Publications by authors named "Aurelie Najm"

27 Publications

  • Page 1 of 1

Immunomodulatory therapies for SARS-CoV-2 infection: a systematic literature review to inform EULAR points to consider.

Ann Rheum Dis 2021 Feb 15. Epub 2021 Feb 15.

Department of Rheumatology, Northwick Park Hospital, London North West University Healthcare NHS Trust, London, UK.

Objective: To summarise the available information on efficacy and safety of immunomodulatory agents in SARS-CoV-2 infection.

Methods: As part of a European League Against Rheumatism (EULAR) taskforce, a systematic literature search was conducted from January 2019 to 11 December 2020. Two reviewers independently identified eligible studies according to the Population, Intervention, Comparator and Outcome framework and extracted data on efficacy and safety of immunomodulatory agents used therapeutically in SARS-CoV-2 infection at any stage. The risk of bias was assessed with validated tools.

Results: Of the 60 372 records, 401 articles were eligible for inclusion. Studies were at variable risk of bias. Randomised controlled trials (RCTs) were available for the following drugs: hydroxychloroquine (n=12), glucocorticoids (n=6), tocilizumab (n=4), convalescent plasma (n=4), interferon beta (n=2), intravenous immunoglobulins (IVIg) (n=2) and n=1 each for anakinra, baricitinib, colchicine, leflunomide, ruxolitinib, interferon kappa and vilobelimab. Glucocorticoids were able to reduce mortality in specific subsets of patients, while conflicting data were available about tocilizumab. Hydroxychloroquine was not beneficial at any disease stage, one RCT with anakinra was negative, one RCT with baricitinib+remdesivir was positive, and individual trials on some other compounds provided interesting, although preliminary, results.

Conclusion: Although there is emerging evidence about immunomodulatory therapies for the management of COVID-19, conclusive data are scarce with some conflicting data. Since glucocorticoids seem to improve survival in some subsets of patients, RCTs comparing glucocorticoids alone versus glucocorticoids plus anticytokine/immunomodulatory treatment are warranted. This systematic literature review informed the initiative to formulate EULAR 'points to consider' on COVID-19 pathophysiology and immunomodulatory treatment from the rheumatology perspective.
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http://dx.doi.org/10.1136/annrheumdis-2020-219725DOI Listing
February 2021

Pathophysiology of acute respiratory syndrome coronavirus 2 infection: a systematic literature review to inform EULAR points to consider.

RMD Open 2021 02;7(1)

Centre for Rheumatology, National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre (BRC), University College London Hospitals (UCLH) NHS Foundation Trus, London, UK.

Background: The SARS-CoV-2 pandemic is a global health problem. Beside the specific pathogenic effect of SARS-CoV-2, incompletely understood deleterious and aberrant host immune responses play critical roles in severe disease. Our objective was to summarise the available information on the pathophysiology of COVID-19.

Methods: Two reviewers independently identified eligible studies according to the following PICO framework: P (population): patients with SARS-CoV-2 infection; I (intervention): any intervention/no intervention; C (comparator): any comparator; O (outcome) any clinical or serological outcome including but not limited to immune cell phenotype and function and serum cytokine concentration.

Results: Of the 55 496 records yielded, 84 articles were eligible for inclusion according to question-specific research criteria. Proinflammatory cytokine expression, including interleukin-6 (IL-6), was increased, especially in severe COVID-19, although not as high as other states with severe systemic inflammation. The myeloid and lymphoid compartments were differentially affected by SARS-CoV-2 infection depending on disease phenotype. Failure to maintain high interferon (IFN) levels was characteristic of severe forms of COVID-19 and could be related to loss-of-function mutations in the IFN pathway and/or the presence of anti-IFN antibodies. Antibody response to SARS-CoV-2 infection showed a high variability across individuals and disease spectrum. Multiparametric algorithms showed variable diagnostic performances in predicting survival, hospitalisation, disease progression or severity, and mortality.

Conclusions: SARS-CoV-2 infection affects both humoral and cellular immunity depending on both disease severity and individual parameters. This systematic literature review informed the EULAR 'points to consider' on COVID-19 pathophysiology and immunomodulatory therapies.
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http://dx.doi.org/10.1136/rmdopen-2020-001549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880117PMC
February 2021

EULAR points to consider on pathophysiology and use of immunomodulatory therapies in COVID-19.

Ann Rheum Dis 2021 Feb 5. Epub 2021 Feb 5.

Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, INSERM UMR1184, Department of Rheumatology, Université Paris-Saclay, Le Kremlin Bicêtre, France

Objectives: Severe systemic inflammation associated with some stages of COVID-19 and in fatal cases led therapeutic agents developed or used frequently in Rheumatology being at the vanguard of experimental therapeutics strategies. The aim of this project was to elaborate EULAR Points to consider (PtCs) on COVID-19 pathophysiology and immunomodulatory therapies.

Methods: PtCs were developed in accordance with EULAR standard operating procedures for endorsed recommendations, led by an international multidisciplinary Task Force, including rheumatologists, translational immunologists, haematologists, paediatricians, patients and health professionals, based on a systemic literature review up to 15 December 2020. Overarching principles (OPs) and PtCs were formulated and consolidated by formal voting.

Results: Two OPs and fourteen PtCs were developed. OPs highlight the heterogeneous clinical spectrum of SARS-CoV-2 infection and the need of a multifaceted approach to target the different pathophysiological mechanisms. PtCs 1-6 encompass the pathophysiology of SARS-CoV-2 including immune response, endothelial dysfunction and biomarkers. PtCs 7-14 focus on the management of SARS-CoV-2 infection with immunomodulators. There was evidence supporting the use of glucocorticoids, especially dexamethasone, in COVID-19 cases requiring oxygen therapy. No other immunomodulator demonstrated efficacy on mortality to date, with however inconsistent results for tocilizumab. Immunomodulatory therapy was not associated with higher infection rates.

Conclusions: Multifactorial pathophysiological mechanisms, including immune abnormalities, play a key role in COVID-19. The efficacy of glucocorticoids in cases requiring oxygen therapy suggests that immunomodulatory treatment might be effective in COVID-19 subsets. Involvement of rheumatologists, as systemic inflammatory diseases experts, should continue in ongoing clinical trials delineating optimal immunomodulatory therapy utilisation in COVID-19.
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http://dx.doi.org/10.1136/annrheumdis-2020-219724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871226PMC
February 2021

Synovial biopsies in clinical practice and research: current developments and perspectives.

Clin Rheumatol 2020 Dec 4. Epub 2020 Dec 4.

Institute of Infection, Immunity and Inflammation, College of Medical Veterinary and Life Sciences, University of Glasgow and Rheumatology Department Greater Glasgow and Clyde, Glasgow, UK.

Synovial biopsy techniques have developed and widely expanded over the past few years, in particular due to the development of ultrasound-guided procedures. This article reviews the different techniques, clinical applications, and the latest advances in translational research as well as current challenges and perspectives. The first part focuses on different techniques available for biopsy, along with their feasibility, success rate, tolerance, and training requirements. In the second part, clinical applications are described. Data on diagnostic performances are reported, especially regarding septic arthritis. Translational research applications are described and explained in the final part, from the early histological studies and the first description of pathotype to more recent technologies involving -omics. Latest developments involving single-cell RNA sequence analysis have allowed the discovery of new cell subpopulations with remarkable roles in RA pathophysiology. These studies pave the ground for the discovery of new therapeutic targets and the implementation of personalized therapy in RA. Key Point •This review provides an overview of synovial biopsy techinques and applications especially in clinical and translational research.
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http://dx.doi.org/10.1007/s10067-020-05512-7DOI Listing
December 2020

Multidisciplinary collaboration among young specialists: results of an international survey by the emerging EULAR network and other young organisations.

RMD Open 2020 09;6(2)

Rheumatology, Zuyderland Medical Centre Heerlen, Heerlen, Netherlands.

Background: Multidisciplinary collaboration is defined as a collective work involving multiple disciplines and is common in clinical care and research. Our aim was to describe current clinical and research collaboration among young specialists and to identify unmet needs in this area.

Methods: An online survey was disseminated by email and social media to members of the EMerging EUlar NETwork, the Young Nephrologists' Platform, the Paediatric Rheumatology European Society Emerging Rheumatologists and Researchers and the European Academy of Allergy and Clinical Immunology Junior Members.

Results: Of 303 respondents from 36 countries, 61% were female, 21% were aged below 30 years and 67% were aged 31-40 years. Young rheumatologists were the most represented (39%), followed by young nephrologists (24%), young paediatricians (20%), young allergologists (11%) then young internists (3%) and 3% other specialities. Collaborations were reported frequently by phone and email, also by various combined clinics while common local multidisciplinary meetings were uncommon. 96% would like to develop clinical research collaborations and 69% basic research collaborations. The majority of young specialists would be interested in online (84%) and/or 1-2 days (85%) common courses including case discussion (81%) and training workshops (85%), as well as webinars recorded with several specialists on a specific disease (96%).

Conclusions: This collaborative initiative highlighted wishes from young specialists for developing (1) regular local multidisciplinary meetings to discuss complex patients, (2) clinical research collaboration with combined grants and (3) multidisciplinary online projects such as common courses, webinars and apps.
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http://dx.doi.org/10.1136/rmdopen-2020-001398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525255PMC
September 2020

Assessment of competences in rheumatology training: results of a systematic literature review to inform EULAR points to consider.

RMD Open 2020 09;6(2)

Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands.

Objective: To summarise the literature on the assessment of competences in postgraduate medical training.

Methods: A systematic literature review was performed within a EULAR taskforce on the assessment of competences in rheumatology training and other related specialities (July 2019). Two searches were performed: one search for rheumatology and one for related medical specialities. Two reviewers independently identified eligible studies and extracted data on assessment methods. Risk of bias was assessed using the medical education research study quality instrument.

Results: Of 7335 articles in rheumatology and 2324 reviews in other specialities, 5 and 31 original studies were included, respectively. Studies in rheumatology were at variable risk of bias and explored only direct observation of practical skills (DOPS) and objective structured clinical examinations (OSCEs). OSCEs, including clinical, laboratory and imaging stations, performed best, with a good to very good internal consistency (Cronbach's α=0.83-0.92), and intrarater reliability (r=0.80-0.95). OSCEs moderately correlated with other assessment tools: r=0.48 vs rating by programme directors; r=0.2-0.44 vs multiple-choice questionnaires; r=0.48 vs DOPS. In other specialities, OSCEs on clinical skills had a good to very good inter-rater reliability and OSCEs on communication skills demonstrated a good to very good internal consistency. Multisource feedback and the mini-clinical evaluation exercise showed good feasibility and internal consistency (reliability), but other data on validity and reliability were conflicting.

Conclusion: Despite consistent data on competence assessment in other specialities, evidence in rheumatology is scarce and conflicting. Overall, OSCEs seem an appropriate tool to assess the competence of clinical skills and correlate well with other assessment strategies. DOPS, multisource feedback and the mini-clinical evaluation exercise are feasible alternatives.
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http://dx.doi.org/10.1136/rmdopen-2020-001330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508213PMC
September 2020

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

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

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

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

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

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

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

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

Strategies for the assessment of competences during rheumatology training across Europe: results of a qualitative study.

RMD Open 2020 07;6(2)

EULAR, Zurich, Switzerland.

Objectives: To gain insight into current methods and practices for the assessment of competences during rheumatology training, and to explore the underlying priorities and rationales for competence assessment.

Methods: We used a qualitative approach through online focus groups (FGs) of rheumatology trainers and trainees, separately. The study included five countries-Denmark, the Netherlands, Slovenia, Spain and the United Kingdom. A summary of current practices of assessment of competences was developed, modified and validated by the FGs based on an independent response to a questionnaire. A prioritising method (9 Diamond technique) was then used to identify and justify key assessment priorities.

Results: Overall, 26 participants (12 trainers, 14 trainees) participated in nine online FGs (2 per country, Slovenia 1 joint), totalling 12 hours of online discussion. Strong nationally (the Netherlands, UK) or institutionally (Spain, Slovenia, Denmark) standardised approaches were described. Most groups identified providing frequent formative feedback to trainees for developmental purposes as the highest priority. Most discussions identified a need for improvement, particularly in developing streamlined approaches to portfolios that remain close to clinical practice, protecting time for quality observation and feedback, and adopting systematic approaches to incorporating teamwork and professionalism into assessment systems.

Conclusion: This paper presents a clearer picture of the current practice on the assessment of competences in rheumatology in five European countries and the underlying rationale of trainers' and trainees' priorities. This work will inform EULAR Points-to-Consider for the assessment of competences in rheumatology training across Europe.
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http://dx.doi.org/10.1136/rmdopen-2020-001183DOI Listing
July 2020

Needs, Experiences, and Views of People With Rheumatic and Musculoskeletal Diseases on Self-Management Mobile Health Apps: Mixed Methods Study.

JMIR Mhealth Uhealth 2020 04 20;8(4):e14351. Epub 2020 Apr 20.

Centre for Rheumatic Diseases, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom.

Background: Despite the growing interest and exponential popularity of mobile health (mHealth) apps for long-term conditions such as rheumatic and musculoskeletal diseases (RMDs) and their self-management, patients are rarely directly consulted and involved in the app development process.

Objective: This study aims to explore the needs, experiences, and views of people diagnosed with RMDs on mHealth apps.

Methods: The study used a mixed methods approach: (1) an initial qualitative phase via a patient focus group in the UK and (2) a survey disseminated through national organizations for patients with RMDs across European countries, the United States, Canada, and Australia.

Results: The focus group included six patients with life-long musculoskeletal conditions. Half had used a self-management app at least once. The use of existing apps was reported as time-consuming due to a lack of functionality. The need for bespoke apps was voiced by all participants. Among 424 patients across European countries, the United States, Canada, and Australia, the main age group was 45 to 54 years (122/424, 28.7%), and 86.8% (368/424) were women. Half of the respondents were aware of the existence of apps to support self-management of their RMDs (188/355, 53%), with 42% (79/188) of them currently using such devices. Patients were mostly interested in an app to self-monitor their health parameters (259/346, 74.9%) and disease activity (221/346, 63.9%) or communicate directly with their health care provider (200/346, 57.8%).

Conclusions: Patients considered that using an app could help them to self-manage their RMD condition if it was tailored to their needs and co-developed with health professionals. The development of such apps will require standardization and regular quality control.
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http://dx.doi.org/10.2196/14351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199138PMC
April 2020

Mobile Health Apps for Self-Management of Rheumatic and Musculoskeletal Diseases: Systematic Literature Review.

JMIR Mhealth Uhealth 2019 11 26;7(11):e14730. Epub 2019 Nov 26.

Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences & Medicine, King's College London, Paris, France.

Background: Although the increasing availability of mobile health (mHealth) apps may enable people with rheumatic and musculoskeletal diseases (RMDs) to better self-manage their health, there is a general lack of evidence on ways to ensure appropriate development and evaluation of apps.

Objective: This study aimed to obtain an overview on existing mHealth apps for self-management in patients with RMDs, focusing on content and development methods.

Methods: A search was performed up to December 2017 across 5 databases. For each publication relevant to an app for RMDs, information on the disease, purpose, content, and development strategies was extracted and qualitatively assessed.

Results: Of 562 abstracts, 32 were included in the analysis. Of these 32 abstracts, 11 (34%) referred to an app linked to a connected device. Most of the apps targeted rheumatoid arthritis (11/32, 34%). The top three aspects addressed by the apps were pain (23/32, 71%), fatigue (15/32, 47%), and physical activity (15/32, 47%). The development process of the apps was described in 84% (27/32) of the articles and was of low to moderate quality in most of the cases. Despite most of the articles having been published within the past two years, only 5 apps were still commercially available at the time of our search. Moreover, only very few studies showed improvement of RMD outcome measures.

Conclusions: The development process of most apps was of low or moderate quality in many studies. Owing to the increasing RMD patients' willingness to use mHealth apps for self-management, optimal standards and quality assurance of new apps are mandatory.
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http://dx.doi.org/10.2196/14730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904900PMC
November 2019

EULAR points to consider for the development, evaluation and implementation of mobile health applications aiding self-management in people living with rheumatic and musculoskeletal diseases.

RMD Open 2019 13;5(2):e001014. Epub 2019 Sep 13.

Rheumatology Department, AP-HP, Hopital Saint-Antoine, Paris, France.

Background: Mobile health applications (apps) are available to enable people with rheumatic and musculoskeletal diseases (RMDs) to better self-manage their health. However, guidance on the development and evaluation of such apps is lacking.

Objectives: The objective of this EULAR task force was to establish points to consider (PtC) for the development, evaluation and implementation of apps for self-management of RMDs.

Methods: A systematic literature review of app content and development strategies was conducted, followed by patient focus group and an online survey. Based on this information and along with task force expert opinion, PtC were formulated in a face-to-face meeting by a multidisciplinary task force panel of experts, including two patient research partners. The level of agreement among the panel in regard to each PtC was established by anonymous online voting.

Results: Three overarching principles and 10 PtC were formulated. Three PtC are related to patient safety, considered as a critical issue by the panel. Three are related to relevance of the content and functionalities. The requirement for transparency around app development and funding sources, along with involvement of relevant health professionals, were also raised. Ease of app access across ages and abilities was highlighted, in addition to considering the cost benefit of apps from the outset. The level of agreement was from 8.8 to 9.9 out of 10.

Conclusion: These EULAR PtC provide guidance on important aspects that should be considered for the development, evaluation and implementation of existing and new apps.
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http://dx.doi.org/10.1136/rmdopen-2019-001014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744072PMC
April 2020

General synovitis score and immunologic synovitis score reflect clinical disease activity in patients with advanced stage rheumatoid arthritis.

Sci Rep 2019 06 11;9(1):8448. Epub 2019 Jun 11.

Department of Orthopaedics, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.

The purpose of this study was to investigate the relationship between clinical disease activity in patients with advanced stage rheumatoid arthritis (RA) on treatment with Disease Modifying Antirheumatic Drugs (DMARDs) and histopathological scores of synovial inflammation. To this end, synovial biopsies of 62 RA patients who underwent surgery for either synovectomy or total joint arthroplasty were assessed by a general synovitis score (GSS) and an immunologic synovitis score (IMSYC). The clinical disease activity index (CDAI) was significantly correlated with both the GSS and the IMSYC (r = 0.65, p = <0.001, r = 0.68, p = <0.001). Compared to patients with moderate and high disease activity, there was a significantly lower expression of T cell (CD3), B cell (CD20) and neutrophil (CD15) markers in synovial tissue of patients with low activity, but similar expression of the macrophage marker CD68. Subgroup analyses revealed no differences between small and large joints, seropositive and seronegative RA and patients with or without prednisolone treatment. However, we found a significantly stronger correlation of CDAI with IMSYC in patients undergoing arthroplasty (r = 0.82) than in patients undergoing synovectomy (r = 0.55). In addition, there was a stronger correlation of CDAI with GSS in patients treated with methotrexate (r = 0.86) than in patients with TNFα blockade (r = 0.55). In summary, the present study demonstrates that the histopathological scores GSS and IMSYC in general reflect clinical disease activity in patients with advanced stage rheumatoid arthritis, but that there is some heterogeneity between subgroups of patients within the cohort. In the future, molecular characterization of synovial inflammatory cell populations, including plasma cell infiltrates, will help to further defined clinically important subtypes of RA and treatment response.
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http://dx.doi.org/10.1038/s41598-019-44895-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560084PMC
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

The 2018 OMERACT Synovial Tissue Biopsy Special Interest Group Report on Standardization of Synovial Biopsy Analysis.

J Rheumatol 2019 10 15;46(10):1365-1368. Epub 2019 Jan 15.

From the Rheumatology Unit, Flinders Medical Centre, Bedford Park and College of Medicine and Public Health, Flinders University, Adelaide, Australia; Rheumatology Department, Centre Hospitalier Universitaire (CHU) de Nantes, and INSERM UMR 1238, Faculty of Biology of Nantes, Nantes, France; The Centre for Arthritis and Rheumatic Diseases, St. Vincent's University Hospital and Dublin Academic Medical Centre, University College Dublin, Elm Park, Dublin, Ireland; Division of Immunology and Rheumatology, Stanford University, Palo Alto, California, USA.

Objective: The Outcome Measures in Rheumatology (OMERACT) synovial tissue biopsy (STB) working group initiated an international effort to standardize STB analyses, define consensual items to inform treatment choices, and predict responses in rheumatoid arthritis (RA).

Methods: (1) A Delphi survey to determine items for STB analyses. (2) A multicenter retrospective study of STB data in patients with RA posttreatment with biological disease-modifying antirheumatic drugs.

Results: The Delphi survey identified 18 STB analyses items. Consensus on histological markers was achieved in the OMERACT 2018 SIG.

Conclusion: Six markers were identified for examination in a multicenter study designed to define an OMERACT-endorsed set of STB markers to predict responses to treatment.
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http://dx.doi.org/10.3899/jrheum.181062DOI Listing
October 2019

Correction to: Standardisation of synovial biopsy analyses in rheumatic diseases: a consensus of the EULAR Synovitis and OMERACT Synovial Tissue Biopsy Groups.

Arthritis Res Ther 2018 12 19;20(1):282. Epub 2018 Dec 19.

The Centre for Arthritis and Rheumatic Diseases, Saint Vincent's University Hospital and Dublin Academic Medical Centre, University College Dublin, Elm Park, Dublin, Ireland.

Following publication of the original article [1], the authors reported an error in the spelling of the ninth author's name.
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http://dx.doi.org/10.1186/s13075-018-1795-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300904PMC
December 2018

Standardisation of synovial biopsy analyses in rheumatic diseases: a consensus of the EULAR Synovitis and OMERACT Synovial Tissue Biopsy Groups.

Arthritis Res Ther 2018 12 3;20(1):265. Epub 2018 Dec 3.

The Centre for Arthritis and Rheumatic Diseases, Saint Vincent's University Hospital and Dublin Academic Medical Centre, University College Dublin, Elm Park, Dublin, Ireland.

Background: The aim of this global collaboration was to develop a consensual set of items for the analysis of synovial biopsies in clinical practice and translational research through the EULAR Synovitis Study Group (ESSG) and OMERACT Synovial Tissue Biopsy Group.

Methods: Participants were consulted through a modified Delphi method. Three sequential rounds occurred over 12 months. Members were sent a written questionnaire containing items divided into two parts. Items were identified and formulated based on a scoping review. The first part of the questionnaire referred to synovial biopsies in clinical practice including five subsections, and the second part to translational research with six subsections. Every participant was asked to score each item on a 5-point Likert scale. Items with a median score above 3.5 and a ≥ 70% agreement were selected for the next round. The last round was conducted orally at EULAR in June 2017.

Results: Twenty-seven participants from 19 centers were contacted by email. Twenty participants from 17 centers answered. Response rates for next rounds were 100%. For the first part relating to clinical practice, 20/44 items (45.5%) were selected. For the second part relating to translational research, 18/43 items (41.9%) were selected for the final set.

Conclusions: We herein propose a consensual set of analysis items to be used for synovial biopsies conducted in clinical practice and translational research.
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http://dx.doi.org/10.1186/s13075-018-1762-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6276172PMC
December 2018

The Utility and Limitations of CRP, ESR and DAS28-CRP in Appraising Disease Activity in Rheumatoid Arthritis.

Front Med (Lausanne) 2018 3;5:185. Epub 2018 Aug 3.

Dublin Academic Medical Centre, Centre for Arthritis and Rheumatic Diseases, University College Dublin, Dublin, Ireland.

Identifying and quantifying inflammatory disease activity in rheumatoid arthritis remains a challenge. Many studies have suggested that a large proportion of patients may have active inflammation, but normal inflammatory markers. Although various disease activity scores have been validated, most rely to a large degree on biomarkers such as CRP and ESR. In this study, we examine the utility and limitations of these biomarkers, as well as the DAS28-CRP in appraising disease activity in RA. Two hundred and twenty three consecutive rheumatoid arthritis reporting knee arthralgia underwent synovial sampling of the affected knee via needle arthroscopy. The synovium was examined by microscopy with H+E staining as well as immunohistochemistry, and related to the ESR, CRP and DAS28-CRP on blood samples taken immediately before arthroscopy. Although a statistically significant positive correlation was observed between CRP and the level of inflammation in the biopsy retrieved ( = 197, rho = 0.43, CI 0.30-0.54, < 0.0001), there was histological evidence of inflammation in the synovium in 49.4% of the patients who had a normal CRP. A positive correlation was also observed between ESR and the level of inflammation in the biopsy retrieved ( = 188, rho = 0.29, CI 0.15-0.42 < 0.0001). A statistically significant but weak positive correlation was observed between the DAS28-CRP and synovial inflammation ( = 189, rho = 0.23, CI 0.09-0.37, = 0.0011). Only the CD19 infiltrate in the synovium correlated with serum CRP ( = 70, rho = 0.32, CI 0.08-0.52, = 0.0068). CRP has a moderately strong relationship with disease activity, but there are significant pitfalls in the use of this biomarker in RA, and therefore a need interpret CRP results judiciously. The results of this study underline the heterogeneity of RA, and the need to develop improved panels of biomarkers, to better stratify RA, and to identify the cohort for whom inflammatory activity cannot be measured accurately with CRP.
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http://dx.doi.org/10.3389/fmed.2018.00185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6085449PMC
August 2018

IMSYC immunologic synovitis score: A new score for synovial membrane characterization in inflammatory and non-inflammatory arthritis.

Joint Bone Spine 2019 01 27;86(1):77-81. Epub 2018 Apr 27.

MVZ-Zentrum für Histologie, Zytologie und Molekulare Diagnostik, 54296 Trier, Germany.

Objectives: Krenn synovitis Score has been developed by Krenn et al. in order to assess synovitis severity and is used in synovial research. Cell signature of synovial tissue can be studied using immunohistochemistry and is of interest as a biomarker for both prognosis and prediction of response to treatment. However, no synovitis score including immunohistochemistry exists yet. In order to answer this unmet need, we propose a new Immunologic Synovitis score (IMSYC) adding 5 components to the Krenn score: CD68, CD3, CD20, CD31 and Ki67 immunostaining. In this study, we aimed to validate this new IMSYC by studying its diagnostic performances in a well-defined collection of synovial samples.

Methods: Synovial samples from patients were obtained during surgical procedures. CD68, CD3, CD20, CD31 and KI67 immunohistochemistry were performed.

Results: In total, 77 patients were included. In total, 45 were females, mean age was 63.1 years. Forty had inflammatory arthritis, mainly rheumatoid arthritis (31/40). Non inflammatory arthritis group included 35 patients with mainly osteoarthritis. Mean Krenn score and IMSYC were significantly higher in the inflammatory group (P<0.001). ROC analysis of diagnostic performances determined the score of 13.5 out of 24 as the cut-off that gave the best ratio for discrimination between inflammatory and non-inflammatory arthritis with a sensitivity of 71.8% and specificity of 98%.

Conclusion: We propose a new synovitis score including immunohistochemistry. This score has a better sensitivity and specificity than the Krenn score and represents a more functional synovitis evaluation. IMSYC could be further used in better categorizing synovial tissue phenotype and give a basis for tissue driven therapy.
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http://dx.doi.org/10.1016/j.jbspin.2018.04.004DOI Listing
January 2019

Knee joint synovitis: study of correlations and diagnostic performances of ultrasonography compared with histopathology.

RMD Open 2018 8;4(1):e000616. Epub 2018 Feb 8.

The Centre for Arthritis and Rheumatic Diseases, Saint Vincent's University Hospital and Dublin Academic Medical Centre, University College Dublin, Dublin, Ireland.

Objectives: Ultrasonography (US) is a fast, available and low-cost imaging tool used for detecting knee synovitis. Our aims were to assess the relationship between US and histology findings in appraising levels of inflammation and vascularity in the knee joint in subjects with inflammatory arthropathies; to determine whether differences exist in the appraisal between varying knee compartments and to compare US performances compared with gold standard histology for knee synovitis detection.

Methods: Subjects with actively inflamed knee joint having crystal arthropathies, rheumatoid arthritis, psoriatic arthritis or ostoearthritis were prospectively recruited from rheumatology clinics after giving their written consent between May and October 2015. Study was approved by the institutional ethics committee. The knee was divided into three compartments (medial, lateral, superior). Patients had a knee US followed by a knee arthroscopy with biopsies retrieval from each compartment. Biopsies were blindly scored for lining layer hyperplasia, inflammation, vascularity, CD68 and factor VIII staining. Correlation was determined using the Spearman's correlation test.

Results: 26 patients with active arthritis in a knee joint and recent onset of disease were prospectively included. Strong correlations were observed between US synovitis grade and histological inflammation score (r=0.63; P=0.002), US Doppler grade and histological score for vascularity (r=0.68; P<0.001); US measured synovial thickness and lining layer hyperplasia (r=0.61; P=0.002). Moderate correlation was found between US synovitis grade and CD68 score (r=0.49; P=0.02).

Conclusion: US findings correlate with histological inflammation and vascularity scores in actively inflamed knee joints. US accurately describes knee synovitis.
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http://dx.doi.org/10.1136/rmdopen-2017-000616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5845411PMC
February 2018

Synovial Immunophenotype and Anti-Citrullinated Peptide Antibodies in Rheumatoid Arthritis Patients: Relationship to Treatment Response and Radiologic Prognosis.

Arthritis Rheumatol 2017 11;69(11):2114-2123

University College Dublin, Dublin, Ireland.

Objective: Serum anti-citrullinated peptide antibodies (ACPAs) may be present before the development of rheumatoid arthritis (RA) and may be predictive of more severe, erosive disease. This study was undertaken to examine the synovial tissue immunophenotype according to ACPA status in patients with RA, as well as the response to treatment and erosion status.

Methods: Consecutive RA patients were prospectively recruited and underwent clinical and serologic assessments before and after treatment. Radiologic assessment was performed at the time of clinical follow-up. Synovial tissue was immunostained for specific markers of B cells (CD19), T cells (CD3, CD4, and CD8), macrophages (CD68), and blood vessels (factor VIII). Serum CXCL13 levels were quantified by enzyme-linked immunosorbent assay. Synovial tissue sections were analyzed for immunophenotype according to ACPA status, using a validated semiquantitative scoring method, and also analyzed for the presence of lymphoid aggregates. Response to treatment with nonbiologic or biologic disease-modifying antirheumatic drugs was assessed using the European League Against Rheumatism (EULAR) response criteria.

Results: In total, 123 subjects (78 ACPA+) were included. Compared to ACPA- RA patients, synovium from ACPA+ RA patients was characterized by significantly higher levels of CD19+ B cells and CD3+ and CD8+ T cells (each P < 0.05), and CD19+ B cell levels were significantly higher in patients who were naive to treatment. The CD19+ B cell infiltrate level was higher in patients with erosions at follow-up (P = 0.0128). Levels of lymphoid aggregates of CD19+ B cells were significantly higher in ACPA+ patients (P < 0.05), and this was associated with increased serum CXCL13 levels. The EULAR response was significantly associated with the level of CD3+ T cell infiltrates (P < 0.05), while CD68+ macrophage and CD8+ T cell levels were predictive of the response to tumor necrosis factor inhibitors (P < 0.05).

Conclusion: The results of this prospective study demonstrate that the levels of synovial B cell infiltrates and lymphoid aggregates were significantly higher in ACPA+ RA patients, especially those who were naive to treatment. In addition, ACPA+ subjects developed more erosions during progression of the disease and had higher serum levels of CXCL13. The EULAR response to therapy in ACPA+ RA patients was associated with increased levels of T cell and macrophage markers.
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http://dx.doi.org/10.1002/art.40218DOI Listing
November 2017

Synovial tissue research: a state-of-the-art review.

Nat Rev Rheumatol 2017 08 13;13(8):463-475. Epub 2017 Jul 13.

Department of Clinical Immunology &Rheumatology, Amsterdam Rheumatology and Immunology Centre, Academic Medical Centre, University of Amsterdam, Room F4-105, POBox 22700, 1100 DE, Amsterdam, Netherlands.

The synovium is the major target tissue of inflammatory arthritides such as rheumatoid arthritis. The study of synovial tissue has advanced considerably throughout the past few decades from arthroplasty and blind needle biopsy to the use of arthroscopic and ultrasonographic technologies that enable easier visualization and improve the reliability of synovial biopsies. Rapid progress has been made in using synovial tissue to study disease pathogenesis, to stratify patients, to discover biomarkers and novel targets, and to validate therapies, and this progress has been facilitated by increasingly diverse and sophisticated analytical and technological approaches. In this Review, we describe these approaches, and summarize how their use in synovial tissue research has improved our understanding of rheumatoid arthritis and identified candidate biomarkers that could be used in disease diagnosis and stratification, as well as in predicting disease course and treatment response.
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http://dx.doi.org/10.1038/nrrheum.2017.115DOI Listing
August 2017

IL-38 overexpression induces anti-inflammatory effects in mice arthritis models and in human macrophages in vitro.

Ann Rheum Dis 2017 Jul 13;76(7):1304-1312. Epub 2017 Mar 13.

INSERM, UMR 957, Equipe Labellisée LIGUE 2012, Nantes, France.

Objectives: Interleukin (IL)-38 is a newly characterised cytokine that belongs to the IL-1 family. This cytokine is expressed in the rheumatoid arthritis (RA) synovial tissue and IL-38 deficient mice have exacerbated arthritis. Here, we analysed the effect of IL-38 overexpression in the joints of arthritic mice, in human macrophages and synovial fibroblasts in vitro.

Methods: Articular injections of an adeno-associated virus (AAV) 2/8 encoding IL-38 were performed in collagen-induced arthritis (CIA), K/BxN serum transfer-induced arthritis (STIA) and antigen-induced arthritis (AIA) in mice. The effect of IL-38 overexpression was evaluated through clinical scores, immunohistochemistry, microCT, Luminex and RT-qPCR analysis. THP-1 macrophages were transduced with a lentiviral vector to overexpress IL-38.

Results: Clinical inflammatory scores were significantly decreased after AAV IL-38 injection in joints of mice with CIA and STIA, but not AIA. This decrease was accompanied by reduced macrophage infiltration and a decreased expression of Th17 cytokines (IL-17, IL-23, IL-22) and TNFα. However, IL-38 overexpression had no effect on cartilage or bone destruction. In vitro, the THP-1 monocytic cell line expressed less IL-6, TNFα and IL-23 after IL-38 overexpression. Conditioned media from these cells, containing released IL-38, also exert an anti-inflammatory effect on human primary macrophages and synovial fibroblasts from patients with RA.

Conclusions: This study shows for the first time that IL-38 overexpression attenuates the severity of experimental arthritis. IL-38 may exert its anti-inflammatory effects by decreasing the production of proinflammatory cytokines by macrophages and synovial fibroblasts. This effect can lead to the development of novel treatment strategies in arthritis.
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http://dx.doi.org/10.1136/annrheumdis-2016-210630DOI Listing
July 2017

Cystic angiomatosis, a heterogeneous condition: Four new cases and a literature review.

Medicine (Baltimore) 2016 Oct;95(43):e5213

Rheumatology Department, Pôle Hospitalo-Universitaire 4, Hôpital Hôtel-Dieu, Centre Hospitalo-Universitaire de Nantes, Nantes Cedex 1, France.

Background: Cystic angiomatosis (CA) is a rare disorder causing bony cysts. It displays some similarity to Gorham-Stout disease (GSD), but has a much better local prognosis, despite the larger number of cysts. These 2 conditions also differ in terms of their location, visceral involvement, and response to treatment.

Methods: We report 4 cases of CA, including 1 sclerosing form, which we compare with cases from a literature review performed with PRISMA methodology.

Results: We reviewed 38 articles describing 44 other patients. Mean age at diagnosis for the 48 patients (our 4 patients + the 44 from the review) was 22.5 years, and 28 of the patients were men. The femur was involved in 81% (n = 39), the pelvis in 73% (n = 35), the humerus in 52% (n = 25), the skull in 48% (n = 23), and the vertebrae in 44% (n = 21). Visceral lymphangiomatosis (either clinical, or detected on autopsy) was also reported in 35% (n = 18) of the patients. The spleen was the most frequently involved organ (n = 12), followed by the lungs and pleura (n = 8). Liver cysts and/or chylothorax were rarely reported (5 cases), but were invariably fatal. Radiation therapy on bone or soft tissue masses was ineffective, as was interferon alpha, in the 2 patients in which this drug was tested. The efficacy of bisphosphonate was at best equivocal.

Conclusion: The progression of CA is unpredictable and treatments effective against GSD, such as bisphosphonates and radiotherapy, have proved ineffective for this condition. New treatments are thus urgently required.
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http://dx.doi.org/10.1097/MD.0000000000005213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5089110PMC
October 2016

Success Rate and Utility of Ultrasound-guided Synovial Biopsies in Clinical Practice.

J Rheumatol 2016 12 15;43(12):2113-2119. Epub 2016 Oct 15.

From the Department of Rheumatology, and Department of Pathology, Hôtel-Dieu Hospital, Nantes, France; University College Dublin Department of Rheumatology, St. Vincent's Hospital, Dublin, Ireland.

Objective: The utility of synovial biopsy in increasing our understanding of the pathogenesis of inflammatory arthropathies, as well as in evaluating treatments, is well established. Ultrasound (US) allows synovial assessment and therefore assists in biopsying synovial tissue in a safe and well-tolerated manner. This study's objectives were to (1) determine the rate of success in retrieving synovial tissue using US guidance, (2) describe the indications for US-guided synovial biopsies in the clinical setting, (3) determine how frequently the synovial biopsy can lead to a clear diagnosis, and (4) assess the quality of the synovial tissue obtained using this technique.

Methods: Synovial biopsies of small and large joints were performed under US guidance between February 2007 and December 2014 using a semiautomatic core biopsy needle. The biopsy procedure was considered successful if synovial tissue was found at histological examination.

Results: Seventy-four patients with undifferentiated arthritis underwent 76 synovial biopsies. The success rate in retrieving synovial tissue was 81.6% (62/76). One patient taking acetyl salicylic acid at 75 mg at the time of the biopsy presented with hemarthrosis 48 h after the procedure, which resolved following simple arthrocentesis. A definitive diagnosis was achieved in 16% of the patients where synovial tissue was sampled successfully.

Conclusion: US-guided synovial biopsies in clinical practice can be performed safely on patients with undifferentiated arthritis and with heterogeneous presentations. The rate of success in acquiring synovial tissue is high. The procedure usually retrieves quality tissue and leads to a definite diagnosis in a significant minority of patients.
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http://dx.doi.org/10.3899/jrheum.151441DOI Listing
December 2016