Publications by authors named "Benoit Le Goff"

107 Publications

Usefulness of real-world patient cohort follow-ups using questionnaires to assess the effect of treatments on the general population.

Joint Bone Spine 2021 Jan 23;88(4):105142. Epub 2021 Jan 23.

Service de Rhumatologie, Hôtel-Dieu, CHU Nantes, Place Alexis Ricordeau, 44093 Nantes cedex 01, France.

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http://dx.doi.org/10.1016/j.jbspin.2021.105142DOI Listing
January 2021

Novel insights into macrophage diversity in rheumatoid arthritis synovium.

Autoimmun Rev 2021 Mar 18;20(3):102758. Epub 2021 Jan 18.

INSERM UMR1238, Bone Sarcoma and Remodelling of Calcified Tissues, Nantes University, Nantes, France. Electronic address:

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease affecting joints and causing progressive damage and disability. Macrophages are of critical importance in the initiation and perpetuation of synovitis in RA, they can function as antigen presenting cells leading to T-cell dependent B-cell activation, assume a variety of inflammatory cell states with the production of destructive cytokines, but also contribute to tissue homeostasis/repair. The recent development of high-throughput technologies, including bulk and single cells RNA-sequencing, has broadened our understanding of synovial cell diversity, and opened novel perspectives to the discovery of new potential therapeutic targets in RA. In this review, we will focus on the relationship between the synovial macrophage infiltration and clinical disease severity and response to treatment. We will then provide a state-of-the-art picture of the biological roles of synovial macrophages and distinct macrophage subsets described in RA. Finally, we will review the effects of approved conventional and biologic drugs on the synovial macrophage component and highlight the therapeutic potential of future strategies to re-program macrophage phenotypes in RA.
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http://dx.doi.org/10.1016/j.autrev.2021.102758DOI Listing
March 2021

MRI Features Associated With the Detection of Microbial Pathogens by CT-Guided Biopsy in Septic Spondylodiscitis.

J Clin Rheumatol 2020 Dec 15;Publish Ahead of Print. Epub 2020 Dec 15.

From the Rheumatology Department, DHU FIRE, Pôle Infection Immunité, Bichat Hospital (AP-HP) Microbiology Department, Lariboisière Hospital, Paris Rheumatology Department, Hôtel Dieu Hospital, Nantes Rheumatology Department, Centre Viggo Petersen, Pole Appareil Locomoteur, Lariboisière Hospital (AP-HP), Inserm UMR 1132, USPC Infectious and Tropical Diseases Department, Bichat Hospital, Paris, France.

Objective: The aim of this study was to assess the magnetic resonance imaging (MRI) features associated with microbial pathogen detection by computed tomography (CT)-guided biopsy in patients with suspected septic spondylodiscitis.

Methods: For the last 10-year period, we analyzed the medical records of patients who underwent MRI and CT-guided biopsy for suspected septic spondylodiscitis. Clinical characteristics were recorded. The following MRI features were assessed: edema or contrast enhancement of the intervertebral disc, adjacent vertebrae, epidural and paravertebral space, presence of abscess, and paravertebral edema size. A positive biopsy was defined by pathogen identification on bacterial analysis or the presence of granuloma on histology. Predictors of a positive biopsy were assessed with a logistic regression model.

Results: We analyzed data for 61 patients (34 [56%] male; mean age, 59.9 ± 18.0 years); for 35 patients (57%), CT-guided biopsy was positive for a pathogen. The 4 MRI findings significantly associated with a positive biopsy were epiduritis, greater than 50% vertebral endplate edema, loss of intradiscal cleft, and abscess. The size of paravertebral edema was greater with a positive than negative biopsy (median, 15.9 [interquartile range, 11.3-21.3] vs 7.3 [4.6-12.9] mm; p = 0.004). On multivariable analysis, epiduritis was the only independent predictor of a positive biopsy (adjusted odds ratio, 7.4 [95% confidence interval, 1.7-31.4]; p = 0.006).

Conclusions: Epiduritis and the size of paravertebral edema on MRI are associated with detection of a microbial pathogen in suspected septic spondylodiscitis. For patients without these MRI signs, the need for further investigations such as enriched or prolonged cultures, a second CT-guided biopsy, or even surgical biopsy need to be discussed.
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http://dx.doi.org/10.1097/RHU.0000000000001683DOI Listing
December 2020

Rheumatic involvement and bone scan features in Schnitzler syndrome: initial and follow-up data from a single-center cohort of 25 patients.

Arthritis Res Ther 2020 11 18;22(1):272. Epub 2020 Nov 18.

Department of Internal Medicine Interne, CHU Nantes, Nantes, France.

Objective: To report on the characteristics and long-term course of rheumatic manifestations in Schnitzler syndrome (SchS).

Methods: A retrospective cohort study of patients with SchS followed between 2000 and 2020. Inclusion criteria included a diagnosis of SchS (Strasbourg criteria). All available bone scans were reviewed and scored according to the intensity and number of pathological sites. The scintigraphic score was compared with the clinical activity score, CRP level, and treatments.

Results: Twenty-five patients were included. Median age at diagnosis was 68 years. Eighty patients (72%) had SchS-related rheumatic pain. Most patients had a long-standing isolated rash before constitutional and/or rheumatic symptoms appeared. The monoclonal component level was usually very low (IgMκ in 22/25). Rheumatic pain predominated around the knees. Bone scans revealed abnormal tracer uptake in 15/18 (85%). The scintigraphic score correlated with clinical activity (r = 0.4, p < 0.02) and CRP level (r = 0.47, p < 0.01). The scintigraphic score was lower in patients receiving corticosteroids or IL1Ra (interleukin 1 receptor antagonist) than in untreated patients (median scores:2, 0, and 13, respectively; p < 0.05). Two patients developed Waldenström macroglobulinemia. Of the 22 surviving patients, median age at follow-up was 76 years. IL1Ra was used in 13 patients, with dramatic efficacy on both symptoms and bone scan features.

Conclusions: Rheumatic manifestations are very prevalent in SchS. However, bone pain can be misleading and contribute to misdiagnosis. Bone scan abnormalities are very prevalent and correlate with disease activity and treatments. IL1-Ra has a dramatic and durable efficacy but may not be required in every patient early on.
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http://dx.doi.org/10.1186/s13075-020-02318-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677784PMC
November 2020

Location of calcifications of rotator cuff on ultrasound in 74 patients: Near the junction between the supraspinatus and infraspinatus tendons in 96% of the cases.

Joint Bone Spine 2020 Nov 10;88(2):105107. Epub 2020 Nov 10.

Department of rheumatology, Nantes university hospital, 1, place Alexis-Ricordeau, 44093 Nantes cedex, France.

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http://dx.doi.org/10.1016/j.jbspin.2020.105107DOI Listing
November 2020

Enhanced BMP-2/BMP-4 ratio in patients with peripheral spondyloarthritis and in cytokine- and stretch-stimulated mouse chondrocytes.

Arthritis Res Ther 2020 10 12;22(1):234. Epub 2020 Oct 12.

Univ Lyon, Univ Claude Bernard Lyon 1, CNRS UMR 5246, ICBMS, F-69622, Lyon, France.

Background: Excessive bone formation in the entheses is one of the features of peripheral spondyloarthritis (SpA). Complex pathological mechanisms connecting inflammation, mechanical stress, and ossification are probably involved. We focused on bone morphogenetic protein (BMP)-2, -4, and -7 as possible mediators of this process.

Methods: BMP-2, -4, and -7 concentration was measured by ELISA in synovial fluids (SFs) of SpA (n = 56) and osteoarthritic (n = 21) patients. Mouse organotypic ankle cultures were challenged by a pro-inflammatory cocktail. Mouse primary chondrocytes, osteoblasts, or tenocytes were treated with TNF-α, interleukin (IL)-17, or IL-22 and/or subjected to cyclic stretch, or with recombinant BMP-2 or -4.

Results: In SpA SFs, if BMP-7 was barely detectable, BMP-2 concentration was higher and BMP-4 was lower than in osteoarthritic samples, so that BMP-2/BMP-4 ratio augmented 6.5 folds (p < 0.001). In SpA patients, TNF-α, IL-6, and IL-17 levels correlated this ratio (n = 21). Bmp-2/Bmp-4 ratio was similarly enhanced by cytokine treatment in explant and cell cultures, at mRNA level. In particular, simultaneous application of TNF-α and cyclical stretch induced a 30-fold increase of the Bmp-2/Bmp-4 ratio in chondrocytes (p = 0.027). Blockade of prostaglandin E and IL-6 production had almost no effect on the stretch-induced regulation of Bmp-2 or -4. Osteoinductive effects of BMP-4, and to a lesser extend BMP-2, were identified on cultured chondrocytes and tenocytes.

Conclusions: Our results first settle that BMP factors are locally deregulated in the SpA joint. An unexpected decrease in BMP-4 could be associated to an increase in BMP-2, possibly in response to mechanical and/or cytokine stimulations.
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http://dx.doi.org/10.1186/s13075-020-02330-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552569PMC
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

Molecular and Structural Effects of Percutaneous Interventions in Chronic Achilles Tendinopathy.

Int J Mol Sci 2020 Sep 23;21(19). Epub 2020 Sep 23.

Rheumatology Department, Nantes University Hospital, 44000 Nantes, France.

Achilles tendinopathy (AT) is a common problem, especially in people of working age, as well as in the elderly. Although the pathogenesis of tendinopathy is better known, therapeutic management of AT remains challenging. Various percutaneous treatments have been applied to tendon lesions: e.g., injectable treatments, platelet-rich plasma (PRP), corticosteroids, stem cells, MMP inhibitors, and anti-angiogenic agents), as well as percutaneous procedures without any injection (percutaneous soft tissue release and dry needling). In this review, we will describe and comment on data about the molecular and structural effects of these treatments obtained in vitro and in vivo and report their efficacy in clinical trials. Local treatments have some impact on neovascularization, inflammation or tissue remodeling in animal models, but evidence from clinical trials remains too weak to establish an accurate management plan, and further studies will be necessary to evaluate their value.
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http://dx.doi.org/10.3390/ijms21197000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582801PMC
September 2020

Ruling out septic arthritis risk in a few minutes using mid-infrared spectroscopy in synovial fluids.

Rheumatology (Oxford) 2020 Sep 4. Epub 2020 Sep 4.

INSERM, Université de Rennes, INRAe, UMR 1241, Institut NUMECAN CHU Rennes, Rennes.

Objectives: The aim of this study was to show the usefulness of a mid-infrared fibre evanescent wave spectroscopy point of care device in the identification of septic arthritis patients in a multicentre cohort, and to apply this technology to clinical practice among physicians.

Methods: SF samples from 402 patients enrolled in a multicentre cohort were frozen for analysis by mid-infrared fibre evanescent wave spectroscopy. The calibration cohort was divided into two groups of patients (septic arthritis and non-septic arthritis) and relevant spectral variables were used for logistic regression model. Model performances were tested on an independent set of 86 freshly obtained SF samples from patients enrolled in a single-centre acute arthritis cohort and spectroscopic analyses performed at the patient's bedside.

Results: The model set-up, using frozen-thawed SFs, provided good performances, with area under the curve 0.95, sensitivity 0.90, specificity 0.90, positive predictive value 0.41 and negative predictive value 0.99. Performances obtained in the validation cohort were area under the curve 0.90, sensitivity 0.92, specificity 0.81, positive predictive value 0.46 and negative predictive value 0.98. The septic arthritis probability has been translated into a risk score from 0 to 4 according to septic risk. For a risk score of 0, the probability of identifying a septic patient is very low (negative predictive value of 1), whereas a risk score of 4 indicates very high risk of septic arthritis (positive predictive value of 1).

Conclusion: Mid-infrared fibre evanescent wave spectroscopy could distinguish septic from non-septic synovial arthritis fluids with good performances, and showed particular usefulness in ruling out septic arthritis. Our data supports the possibility of technology transfer.

Trial Registration: ClinicalTrials.gov, http://clinicaltrials.gov, NCT02860871.
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http://dx.doi.org/10.1093/rheumatology/keaa373DOI Listing
September 2020

Long-term follow up after denosumab treatment for osteoporosis - rebound associated with hypercalcemia, parathyroid hyperplasia, severe bone mineral density loss, and multiple fractures: a case report.

J Med Case Rep 2020 Aug 11;14(1):130. Epub 2020 Aug 11.

Rheumatology Department, Nantes University Hospital, 1 place Alexis Ricordeau, 44093, Nantes, Cedex, France.

Background: The rebound effect after stopping treatment with denosumab may be associated with rapid loss of the gains in bone mineral density achieved with treatment, high levels of bone remodeling markers, the occurrence of vertebral fractures, and even hypercalcemia.

Case Presentation: A 64-year-old osteoporotic Caucasian woman suffered from a fracture of her second lumbar vertebra in 2004. From January 2005, she was treated with denosumab for 9 years, with good densitometry results for her hip and lumbar areas, and no fractures over the last 6 years of treatment. Ten months after the treatment with denosumab was stopped, a cascade of vertebral fractures, including some in unusual locations (third thoracic vertebra), and multiple rib fractures in a context of hypercalcemia, suggested possible malignancy. A complete evaluation, including systemic, biological, and biopsy analyses, ruled out this hypothesis. The hypercalcemia was associated with normal plasma phosphate and vitamin D concentrations, and a high parathyroid hormone level, with an abnormal fixation of the lower lobe of the thyroid on sesta-methoxy-isobutyl-isonitrile scintigraphy. Histological analysis of the excised parathyroid tissue revealed hyperplasia. The associated thyroidectomy (goiter) led to the discovery of a thyroid papillary microcarcinoma.

Conclusions: We consider the consequences of this rebound effect, not only in terms of the major loss of bone density (return to basal values within 3 years) and the multiple disabling fracture episodes, but also in terms of the hypercalcemia observed in association with apparently autonomous tertiary hyperparathyroidism. Several cases of spontaneous reversion have been reported in children, but the intervention in our patient precluded any assessment of the possible natural course. The discovery of an associated thyroid neoplasm appears to be fortuitous. Better understanding of the various presentations of the rebound effect after stopping treatment with denosumab would improve diagnostic management of misleading forms, as in this case. Bisphosphonates could partially prevent this rebound effect.
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http://dx.doi.org/10.1186/s13256-020-02401-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427054PMC
August 2020

MicroRNA-17-5p Reduces Inflammation and Bone Erosions in Mice With Collagen-Induced Arthritis and Directly Targets the JAK/STAT Pathway in Rheumatoid Arthritis Fibroblast-like Synoviocytes.

Arthritis Rheumatol 2020 12 29;72(12):2030-2039. Epub 2020 Oct 29.

PHY-OS Laboratory, INSERM UMR 1238, Nantes University of Medicine, Nantes, France.

Objective: We undertook this study to examine microRNA (miRNA) expression across rheumatoid arthritis (RA) phenotypes, along with the effects and mechanisms of action of miRNA-17-5p (miR-17).

Methods: A miRNA array was performed in synovial tissue biopsied from patients with naive erosive RA (n = 3) and patients with nonerosive RA (n = 3). MicroRNA-17 lipoplex was delivered intraarticularly in the murine collagen-induced arthritis model. Clinical, histologic, and structural effects were studied over the course of arthritis. In-depth studies of the mechanisms of action of miR-17 were performed in primary RA fibroblast-like synoviocytes (FLS) isolated from synovial tissue.

Results: Fifty-five miRNAs including miR-17 were reduced in erosive RA. The miR-17 transfection into arthritic paws reduced the clinical inflammation score between day 2 and day 7 (2.8 versus 1.9; P = 0.03). Synovial B cell, T cell, macrophage, and polynuclear neutrophil infiltration was significantly reduced. Structural damage was also decreased, as shown by a reduction in the number of osteoclasts detected using tartrate-resistant acid phosphatase staining (osteoclast surface/bone surface 32% versus 18%; P = 0.005) and erosion score by computed tomography analysis (2.9 versus 1.7; P = 0.023). Proinflammatory cytokines from the interleukin-6 (IL-6) family and IL-1β expression were also significantly reduced, but tumor necrosis factor was not. MicroRNA-17 directly targeted the 3'-untranslated regions of STAT3 and JAK1. STAT3 and JAK1 messenger RNA (mRNA) and protein expression were reduced in RA FLS following miR-17 transfection. STAT3 and JAK1 mRNA and activation of STAT3, as assessed by immunohistochemistry, were also reduced in injected paws (% stained area 93% versus 62%; P = 0.035).

Conclusion: We demonstrate an antiinflammatory and antierosive role of miR-17 in vivo. This effect involves the suppression of the IL-6 family autocrine-amplifying loop through the direct targeting of JAK1 and STAT3.
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http://dx.doi.org/10.1002/art.41441DOI Listing
December 2020

Inadequacies of the Lasègue test, and how the Slump and Bowstring tests are useful for the diagnosis of sciatica.

Joint Bone Spine 2021 01 16;88(1):105030. Epub 2020 Jun 16.

Service de rhumatologie, Hôtel-Dieu, CHU of Nantes, 44093, Nantes cedex 01, France.

Diagnosis of sciatica mainly relies on pain reproduction by stretching of the lumbar roots since neurological examination and medical history are usually not sufficient to guarantee diagnosis. The Lasègue test is the most popular method, which starts with the straight leg-raising test (SLR). However it is not perfect, and is not always well performed or interpreted. Passive ankle dorsiflexion at the end of the SLR (Bragard test) is more sensitive, but can also remain normal in some cases of sciatica. Other stretching tests can help to recognise lumbar root damage in patients with poorly defined pain in a lower extremity: firstly, the Christodoulides test, i.e. reproduction of L5 sciatic pain by a femoral stretch test; secondly, the Slump test, performed on a patient in a sitting position, by slowly extending their painful leg then passively bending their neck (or the opposite); and thirdly, the Bowstring test, which requires, at the end of the Lasègue test, once the knee has been slightly flexed, pressing on the course of the peroneal and/or tibial nerves in the popliteal fossea to try and reproduce the exact pain felt by the patient. The combination of all these tests takes less than 2minutes, and could improve both the sensitivity and specificity of the physical examination for the diagnosis of sciatica. This article is a review of the limitations of the Lasègue/SLR tests and of the efficacy of these other tests for stretching the lumbar roots.
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http://dx.doi.org/10.1016/j.jbspin.2020.06.004DOI Listing
January 2021

Acromegaly is associated with vertebral deformations but not vertebral fractures: Results of a cross-sectional monocentric study.

Joint Bone Spine 2020 Dec 16;87(6):618-624. Epub 2020 May 16.

Department of Rheumatology, CHU de Nantes, Nantes, France.

Objectives: Patients with acromegaly appear to be at increased risk of vertebral fractures despite normal bone mineral density. We investigated the prevalence of vertebral fractures in a cohort of acromegalic patients under 80 years of age.

Methods: Monocentric cross-sectional study performed at Nantes University Hospital from 1988 to 2018. Fifty patients (18 females, 32 males) with a median age of 52.3 years (range: 27-78) were included. Radiological vertebral fractures were evaluated on conventional lumbar and thoracic spine radiographs using Genant's semiquantitative fracture assessment. We studied qualitative abnormalities of the spine using three criteria: osteophytes, disc-space narrowing and wedge-shaped vertebrae. We analysed bone mineral density and endocrine status.

Results: Three patients (6%) had a vertebral fracture: one grade 1 and two grade 2 according to Genant's assessment, with two osteoporotic and one osteopenic patients. They had no unsubstituted pituitary deficiency. Considering the frank deformations (osteophyte or disc narrowing≥grade 2 or wedge-shaped), the thoracic spine was deformed in 22 patients (44%) and the lumbar spine in 21 patients (42%).

Conclusion: Acromegalic patients had a low prevalence of vertebral fractures but had a significant amount of vertebral deformations. We speculate that this high prevalence of frank deformations could explain the previously reported high prevalence of vertebral fractures.
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http://dx.doi.org/10.1016/j.jbspin.2020.04.020DOI Listing
December 2020

Correction: Performance in delayed non-matching to sample task predicts the diagnosis of obsessive-compulsive disorder.

Transl Psychiatry 2020 Jan 29;10(1):44. Epub 2020 Jan 29.

Departement de Psychiatrie adulte, boulevard de l'Hopital, Hopital Universitaire de la Pitie Salpetriere, Assistance Publique - Hopitaux de Paris, 75013, Paris, France.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41398-020-0735-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026033PMC
January 2020

Methotrexate effect on immunogenicity and long-term maintenance of adalimumab in axial spondyloarthritis: a multicentric randomised trial.

RMD Open 2020 01 9;6(1). Epub 2020 Jan 9.

Department of Rheumatology, University of Tours, EA 7501 GICC, CHRU de Tours, Tours, France

Objectives: Anti-drug antibodies (ADA) are responsible for decreased adalimumab efficacy in axial spondyloarthritis (SpA). We aimed to evaluate the ability of methotrexate (MTX) to decrease adalimumab immunisation.

Methods: A total of 110 patients eligible to receive adalimumab 40 mg subcutaneously (s.c.) every other week were randomised (1:1 ratio) to receive, 2 weeks before adalimumab (W-2) and weekly, MTX 10 mg s.c. (MTX+) or not (MTX-). ADA detection and adalimumab serum concentration were assessed at weeks 4 (W4), 8 (W8), 12 (W12) and 26 (W26) after starting adalimumab (W0). The primary outcome was the proportion of patients with ADA at W26. Four years after the study completion, we retrospectively analysed adalimumab maintenance in relation with MTX co-treatment duration.

Results: We analysed data for 107 patients (MTX+; n=52; MTX-; n=55). ADA were detected at W26 in 39/107 (36.4%) patients: 13/52 (25%) in the MTX+ group and 26/55 (47.3%) in the MTX- group (p=0.03). Adalimumab concentration was significantly higher in the MTX+ than MTX- group at W4, W8, W12 and W26. The two groups did not differ in adverse events or efficacy. In the follow-up study, MTX co-treatment >W26 versus no MTX or ≤W26 was significantly associated with adalimumab long-term maintenance (p=0.04).

Conclusion: MTX reduces the immunogenicity and ameliorate the pharmacokinetics of adalimumab in axial SpA. A prolonged co-treatment of MTX>W26 seems to increase adalimumab long-term maintenance.
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http://dx.doi.org/10.1136/rmdopen-2019-001047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046954PMC
January 2020

Performance in delayed non-matching to sample task predicts the diagnosis of obsessive-compulsive disorder.

Transl Psychiatry 2019 12 10;9(1):338. Epub 2019 Dec 10.

Departement de Psychiatrie adulte, boulevard de l'Hopital, Hopital Universitaire de la Pitie Salpetriere, Assistance Publique - Hopitaux de Paris, 75013, Paris, France.

Electrical stimulation studies have recently evidenced the involvement of orbitofrontal cortex (OFC) in obsessive-compulsive disorder (OCD). In addition, lateral OFC is activated in healthy subjects during delayed non-matching-to-sample task (DNMS). In the present study, we hypothesized that OCD results from a specific defect of lateral OFC processing that can be evidenced via a DNMS task. To this end, we compared the DNMS performances of 20 OCD patients vs 20 demographically matched healthy controls. As predicted, our results showed that OCD patients performed worse than healthy controls at DNMS task. To test for the specificity of this behavioral impairment, we furthermore compared OCD patients and healthy subjects on a different task not involving directly the lateral OFC: the delayed match-to-sample task (DMS). As expected, OCD patients are more impaired for both the DNMS and the DMS task, compared with healthy subjects. Moreover, OCD patients tend statistically to perform worse for the DNMS task than for DMS task. Our results suggest the DNMS task specifically target the malfunctioning areas in OCD, such as the lateral OFC. In light of these results, lateral OFC should therefore be the focus of future therapeutic interventions.
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http://dx.doi.org/10.1038/s41398-019-0667-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904547PMC
December 2019

Is ultrasound-guided caudal steroid injection effective in the management of lower lumbar radicular pain? A two-center prospective observational study on 150 patients.

Joint Bone Spine 2020 07 4;87(4):364-365. Epub 2019 Dec 4.

Department of rheumatology, CHU de Rennes, 16, boulevard de Bulgarie, 35200 Rennes, France; Inserm NuMeCan UMR 1274, CIMIAD, university of Rennes, 35000 Rennes, France.

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http://dx.doi.org/10.1016/j.jbspin.2019.11.006DOI Listing
July 2020

Bone marrow mesenchymal stem cells in rheumatoid arthritis, spondyloarthritis, and ankylosing spondylitis: problems rather than solutions?

Arthritis Res Ther 2019 11 13;21(1):239. Epub 2019 Nov 13.

Centre Hospitalier Universitaire de Nantes, Nantes, France.

Background: Bone marrow mesenchymal stem cells (BM-MSCs) can dampen inflammation in animal models of inflammatory rheumatisms and human osteoarthritis. They are expected to be a solution for numerous human conditions. However, in rheumatoid arthritis (RA) and spondyloarthritis (SpA), subsets of subchondral BM-MSCs might conversely fuel synovitis and enthesitis.

Main Text: Abnormal behaviour of BM-MSCs and/or their progeny has been found in RA and SpA. BM-MSCs also contribute to the ossifying processes observed in ankylosing spondylitis. Some synovial fibroblastic stem cells probably derive from BM-MSCs, but some stem cells can also migrate through the bare zone area of joints, not covered by cartilage, into the synovium. BM-MSCs can also migrate in the synovium over tendons. Sub-populations of bone marrow stem cells also invade the soft tissue side of enthesis via small holes in the bone cortex. The present review aims (1) to make a focus on these two aspects and (2) to put forward the hypothesis that lasting epigenetic changes of some BM-MSCs, induced by transient infections of the bone marrow close to the synovium and/or entheses (i.e. trained immunity of BM-MSCs and/or their progeny), contribute to the pathogenesis of inflammatory rheumatisms. Such hypothesis would fit with (1) the uneven distribution and/or flares of arthritis and enthesitis observed at the individual level in RA and SpA (reminiscent of what is observed following reactive arthritis and/or in Whipple's disease); (2) the subchondral bone marrow oedema and erosions occurring in many RA patients, in the bare zone area; and (3) the frequent relapses of RA and SpA despite bone marrow transplantation, whereas most BM-MSCs resist graft preconditioning.

Conclusion: Some BM-MSCs might be more the problem than the solution in inflammatory rheumatisms. Subchondral bone marrow BM-MSCs and their progeny trafficking through the bare zone area of joints or holes in the bone cortex of entheses should be thoroughly studied in RA and SpA respectively. This may be done first in animal models. Mini-arthroscopy of joints could also be used in humans to specifically sample tissues close to the bare zone and/or enthesis areas.
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http://dx.doi.org/10.1186/s13075-019-2014-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854713PMC
November 2019

Are painDETECT scores in musculoskeletal disorders associated with duration of daily pain and time elapsed since current pain onset?

Pain Rep 2019 May-Jun;4(3):e739. Epub 2019 Apr 9.

Rheumatology Department, Nantes University Hospital, Hôtel-Dieu, CHU Nantes, Nantes, France.

Objectives: We aimed to compare painDETECT scores in outpatients seen in a rheumatology department over a 1-month period and search for correlations between painDETECT scores and the estimated duration of daily pain and time elapsed since the onset of current pain.

Patients And Methods: A total of 529 of 738 outpatients agreed to complete a set of questionnaires, including painDETECT.

Results: The mean painDETECT score was 14.14 ± 7.59, and 31% of the patients had painDETECT scores of >18. Fibromyalgia ranked first (21.2 ± 6.0), followed by osteoarthritis of the lower limbs (17.8 ± 8.2), back pain and radiculopathies (16.1 ± 6.8), osteoarthritis of the upper limbs (15.7 ± 8.1), spondylarthrosis (15.1 ± 7.2), entrapment neuropathies (14.1 ± 2.4), rheumatoid arthritis (13.8 ± 7.1), miscellaneous conditions (13.8 ± 8.2), tendinitis (13.4 ± 7.9), connectivitis (11.5 ± 6.7), and osteoporosis (8.5 ± 6.9). The duration of daily pain was much longer in patients with painDETECT scores of >18 (12.41 ± 8.45 vs 6.53 ± 7.45 hours) ( = 0.0000), but very similar painDETECT scores were observed for patients suffering from pain for less than 1 week (13.7 ± 8.2; 38% > 18), for 1 month (14.5 ± 8.2; 25% > 18), several months (12.7 ± 7.3; 23% > 18), 1 year (13.8 ± 7.7; 29% > 18), or several years (14.7 ± 7.4; 33% > 18).

Conclusion: PainDETECT scores differed little depending on the musculoskeletal condition, strongly correlated with the duration of daily pain, and appeared to be as high in patients with recent pain as in those suffering for years.
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http://dx.doi.org/10.1097/PR9.0000000000000739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749904PMC
April 2019

Rotator Cuff Tenocytes Differentiate into Hypertrophic Chondrocyte-Like Cells to Produce Calcium Deposits in an Alkaline Phosphatase-Dependent Manner.

J Clin Med 2019 Sep 26;8(10). Epub 2019 Sep 26.

INSERM UMR1238, Bone Sarcoma and remodeling of calcified tissues, Nantes University, 44093 Nantes, France.

Calcific tendonitis is a frequent cause of chronic shoulder pain. Its cause is currently poorly known. The objectives of this study were to better characterize the cells and mechanisms involved in depositing apatite crystals in human tendons. Histologic sections of cadaveric calcified tendons were analyzed, and human calcific deposits from patients undergoing lavage of their calcification were obtained to perform infrared spectroscopy and mass spectrometry-based proteomic characterizations. In vitro, the mineralization ability of human rotator cuff cells from osteoarthritis donors was assessed by alizarin red or Von Kossa staining. Calcifications were amorphous areas surrounded by a fibrocartilaginous metaplasia containing hypertrophic chondrocyte-like cells that expressed tissue non-specific alkaline phosphatase (TNAP) and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), which are two key enzymes of the mineralization process. Calcific deposits were composed of apatite crystals associated with proteins involved in bone and cartilage development and endochondral bone growth. In vitro, tenocyte-like cells extracted from the rotator cuff were able to mineralize in osteogenic cultures, and expressed , , and , which are hypertrophic chondrocytes markers. The use of a TNAP inhibitor significantly prevented mineral deposits. We provide evidence that tenocytes have a propensity to differentiate into hypertrophic chondrocyte-like cells to produce TNAP-dependent calcium deposits. We believe that these results may pave the way to identifying regulating factors that might represent valuable targets in calcific tendonitis.
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http://dx.doi.org/10.3390/jcm8101544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6833470PMC
September 2019

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

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

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

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

Monocyte/Macrophage Abnormalities Specific to Rheumatoid Arthritis Are Linked to miR-155 and Are Differentially Modulated by Different TNF Inhibitors.

J Immunol 2019 10 4;203(7):1766-1775. Epub 2019 Sep 4.

Université Paris-Sud, INSERM U1184, Center for Immunology of Viral Infections and Autoimmune Diseases, 94270 Le Kremlin Bicêtre, France;

Proinflammatory macrophages and miR-155 are increased in patients with rheumatoid arthritis (RA). We studied membrane TNF (mTNF) expression on blood monocytes, polarization into macrophages, miR-155 expression, and the effect of anti-TNF on these biomarkers in RA patients. Sixty-seven RA patients and 109 controls (55 healthy, 54 with spondyloarthritis and connective tissue diseases) were studied. Monocytes were isolated and differentiated into macrophages with or without anti-TNF. mTNF expression was increased on monocytes from RA patients, but not from other inflammatory diseases, correlated with disease activity. Under human serum AB or M-CSF, only monocytes from RA had a defect of differentiation into M2-like macrophages and had a propensity for preferential maturation toward M1-like macrophages that contributed to synovial inflammation. This defect was correlated to mTNF expression and was partially reversed by monoclonal anti-TNF Abs but not by the TNF soluble receptor. miR-155 was increased in M2-macrophages except in adalimumab-treated patients. Transfection of healthy monocytes with miR-155 induced a decrease in M2-like markers, and transfection of RA monocytes with antagomir-155 allowed restoration of M2-like polarization. Defect in differentiation of monocytes into M2-like-macrophages linked to increased miR-155 and correlated with increased mTNF on monocytes could play a key role in RA pathogenesis. Monoclonal anti-TNF Abs but not the TNF soluble receptor partially restored this defect.
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http://dx.doi.org/10.4049/jimmunol.1900386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755128PMC
October 2019

Prevalence and characteristics of proximal tibiofibular joint cysts on MRI.

Joint Bone Spine 2020 Jan 18;87(1):97-98. Epub 2019 Jul 18.

Service de rhumatologie, CHU de Nantes, 44093 Nantes, France.

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http://dx.doi.org/10.1016/j.jbspin.2019.07.002DOI Listing
January 2020

Cytokine-Induced and Stretch-Induced Sphingosine 1-Phosphate Production by Enthesis Cells Could Favor Abnormal Ossification in Spondyloarthritis.

J Bone Miner Res 2019 12 10;34(12):2264-2276. Epub 2019 Sep 10.

Univ Lyon, Univ Claude Bernard Lyon 1 (UCBL), CNRS, UMR5246, Lyon, France.

Spondyloarthritis (SpA) is a common rheumatic disease characterized by enthesis inflammation (enthesitis) and ectopic ossification (enthesophytes). The current pathogenesis model suggests that inflammation and mechanical stress are both strongly involved in SpA pathophysiology. We have previously observed that the levels of sphingosine 1-phosphate (S1P), a bone anabolic molecule, were particularly high in SpA patients' serum compared to healthy donors. Therefore, we wondered how this deregulation was related to SpA molecular mechanisms. Mouse primary osteoblasts, chondrocytes, and tenocytes were used as cell culture models. The sphingosine kinase 1 (Sphk1) gene expression and S1P secretion were significantly enhanced by cyclic stretch in osteoblasts and chondrocytes. Further, TNF-α and IL-17, cytokines implicated in enthesitis, increased Sphk1 mRNA in chondrocytes in an additive manner when combined to stretch. The immunochemistry on mouse ankles showed that sphingosine kinase 1 (SK1) was localized in some chondrocytes; the addition of a pro-inflammatory cocktail augmented Sphk1 expression in cultured ankles. Subsequently, fingolimod was used to block S1P metabolism in cell cultures. It inhibited S1P receptors (S1PRs) signaling and SK1 and SK2 activity in both osteoblasts and chondrocytes. Fingolimod also reduced S1PR-induced activation by SpA patients' synovial fluid (SF), demonstrating that the stimulation of chondrocytes by SFs from SpA patients involves S1P. In addition, when the osteogenic culture medium was supplemented with fingolimod, alkaline phosphatase activity, matrix mineralization, and bone formation markers were significantly reduced in osteoblasts and hypertrophic chondrocytes. Osteogenic differentiation was accompanied by an increase in S1prs mRNA, especially S1P , but their contribution to S1P-impact on mineralization seemed limited. Our results suggest that S1P might be overproduced in SpA enthesis in response to cytokines and mechanical stress, most likely by chondrocytes. Moreover, S1P could locally favor the abnormal ossification of the enthesis; therefore, blocking the S1P metabolic pathway could be a potential therapeutic approach for the treatment of SpA. © 2019 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3844DOI Listing
December 2019

Ultrasonography changes observed in 3 cases of bone marrow edema syndrome of the femoral head.

Joint Bone Spine 2020 Jan 18;87(1):101-102. Epub 2019 Jul 18.

Service de rhumatologie, Hôtel-Dieu, CHU de Nantes, 44093 Nantes cedex 01, France.

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http://dx.doi.org/10.1016/j.jbspin.2019.07.004DOI Listing
January 2020

Is it currently reasonable to offer short, 14-day antibiotic therapies after a surgical synovectomy in native joint septic arthritis?

Ann Rheum Dis 2020 11 5;79(11):e146. Epub 2019 Jul 5.

Osteoarticular Infections Working Group of the French Society of Rheumatology, Paris, France.

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http://dx.doi.org/10.1136/annrheumdis-2019-215887DOI Listing
November 2020

Are corticosteroid injections needed after needling and lavage of calcific tendinitis? Randomised, double-blind, non-inferiority trial.

Ann Rheum Dis 2019 06 11;78(6):837-843. Epub 2019 Apr 11.

Department of Rheumatology, CHU Nantes, Nantes, France

Objective: Steroid injections are common after an ultrasound-guided puncture and lavage (UGPL) of calcific tendonitis of the rotator cuff. However, steroids may prevent calcification resorption and negatively affect tendon healing. Our study was designed to determine whether saline solution was non-inferior to steroids in the prevention of acute pain reactions in the week following UGPL.

Methods: This was a randomised, double-blinded, controlled non-inferiority trial with 12-month follow-up. We included 132 patients (66 in each group) with symptomatic calcification measuring more than 5 mm. Patients received 1 mL of saline or steroid (methylprednisolone 40 mg) in the subacromial bursa at the end of UGPL. Primary outcome was the maximal pain during the week following the procedure with a prespecified non-inferiority margin of 10 mm (0-100 visual analogue scale). Secondary outcomes included pain at rest and during activity, function (disabilities of the arm, shoulder and hand score) and radiological evolution of the calcification over the 12-month follow-up.

Results: The estimated mean difference in the first week's maximal pain between these two groups was 11.76 (95% CI 3.78 to 19.75). Steroids significantly improved VAS pain at rest and during activities, as well as function at 7 days and 6 weeks. They did not change the rate of calcification resorption, which occurred in 83% and 74% of patients at 12 months in the saline and steroid groups.

Conclusion: Non-inferiority of saline when compared with steroids could not be established. However, steroid injection improved pain in the 6 weeks following the procedure, and function in the 3 months after, with no significant effect on calcification resorption.

Trial Registration Number: NTC02403856.
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http://dx.doi.org/10.1136/annrheumdis-2018-214971DOI Listing
June 2019

Micro-RNAs in inflammatory arthritis: From physiopathology to diagnosis, prognosis and therapeutic opportunities.

Biochem Pharmacol 2019 07 27;165:134-144. Epub 2019 Feb 27.

Rheumatology Department, Nantes University Hospital, Nantes, France; INSERM UMR 1238, Nantes Faculty of Medicine, France.

Micro-RNAs are an area of research exponentially expanding over the past years. These small sequences of 20-22 nucleotides have a strong role as post-transcriptional regulators of gene expression. Inflammatory arthritis pathophysiology involves various key players from innate to adaptive immunity, as well as various signalling pathways of inflammation. In this review, we discuss how micro-RNAs are involved in rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and juvenile inflammatory arthritis, from pre-clinical phases to established diseases. We describe mi-RNAs key roles in fibroblast like synoviocytes migration, proliferation, apoptosis and cytokine production, in macrophages polarization, as well as in B cells and T cell proliferation and differentiation, with a special emphasis on Treg/Th17 imbalance. We finally discuss the application of these findings in pre-clinical models and highlight opportunities and limits of a therapeutic approach using mi-RNAs agonists or antagonists.
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http://dx.doi.org/10.1016/j.bcp.2019.02.031DOI Listing
July 2019

Corticosteroids injections versus corticosteroids with hyaluronic acid injections in rhizarthrosis: the randomised multicentre RHIZ'ART trial study protocol.

BMJ Open 2019 01 9;9(1):e022553. Epub 2019 Jan 9.

Methodologist, centre de Recherche Clinique, CHD Vendée, La Roche-sur-Yon, Pays de la Loire, France.

Introduction: Osteoarthritis of the trapeziometacarpal joint affects approximately 10%-25% of women, especially those who are postmenopausal. It may result in thumb dysfunction. Among the treatments, intra-articular injections of corticosteroid (CS) and hyaluronic acid (HA) are both effective and recommended. However, clinical trials have shown that HA improves functional capacity, whereas CS only produces a decrease in pain. The synergy of these two drugs has not been evaluated. The primary goal of this study was to determine whether the association between HA and CS produce an additional decrease of more pain during thumb movement at three months postinjection, compared to the level of pain relief from CS alone.

Methods And Analysis: RHIZ'ART is a prospective, multicentre, comparative, randomised, controlled, double-blind trial. Patients referred to the rheumatology department for thumb rhizarthrosis will receive an injection of betamethasone with HA or placebo (serum saline) based on central randomisation and stratification by centre. Injections will be given under ultrasound guidance. The primary outcome will compare the pain Visual Analogue Scale with motion at three months for both groups using a mixed model. The expected decrease in pain intensity in the CS group is 25% and 35% in the CS with HA group. In order to achieve a 80% power for detecting this difference with α set at 5%, 73 patients are needed in each group (146 total). The main secondary outcomes are the Cochin score (hand function) and grip strength. Follow-up visits are at 1, 3, 6 and 12 months.

Ethics And Dissemination: The study project has been approved by the appropriate ethics committee (CPP île de France III, 2017-002298-20). In agreement with current French regulations, a signed informed written consent will be obtained from each patient. Results of the main trial and of the secondary endpoints will be submitted for publication in a peer-reviewed journal.

Trial Registration Number: NCT03431584.
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http://dx.doi.org/10.1136/bmjopen-2018-022553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340006PMC
January 2019