Gene expression profiling in the synovium identifies a predictive signature of absence of response to adalimumab therapy in rheumatoid arthritis

To identify markers and mechanisms of resistance to adalimumab therapy, we studied global gene expression profiles in synovial tissue specimens obtained from severe rheumatoid arthritis (RA) patients before and after initiation of treatment

Diagnostic précoce de la polyarthrite rhumatoïde

Rheumatoid arthritis is the most common chronic inflammatory rheumatic disorder, and is characterized by inflammation of the joint, which can lead to irreversible bone damage, joint deformity and disability, if not diagnosed timely or treated adequately. New classification criteria were developed in 2010 in order to identify patients at risk of developing persistent or erosive arthritis, and requiring early therapy. In order to detect early arthritis or bone erosions before their appearance on X-rays, ultrasound and magnetic resonance imaging are now routinely used by clinicians, and also seem to deliver prognostic information about the disease. Synovial biopsies are potentially interesting in case of early arthritis to identify markers of diagnosis, prognosis or therapeutic response. Genetic or environmental risk factors were described to play a role in the development or maintenance of the disease; they could also help to screen early RA. A rapid diagnosis is eventually based on the right information and a tight collaboration between the primary care physician and the rheumatology care specialist.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Etudes des mécanismes synoviaux impliqués dans la résistance aux agents bloquant le TNF-alpha dans la polyarthrite rhumatoïde

The identification of new markers of response to therapy is a major medical need in the care of patients with rheumatoid arthritis (RA). The introduction of TNF blocking agents in the therapy of RA patients resulted in a dramatic improvement in terms of disease course and functional outcomes. However, 30% of the patients do not respond to the drugs, and require alternative therapies. This results in disease progression in these very patients and unnecessary exposure to a costly, and potentially toxic, drug. There is therefore a need of markers predicting response to TNF blockade in RA. In order to understand the mechanisms of action of TNF blockade in the RA synovium, and identify potential markers of response to therapy, we performed high-density transcriptomic studies using synovial biopsies of 25 methotrexate-resistant RA patients, obtained before and 3 months after initiation of adalimumab therapy (an anti-TNFα blocking antibody). We found that genes involved in “cell proliferation” and “regulation of immune responses” pathways are significantly over-expressed at baseline in synovial biopsies of patients displaying a poor-response to TNF blockade compared to patients displaying a good- or a moderate-response to the drug. These results were confirmed by RT-PCR and immunostaining experiments. We next studied the regulation of the expression of a panel of those genes associated with poor-response to TNF blockade : genes involved in cell proliferation (Ki67, CDC2, GTSE1) and genes involved in the regulation of immune responses (IL-7Rα, IL-6, IDO). We found that they are induced in vitro in fibroblast-like synovial cells by the addition of TNF-α, IL-1β and additive or synergistic combinations of TNFα and IL-1β or TNFα and IL-17, thereby suggesting that these cytokines, or combinations of cytokines, play a role in the resistance to TNF blockade in RA. Next, we focused on one particular gene, encoding the IL-7Rα molecule. In our previous work, we described that over-expression of this gene is characteristic of the RA synovium. Here, we found that over-expression of the gene predicts poor-response to TNF blockade in RA. We found that RAFLS produce two isoforms of the IL-7Rα transcript : one full-length, and one soluble form (sIL-7R), which results from an alternative splicing of the gene. TNFα and IL-1β, alone or in combination, (or the combination of TNFα and IL-17) induce the expression of sIL-7R in RAFLS. We also demonstrated that sIL-7R plays an inhibitory role on the activation of synovial CD4 T cells. Finally, we detected sIL-7R in sera of controls and RA patients. Higher sIL-7R serum concentrations are found in RA patients, in particular in patients who will not respond to TNF blockade, thereby suggesting that serum levels of the protein could be a novel marker of response to TNF blockade in RA.Identifier des marqueurs prédictifs de la réponse au traitement est un besoin majeur dans la prise en charge de la polyarthrite rhumatoïde (PR). Les biothérapies, tels que les agents bloquant le TNFα, ont révolutionné l’évolution et le devenir fonctionnel des patients atteints de PR. Cependant, certains patients résistent aux agents bloquant le TNFα et nécessitent le passage vers une autre molécule laissant libre cours à la maladie de progresser au prix d’un traitement couteux et potentiellement toxique. C’est pourquoi des marqueurs prédictifs de réponse sont indispensables avant la mise en route de ces traitements. Dans le but d’identifier des marqueurs de réponse et de comprendre les mécanismes synoviaux impliqués dans la résistance aux agents bloquant le TNFα, nous avons réalisé, en utilisant des micropuces de haute densité, des analyses trancriptomiques sur du tissu synovial provenant de 25 patients atteints de PR, résistants aux traitements de fond, avant et après 3 mois de traitement par adalimumab, un agent bloquant le TNFα. Nous avons observé une signature de non réponse au traitement caractérisée par une surexpression de gènes impliqués essentiellement dans la prolifération cellulaire et la réponse immunitaire. Nous avons confirmé nos résultats, soit en réalisant des mesures d’expression synoviale de certains de ces gènes par RT-PCR en temps réel, soit en réalisant des quantifications de marquages immunohistochimiques des biopsies synoviales de l’ensemble des 25 patients. Ensuite, nous avons démontré in vitro par RT-PCR en temps réel, qu’un panel de gènes appartenant à la signature de non réponse au traitement, impliqué dans la prolifération cellulaire (Ki67, CDC2, GTSE1) ou la réponse immunitaire (IL-7Rα, IL-6, IDO), pouvait être induit par des cytokines inflammatoires (TNFα ou IL-1β) ou par des combinaisons de ces cytokines (TNFα et d’ IL-1β, ou de TNFα et d’IL-17) dans le RAFLS (Rheumatoid Arthritis Fibroblast-like-synoviocyte) suggérant que ces cytokines (ou leur combinaison) participent aux mécanismes de résistance aux agents bloquant le TNFα. Puis, nous nous sommes intéressés à un des ces gènes en particulier, l’IL-7Rα, d’une part car des travaux antérieurs de notre laboratoire avaient déjà démontré qu’il appartenait à la signature de la PR et d’autre part puisque nous l’avons identifié comme un gène de non réponse au traitement par adalimumab. Nous avons découvert que in vitro les RAFLS sont capables de produire deux formes d’IL-7R, une forme membranaire et une forme soluble (IL-7Rs) qui est le résultat d’un épissage alternatif du gène. Le TNFα et l’IL-1β, seul ou en combinaison (ou la combinaison de TNα et d’IL-17) augmentent la production de l’IL-7Rs dans les RAFLS. Nous avons également montré que l’IL7Rs joue un rôle inhibiteur sur l’activation des lymphocytes T CD4 synoviaux. Enfin, nous avons détecté l’IL-7Rs dans le sérum de patients contrôles et atteints de PR. Des taux élevés d’IL-7Rs sériques sont observés dans la PR ainsi que chez les patients réfractaires aux agents bloquant le TNFα suggérant que l’IL-7Rs pourrait être un marqueur prédictif d’une non réponse aux agents bloquant le TNFα.(MED 3) -- UCL, 201

Spontaneous coronary artery dissection: favorable outcome illustrated by angiographic data.

Spontaneous coronary artery dissection is a rare cause of acute myocardial infarction. It typically occurs in young women receiving oral contraceptive therapy or during the peripartum period. In the case presented here, spontaneous complete healing at angiography and the favorable outcome may support the role of conservative treatment in such patients.Case ReportsJournal ArticleSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Place des nouveaux critères de classification des spondyloarthrites en pratique clinique

"Spondyloarthritis" consists of a group of several diseases sharing clinical, radiological and genetic similarities. Ankylosing spondylitis is the main representative of this group and is characterized by a predominant axial involvement. The presence of radiographic sacroiliitis is essential for the diagnosis of ankylosing spondylitis according to the modified New York criteria. Because the occurence of radiographic sacroiliitis takes 8 to 11 years, the diagnosis of spondyloarthritis is often delayed. Magnetic resonance imaging can depict sacroiliac joint inflammation before the appearance of radiographic damage thereby defining the concept of "non-radiographic axial spondylo-arthritis". This entity was defined by the axial spondyloarthritis classification criteria published by the Assessment of SpondyloArthritis international Society (ASAS). Some factors, such as elevated levels of C-reactive protein at baseline, have been identified as predictors of radiographic sacroiliitis progression, leading to a definite diagnosis of ankylosing spondylitis. These two entities show similar clinical expression (clinical features and activity levels), suggesting continuity between the two diseases. Non-radiographic forms most often affect women and patients with recent symptoms, and are therefore considered as a pre-radiographic status. If the use of magnetic resonance imaging is necessary for the identification of non-radiographic axial spondyloarthritis according to the ASAS criteria, the presumptive diagnosis is mainly based on complaints of inflammatory back pain. The presence of other typical clinical features, such as HLA B27 positivity and/or radiographic sacroiliitis increases the diagnostic probability and indicates the need for referral to a specialist.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

A case of left foot drop as initial symptom of granulomatosis with polyangiitis: Triggered by COVID‐19 disease?

Abstract In Granulomatosis with polyangiitis (GPA), involvement of the peripheral nervous system is frequent but its occurrence as an initial presentation is unusual. This case highlights the importance of this occurrence to permit an early diagnosis. Moreover, GPA started after a coronavirus disease 2019 infection and could have been induced by this

Determinants of osteoblastic function among hospitalized elderly: Evaluation of basal and stimulated serum osteocalcin

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Evaluation de la fonction ostéoblastique chez des patients âgés

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Démence réversible et polynévrite chez une femme âgée: un cas de lupus érythémateux disséminé de début tardif.

Reversible dementia and polyneuropathy in an elderly woman: a case of late onset systemic lupus erythematosus. We report the case of a 76-year-old woman with undiagnosed systemic lupus erythematosus. She presented with severe dementia. She was given prednisolone 20 mg daily with dramatic improvement occurring within one month. Electrophysiological study showed evidence of axonal neuropathy.Case ReportsEnglish AbstractJournal Articleinfo:eu-repo/semantics/publishe

sIL7R concentrations in the serum reflect disease activity in the lupus kidney.

Evaluation of disease activity in systemic lupus erythematosus (SLE) nephritis is a challenge, and repeated renal biopsies are usually needed in order to confirm a suspicion of flare. In a previous cross-sectional study, we reported that serum soluble form of the interleukin-7 receptor (sIL7R) levels is strongly associated with nephritis in SLE patients. In the present study, we wanted to confirm the association between changes in serum sIL7R concentrations and renal disease activity in a large longitudinal cohort of SLE nephritis patients