Association between the TNFRII 196R allele and diagnosis of rheumatoid arthritis

Tumour necrosis factor (TNF)-α plays a key role in the pathogenesis of rheumatoid arthritis (RA). It binds to two receptors, namely TNF receptor (TNFR)I and TNFRII. Several studies have suggested an association between TNFRII 196R/R genotype and RA. The objective of the present study was to evaluate the predictive value of the TNFRII 196R allele for RA diagnosis and prognosis in a cohort of patients with very early arthritis. We followed up a total of 278 patients recruited from the community, who had swelling of at least two joints that had persisted for longer than 4 weeks but had been evolving for less than 6 months, and who had not received disease-modifying antirheumatic drugs or steroid therapy. At 2 years, patients were classified according to the American College of Rheumatology criteria. All patients were genotyped with respect to TNFRII 196M/R polymorphism. Radiographs of hands and feet (read according to the modified Sharp method) and the Health Assessment Questionnaire were used to quantify structural and functional severity. The cohort of 278 patients was found to include 156 and 122 RA and non-RA patients, respectively. The TNFRII 196R allele was found to be associated with RA (P = 0.002). However, progression of radiographic severity and Health Assessment Questionnaire scores over 1 year did not differ between carriers of the 196R allele and noncarriers. Our findings suggest that the TNFRII 196R allele may be associated with RA diagnosis but that it does not predict early radiographic progression or functional severity in patients with very early, unclassified arthritis

Gene profiling in white blood cells predicts infliximab responsiveness in rheumatoid arthritis

As indicators of responsiveness to a tumour necrosis factor (TNF)α blocking agent (infliximab) are lacking in rheumatoid arthritis, we have used gene profiling in peripheral blood mononuclear cells to predict a good versus poor response to infliximab. Thirty three patients with very active disease (Disease Activity Score 28 >5.1) that resisted weekly methotrexate therapy were given infliximab at baseline, weeks 2 and 6, and every 8th week thereafter. The patients were categorized as responders if a change of Disease Activity Score 28 = 1.2 was obtained at 3 months. Mononuclear cell RNAs were collected at baseline and at three months from responders and non-responders. The baseline RNAs were hybridised to a microarray of 10,000 non-redundant human cDNAs. In 6 responders and 7 non-responders, 41 mRNAs identified by microarray analysis were expressed as a function of the response to treatment and an unsupervised hierarchical clustering perfectly separated these responders from non-responders. The informativeness of 20 of these 41 transcripts, as measured by qRT-PCR, was re-assessed in 20 other patients. The combined levels of these 20 transcripts properly classified 16 out of 20 patients in a leave-one-out procedure, with a sensitivity of 90% and a specificity of 70%, whereas a set of only 8 transcripts properly classified 18/20 patients. Trends for changes in various transcript levels at three months tightly correlated with treatment responsiveness and a down-regulation of specific transcript levels was observed in non-responders only. Our gene profiling obtained by a non-invasive procedure should now be used to predict the likely responders to an infliximab/methotrexate combination

Early and long-standing rheumatoid arthritis: distinct molecular signatures identified by gene-expression profiling in synovia

International audienc

Mutations in STAT3 and IL12RB1 impair the development of human IL-17–producing T cells

The cytokines controlling the development of human interleukin (IL) 17–producing T helper cells in vitro have been difficult to identify. We addressed the question of the development of human IL-17–producing T helper cells in vivo by quantifying the production and secretion of IL-17 by fresh T cells ex vivo, and by T cell blasts expanded in vitro from patients with particular genetic traits affecting transforming growth factor (TGF) β, IL-1, IL-6, or IL-23 responses. Activating mutations in TGFB1, TGFBR1, and TGFBR2 (Camurati-Engelmann disease and Marfan-like syndromes) and loss-of-function mutations in IRAK4 and MYD88 (Mendelian predisposition to pyogenic bacterial infections) had no detectable impact. In contrast, dominant-negative mutations in STAT3 (autosomal-dominant hyperimmunoglobulin E syndrome) and, to a lesser extent, null mutations in IL12B and IL12RB1 (Mendelian susceptibility to mycobacterial diseases) impaired the development of IL-17–producing T cells. These data suggest that IL-12Rβ1– and STAT-3–dependent signals play a key role in the differentiation and/or expansion of human IL-17–producing T cell populations in vivo

Mutations in STAT3 and IL12RB1 impair the development of human IL-17 producing T cells

L

Intérêt clinique et physiopathologique des autoanticorps dans la polyarthrite rhumatoïde

La polyarthrite rhumatoïde (PR), qui est le plus fréquent et le plus invalidant des rhumatismes inflammatoires chroniques, se caractérise essentiellement par une inflammation du tissu synovial des articulations à l'origine d'une destruction ostéocartilagineuse. Plusieurs arguments, dont certains sont développés ou suggérés dans ce travail, plaident pour un rôle majeur du répertoire lymphocytaire B et de ses effecteurs dans les mécanismes pathogéniques de la PR. Il s'agit entre autres de données histologiques (présence de follicules lymphoïdes avec centres clairs germinatifs dans le tissu synovial), sérologiques (identification d'un nombre croissant de populations d'auto anticorps [autoAc] reconnaissant des exo antigènes et des auto antigènes ubiquitaires ou spécifiques de l'articulation) et expérimentales (transfert de la maladie par des autoAc dirigés contre la glucose-6-phosphate isomérase dans le modèle murin KRN/NOD). A partir de 2 cohortes de malades, l'une constituée d'arthrites débutantes (<6 mois), non traitées, de recrutement communautaire et l'autre composée de PR semi-récentes (ancienneté médiane de 2 ans), de recrutement majoritairement libéral et suivies pendant 3 ans, nous avons étudié l'intérêt diagnostique et pronostique des différents autoAc associés à la PR. Trois autoAc, qui sont complémentaires, ont une valeur diagnostique pour la PR. Il s'agit des facteurs rhumatoïdes (FR), notamment de l'association des isotypes IgM et IgA, des Ac anti-filaggrine et des Ac anti-Sa. Toutefois, leur sensibilité cumulative est insiffisante pour diagnostiquer l'ensemble des PR récentes dont plus de 40% restent sans autoAc spécifique. A moindre degré, les Ac dirigés contre le fragment C-terminal de la calpastatine pourraient contribuer au diagnostic de PR dans certains cas. Seuls les FR de classe IgM sont capables de prédire, à l'échelon d'un groupe, le pronostic de la PR défini par l'importance de la destruction ostéocartilagineuse. Les autoAc actuellement disponibles étant insuffisants, nous avons tenté d'identifier de nouveaux marqueurs par une double approche. Le criblage d'une banque d'expression de cDNA a permis d'identifier le domaine I de la calpastatine comme un nouvel auto antigène. L'utilisation de l'électrophorèse bidimensionnelle a permis l'identification d'une des protéines cibles de l'autoAc anti-Sa. Il pourrait s'agir de l'alpha-énolase qui, comme la fillagrine, aurait subi des modifications post-traductionnelles. Ce dernier outil, qui permet une analyse fine de l'antigène, nous paraît également pertinent pour comprendre l'origine du processus auto-immun, ce d'autant que nos tentatives de production d'anticorps monoclonaux se sont avérées vaines en dehors de la production d'un FR de classe IgM ayant la particularité d'avoir une activité anti-MPO.ROUEN-BU Sciences (764512102) / SudocSudocFranceF

PREVALENCE ET SIGNIFICATION CLINIQUE DES ANTICORPS ANTI-CALPASTATINE AU COURS DU LUPUS ERYTHEMATEUX DISSEMINE (ETUDE RETROSPECTIVE DE 84 PATIENTS)

AMIENS-BU Santé (800212102) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF