidity management score (0 to 100 where 0= optimal management).

Results: 502 patients were included (252 and 250 in the active and control groups, respectively): age: 47±12 years, male gender: 63%, disease duration: 14±11y. After one year, no differences were observed in a weighted comorbidity management score. However, the number of patients in agreement with recommendations was significantly higher in the active group for vaccinations (flu vaccination: 28.6% vs. 9.9%, p<0.01; pneumococcal vaccination:40.0% vs. 21.1%,p=0.04), for cancer screening (skin cancer screening: 36.3% vs. 17.2%, p=0.04) and for osteoporosis (bone densitometry performed: 22.6% vs. 8.7%, p<0.01; Vitamin D supplementation initiation: 51.9% vs. 9.4%, p<0.01).

Conclusions And Relevance: This study suggests the short-term benefit of a single-visit nurse-led program for systematic screening of comorbidities for its management in agreement with recommendations, even in this young population of patients with axSpA.
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http://dx.doi.org/10.1016/j.semarthrit.2020.05.012DOI Listing
August 2020

Rheumatoid Meningitis a Rare Extra-Articular Manifestation of Rheumatoid Arthritis: Report of 6 Cases and Literature Review.

J Clin Med 2020 May 27;9(6). Epub 2020 May 27.

Rheumatology department, CHU Grenoble Alpes, Hôpital Sud, 38130 Echirolles, France.

Objectives: Central neurological manifestations of rheumatoid arthritis (RA) like rheumatoid meningitis (RM) are rare, little known and have a high rate of morbi-mortality.

Methods: We described six cases of RM that were directly related to RA activity after exhaustive assessment.

Results: They were mainly women, aged of 50 to 69. All were positive for anti-cyclic citrullinated peptide antibodies and half for rheumatoid factors. RA activity, duration, and treatments were heterogeneous including oral steroids, conventional synthetic disease modifying anti-rheumatic drugs (DMARDs) and biologic DMARDs. Symptoms were various, with acute or progressive beginning; main were: generalized or focal seizure (4/6), fever (3/6), headaches (3/6), and frontal syndrome (2/6). Imaging lesions were four leptomeningitis, one pachymeningitis, and one association of both. MRI usually showed hypersignal in various territories in T2-FLAIR (fluid attenuated inversion recovery) mode, and enhancement in T1-weighted mode after gadolinium injection. All patients had lumbar puncture that found sterile cerebrospinal fluid, no neoplasic cell, elevated cell count in 5/6 cases and elevated proteins concentration in 3/6 cases. Cerebral biopsy was possible for three patients, and definitively confirmed the diagnosis of aseptic lepto- or pachymenintis, excluding vasculitis and lymphoma. Different treatments were used like intravenous high dose steroids, immunoglobulins or biologic DMARDs, with variable clinical and imaging outcome: one death, one complete recovery, and four recoveries with sequelae.

Conclusions: Clinical symptoms, imaging, lumbar puncture, and serological studies are often nonspecific, only histologic examination can confirm the diagnosis of RM. Any central neurological manifestation in RA patients, even in quiescent and ancient RA, should warn the physician.
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http://dx.doi.org/10.3390/jcm9061625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356493PMC
May 2020

Data to be collected for an optimal management of axial spondyloarthritis in daily practice: Proposal from evidence-based and consensual approaches.

Joint Bone Spine 2020 Oct 16;87(5):405-411. Epub 2020 May 16.

Paris Descartes University, Department of Rheumatology - Hôpital Cochin. Assistance publique-Hôpitaux de Paris. inserm (U1153): Clinical epidemiology and biostatistics, Université de Paris, Paris, France.

Objective: To propose a list of variables to be collected right after the diagnosis has been made and during the follow-up of patients with axial spondyloarthritis (ax-SpA) for an optimal management in daily practice.

Methods: The process comprised (1) the evaluation of the interest of 51 variables proposed for the assessment of ax-SpA by means of a systematic literature research; (2) a consensus process involving 78 hospital-based or office-based rheumatologists, considering the collection of each variable in a 4 grade scale from "not very useful/useless" to "mandatory"; (3) a consensus on the minimum interval of time for periodic assessment of the selected variables on a 5 grade scale from "at each visit" to "never to be re-collected".

Results: The systematic literature research retrieved a total of 14,133 abstracts, of which 213 were included in the final qualitative synthesis. Data to be collected at the initial systematic review comprised 5 patient's self-administered questionnaires, 3 variables of the physician's interview, 2 variables of the physical examination, 2 variables of the specific ax-SpA imaging and 2 other investigations. Two variables were recommended to be systematically collected at each visit, 1 variable twice a year, 6 variables yearly and 1 variable every 2 years.

Conclusions: Using an evidence-based and an expert consensus approaches, this initiative defined a core set of variables to be collected and reported right after the diagnosis and during follow-up of patients with ax-SpA in daily practice.
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http://dx.doi.org/10.1016/j.jbspin.2020.04.019DOI Listing
October 2020

Implementation of comorbidities' systematic screening program in daily practice in France.

Joint Bone Spine 2020 12 6;87(6):663-665. Epub 2020 May 6.

Department of Rheumatology, Grenoble Alpes University Hospital, 38130 Grenoble, France; TIMC-IMAG UMR CNRS 5525, Grenoble Alpes University, Grenoble, France.

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http://dx.doi.org/10.1016/j.jbspin.2020.04.011DOI Listing
December 2020

Agreement with the French 2019 recommendations on treatment adherence in rheumatic diseases among 357 health professionals.

Joint Bone Spine 2020 10 5;87(5):513-515. Epub 2020 May 5.

Rheumatology Department, Cochin Hospital, AP-HP, Centre, 75014 Paris, France; Inserm Unit 1153, Université de Paris, PRES Sorbonne Paris-Cité, 75014 Paris, France.

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http://dx.doi.org/10.1016/j.jbspin.2020.04.008DOI Listing
October 2020

Apolipoprotein C1 in synovial fluid discriminates septic arthritis from rheumatoid arthritis but not from pseudogout.

Clin Rheumatol 2020 07 12;39(7):2239-2241. Epub 2020 Apr 12.

GREPI University Grenoble-Alpes (UGA) EA74 08, Grenoble, France.

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http://dx.doi.org/10.1007/s10067-019-04912-8DOI Listing
July 2020

Fetuin-A and thyroxin binding globulin predict rituximab response in rheumatoid arthritis patients with insufficient response to anti-TNFα.

Clin Rheumatol 2020 Sep 24;39(9):2553-2562. Epub 2020 Mar 24.

GREPI EA 7408, Université Grenoble Alpes, 38000, Grenoble, France.

Objectives: Rheumatoid arthritis (RA) is a debilitating disease, but patient management and treatment have been revolutionized since the advent of bDMARDs. However, about one third of RA patients do not respond to specific bDMARD treatment without clear identified reasons. Different bDMARDs must be tried until the right drug is found. Here, we sought to identify a predictive protein signature to stratify patient responsiveness to rituximab (RTX) among patients with an insufficient response to a first anti-TNFα treatment.

Methods: Serum samples were collected at baseline before RTX initiation. A proteomics study comparing responders and nonresponders was conducted to identify and select potential predictive biomarkers whose concentration was measured by quantitative assays. Logistic regression was performed to determine the best biomarker combination to predict good or nonresponse to RTX (EULAR criteria after 6 months' treatment).

Results: Eleven biomarkers potentially discriminating between responders and nonresponders were selected following discovery proteomics. Quantitative immunoassays and univariate statistical analysis showed that fetuin-A and thyroxine binding globulin (TBG) presented a good capacity to discriminate between patient groups. A logistic regression analysis revealed that the combination of fetuin-A plus TBG could accurately predict a patient's responsiveness to RTX with an AUC of 0.86, sensitivity of 80%, and a specificity of 79%.

Conclusion: In RA patients for whom a first anti-TNFα treatment has failed, the serum abundance of fetuin-A and TBG before initiating RTX treatment is an indicator for their response status at 6 months. ClinicalTrials.gov identifier: NCT01000441. Key Points • Proteomic analysis revealed 11 putative predictive biomarkers to discriminate rituximab responder vs. nonresponder RA patients. • Fetuin-A and TBG are significantly differentially expressed at baseline in rituximab responder vs. nonresponder RA patients. • Algorithm combining fetuin-A and TBG accurately predicts response to rituximab in RA patients with insufficient response to TNFi.
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http://dx.doi.org/10.1007/s10067-020-05030-6DOI Listing
September 2020

Ultrasound prevalence of wrist, hand, ankle and foot synovitis and tenosynovitis in systemic sclerosis, and relationship with disease features and hand disability.

Joint Bone Spine 2020 May 9;87(3):229-233. Epub 2020 Feb 9.

Grenoble Alpes University Hospital, Hopital Michallon, Department of Vascular Medicine, CS 10217, 38043 Grenoble cedex 9, France.

Introduction: In systemic sclerosis, few studies have shown that hand and wrist ultrasound is more sensitive than clinical examination in the detection of synovitis and tenosynovitis. Even fewer studies have investigated ankle and foot involvement with ultrasound. Our objectives were to investigate ultrasound prevalence of wrist, hand, ankle and foot synovitis and tenosynovitis in patients with systemic sclerosis classified with ACR/EULAR 2013 criteria, and to study their relationship with disease features and hand disability.

Methods: Consecutive patients with systemic sclerosis, classified with ACR/EULAR 2013 criteria, were included in a monocentric cross-sectional study. They underwent standardized musculoskeletal clinical examination and hand, wrist, ankle and foot ultrasound. Clinical, biological and imaging data were also collected.

Results: Fifty-five patients were included. Ultrasound was more sensitive than clinical examination to detect at least one synovitis (respectively 52% versus 25%, P=0.025) and at least one tenosynovitis (respectively 16% versus 4%, P=0.009); 18% of patients had ankle tenosynovitis and 29% had ankle and/or foot synovitis, mostly located at metatarsophalangeal joints (25.5%). Having at least one ultrasound hand synovitis was associated with higher Cochin hand functional disability scale (mean 25±3 versus 12±2, P=0.003) and diffuse cutaneous subset (P=0.038).

Conclusion: Our study shows that ultrasound is more sensitive than clinical examination to detect synovitis and tenosynovitis in systemic sclerosis. The foot involvement is less frequent than hand involvement, mainly localized at metatarsophalangeal joint. Finally, having at least one synovitis of the hand is associated with diffuse cutaneous subset and higher hand disability.
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http://dx.doi.org/10.1016/j.jbspin.2020.01.011DOI Listing
May 2020

X-ray Phase Contrast osteo-articular imaging: a pilot study on cadaveric human hands.

Sci Rep 2020 02 5;10(1):1911. Epub 2020 Feb 5.

Inserm UA7 Strobe, Université Grenoble Alpes, Grenoble, 38000, France.

X-ray Phase Contrast Imaging (PCI) is an emerging modality whose availability in clinics for mammography and lung imaging is expected to materialize within the coming years. In this study, we evaluate the PCI Computed Tomography (PCI-CT) performances with respect to current conventional imaging modalities in the context of osteo-articular disorders diagnosis. X-ray PCI-CT was performed on 3 cadaveric human hands and wrists using a synchrotron beam. Conventional CT, MRI and Ultrasound were also performed on these three samples using routine procedures as well as research protocols. Six radiologists and rheumatologists independently evaluated qualitatively and semi quantitatively the 3D images' quality. Medical interpretations were also made from the images. PCI-CT allows the simultaneous visualization of both the high absorbing and the softer tissues. The 6 reader evaluations characterized PCI-CT as a visualization tool with improved performances for all tissue types (significant p-values), which provides sharper outlines and clearer internal structures than images obtained using conventional modalities. The PCI-CT images contain overall more information, especially at smaller scales with for instance more visible micro-calcifications in our chondrocalcinosis case. Despite a reduced number of samples used, this pilot study highlights the possible medical benefits of PCI for osteo-articular disorders evaluation. Although PCI-CT is not yet available in hospitals, the improved visualization capabilities demonstrated so far and the enhanced tissue measurement quality let suggest strong diagnosis benefits for rheumatology in case of a widespread application of PCI.
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http://dx.doi.org/10.1038/s41598-020-58168-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002527PMC
February 2020

Implementation by smokers of the recommendations made during the systematic screening of comorbidities associated with chronic inflammatory diseases in daily practice.

Joint Bone Spine 2020 07 20;87(4):362-364. Epub 2019 Nov 20.

Department of Rheumatology Grenoble Alpes University, hôpital Sud, avenue de Kimberley, 38130 Echirolles, France; GREPI - UGA EA 7408, Domaine de la Merci, 38700 La Tronche, France.

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http://dx.doi.org/10.1016/j.jbspin.2019.11.002DOI Listing
July 2020

Gait as predictor of physical function in axial spondyloarthritis: the prospective longitudinal FOLOMI (Function, Locomotion, Measurement, Inflammation) study protocol.

Rheumatol Int 2019 Oct 7;39(10):1681-1688. Epub 2019 Aug 7.

Univ. Grenoble Alpes, AGEIS, 38000, Grenoble, France.

Axial spondyloarthritis (axSpA) is a chronic inflammatory rheumatic disease affecting predominantly sacroiliac joints and axial skeleton. axSpA progression being irregular and hardly predictable, identifying functional decline is particularly important in patient with axSpA to allow delivery of timely and targeted interventions. Pain, reduced range of motion or altered posture can have adverse consequences on gait. Although gait has previously been used as a sensitive measure of physical outcomes in elderly and pathological populations, to the best of our knowledge, no study has used gait as a predictor of physical function in patients with axSpA. The objective of our study is hence to determine if gait parameters measured in patients with axSpA could predict the evaluation at 18 months of physical function as assessed by the Bath Ankylosing Spondylitis Functional Index (BASFI). This is a prospective and longitudinal study. Sixty patients with axSpA and 30 healthy age- and sex-matched controls will be included. Patients should be aged 18-65 years at time of their first evaluation, followed at Grenoble Alpes University Hospital for axSpA or ankylosing spondylitis, able to walk 180 m without technical help and with stable treatment for at least 12 months. Clinical characteristics, BASFI, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), clinical and laboratory measurements of gait will be assessed during four visits (at baseline and at months 6, 12, and 18). Similar assessments will be performed once for the healthy control group. A linear mixed model at 6, 12 and 18 months will be constructed to answer to the first objective, with the BASFI as dependent variable and gait parameters as explanatory variables. The data collection started in August 2018 and will be completed with the inclusion and follow-up of all the participants. We believe that the combination of clinical and laboratory measurements of gait in patients with axSpA could strengthen the capacity to monitor disease's evolution and to predict changes in patients' physical function. Results of the present study could ultimately allow delivering targeted, timely, personalized interventions and treatment in patients with axSpA.Trial registration: The study was approved by local ethic committee (CPP Ile De France 1, RCB: 2017-A03468-45, date of agreement: July 17th, last version: V4.0, 2018, March 5th, 2019) and is retrospectively registered in Clinical trials (NCT03761212).
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http://dx.doi.org/10.1007/s00296-019-04396-4DOI Listing
October 2019

Two-year abatacept retention rate in clinical practice in the French ACTION cohort.

Joint Bone Spine 2019 11 25;86(6):753-759. Epub 2019 Jul 25.

Centre de rhumatologie, hôpital Pierre-Paul-Riquet, CHU de Toulouse, place du Dr Baylac, TSA 40 031, 31059 Toulouse cedex 9, France; CPTP, Inserm UMR 1043, CHU Purpan, BP 3028, 31024 Toulouse cedex 3, France.

Objectives: Abatacept retention rates were evaluated in the French cohort in the prospective ACTION study (2010-2013), which included patients with moderate-to-severe rheumatoid arthritis managed in everyday clinical practice and started on intravenous abatacept therapy.

Methods: Two-year abatacept retention rates were evaluated in 455 patients classified according to treatment line, body mass index (BMI), and status for rheumatoid factor (RF) and anti-citrullinated peptide antibody (ACPA).

Results: After 2 years, the overall abatacept retention rate was 44%. The retention rate was non-significantly higher in the patients with vs. without a history of unresponsiveness to at least one biologic (48.1% vs. 41.8%, respectively). No significant retention rate differences were found across BMI categories (444 patients; <25, 45.5%; ≥25 to <30, 48.9%; and ≥30, 36.6%). Neither were any significant differences demonstrated according to RF and ACPA status (RF+ and ACPA+, 45.7%; RF+ or ACPA+, 43.8%; and FR- and ACPA-, 39.1%).

Conclusion: The 44% 2-year retention rate in the French ACTION cohort supports the usefulness of abatacept therapy. In this study, retention was not associated with treatment line, BMI, or antibody status.
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http://dx.doi.org/10.1016/j.jbspin.2019.07.006DOI Listing
November 2019

Calprotectin alone is not sufficient to predict response to methotrexate in early ACR/EULAR 2010 rheumatoid arthritis: Analysis of the ESPOIR cohort.

Joint Bone Spine 2020 Jan 17;87(1):99-100. Epub 2019 Jul 17.

Rheumatology department, hôpital Sud, Grenoble Teaching Hospital, CHU de Grenoble-Alpes, Avenue de Kimberley, BP 338, 38434 Échirolles Cedex, France; University Grenoble-Alpes, GREPI EA7408, 38000 Grenoble, France.

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http://dx.doi.org/10.1016/j.jbspin.2019.07.001DOI Listing
January 2020

Alcohol is not the missing link between -related periodontitis and radiological progression in early rheumatoid arthritis.

Ann Rheum Dis 2020 09 14;79(9):e107. Epub 2019 Jun 14.

Rheumatology Department, Centre Hospitalier Universitaire Grenoble Alpes Hôpital Sud, Echirolles, France.

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http://dx.doi.org/10.1136/annrheumdis-2019-215603DOI Listing
September 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

Calprotectin discriminates septic arthritis from pseudogout and rheumatoid arthritis.

Rheumatology (Oxford) 2019 09;58(9):1644-1648

Infectious Diseases Unit, Centre Hospitalier Universitaire Grenoble Alpes.

Objective: We aimed to determine whether calprotectin and α-defensins could discriminate septic from other inflammatory arthritides.

Methods: Synovial fluids with a predominance of neutrophils from patients with septic arthritis, pseudogout and RA were prospectively collected. Neutrophil-related proteins calprotectin and human neutrophil α-defensins levels were assessed in synovial fluids. Demographic parameters and biomarkers with P-value ⩽0.05 for differentiating septic from non-septic arthritis were included in a multivariable model. Multivariable logistic regression with stepwise selection was performed to build the final combined model.

Results: A total of 74 patients were included: septic arthritis (n = 26), pseudogout (n = 28) and RA (n = 20). Patients with septic arthritis were more likely to be male and young, and to display higher synovial neutrophil count. Calprotectin was significantly increased in patients with septic arthritis. The multivariable model included calprotectin, synovial fluid neutrophil count and gender. Calprotectin was the only biomarker that discriminated septic arthritis from non-septic inflammatory arthritides, with 76% sensitivity, 94% specificity and a positive likelihood ratio = 12.2 at the threshold for calprotectin of 150 mg/l.

Conclusion: Synovial fluid calprotectin is a relevant biomarker to discriminate septic arthritis from other inflammatory arthritides. This biomarker should be tested in an independent cohort.
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http://dx.doi.org/10.1093/rheumatology/kez098DOI Listing
September 2019

Systemic calprotectin and chronic inflammatory rheumatic diseases.

Joint Bone Spine 2019 Nov 17;86(6):691-698. Epub 2019 Jan 17.

GREPI, EA 7408, University Grenoble Alpes, 38700 La Tronche, France; Sinnovial SAS, avenue de Kimberley, 38130 Échirolles, France.

Calprotectin is a calcium binding protein produced by neutrophils and monocytes locally at the site of inflammation in order to trigger the innate immunity receptors. This unique characteristic makes it a good proxy for evaluation of local inflammation in chronic inflammatory rheumatic diseases. Complete data suggest, in inflammatory rheumatic diseases, a relevant role of calprotectin in the inflammatory process. The interest of serum or plasma calprotectin dosage has been studied intensively, in the current years, especially in rheumatoid arthritis, spondyloarthritis, juvenile idiopathic arthritis and ANCA associated vasculitis. Calprotectin seems to be a great candidate as biomarker to assess and monitor disease activity, to predict structural progression or response to the treatment. Calprotectin showed its ability to predict radiological progression in rheumatoid arthritis and ankylosing spondylitis. Serum calprotectin can predict the risk of relapse in ANCA associated vasculitis and the risk of inflammatory bowel disease in spondyloarthritis. Nevertheless, studies report controversial result requiring replication in other large cohort. The lack of assay standardization between studies is a problem to replicate and compare studies. In this review, we discuss on the interest of systemic calprotectin in chronic inflammatory rheumatic disease as a diagnostic, activity or prognostic biomarker.
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http://dx.doi.org/10.1016/j.jbspin.2019.01.003DOI Listing
November 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

Short-term Efficiency and Tolerance of Ketoprofen and Methylprednisolone in Acute Sciatica: A Randomized Trial.

Pain Med 2019 07;20(7):1294-1299

Rheumatology Department, CHU Grenoble Alpes Hôpital Sud, Echirolles, France.

Objective: Although anti-inflammatory drugs are commonly used in acute discogenic sciatica, data regarding their efficacy are scarce and controversial. We compared the efficacy and safety of intravenous ketoprofen and methylprednisolone with placebo in sciatica.

Design: Multicenter, double-blinded randomized controlled trial.

Subjects: Patients with confirmed discogenic acute sciatica, without neurologic deficit, were randomized into three arms.

Methods: Besides standard-of-care analgesic therapy, they received intravenous injections of methylprednisolone (60 mg/d) or ketoprofen (200 mg/d) or placebo for five days. The primary outcome was leg pain over five days. Secondary outcomes were clinical responses at days 3 and 5, lumbar pain, Straight Leg Raise Test and lumbar flexion index, analgesic consumption, realization of lumbar spine injections, and surgery during the study period.

Results: Fifty-four patients were randomized, and 50 completed the study. In patients admitted to the hospital for pain control with acute lumbar radicular pain due to intervertebral disc herniation and receiving an oral analgesic protocol including paracetamol, nefopam, tramadol, and morphine, there was no additional analgesic effect seen between groups. There was no significant difference in leg pain between the three groups over the study period. In the methylprednisolone group, however, we observed a higher rate of clinically relevant responses at day 3. No difference was observed on other secondary efficacy outcomes and safety.

Conclusion: No significant difference in leg pain was observed between groups. However, there was a higher proportion of patients relieved with intravenous methylprednisolone at day 3, compared with ketoprofen or placebo.
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http://dx.doi.org/10.1093/pm/pny252DOI Listing
July 2019

Identification of cartilage oligomeric matrix protein as biomarker predicting abatacept response in rheumatoid arthritis patients with insufficient response to a first anti-TNFα treatment.

Joint Bone Spine 2019 05 19;86(3):401-403. Epub 2018 Sep 19.

Université Grenoble Alpes, GREPI, EA 7408, 38400 Saint-Martin-d'Hères, France; Rheumatology department, CHU Grenoble Alpes, hôpital Sud Échirolles, 38130 Échirolles, France.

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http://dx.doi.org/10.1016/j.jbspin.2018.09.005DOI Listing
May 2019