Publications by authors named "Frédéric Lioté"

151 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

Lymphocyte Changes in Severe COVID-19: Delayed Over-Activation of STING?

Front Immunol 2020;11:607069. Epub 2020 Dec 1.

Service de rhumatologie, Hopitaux Universitaires de Strasbourg, RESO: Centre de Reference des Maladies Autoimmunes Systemiques Rares Est Sud-Ouest, Strasbourg, France.

Upon recognition of microbial DNA or self-DNA, the cyclic-GMP-AMP synthase (cGAS) of the host catalyzes the production of the cyclic dinucleotide cGAMP. cGAMP is the main activator of STING, stimulator of interferon genes, leading to interferon synthesis through the STING-TBK1-IRF3 pathway. STING is also a hub for activation of NF-κB and autophagy. The present review details the striking similarities between T and B cell responses in severe coronavirus disease 2019 (COVID-19) and both animal or human models of STING gain of function (SAVI syndromes: STING-associated vasculopathy with onset in infancy). Those similarities may be further clues for a delayed activation of STING in severe COVID-19 patients, due to DNA damages following severe acute respiratory syndrome coronaviruses (SARS-CoV-2) infection and unusual role of STING in SARS-CoV-2 control. In early stages, Th2 differentiation are noticed in both severe COVID-19 and SAVI syndromes; then, CD4+ and CD8+ T cells functional exhaustion/senescent patterns due to TCR hyper-responsiveness are observed. T cell delayed over-responses can contribute to pneumonitis and delayed cytokine secretion with over-production of IL-6. Last, STING over-activation induces progressive CD4+ and CD8+ T lymphopenia in SAVI syndromes, which parallels what is observed in severe COVID-19. ACE2, the main receptor of SARS-CoV-2, is rarely expressed in immune cells, and it has not been yet proven that some human lymphocytes could be infected by SARS-CoV-2 through CD147 or CD26. However, STING, expressed in humans T cells, might be triggered following excessive transfer of cGAMP from infected antigen presenting cells into activated CD4+ and CD8+ T cells lymphocytes. Indeed, those lymphocytes highly express the cGAMP importer SLC19A1. Whereas STING is not expressed in human B cells, B cells counts are much less affected, either in COVID-19 or SAVI syndromes. The recognition of delayed STING over-activation in severe COVID-19 patients could prompt to target STING with specific small molecules inhibitors already designed and/or aspirin, which inhibits cGAS.
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http://dx.doi.org/10.3389/fimmu.2020.607069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736628PMC
December 2020

Adrenomedullin and truncated peptide adrenomedullin(22-52) affect chondrocyte response to apoptotis in vitro: downregulation of FAS protects chondrocyte from cell death.

Sci Rep 2020 10 7;10(1):16740. Epub 2020 Oct 7.

INSERM, UMR-S 1132 Bioscar, Centre Viggo Petersen, Hôpital Lariboisière, 2, Rue Ambroise Paré, 75010, Paris, France.

Chondrocyte apoptosis may have a pivotal role in the development of osteoarthritis. Interest has increased in the use of anti-apoptotic compounds to protect against osteoarthritis development. In this work, we investigated the effect of adrenomedullin (AM), a 52 amino-acid hormone peptide, and a 31 amino-acid truncated form, AM(22-52), on chondrocyte apoptosis. Bovine articular chondrocytes (BACs) were cultured under hypoxic conditions to mimic cartilage environment and then treated with Fas ligand (Fas-L) to induce apoptosis. The expression of AM and its calcitonin receptor-like receptor (CLR)/receptor activity-modifying protein (RAMP) (receptor/co-receptor) was assessed by immunostaining. We evaluated the effect of AM and AM(22-52) on Fas-L-induced chondrocyte apoptosis. FAS expression was appreciated by RT-qPCR and immunostainings. The expression of hypoxia-inducible factor 1α (HIF-1α), CLR and one co-receptor (RAMP2) was evidenced. With BACs under hypoxia, cyclic adenosine monophosphate production increased dose-dependently with AM stimulation. AM significantly decreased caspase-3 activity (mean 35% decrease; p = 0.03) as a marker of Fas-L-induced apoptosis. Articular chondrocytes treated with AM showed significantly reduced cell death, along with downregulated Fas expression and production, as compared with AM(22-52). AM decreased articular chondrocyte apoptosis by downregulating a Fas receptor. These findings may pave the way for novel therapeutic approaches in osteoarthritis.
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http://dx.doi.org/10.1038/s41598-020-73924-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541509PMC
October 2020

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

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

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

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

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

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

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

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

UltraSound evaluation in follow-up of urate-lowering therapy in gout phase 2 (USEFUL-2): Duration of flare prophylaxis.

Joint Bone Spine 2020 Dec 23;87(6):647-651. Epub 2020 Sep 23.

Rheumatology Department, DHU FIRE, Pôle infection immunité, Bichat Hospital (AP-HP), 75018 Paris, France. Electronic address:

Objectives: To determine whether changes in ultrasonography (US) features of monosodium urate crystal deposition is associated with the number of gouty flares after stopping gout flare prophylaxis.

Methods: We performed a 1-year multicentre prospective study including patients with proven gout and US features of gout. The first phase of the study was a 6-month US follow-up after starting urate-lowering therapy (ULT) with gout flare prophylaxis. After 6 months of ULT, gout flare prophylaxis was stopped, followed by a clinical follow-up (M6 to 12) and ULT was maintained. Outcomes were the proportion of relapsing patients between M6 and M12 according to changes of US features of gout and determining a threshold decrease in tophus size according to the probability of relapse.

Results: We included 79 gouty patients [mean (±SD) age 61.8±14 years, 91% males, median disease duration 4 (IQR 1.5;10) years]. Among the 49 completers at M12, 23 (47%) experienced relapse. Decrease in tophus size ≥50% at M6 was more frequent without than with relapse (54% vs. 26%, P=0.049). On ROC curve analysis, a threshold decrease of 50.8% in tophus size had the best sensitivity/specificity ratio to predict relapse [AUC 0.649 (95% confidence interval 0.488; 0.809)]. Probability of relapse was increased for patients with a decrease in tophus size <50% between M0 and M6 [OR 3.35 (95% confidence interval 0.98; 11.44)].

Conclusion: A high reduction in US tophus size is associated with lower probability of relapse after stopping gout prophylaxis. US follow-up may be useful for managing ULT and gout flare prophylaxis.
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http://dx.doi.org/10.1016/j.jbspin.2020.09.014DOI Listing
December 2020

Hydroxychloroquine levels in patients with systemic lupus erythematosus: whole blood is preferable but serum levels also detect non-adherence.

Arthritis Res Ther 2020 09 25;22(1):223. Epub 2020 Sep 25.

AP-HP, Hôpital Cochin, Centre de référence maladies auto-immunes et systémiques rares, service de médecine interne, 27 rue du Faubourg Saint-Jacques, 75014, Paris, France.

Background: Hydroxychloroquine (HCQ) levels can be measured in both serum and whole blood. No cut-off point for non-adherence has been established in serum nor have these methods ever been compared. The aims of this study were to compare these two approaches and determine if serum HCQ cut-off points can be established to identify non-adherent patients.

Methods: HCQ levels were measured in serum and whole blood from 573 patients with systemic lupus erythematosus (SLE). The risk factors for active SLE (SLEDAI score > 4) were identified by multiple logistic regression. Serum HCQ levels were measured in 68 additional patients known to be non-adherent, i.e. with whole-blood HCQ < 200 ng/mL.

Results: The mean (± SD) HCQ levels were 469 ± 223 ng/mL in serum and 916 ± 449 ng/mL in whole blood. The mean ratio of serum/whole-blood HCQ levels was 0.53 ± 0.15. In the multivariate analysis, low whole-blood HCQ levels (P = 0.023), but not serum HCQ levels, were independently associated with active SLE. From the mean serum/whole-blood level ratio, a serum HCQ level of 106 ng/mL was extrapolated as the corresponding cut-off to identify non-adherent patients with a sensitivity of 0.87 (95% CI 0.76-0.94) and specificity of 0.89 (95% CI 0.72-0.98). All serum HCQ levels of patients with whole-blood HCQ below the detectable level (< 20 ng/mL) were also undetectable (< 20 ng/mL).

Conclusions: These data suggest that whole blood is better than serum for assessing the pharmacokinetic/pharmacodynamic relation of HCQ. Our results support the use of serum HCQ levels to assess non-adherence when whole blood is unavailable.
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http://dx.doi.org/10.1186/s13075-020-02291-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7517694PMC
September 2020

2019 EULAR points to consider for the assessment of competences in rheumatology specialty training.

Ann Rheum Dis 2021 01 11;80(1):65-70. Epub 2020 Aug 11.

Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.

Background And Aim: Striving for harmonisation of specialty training and excellence of care in rheumatology, the European League Against Rheumatism (EULAR) established a task force to develop points to consider (PtCs) for the assessment of competences during rheumatology specialty training.

Methods: A systematic literature review on the performance of methods for the assessment of competences in rheumatology specialty training was conducted. This was followed by focus groups in five selected countries to gather information on assessment practices and priorities. Combining the collected evidence with expert opinion, the PtCs were formulated by the multidisciplinary task force, including rheumatologists, medical educationalists, and people with rheumatic and musculoskeletal diseases. The level of agreement (LoA) for each PtC was anonymously voted online.

Results: Four overarching principles and 10 PtCs were formulated. The overarching principles highlighted the importance of assessments being closely linked to the rheumatology training programme and protecting sufficient time and resources to ensure effective implementation. In the PtCs, two were related to overall assessment strategy (PtCs 1 and 5); three focused on formative assessment and portfolio (PtCs 2-4); three focused on the assessment of knowledge, skills or professionalism (PtCs 6-8); one focused on trainees at risk of failure (PtC 9); and one focused on training the trainers (PtC 10). The LoA (0-10) ranged from 8.75 to 9.9.

Conclusion: These EULAR PtCs provide European guidance on assessment methods throughout rheumatology training programmes. These can be used to benchmark current practices and to develop future strategies, thereby fostering continuous improvement in rheumatology learning and, ultimately, in patient care.
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http://dx.doi.org/10.1136/annrheumdis-2020-218015DOI Listing
January 2021

Gout and pseudo-gout-related crystals promote GLUT1-mediated glycolysis that governs NLRP3 and interleukin-1β activation on macrophages.

Ann Rheum Dis 2020 11 22;79(11):1506-1514. Epub 2020 Jul 22.

Universite de Paris, Paris, France

Objective: Macrophage activation by monosodium urate (MSU) and calcium pyrophosphate (CPP) crystals mediates an interleukin (IL)-1β-dependent inflammation during gout and pseudo-gout flare, respectively. Since metabolic reprogramming of macrophages goes along with inflammatory responses dependently on stimuli and tissue environment, we aimed to decipher the role of glycolysis and oxidative phosphorylation in the IL-1β-induced microcrystal response.

Methods: Briefly, an in vitro study (metabolomics and real-time extracellular flux analysis) on MSU and CPP crystal-stimulated macrophages was performed to demonstrate the metabolic phenotype of macrophages. Then, the role of aerobic glycolysis in IL-1β production was evaluated, as well in vitro as in vivo using F-fluorodeoxyglucose positron emission tomography imaging and glucose uptake assay, and molecular approach of glucose transporter 1 (GLUT1) inhibition.

Results: We observed that MSU and CPP crystals led to a metabolic rewiring toward the aerobic glycolysis pathway explained by an increase in GLUT1 plasma membrane expression and glucose uptake on macrophages. Also, neutrophils isolated from human synovial fluid during gout flare expressed GLUT1 at their plasma membrane more frequently than neutrophils isolated from bloodstream. Both glucose deprivation and treatment with either 2-deoxyglucose or GLUT1 inhibitor suppressed crystal-induced NLRP3 activation and IL-1β production, and microcrystal inflammation in vivo.

Conclusion: In conclusion, we demonstrated that GLUT1-mediated glucose uptake is instrumental during the inflammatory IL-1β response induced by MSU and CPP crystals. These findings open new therapeutic paths to modulate crystal-related inflammation.
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http://dx.doi.org/10.1136/annrheumdis-2020-217342DOI Listing
November 2020

Kawasaki-like diseases and thrombotic coagulopathy in COVID-19: delayed over-activation of the STING pathway?

Emerg Microbes Infect 2020 Dec;9(1):1514-1522

Rheumatology Department, centre Viggo Petersen, Paris, France.

We previously made the hypothesis that STING contributes to COVID-19. The present review detail new arguments for over-activation of STING pathways in COVID-19, following the description of hyper-coagulability and Kawasaki-like diseases in children. Indeed, Kawasaki disease is induced by overreaction of innate cells following exposition to various viruses, including herpes viruses which trigger STING. It predisposes to diffuse vasculitis and aneurysms, whereas STING is over-expressed in arterial aneurisms. The redness at the inoculation site of bacillus Calmette-Guérin, a specific feature of Kawasaki disease, is reproduced by activation of the STING pathway, which is inhibited upstream by aspirin, intravenous immunoglobulins, and Vitamin-D. SARS-CoV2 binding to ACE2 can lead to excessive angiotensin II signaling, which activates the STING pathway in mice. Over-activation of the STING-pathway promotes hyper-coagulability through release of interferon-β and tissue factor by monocytes-macrophages. Aspirin and dipyridamole, besides their anti-platelet activity, also reduce tissue factor procoagulant activity, and aspirin inhibits the STING pathway upstream of STING. Aspirin and dipyridamole may be used, in combination with drugs blocking downstream the activation of the STING pathway, like inhibitors of IL-6R and JAK/STAT pathways. The risk of bleeding should be low as bleeding has not been reported in severe COVID-19 patients.
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http://dx.doi.org/10.1080/22221751.2020.1785336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473058PMC
December 2020

Spondyloarthritis-Associated IgA Nephropathy.

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

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

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

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

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

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

COVID-19 as a STING disorder with delayed over-secretion of interferon-beta.

EBioMedicine 2020 Jun 23;56:102801. Epub 2020 May 23.

Rheumatology Department & Inserm UMR 1132 (centre Viggo Petersen), Hôpital Lariboisière, 2 rue Ambroise Paré, F-75010 Paris, Université de Paris, UFR de Médecine, F-75010 Paris, France.

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http://dx.doi.org/10.1016/j.ebiom.2020.102801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244443PMC
June 2020

2020 Recommendations from the French Society of Rheumatology for the management of gout: Management of acute flares.

Joint Bone Spine 2020 Oct 15;87(5):387-393. Epub 2020 May 15.

Service de rhumatologie, hôpital Lariboisière, AP-HP, 2, rue Ambroise-Paré, 75010 Paris, France; Inserm U1132 BIOSCAR, université de Paris, Paris, France. Electronic address:

Objective: To develop French Society of Rheumatology-endorsed recommendations for the management of gout flares.

Methods: These evidence-based recommendations were developed by 9 rheumatologists (academic or community-based), 3 general practitioners, 1 cardiologist, 1 nephrologist and 1 patient, using a systematic literature search, one physical meeting to draft recommendations and 2 Delphi rounds to finalize them.

Results: A set of 4 overarching principles and 4 recommendations was elaborated. The overarching principles emphasize the importance of patient education, including the need to auto-medicate for gout flares as early as possible, if possible within the first 12h after the onset, according to a pre-defined treatment. Patients must know that gout is a chronic disease, often requiring urate-lowering therapy in addition to flare treatment. Comorbidities and the risk of drug interaction should be screened carefully in every patient as they may contraindicate some anti-inflammatory treatments. Colchicine must be early prescribed at the following dosage: 1mg then 0.5mg one hour later, followed by 0.5mg,2 to 3 times/day over the next days. In case of diarrhea, which is the first symptom of colchicine poisoning, dosage must be reduced. Colchicine dosage must also be reduced in patients with chronic kidney disease or taking drugs, which interfere with its metabolism. Other first-line treatment options are systemic/intra-articular corticosteroids, or non-steroidal anti-inflammatory agents (NSAIDs). IL-1 inhibitors can be considered as a second-line option in case of failure, intolerance or contraindication to colchicine, corticosteroids and NSAIDs. They are contraindicated in cases of infection and neutrophil blood count should be monitored.

Conclusion: These recommendations aim to provide strategies for the safe use of anti-inflammatory agents, in order to improve the management of gout flares.
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http://dx.doi.org/10.1016/j.jbspin.2020.05.001DOI Listing
October 2020

2020 recommendations from the French Society of Rheumatology for the management of gout: Urate-lowering therapy.

Joint Bone Spine 2020 Oct 15;87(5):395-404. Epub 2020 May 15.

Service de rhumatologie, hôpital Lariboisière, AP-HP, 2, rue Ambroise-Paré, 75010 Paris, France; Inserm U1132 BIOSCAR, université de Paris, Paris, France. Electronic address:

Objective: To develop French Society of Rheumatology-endorsed recommendations for the management of urate-lowering therapy (ULT).

Methods: Evidence-based recommendations were developed by 9 rheumatologists (academic or community-based), 3 general practitioners, 1 cardiologist, 1 nephrologist and 1 patient, using a systematic literature search, one physical meeting to draft recommendations and two Delphi rounds to finalize them.

Results: A set of 3 overarching principles and 5 recommendations was elaborated. The overarching principles emphasize the importance of patient education, especially the need for explaining the objective of lowering serum urate (SU) level to obtain crystal dissolution, clinical symptoms disappearance and avoidance of complications. ULT is indicated as soon as the diagnosis of gout is established. SU level must be decreased below 300μmol/l (50mg/l) in all gout patients or at least below 360μmol/l (60ml/l) when the 300μmol/l target cannot be reached, and must be maintained at these targets and monitored life-long. The choice of the ULT primarily relies on renal function: in patients whose estimated glomerular filtration rate (eGFR) is above 60ml/min/1.73m, first-line ULT is allopurinol; in those with eGFR between 30 and 60ml/min/1.73m, allopurinol use must be cautious and febuxostat can be considered as an alternative; and in those whose eGFR is below 30ml/min/1.73m, allopurinol must be avoided and febuxostat should be preferred. Prophylaxis of ULT-induced gout flares involves progressive increase of ULT dosage and low-dose colchicine for at least 6 months. Cardiovascular risk factors and diseases, the metabolic syndrome and chronic kidney disease must be screened and managed.

Conclusion: These recommendations aim to provide simple and clear guidance for the management of ULT in France.
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http://dx.doi.org/10.1016/j.jbspin.2020.05.002DOI Listing
October 2020

BCP crystals promote chondrocyte hypertrophic differentiation in OA cartilage by sequestering Wnt3a.

Ann Rheum Dis 2020 07 5;79(7):975-984. Epub 2020 May 5.

Division of Mol Medicine of Musculoskeletal Tissue, University Munster, Munster, Germany.

Objective: Calcification of cartilage with basic calcium phosphate (BCP) crystals is a common phenomenon during osteoarthritis (OA). It is directly linked to the severity of the disease and known to be associated to hypertrophic differentiation of chondrocytes. One morphogen regulating hypertrophic chondrocyte differentiation is Wnt3a.

Methods: Calcification and sulfation of extracellular matrix of the cartilage was analysed over a time course from 6 to 22 weeks in mice and different OA grades of human cartilage. Wnt3a and ß-catenin was stained in human and murine cartilage. Expression of sulfation modulating enzymes (HS2St1, HS6St1) was analysed using quantitative reverse transcription PCR (RT-PCR). The influence of BCP crystals on the chondrocyte phenotype was investigated using quantitative RT-PCR for the marker genes Axin2, Sox9, Col2, MMP13, ColX and Aggrecan. Using western blot for β-catenin and pLRP6 we investigated the activation of Wnt signalling. The binding capacity of BCP for Wnt3a was analysed using immunohistochemical staining and western blot.

Results: Here, we report that pericellular matrix sulfation is increased in human and murine OA. Wnt3a co-localised with heparan sulfate proteoglycans in the pericellular matrix of chondrocytes in OA cartilage, in which canonical Wnt signalling was activated. In vitro, BCP crystals physically bound to Wnt3a. Interestingly, BCP crystals were sufficient to induce canonical Wnt signalling as assessed by phosphorylation of LRP6 and stabilisation of β-catenin, and to induce a hypertrophic shift of the chondrocyte phenotype.

Conclusion: Consequently, our data identify BCP crystals as a concentrating factor for Wnt3a in the pericellular matrix and an inducer of chondrocyte hypertrophy.
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http://dx.doi.org/10.1136/annrheumdis-2019-216648DOI Listing
July 2020

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

Galectin 3 Deficiency Alters Chondrocyte Primary Cilium Formation and Exacerbates Cartilage Destruction via Mitochondrial Apoptosis.

Int J Mol Sci 2020 Feb 22;21(4). Epub 2020 Feb 22.

Université de Paris, BIOSCAR UMR 1132, Inserm, F-75010 Paris, France.

Mechanical overload and aging are the main risk factors of osteoarthritis (OA). Galectin 3 (GAL3) is important in the formation of primary cilia, organelles that are able to sense mechanical stress. The objectives were to evaluate the role of GAL3 in chondrocyte primary cilium formation and in OA in mice. Chondrocyte primary cilium was detected in vitro by confocal microscopy. OA was induced by aging and partial meniscectomy of wild-type (WT) and -null 129SvEV mice (). Primary chondrocytes were isolated from joints of new-born mice. Chondrocyte apoptosis was assessed by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), caspase 3 activity and cytochrome c release. Gene expression was assessed by qRT-PCR. GAL3 was localized at the basal body of the chondrocyte primary cilium. Primary cilia of chondrocytes were frequently abnormal and misshapen. Deletion of triggered premature OA during aging and exacerbated joint instability-induced OA. In both aging and surgery-induced OA cartilage, levels of chondrocyte catabolism and hypertrophy markers and apoptosis were more severe in than WT samples. In vitro, knockout favored chondrocyte apoptosis via the mitochondrial pathway. GAL3 is a key regulator of cartilage homeostasis and chondrocyte primary cilium formation in mice. deletion promotes OA development.
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http://dx.doi.org/10.3390/ijms21041486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073077PMC
February 2020

Benefits of Polymerase Chain Reaction Combined With Culture for the Diagnosis of Bone and Joint Infections: A Prospective Test Performance Study.

Open Forum Infect Dis 2019 Dec 2;6(12):ofz511. Epub 2019 Dec 2.

Laboratory of Bacteriology, Infectious Agents Department, Saint Louis-Lariboisiere-Fernand Widal Hospital Group, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.

Background: The microbiological diagnosis of bone and joint infections (BJI) currently relies on cultures, and the relevance of molecular methods is still debated. The aim of this study was to determine whether polymerase chain reaction (PCR) could improve the etiological diagnosis of BJI.

Methods: A prospective study was conducted during a 4-year period at Lariboisiere University Hospital (Paris, France), including patients with suspicion of infectious spondylodiscitis, septic arthritis, prosthetic joint infections, and respective noninfected groups. Clinical and radiological data were collected at inclusion and during follow-up. All samples were analyzed by conventional cultures and 16S ribosomal deoxyribonucleic acid (rDNA) gene (16S-PCR). Specific cultures and PCR targeting were also performed for spondylodiscitis samples. Case records were subsequently analyzed by an independent expert committee to confirm or invalidate the suspicion of infection and definitively classify the patients in a case or control group. The sensitivity of the combination of culture and PCR was compared with culture alone.

Results: After expert committee analysis, 105 cases of BJI cases and 111 control patients were analyzed. The most common pathogens of BJI were staphylococci (30%), (19%), and streptococci (14%). Adding PCR enhanced the sensitivity compared with culture alone (1) for the diagnosis of spondylodiscitis (64.4% vs 42.2%; < .01) and (2) for nonstaphylococci BJI (81.6% vs 71.3%; < .01). It is interesting to note that 16S-PCR could detect BJI due to uncommon bacteria such as and fastidious bacteria.

Conclusions: Our study showed the benefit of 16S-PCR and PCR targeting as add-on tests in cases of suspected BJI.
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http://dx.doi.org/10.1093/ofid/ofz511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935679PMC
December 2019

Gout, Hyperuricaemia and Crystal-Associated Disease Network (G-CAN) consensus statement regarding labels and definitions of disease states of gout.

Ann Rheum Dis 2019 11 9;78(11):1592-1600. Epub 2019 Sep 9.

Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.

Objective: There is a lack of standardisation in the terminology used to describe gout. The aim of this project was to develop a consensus statement describing the recommended nomenclature for disease states of gout.

Methods: A content analysis of gout-related articles from rheumatology and general internal medicine journals published over a 5-year period identified potential disease states and the labels commonly assigned to them. Based on these findings, experts in gout were invited to participate in a Delphi exercise and face-to-face consensus meeting to reach agreement on disease state labels and definitions.

Results: The content analysis identified 13 unique disease states and a total of 63 unique labels. The Delphi exercise (n=76 respondents) and face-to-face meeting (n=35 attendees) established consensus agreement for eight disease state labels and definitions. The agreed labels were as follows: 'asymptomatic hyperuricaemia', 'asymptomatic monosodium urate crystal deposition', 'asymptomatic hyperuricaemia with monosodium urate crystal deposition', 'gout', 'tophaceous gout', 'erosive gout', 'first gout flare' and 'recurrent gout flares'. There was consensus agreement that the label 'gout' should be restricted to current or prior clinically evident disease caused by monosodium urate crystal deposition (gout flare, chronic gouty arthritis or subcutaneous tophus).

Conclusion: Consensus agreement has been established for the labels and definitions of eight gout disease states, including 'gout' itself. The Gout, Hyperuricaemia and Crystal-Associated Disease Network recommends the use of these labels when describing disease states of gout in research and clinical practice.
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http://dx.doi.org/10.1136/annrheumdis-2019-215933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288724PMC
November 2019

Difficult-to-treat gout flares: eligibility for interleukin-1 inhibition in private practice is uncommon according to current EMA approval.

Rheumatology (Oxford) 2019 12;58(12):2181-2187

Sorbonne Paris Cité, Université Paris Diderot, Paris, France.

Objective: The objective was to determine the proportion of patients with difficult-to-treat or difficult-to-prevent acute gout attacks eligible for IL-1 inhibition.

Methods: Participants included in the French cross-sectional GOSPEL cohort (n = 1003 gout patients) were examined for contraindications and intolerance to standard of care (SoC) drugs of gout flares (colchicine, non-steroidal anti-inflammatory drugs and systemic glucocorticoids). Patients were classified as definitely eligible for first-line IL-1 inhibition (canakinumab) according to European summary of product characteristics (contraindications/intolerance to SoC and at least three flares per year) without any other anti-inflammatory options (contraindications/intolerance only), or potentially eligible (precaution of use). Eligibility to receive IL-1 during an on-going flare related to insufficient efficacy was assessed (second-line eligibility).

Results: Definite first-line eligibility for IL-1 therapy was found in 10 patients (1%) and contraindication to all SoC therapies in nine patients who had presented <3 flares in the past 12 months. At least precaution of use for SoC therapies was noted for 218/1003 patients (21.7%). Of 487 patients experiencing flares at baseline, 114 (23.4%) were still experiencing pain scored ⩾4/10 numeric scale on day 3, one of whom could not receive further SoC drugs. Only nine of them had three or more flares in the past year and were eligible for second-line IL-1 inhibition.

Conclusion: Despite significant numbers of patients without any SoC anti-inflammatory therapeutic options for gout flares, eligibility for IL-1 inhibition therapy according to current European approval is rare.
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http://dx.doi.org/10.1093/rheumatology/kez203DOI Listing
December 2019

2018 updated European League Against Rheumatism evidence-based recommendations for the diagnosis of gout.

Ann Rheum Dis 2020 01 5;79(1):31-38. Epub 2019 Jun 5.

Rheumatology, Assistance Publique - Hopitaux de Paris, Paris, France.

Although gout is the most common inflammatory arthritis, it is still frequently misdiagnosed. New data on imaging and clinical diagnosis have become available since the first EULAR recommendations for the diagnosis of gout in 2006. This prompted a systematic review and update of the 2006 recommendations. A systematic review of the literature concerning all aspects of gout diagnosis was performed. Recommendations were formulated using a Delphi consensus approach. Eight key recommendations were generated. A search for crystals in synovial fluid or tophus aspirates is recommended in every person with suspected gout, because demonstration of monosodium urate (MSU) crystals allows a definite diagnosis of gout. There was consensus that a number of suggestive clinical features support a clinical diagnosis of gout. These are monoarticular involvement of a foot or ankle joint (especially the first metatarsophalangeal joint); previous episodes of similar acute arthritis; rapid onset of severe pain and swelling; erythema; male gender and associated cardiovascular diseases and hyperuricaemia. When crystal identification is not possible, it is recommended that any atypical presentation should be investigated by imaging, in particular with ultrasound to seek features suggestive of MSU crystal deposition (double contour sign and tophi). There was consensus that a diagnosis of gout should not be based on the presence of hyperuricaemia alone. There was also a strong recommendation that all people with gout should be systematically assessed for presence of associated comorbidities and risk factors for cardiovascular disease, as well as for risk factors for chronic hyperuricaemia. Eight updated, evidence-based, expert consensus recommendations for the diagnosis of gout are proposed.
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http://dx.doi.org/10.1136/annrheumdis-2019-215315DOI Listing
January 2020

Adsorption of Proteins on m-CPPD and Urate Crystals Inhibits Crystal-induced Cell Responses: Study on Albumin-crystal Interaction.

J Funct Biomater 2019 Apr 25;10(2). Epub 2019 Apr 25.

CIRIMAT, Université de Toulouse, CNRS, Université Toulouse 3, Toulouse INP - ENSIACET, Toulouse 31030, France.

The biological effects and cellular activations triggered by monosodium urate (MSU) and calcium pyrophosphate dihydrate (monoclinic: m-CPPD) crystals might be modulated by protein coating on the crystal surface. This study is aimed at: (i) Identifying proteins adsorbed on m-CPPD crystals, and the underlying mechanisms of protein adsorption, and (ii) to understand how protein coating did modulate the inflammatory properties of m-CPPD crystals. The effects of protein coating were assessed in vitro using primary macrophages and THP1 monocytes. Physico-chemical studies on the adsorption of bovine serum albumin (BSA) upon m-CPPD crystals were performed. Adsorption of serum proteins, and BSA on MSU, as well as upon m-CPPD crystals, inhibited their capacity to induce interleukin-1-β secretions, along with a decreased ATP secretion, and a disturbance of mitochondrial membrane depolarization, suggesting an alteration of NLRP3 inflammasome activation. Proteomic analysis identified numerous m-CPPD-associated proteins including hemoglobin, complement, albumin, apolipoproteins and coagulation factors. BSA adsorption on m-CPPD crystals followed a Langmuir-Freundlich isotherm, suggesting that it could modulate m-CPPD crystal-induced cell responses through crystal/cell-membrane interaction. BSA is adsorbed on m-CPPD crystals with weak interactions, confirmed by the preliminary AFM study, but strong interactions of BSA molecules with each other occurred favoring crystal agglomeration, which might contribute to a decrease in the inflammatory properties of m-CPPD crystals. These findings give new insights into the pathogenesis of crystal-related rheumatic diseases and subsequently may open the way for new therapeutic approaches.
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http://dx.doi.org/10.3390/jfb10020018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616386PMC
April 2019

Reassessing the Safety Profile of Lesinurad in Combination with Xanthine Oxidase Inhibitor Therapy.

Rheumatol Ther 2019 Mar 14;6(1):101-108. Epub 2019 Feb 14.

Nephrology Division, University Hospital Limerick, Graduate Entry Medical School, Health Research Institute, University of Limerick, Limerick, Ireland.

Introduction: The rate of adverse renal events has been shown to be higher in patients treated with lesinurad plus a xanthine-oxidase inhibitor (XOI) than in patients treated only with a XOI. We reassessed the risks for various adverse renal events from a different perspective and devised a hypothesis to explain the results.

Methods: We used data from phase 3 trials that were publicly available from the full prescribing information document and estimated the relative risk and the number needed to treat for increased serum creatinine (sCri), renal failure, and renal lithiasis. We examined these risks for each treatment group and the risks stratified by estimated glomerular filtration rate (eGFR).

Results: Overall, the relative risk for sCri was > 1.0 with the 400 mg/day dose of lesinurad and higher with the 200 mg/day dose, but it was < 1.0 for both lithiasis and renal failure with the 200 mg/day dose. The relative risk was only statistically significant for sCri with the highest dose of lesinurad. When results stratified by eGFR were considered, the rates of adverse events increased with declining renal function, but the relative risks decreased in parallel, as the rate of adverse events increased much more in the placebo arm than in the active arm (200 mg/day dose). Indeed, the relative risk was only significant for the highest dose of lesinurad in patients with normal eGFR.

Conclusion: The rate of sCri events was higher in patients treated with both lesinurad and a XOI rather than a XOI alone. This rate was found to increase with decreasing eGFR, but as it does in for both active and placebo arms the relative risk is not different from that observed in the placebo arms in the labeled 200 mg/day dose. This may be explained by pathophysiological changes that develop in chronic kidney disease.
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http://dx.doi.org/10.1007/s40744-019-0143-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393267PMC
March 2019

Management of immune-related adverse events resulting from immune checkpoint blockade.

Expert Rev Anticancer Ther 2019 03 9;19(3):209-222. Epub 2019 Jan 9.

a Dermatology Department , Saint-Louis Hospital , Paris , France.

Introduction: Immune checkpoint inhibitors (ICI) are now a standard of care in the treatment of many cancers leading to durable responses in patients with metastatic disease. These agents are generally well tolerated but may lead to the occurrence of immune-related adverse events (irAEs). As any organ may be affected, clinicians should be aware of the broad range of clinical manifestations and symptoms and keep in mind that toxicities may occur late, at any point along a patient's treatment course. Although the most common irAEs are rarely severe, some of them may be associated with great morbidity and even become life-threatening. The rate of occurrence, type and severity of irAEs may vary with the type of ICI; thus, grade 3 and 4 irAEs are reported in more than 55% of patients treated with the combination of ipilimumab 3 mg/kg and nivolumab 1 mg/kg. Area covered: This review presents the management of irAEs resulting from checkpoint blockade, with a focus on rare irAEs. Expert commentary: With the development of immuno-oncology and the expanding role of ICI, physicians have learnt to diagnose and treat most of the irAEs that can occur. This review provides an overview of current guidelines, previously published studies and our multidisciplinary team based practices.
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http://dx.doi.org/10.1080/14737140.2019.1562342DOI Listing
March 2019

Inflammatory Potential of Four Different Phases of Calcium Pyrophosphate Relies on NF-κB Activation and MAPK Pathways.

Front Immunol 2018 9;9:2248. Epub 2018 Oct 9.

INSERM, UMR-S 1132, Université Paris Diderot (UFR Médecine), Sorbonne Paris Cité, Paris, France.

Calcium pyrophosphate (CPP) microcrystal deposition is associated with wide clinical phenotypes, including acute and chronic arthritis, that are interleukin 1β (IL-1β)-driven. Two CPP microcrystals, namely monoclinic and triclinic CPP dihydrates (m- and t-CPPD), have been identified in human tissues in different proportions according to clinical features. m-CPP tetrahydrate beta (m-CPPTβ) and amorphous CPP (a-CPP) phases are considered as m- and t-CPPD crystal precursors . We aimed to decipher the inflammatory properties of the three crystalline phases and one amorphous CPP phase and the intracellular pathways involved. The four synthesized CPP phases and monosodium urate crystals (MSU, as a control) were used to stimulate the human monocytic leukemia THP-1 cell line or bone marrow-derived macrophages (BMDM) isolated from WT or NLRP3 KO mice. The gene expression of pro- and anti-inflammatory cytokines was evaluated by quantitative PCR; IL-1β, IL-6 and IL-8 production by ELISA; and mitogen-activated protein kinase (MAPK) activation by immunoblot analysis. NF-κB activation was determined in THP-1 cells containing a reporter plasmid. , the inflammatory potential of CPP phases was assessed with the murine air pouch model via cell analysis and production of IL-1β and CXCL1 in the exudate. The role of NF-κB was determined by a pharmacological approach, both and . , IL-1β production induced by m- and t-CPPD and m-CPPTβ crystals was NLRP3 inflammasome dependent. m-CPPD crystals were the most inflammatory by inducing a faster and higher production and gene expression of IL-1β, IL-6, and IL-8 than t-CPPD, m-CPPTβ and MSU crystals. The a-CPP phase did not show an inflammatory property. Accordingly, m-CPPD crystals led to stronger activation of NF-κB, p38, extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) MAPKs. Inhibition of NF-κB completely abrogated IL-1β and IL-8 synthesis and secretion induced by all CPP crystals. Also, inhibition of JNK and ERK1/2 MAPKs decreased both IL-1β secretion and NF-κB activation induced by CPP crystals. , IL-1β and CXCL1 production and neutrophil infiltration induced by m-CPPD crystals were greatly decreased by NF-κB inhibitor treatment. Our results suggest that the inflammatory potential of different CPP crystals relies on their ability to activate the MAPK-dependent NF-κB pathway. Studies are ongoing to investigate the underlying mechanisms.
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http://dx.doi.org/10.3389/fimmu.2018.02248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6189479PMC
September 2019

Reply to the comment of Mourgues et al., 2012. American guidelines for the management of gout as seen by general practitioners.

Joint Bone Spine 2019 03 3;86(2):279-280. Epub 2018 Oct 3.

Service de rhumatologie, hôpital Lariboisière, AP-HP, centre Viggo-Petersen, 75010 Paris, France; University Paris Diderot, Sorbonne Paris cité,75205 Paris, France; Inserm, UMR 1132, centre Viggo-Petersen, 75010 Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.jbspin.2018.09.018DOI Listing
March 2019

Ultrasound evaluation in follow-up of urate-lowering therapy in gout: the USEFUL study.

Rheumatology (Oxford) 2019 03;58(3):410-417

Rheumatology Department, DHU FIRE, Pôle Infection Immunité, Bichat Hospital (APHP), Paris, France.

Objectives: We aimed to determine the ability of ultrasonography (US) to show disappearance of urate deposits in gouty patients requiring urate-lowering therapy (ULT).

Methods: We performed a 6-month multicentre prospective study including patients with: proven gout; presence of US features of gout (tophus and/or double contour sign) at the knee and/or first metatarsophalangeal joints; and no current ULT. US evaluations were performed at baseline and at months 3 and 6 (M3, M6) after starting ULT. Outcomes were: the change in US features of gout at M6 according to final (M6) serum urate (SU) level (high, > 360 μmol/l, i.e. > 6 mg/dl; low, 300-360 μmol/l, i.e. 5-6 mg/dl; very low, < 300 μmol/l, i.e. < 5 mg/dl); and correlation between changed US features and final SU level.

Results: We included 79 gouty patients (mean ± s.d., age 61.8 (14) years, 91% males, disease duration 6.3 (6.1) years). Baseline SU level was 530 ± 97 µmol/l (i.e. 8.9 mg/dl ± 1.6mg/dl). At least one US tophus and double contour sign was observed in 74 (94%) and 68 (86%) patients, respectively. Among the 67 completers at M6, 18 and 39 achieved a very low and low SU level, respectively. We found a significant decrease in US features of gout among patients with the lowest SU level (P < 0.001). Final M6 SU level was positively correlated with decreased size of tophus (r = 0.54 [95% CI: 0.34, 0.70], P < 0.0001), and inversely correlated with proportion of double contour sign disappearance (r=-0.59 [-0.74, -0.40]).

Conclusion: US can show decreased urate deposition after ULT, which is correlated with decreased SU level. The responsiveness of US in gout is demonstrated and can be useful for gout follow-up and adherence to ULT.
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http://dx.doi.org/10.1093/rheumatology/key303DOI Listing
March 2019

Cross-sectional survey of the undergraduate rheumatology curriculum in European medical schools: a EULAR School of Rheumatology initiative.

RMD Open 2018 21;4(2):e000743. Epub 2018 Sep 21.

Université Paris Diderot, USPC, UFR de Médecine, Paris, France.

Objectives: To survey the undergraduate rheumatic and musculoskeletal diseases (RMDs) curriculum content in a sample of medical schools across Europe.

Methods: The undergraduate musculoskeletal diseases and disability curriculum of University of Nottingham, UK, was used as a template to develop a questionnaire on curriculum content. The questionnaire elicited binary (yes/no) responses and included the option to provide additional information as free text. The survey was mailed to members of the European League Against Rheumatism (EULAR) School of Rheumatology (Undergraduate Classroom) and to EULAR Standing Committee on Education and Training members in January 2017, with a reminder in February 2017.

Results: Responses were received from 21 schools belonging to 11 countries. Assessment of gait, hyperalgesic tender site response and hypermobility were not included in many curricula. Similarly, interpretation of investigations undertaken on synovial fluid was taught in only 16 schools. While disease-modifying anti-rheumatic drugs and biological agents, and urate-lowering treatment were included in the curricula of 20 and 21 institutions, respectively, only curricula from 18 schools included core non-pharmacological interventions. Osteoarthritis, gout, rheumatoid arthritis, spondyloarthropathy, polymyalgia rheumatica and lupus were included in the curriculum of all institutions. However, common RMDs such as calcium pyrophosphate deposition, fibromyalgia, giant cell arteritis and bone and joint infection were included in 19 curricula.

Conclusion: This survey highlights areas of similarities and differences in undergraduate curricula across Europe. It is hoped that the results of this survey will catalyse the development and agreement of a minimum core European Curriculum for undergraduate education in RMDs.
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http://dx.doi.org/10.1136/rmdopen-2018-000743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6157535PMC
September 2018

Reply.

Arthritis Rheumatol 2019 01 24;71(1):171-172. Epub 2018 Nov 24.

Lariboisière Fernand Widal Hospital and Paris Diderot University, Paris, France.

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http://dx.doi.org/10.1002/art.40714DOI Listing
January 2019

Osteopenia and fractures associated with long-term therapy with MEK inhibitors.

Melanoma Res 2018 12;28(6):641-644

Hôpital Lariboisière, Department of Rheumatology, Inserm UMR 1132, Université Paris Diderot, Sorbonne Paris Cité, AP-HP.

Targeted therapies have markedly improved the survival of patients with melanoma. We report the case of two patients with advanced melanoma controlled by long-term MEK inhibitor or combination of BRAF and MEK inhibitors, who developed fractures related to severe osteopenia. A 48-year-old woman was treated by pimasertib after the failure of two lines of chemotherapy, and a 42-year-old man was treated by an association of BRAFi (dabrafenib) and MEKi (trametinib) after the failure of one line of chemotherapy. During follow-up, both complained of buttock pain, revealing primary fractures of the pelvis and lumbar vertebra. In both patients, none had osteoporosis risk factors; DEXA scan revealed osteopenia, and analysis ruled out metastatic bone lesion or secondary osteoporosis. Zoledronic acid, cholecalciferol (vitamin D3), oral calcium, and pain killers were introduced, leading to no further bone event. Numerous pathways are involved in the homeostasis of bone turnover, and the effect of tyrosine kinase inhibitors on those pathways is not well known yet. The absence of usual causes of osteoporosis or metastatic bone lesion and kinetics of symptoms lead us to suggest that MEK inhibitors were responsible for the development of osteoporosis. To the best of our knowledge, this is the first report of fractures associated with osteopenia in patients treated with MEKi. Long-term survival owing to new targeted treatment could be associated with yet underestimated adverse effects such as osteopenia/osteoporosis that could impair patient's quality of life and should be investigated.
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http://dx.doi.org/10.1097/CMR.0000000000000490DOI Listing
December 2018

Non-pharmacologic measures for gout management in the prospective GOSPEL cohort: Physicians' practice and patients' compliance profiles.

Joint Bone Spine 2019 03 17;86(2):225-231. Epub 2018 Jul 17.

Université de Rennes, 35000 Rennes, France; Service de rhumatologie, CHU de Rennes, 35000 Rennes, France; Inserm, U1241, institut NUMECAN, Inra U 1341, 35000 Rennes, France.

Objectives: Gout management includes non-pharmacological measures (NPM). The main objective of this study was to describe the NPM proposed by physicians and their implementation by patients after 3-6 months. The secondary objective was to identify NPM compliance profiles among these patients.

Methods: Ancillary observational study using the GOSPEL French cohort of 1003 patients with gout, based on questionnaires for physicians and patients at inclusion and then after 3-6 months. Patients were included by a representative sample of 398 general practitioners (GP) and 109 private-practice rheumatologists. Modifiable risk factors of hyperuricemia and proposed NPM were compared. Patient compliance profiles were identified by multiple correspondence and hierarchical clustering analysis.

Results: The study included 630 patients: 80.7% were obese or overweight, 51% reported excessive alcohol consumption. Physicians identified fewer modifiable risk factors than their real prevalence in the cohort. Physicians proposed NPM to 57% of patients, particularly diet modifications (46.4%). Increasing physical activity (P < 0.0001) was the best followed NPM. The physician's influence in the decision of starting NPM was more frequent among GPs' patients (P = 0.01). Three patients' compliance profiles were identified. "Very good responders" (55.8%) implemented all the proposed NPM. "Good responders" (12.7%) had a more severe disease and followed the proposed NPM, but for alcohol consumption. "Bad responders" (31.5%) did not modify their life style: these were older patients with a very recent gout diagnosis.

Conclusion: More personalized care about NPM requires adapting the practitioner's approach to patients' compliance profiles, especially elderly patients with recent gout.
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http://dx.doi.org/10.1016/j.jbspin.2018.06.013DOI Listing
March 2019