Publications by authors named "Hang-Korng Ea"

104 Publications

Pain in women with knee and/or hip osteoarthritis is related to systemic inflammation and to adipose tissue dysfunction: Cross-sectional results of the KHOALA cohort.

Semin Arthritis Rheum 2021 Feb 18;51(1):129-136. Epub 2020 Dec 18.

Hôpitaux de Paris (AP-HP), Rheumatology department, Saint-Antoine Hospital, DMU 3iD, 184 rue du Faubourg Saint-Antoine, Paris 75012, France; Sorbonne Université, 15-21 Rue de l'École de Médecine, Paris 75006, France; Inserm UMRS_938, CRSA, 19 Rue de Chaligny, Paris 75012, France.

Background: Considering the role of metabolic diseases in osteoarthritis (OA), we investigated whether biomarkers of adipose tissue dysfunction could be associated with OA-related pain.

Design: We cross-sectionally analyzed patients with knee and/or hip OA at inclusion in the KHOALA cohort. We used visual analogic scale (VAS) for pain, the Western Ontario and McMaster Universities Arthritis Index (WOMAC) and Osteoarthritis Knee and Hip Quality of Life (OAKHQOL) pain subscores. At inclusion, we measured ultra-sensitive CRP (usCRP), leptin and adiponectin for calculation of leptin:adiponectin ratio (LAR), a marker of adipose tissue dysfunction associated with central adiposity, high-molecular-weight adiponectin, visfatin and apolipoproteins. Univariate and multivariable analyses using stepwise linear regression models were performed to search for correlation between pain assessments and these biomarkers, with systematic adjustment on age.

Results: In 596 women with hip and/or knee OA, multivariable analyses indicated that higher pain intensity was associated with higher LAR (VAS pain: β=0.49; p = 0.0001, OAKHQOL pain: β=-0.46; p = 0.0002, WOMAC pain: β=0.30; p = 0.001) in the whole group as well as in hip or knee OA patients considered separately. Pain intensity correlated also with usCRP level (VAS pain: β= 0.27; p = 0.02, OAKHQOL pain: β =-0.30; p = 0.01) and Kellgren-Lawrence score. In 267 men, no correlation between biomarkers and pain was found.

Conclusion: Serum LAR and usCRP level are associated with pain level, independently of radiographic structural severity in women with hip and/or knee OA, emphasizing the role of adipose tissue dysfunction and of meta-inflammation in pain experience in the female population.
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http://dx.doi.org/10.1016/j.semarthrit.2020.10.004DOI Listing
February 2021

EZH2 inhibition reduces cartilage loss and functional impairment related to osteoarthritis.

Sci Rep 2020 11 11;10(1):19577. Epub 2020 Nov 11.

EA7451 BioConnect, Normandie Univ, Université de Caen, 14032, Caen, France.

Histone methyltransferase EZH2 is upregulated during osteoarthritis (OA), which is the most widespread rheumatic disease worldwide, and a leading cause of disability. This study aimed to assess the impact of EZH2 inhibition on cartilage degradation, inflammation and functional disability. In vitro, gain and loss of EZH2 function were performed in human articular OA chondrocytes stimulated with IL-1β. In vivo, the effects of EZH2 inhibition were investigated on medial meniscectomy (MMX) OA mouse model. The tissue alterations were assayed by histology and the functional disabilities of the mice by actimetry and running wheel. In vitro, EZH2 overexpression exacerbated the action of IL-1β in chondrocytes increasing the expression of genes involved in inflammation, pain (NO, PGE2, IL6, NGF) and catabolism (MMPs), whereas EZH2 inhibition by a pharmacological inhibitor, EPZ-6438, reduced IL-1β effects. Ex vivo, EZH2 inhibition decreased IL-1β-induced degradation of cartilage. In vivo, intra-articular injections of the EZH2 inhibitor reduced cartilage degradation and improved motor functions of OA mice. This study demonstrates that the pharmacological inhibition of the histone methyl-transferase EZH2 slows the progression of osteoarthritis and improves motor functions in an experimental OA model, suggesting that EZH2 could be an effective target for the treatment of OA by reducing catabolism, inflammation and pain.
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http://dx.doi.org/10.1038/s41598-020-76724-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658239PMC
November 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

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

Recommendations of the French Society of Rheumatology on pharmacological treatment of knee osteoarthritis.

Joint Bone Spine 2020 Dec 12;87(6):548-555. Epub 2020 Sep 12.

Faculté de santé, UFR médecine de Paris-Centre, 75006 Paris, France.

Objectives: To establish recommendations for pharmacological treatment of knee osteoarthritis specific to France.

Methods: On behalf of the French Society of Rheumatology (SFR), a bibliography group analyzed the literature on the efficacy and safety of each pharmacological treatment for knee osteoarthritis. This group joined a multidisciplinary working group to draw up recommendations. Strength of recommendation and quality of evidence level were assigned to each recommendation. A review committee gave its level of agreement.

Results: Five general principles were established: 1) need to combine pharmacological and non-pharmacological treatments, 2) personalization of treatment, 3) symptomatic and/or functional aim of pharmacological treatments, 4) need to regularly re-assess the treatments and 5) discussion about arthroplasty if medical treatment fails. Six recommendations involved oral treatments: 1) paracetamol should not necessarily be prescribed systematically and/or continuously, 2) NSAIDs, possibly as first-line, 3) weak opioids, 4) strong opioids, 5) symptomatic slow-acting drugs of osteoarthritis, and 6) duloxetine (off-label use). Two recommendations involved topical agents (NSAIDs and capsaicin<1%). Three recommendations involved intra-articular treatments: corticosteroid or hyaluronic acid injections that can be proposed to patients. The experts did not draw a conclusion about the benefits of platelet-rich plasma injections.

Conclusion: These are the first recommendations of the SFR on the pharmacological treatment of knee osteoarthritis.
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http://dx.doi.org/10.1016/j.jbspin.2020.09.004DOI Listing
December 2020

Calcium Pyrophosphate Dihydrate Crystal Deposition in Gouty Tophi.

Arthritis Rheumatol 2021 02 5;73(2):324-329. Epub 2020 Dec 5.

Université de Paris, INSERM UMR 1132, Hôpital Lariboisière, AP-HP, Paris, France, and Vien Gut Medical Center and French-Vietnamese research center on gout and chronic diseases, Ho Chi Minh City, Vietnam.

Objective: The coexistence of calcium pyrophosphate dihydrate (CPPD) and monosodium urate monohydrate crystals in gouty tophi has rarely been reported. We undertook this study to investigate CPPD crystal deposits in a series of surgically removed gouty tophi and to identify factors associated with these deposits.

Methods: Twenty-five tophi from 22 gout patients were analyzed using polarized light microscopy, field emission scanning electron microscopy (FESEM), and μ Fourier transform infrared (μFTIR) spectroscopy.

Results: Tophi consisted of multiple lobules separated by fibrous septa and surrounded by a foreign-body giant cell reaction. CPPD crystal aggregates were identified in 9 of 25 tophi from 6 patients. CPPD crystals were dispersed or highly compacted, localized at the edge or inside the tophus lobules, with some lobules completely filled with crystals. Both monoclinic and triclinic CPPD crystal phases were identified using FESEM and μFTIR. Compared to patients without CPPD, those with CPPD-containing tophi were older (mean 60.5 years versus 47.2 years; P = 0.009), and had longer-term gout duration (mean 17.0 years versus mean 9.0 years; P < 0.05) and tophi duration (mean 10.0 years versus mean 4.6 years; P < 0.01). None of the patients had radiographic chondrocalcinosis of the knee or wrist.

Conclusion: CPPD crystal formation seems to be a late and frequent event of tophus maturation, occurring more frequently with aging, and could contribute to the speed of tophus dissolution and the apparent persistence of tophus sometimes observed even after effective, long-lasting urate-lowering therapy.
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http://dx.doi.org/10.1002/art.41515DOI Listing
February 2021

Answer to Checa « Coexistence of gout and chondrocalcinosis instead? », Joint Bone Spine 2020. doi:10.1016/j.jbspin.2020.07.007.

Joint Bone Spine 2020 12 6;87(6):678-679. Epub 2020 Aug 6.

Service de radiologie ostéo-Articulaire, hôpital Lariboisière, AP-HP-Nord, université de Paris, 2, rue Ambroise-Paré, 75010 Paris, France.

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http://dx.doi.org/10.1016/j.jbspin.2020.07.010DOI Listing
December 2020

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

Dual-energy computed-tomography-based discrimination between basic calcium phosphate and calcium pyrophosphate crystal deposition .

Ther Adv Musculoskelet Dis 2020 24;12:1759720X20936060. Epub 2020 Jun 24.

EA 4490, PMOI, Physiopathologie des Maladies Osseuses Inflammatoires, University of Lille, Lille, France.

Background: Dual-energy computed tomography (DECT) is being considered as a non-invasive diagnostic and characterization tool in calcium crystal-associated arthropathies. Our objective was to assess the potential of DECT in distinguishing between basic calcium phosphate (BCP) and calcium pyrophosphate (CPP) crystal deposition in and around joints .

Methods: A total of 13 patients with calcific periarthritis and 11 patients with crystal-proven CPPD were recruited prospectively to undergo DECT scans. Samples harvested from BCP and CPP calcification types were analyzed using Raman spectroscopy and validated against synthetic crystals. Regions of interest were placed in BCP and CPP calcifications, and the following DECT attenuation parameters were obtained: CT numbers (HU) at 80 and 140 kV, dual-energy index (DEI), electron density (Rho), and effective atomic number (). These DECT attenuation parameters were compared and validated against crystal calibration phantoms at two known equal concentrations. Receiver operating characteristic (ROC) curves were plotted to determine the highest accuracy thresholds for DEI and .

Results: Raman spectroscopy enabled chemical fingerprinting of BCP and CPP crystals both and . DECT was able to distinguish between HA and CPP in crystal calibration phantoms at two known equal concentrations, most notably by DEI (200 mg/cm: 0.037 ± 0 0.034 ± 0,  = 0.008) and (200 mg /cm: 9.4 ± 0 9.3 ± 0,  = 0.01) analysis. Likewise, BCP calcifications had significantly higher DEI (0.041 ± 0.005 0.034 ± 0.005,  = 0.008) and (9.5 ± 0.2 9.3 ± 0.2,  = 0.03) than CPP crystal deposits with comparable CT numbers in patients. With an area under the ROC curve of 0.83 [best threshold value = 0.0 39, sensitivity = 90. 9% (81.8, 97. 7%), specificity = 64.6% (50.0, 64. 6%)], DEI was the best parameter in distinguishing between BCP and CPP crystal depositions.

Conclusion: DECT can help distinguish between crystal-proven BCP and CPP calcification types and, thus, aid in the diagnosis of challenging clinical cases, and in the characterization of CPP and BCP crystal deposition occurring in osteoarthritis.
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http://dx.doi.org/10.1177/1759720X20936060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315653PMC
June 2020

Risk factors for hydroxychloroquine retinopathy in systemic lupus erythematosus: a case-control study with hydroxychloroquine blood-level analysis.

Rheumatology (Oxford) 2020 12;59(12):3807-3816

Department of Internal Medicine, Centre de Référence Maladies Auto-Immunes et Systémiques Rares d'Ile de France, Cochin Hospital, APHP.

Objective: HCQ is an essential medication in SLE, proven to lengthen survival and reduce flares. Its use, however, is limited by its rare but severe ophthalmological complications. Here, we aimed to analyse factors associated with HCQ retinopathy including HCQ blood levels.

Methods: This case-control study compared SLE patients with and without HCQ retinopathy, defined by abnormal results for at least two of the following ophthalmological tests: automated visual fields, spectral-domain optical coherence tomography (SD-OCT), multifocal electroretinogram (mfERG) and fundus autofluorescence. We compared clinical and laboratory findings to assess risk factors for HCQ retinopathy.

Results: The study included 23 patients with confirmed retinopathy (cases) and 547 controls. In the univariate analysis, age (P < 0.001), height (P = 0.045), creatinine clearance (P < 0.001), haemoglobin concentration (P = 0.01), duration of HCQ intake, (P < 0.001), higher cumulative HCQ dose (P < 0.001) and geographical origin (West Indies and sub-Saharan Africa) (P = 0.007) were associated with the risk of retinopathy, while HCQ blood levels were not. In the multivariate analysis, only cumulative dose (P = 0.016), duration of intake (P = 0.039), creatinine clearance (P = 0.002) and geographical origin (P < 0.0001, odds ratio 8.7) remained significantly associated with retinopathy.

Conclusion: SLE patients on HCQ should be closely monitored for retinopathy, especially those from the West Indies or sub-Saharan Africa, or with renal insufficiency, longer HCQ intake or a high cumulative dose. Although reducing the daily dose of HCQ in patients with persistently high HCQ blood levels seems logical, these concentrations were not associated with retinopathy in this study with controls adherent to treatment.
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http://dx.doi.org/10.1093/rheumatology/keaa157DOI Listing
December 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

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

Chondrocalcinosis of the Knee and the Risk of Osteoarthritis Progression: Data From the Knee and Hip Osteoarthritis Long-term Assessment Cohort.

Arthritis Rheumatol 2020 05 3;72(5):726-732. Epub 2020 Apr 3.

Lariboisière Hospital, AP-HP, INSERM U1132, UFR de Médecine, and Paris Diderot University, Paris, France.

Objective: To assess the impact of knee chondrocalcinosis (CC) on the 5-year risk of joint replacement and disease progression in patients with knee osteoarthritis (OA).

Methods: Patients with symptomatic knee OA without previous total joint (knee or hip) replacement (TJR) were recruited from the Knee and Hip Osteoarthritis Long-term Assessment cohort. Cox proportional hazards regression and generalized estimating equation models were used to compare the time from inclusion or OA diagnosis to total knee replacement (TKR) or TJR between patients with and those without knee CC at inclusion. In patients without incident TKR, logistic regression was performed to examine the association between CC and radiographic progression (Kellgren/Lawrence [K/L] grade) or worsening of Western Ontario and McMaster Universities Arthritis Index (WOMAC) subscores for OA pain or function between years 0 and 5. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated. Analyses were adjusted for age, sex, body mass index, WOMAC subscores, and K/L grade.

Results: Among the 656 patients included, 93 (14.2%) had knee CC, and 91 (13.9%) underwent TKR during the follow-up. Risk of TKR was not affected by the presence of knee CC (HR 1.26 [95% CI 0.74-2.17]). Similar results were obtained for the risk of incident TJR. For patients without incident TKR, knee CC did not affect the risk of worsening of K/L grade (odds ratio [OR] 0.9 [95% CI 0.4-1.7]), WOMAC pain subscore (OR 1.1 [95% CI 0.7-1.4]), or WOMAC function subscore (OR 0.9 [95% CI 0.4-2.0]).

Conclusion: In patients with symptomatic knee OA, the presence of knee CC did not affect the risk of arthroplasty or disease progression at 5 years.
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http://dx.doi.org/10.1002/art.41186DOI Listing
May 2020

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

Monosodium urate deposition in the articular cartilage and meniscus can mimic chondrocalcinosis.

Joint Bone Spine 2020 Jan 17;87(1):95-96. Epub 2019 Jul 17.

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

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http://dx.doi.org/10.1016/j.jbspin.2019.06.014DOI Listing
January 2020

Hyaluronan derivative HYMOVIS® increases cartilage volume and type ii collagen turnover in osteoarhritic knee: data from MOKHA study.

BMC Musculoskelet Disord 2019 Jun 18;20(1):293. Epub 2019 Jun 18.

Service de Rhumatologie - Centre Viggo Petersen, Hôpital Lariboisière, Paris, France.

Background: The objective of this pilot study was to identify biological, clinical or structural biomarkers of an intra-articular hyaluronic acid injection efficacy (HYMOVIS®) for the design of a larger placebo-controlled clinical trial studying the disease-modifying activity of this treatment.

Methods: Forty six patients with symptomatic knee Osteoarthritis (OA) were enrolled in this open-label, prospective, multicenter, pilot study. Patients received two treatment cycles of intra-articular injections (3 mL) of HYMOVIS® (8 mg/mL of hyaluronic acid hexadecylamide) at 6 months interval. Each treatment cycle involved two intra-articular injections 1 week apart. All patients had Magnetic Resonance Imaging (MRI) of the target knee at baseline and 1 year, and blood samples to assess joint biomarkers. The primary outcome was the change in type II collagen-specific biomarkers (Coll2-1, Coll2-1NO2 and CTX-II) after HYMOVIS® treatment versus baseline. Secondary endpoints included levels changes in aggrecan chondroitin sulfate 846 epitope (CS-846), Cartilage Oligomeric Matrix Protein (COMP), procollagen type II N-terminal propeptide (PIIANP), Matrix Metalloprotease (MMP)-3, Myeloperoxidase (MPO) and Interleukin (IL)-6 serum biomarkers, the ratio Coll2-1/PIIANP, CTX-II/PIIANP, variation of MRI cartilage volume, and Knee injury and Osteoarthritis Outcome Score (KOOS) index.

Results: Coll2-1 serum levels significantly increased overtime while Coll2-1NO2 levels were only increased at D360. Serum PIIANP levels also progressively and significantly enhanced with time. In contrast, other serum biomarker levels including CTX-II, CS-846, COMP, MMP-3, MPO or IL-6 did not change significantly overtime. Interestingly, the ratios Coll2-1/PIIANP and CTX-II/PIIANP decreased, indicating a decrease of cartilage catabolism. Compared to baseline value, MRI cartilage volume and thickness increased in lateral femoral and lateral trochlea compartments and not in medial compartment. These results, in addition to an improvement of T2 mapping score suggest a positive structural effect of the product. Interestingly, WORMS effusion score, an indicator of synovitis, significantly decreased. Finally, global KOOS score and subscales significantly increased overtime while pain at rest, walking pain and patients or investigators global assessment of disease activity decreased. The safety profile was favorable with a low incidence of injection-site pain.

Conclusion: HYMOVIS®, a well-tolerated intra-articular treatment, significantly enhanced type II collagen turnover as suggested by the increase in Coll2-1 and PIIANP levels and cartilage volume observed by MRI in lateral knee compartment. Importantly, this study provides critical information for the design of a larger phase III clinical trial investigating Disease Modifying effect of HYMOVIS®.

Trial Registration: http://www.isrctn.com/ISRCTN12227846 11/02/2015.
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http://dx.doi.org/10.1186/s12891-019-2667-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580647PMC
June 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

Intracellular iron uptake is favored in Hfe-KO mouse primary chondrocytes mimicking an osteoarthritis-related phenotype.

Biofactors 2019 Jul 27;45(4):583-597. Epub 2019 May 27.

Centre of Marine Sciences (CCMAR), University of Algarve, Faro, Portugal.

HFE-hemochromatosis is a disease characterized by a systemic iron overload phenotype mainly associated with mutations in the HFE protein (HFE) gene. Osteoarthritis (OA) has been reported as one of the most prevalent complications in HFE-hemochromatosis patients, but the mechanisms associated with its onset and progression remain incompletely understood. In this study, we have characterized the response to high iron concentrations of a primary culture of articular chondrocytes isolated from newborn Hfe-KO mice and compared the results with that of a similar experiment developed in cells from C57BL/6 wild-type (wt) mice. Our data provide evidence that both wt- and Hfe-KO-derived chondrocytes, when exposed to 50 μM iron, develop characteristics of an OA-related phenotype, such as an increased expression of metalloproteases, a decreased extracellular matrix production, and a lower expression level of aggrecan. In addition, Hfe-KO cells also showed an increased expression of iron metabolism markers and MMP3, indicating an increased susceptibility to intracellular iron accumulation and higher levels of chondrocyte catabolism. Accordingly, upon treatment with 50 μM iron, these chondrocytes were found to preferentially differentiate toward hypertrophy with increased expression of collagen I and transferrin and downregulation of SRY (sex-determining region Y)-box containing gene 9 (Sox9). In conclusion, high iron exposure can compromise chondrocyte metabolism, which, when simultaneously affected by an Hfe loss of function, appears to be more susceptible to the establishment of an OA-related phenotype.
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http://dx.doi.org/10.1002/biof.1520DOI Listing
July 2019

Partners and nurses' knowledge and representations of gout: A qualitative study.

Joint Bone Spine 2019 Nov 5;86(6):769-776. Epub 2019 May 5.

Hôpital Lariboisière, service de rhumatologie, pôle locomoteur, AP-HP, 2, rue Ambroise Paré 75010 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, 75018 Paris, France; Inserm U1132 Bioscar, Paris 75010, France. Electronic address:

Adherence to gout treatment is poor. Partners of patients and nurses are two major communicators with gouty patients, and their perceptions of illness may affect patient behavior.

Objective: To explore partners' and nurses' knowledge and representations of gout.

Methods: We used a qualitative grounded approach with semi-structured face-to-face individual interviews with a purposive sample of hospital nurses working in rheumatology and internal medicine departments and patient partners. Interviews were audio-recorded and transcribed. All authors met regularly to discuss coding and data interpretation.

Results: Overall, 20 nurses and 12 partners participated in the interviews. Four major themes were evidenced: knowledge gaps (gout cause was unknown, unawareness of urate-lowering therapy and the possibility to cure gout, focus in gout flare and diet); lack of information and education on gout (knowledge acquired by personal experiences, nurses complained to be insufficiently educated, partners highlighted the lack of information and that general practitioners did not have time to educate patients); gout consequences and social impacts (handicapping disease, avoid social activities like dinner with friends); attitudes towards gout flare and patient management (feeling powerless during flare, negative feelings such as being ashamed leading to postpone medical seek or unconcerned about their partner disease). Nurses regretted that they had not enough time to discuss issues with patients.

Conclusion: Partners and nurses' knowledge of gout is based on daily experiences. Participants were eager to learn more about gout. Nurses' education and education programs including partners may improve gout management and patient adherence to treatment.
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http://dx.doi.org/10.1016/j.jbspin.2019.04.010DOI Listing
November 2019

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

The classical NLRP3 inflammasome controls FADD unconventional secretion through microvesicle shedding.

Cell Death Dis 2019 02 25;10(3):190. Epub 2019 Feb 25.

Department of Infection, Immunity and Inflammation, Cochin Institute, 75014, Paris, France.

Fas-associated death domain (FADD) is a key adaptor molecule involved in numerous physiological processes including cell death, proliferation, innate immunity and inflammation. Therefore, changes in FADD expression have dramatic cellular consequences. In mice and humans, FADD regulation can occur through protein secretion. However, the molecular mechanisms accounting for human FADD secretion were still unknown. Here we report that canonical, non-canonical, but not alternative, NLRP3 inflammasome activation in human monocytes/macrophages induced FADD secretion. NLRP3 inflammasome activation by the bacterial toxin nigericin led to the proinflammatory interleukin-1β (IL-1β) release and to the induction of cell death by pyroptosis. However, we showed that FADD secretion could occur in absence of increased IL-1β release and pyroptosis and, reciprocally, that IL-1β release and pyroptosis could occur in absence of FADD secretion. Especially, FADD, but not IL-1β, secretion following NLRP3 inflammasome activation required extracellular glucose. Thus, FADD secretion was an active process distinct from unspecific release of proteins during pyroptosis. This FADD secretion process required K efflux, NLRP3 sensor, ASC adaptor and CASPASE-1 molecule. Moreover, we identified FADD as a leaderless protein unconventionally secreted through microvesicle shedding, but not exosome release. Finally, we established human soluble FADD as a new marker of joint inflammation in gout and rheumatoid arthritis, two rheumatic diseases involving the NLRP3 inflammasome. Whether soluble FADD could be an actor in these diseases remains to be determined. Nevertheless, our results advance our understanding of the mechanisms contributing to the regulation of the FADD protein expression in human cells.
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http://dx.doi.org/10.1038/s41419-019-1412-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389912PMC
February 2019

Iron-enriched diet contributes to early onset of osteoporotic phenotype in a mouse model of hereditary hemochromatosis.

PLoS One 2018 14;13(11):e0207441. Epub 2018 Nov 14.

Centre of Marine Sciences (CCMAR), University of Algarve, Faro, Portugal.

Osteoporosis is associated with chronic iron overload secondary to hereditary hemochromatosis (HH), but the causative mechanisms are incompletely understood. The main objective of this study was to investigate the role of dietary iron on osteoporosis, using as biological model the Hfe-KO mice, which have a systemic iron overload. We showed that these mice show an increased susceptibility for developing a bone loss phenotype compared to WT mice, which can be exacerbated by an iron rich diet. The dietary iron overload caused an increase in inflammation and iron incorporation within the trabecular bone in both WT and Hfe-KO mice. However, the osteoporotic phenotype was only evident in Hfe-KO mice fed the iron-enriched diet. This appeared to result from an imbalance between bone formation and bone resorption driven by iron toxicity associated to Hfe-KO and confirmed by a decrease in bone microarchitecture parameters (identified by micro-CT) and osteoblast number. These findings were supported by the observed downregulation of bone metabolism markers and upregulation of ferritin heavy polypeptide 1 (Fth1) and transferrin receptor-1 (Tfrc), which are associated with iron toxicity and bone loss phenotype. In WT mice the iron rich diet was not enough to promote a bone loss phenotype, essentially due to the concomitant depression of bone resorption observed in those animals. In conclusion the dietary challenge influences the development of osteoporosis in the HH mice model thus suggesting that the iron content in the diet may influence the osteoporotic phenotype in systemic iron overload conditions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0207441PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6241130PMC
April 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

Tendon thickening in dialysis-related joint arthritis is due to amyloid deposits at the surface of the tendon.

Joint Bone Spine 2019 03 19;86(2):233-238. Epub 2018 Sep 19.

Department of rheumatology, hôpital Lariboisière, 75010 Paris, France; University Paris 7, 75013 Paris, France. Electronic address:

Objectives: Beta-2-microglobulin (β2M) dialysis-related amyloidosis (DRA), a disabiliting joint disease, has been initially reported in patients under long-term dialysis. The incidence and prevalence has significantly decreased with the improvement in dialysis techniques. Here, we attempted to clarify the clinical and MRI features to improve the diagnosis.

Methods: We retrospectively reviewed the files of 19 patients under dialysis treatment referred for suspicion of β2M DRA. The diagnosis was based on MRI criteria (low signal intensity on both T1- and T2-weighted MR sequences). MRI analysis included a scoring of the several joint lesions. Scores were quantified according to a severity scale (0 to 3).

Results: Patients had a mean age of 66.0 ± 10.5 years and mean dialysis duration of 23.7 ± 10.5 years. DRA affected mainly large joints (shoulder in 73.7%, hip in 47.3%) and spine (36.8%). MRI images for 8 shoulders, 8 hips, and 3 spines were analysed. Amyloid synovitis was present in all cases, with high mean scores in the three sites. In all joints, the most common lesions were tendon thickening (68.4%) and bone erosions (68.4%). The mean tendon thickening score was high, particularly at the shoulders and also at the spine. Bone erosions were most frequent in the shoulder and pelvis.

Conclusion: In patients under long-term dialysis, β2M DRA involves large joints but also the spine. Special awareness should be drawn by the thickening of the tendon. MRI is required to characterize the pattern of the lesions and to achieve the diagnosis.
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http://dx.doi.org/10.1016/j.jbspin.2018.08.005DOI Listing
March 2019

Calpain-6 controls the fate of sarcoma stem cells by promoting autophagy and preventing senescence.

JCI Insight 2018 09 6;3(17). Epub 2018 Sep 6.

Inserm UMR-1132, Paris, France.

Sarcomas are still unsolved therapeutic challenges. Cancer stem cells are believed to contribute to sarcoma development, but lack of specific markers prevents their characterization and targeting. Here, we show that calpain-6 expression is associated with cancer stem cell features. In mouse models of bone sarcoma, calpain-6-expressing cells have unique tumor-initiating and metastatic capacities. Calpain-6 levels are especially high in tumors that have been successfully propagated in mouse to establish patient-derived xenografts. We found that calpain-6 levels are increased by hypoxia in vitro and calpain-6 is detected within hypoxic areas in tumors. Furthermore, calpain-6 expression depends on the stem cell transcription network that involves Oct4, Nanog, and Sox2 and is activated by hypoxia. Calpain-6 knockdown blocks tumor development in mouse and induces depletion of the cancer stem cell population. Data from transcriptomic analyses reveal that calpain-6 expression in sarcomas inversely correlates with senescence markers. Calpain-6 knockdown suppresses hypoxia-dependent prevention of senescence entry and also promotion of autophagic flux. Together, our results demonstrate that calpain-6 identifies sarcoma cells with stem-like properties and is a mediator of hypoxia to prevent senescence, promote autophagy, and maintain the tumor-initiating cell population. These findings open what we believe is a novel therapeutic avenue for targeting sarcoma stem cells.
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http://dx.doi.org/10.1172/jci.insight.121225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6171816PMC
September 2018