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La experiencia que se presenta es un trabajo realizado conjuntamente por los estudiantes y los profesores de Filología francesa de la Universidad Autónoma de Barcelona. La preparación de un viaje cultural en la región de Toulouse tenía como objetivo suscitar en los estudiantes una reflexión sobre su percepción del medio. Galicia ESP

Objectives: The analysis of annotated transcripts from genome-wide expression studies may help to understand the pathogenesis of complex diseases, such as systemic sclerosis (SSc). We performed a whole blood (WB) transcriptome analysis on RNA collected in the context of the European PRECISESADS project, aiming at characterising the pathways that differentiate SSc from controls and that are reproducible in geographically diverse populations. Methods: Samples from 162 patients and 252 controls were collected in RNA stabilisers. Cases and controls were divided into a discovery (n=79+163; Southern Europe) and validation cohort (n=83+89; Central-Western Europe). RNA sequencing was performed by an Illumina assay. Functional annotations of Reactome pathways were performed with the Functional Analysis of Individual Microarray Expression (FAIME) algorithm. In parallel, immunophenotyping of 28 circulating cell populations was performed. We tested the presence of differentially expressed genes/pathways and the correlation between absolute cell counts and RNA transcripts/FAIME scores in regression models. Results significant in both populations were considered as replicated. Results: Overall, 15 224 genes and 1277 functional pathways were available; of these, 99 and 225 were significant in both sets. Among replicated pathways, we found a deregulation in type-I interferon, Toll-like receptor cascade, tumour suppressor p53 protein function, platelet degranulation and activation. RNA transcripts or FAIME scores were jointly correlated with cell subtypes with strong geographical differences; neutrophils were the major determinant of gene expression in SSc-WB samples. Conclusions: We discovered a set of differentially expressed genes/pathways validated in two independent sets of patients with SSc, highlighting a number of deregulated processes that have relevance for the pathogenesis of autoimmunity and SSc., This work was supported by eU/eFPia/innovative Medicines initiative Joint Undertaking PrecisesaDs Grant no. 115 565.

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INTRODUCTION:The objective of the study was to compare compliance and acceptability of a new auto-injector (AI) versus syringe for administration of methotrexate (MTX) in patients with rheumatoid arthritis (RA).METHODS:We conducted a randomized, open-label, parallel group study comparing AI to pre-filled syringe (PFS). Adult patients with RA (ACR/EULAR 2010) receiving MTX (orally or by injection) for at least 3 months were allocated to AI or PFS for 6 months and then were allocated to AI for 6 further months. Two co-primary endpoints were defined at M6: percentage of patients with compliance at least 80%; change in functional capacity assessed by Health Assessment Questionnaire (HAQ). Secondary endpoints included quality of life (RaQoL), RA activity (DAS28), and acceptability. Local safety at injection site was assessed at each visit.RESULTS:Two-hundred and sixty-five patients were randomized. The main analysis was conducted on per protocol set (99 AI and 98 PFS). Compliance was 96.2% in AI and 98.9% in PFS. Good complier rates were 89.9% and 94.9%, thus a difference of - 5.0% (- 18.9%; 8.9%). HAQ remained stable in both groups. No difference was found on RaQoL, change in RA activity, and safety profile. Autonomy, acceptability, and patient satisfaction were better with AI, and patients having had the experience of both AI and PFS preferred AI (p, ClinicalTrials.gov identifier, NCT02553018.

International audience; Acute myeloid leukemia (AML) is an aggressive myeloid malignancy with poor outcomes despite very intensive therapeutic approaches. For the majority of patients which are unfit and treated less intensively, the prognosis is even worse. There has been unspectacular progress in outcome improvement over the last decades and the development of new approaches is of tremendous interest. The tumor microenvironment is credited with an important role in supporting cancer growth, including leukemogenesis. Macrophages are part of the tumor microenvironment and their contribution in this setting is increasingly being deciphered, these cells being credited with a tumor supporting role. Data on macrophage role and polarization in leukemia is scarce. MicroRNAs (miRNAs) have a role in the post-transcriptional regulation of gene expression, by impending translation and promoting degradation of messenger RNAs. They are important modulators of cellular pathways, playing major roles in normal hematopoietic differentiation. miRNA expression is significantly correlated with the prognosis of hematopoietic malignancies, including AML. Oncogenic miRNAs correlate with poor prognosis, while tumor suppressor miRNAs, which inhibit the expression of proto-oncogenes, are correlated with a favorable prognosis. miRNAs are proposed as biomarkers for diagnosis and prognosis and are regarded as therapeutic approaches in many cancers, including AML. miRNAs with epigenetic or modulatory activity, as well as with synergistic activity with chemotherapeutic agents, proved to be promising therapeutic targets in experimental, pre-clinical approaches. The clinical availability of emerging compounds with mimicking or suppressor activity provides the opportunity for future therapeutic targeting of miRNAs. The present paper is focusing on miRNAs which, according to current knowledge, favorably impact on AML outcomes, being regarded as tumor suppressors, and reviews their role in macrophage polarization. We are focusing on miRNA expression in the setting of AML, but data on correlations between miRNA expression and macrophage polarization is mostly coming from studies involving normal tissue.

Introduction Ulnar tunnel syndrome at the elbow is a common pathology. The ultrasound cross-sectional area is a well-known metric widely accepted in radiology for the description of nerve entrapment. However, the pathological cut-off value remains challenging. The objectives of this study were to (1) describe the ultrasound cross-sectional area measurement of the ulnar nerve at three locations, and (2) to evaluate the inter-observer reliability by two independent ultrasonographers. Methods One-hundred ulnar nerves of 50 asymptomatic individuals were scanned using B-mode and power Doppler ultrasonography. The ultrasound cross-sectional area measurements of the ulnar nerve were performed at three different levels: 2 cm proximal to the epicondyle, at the level of the epicondyle, and 2 cm distal to the epicondyle. Results In our healthy population, we found 21, 24 and 7% of ultrasound cross-sectional area ulnar nerve > 8 mm2, respectively, at three different levels of measurement and 4, 7, and 0% US-CSA ulnar nerve > 10 mm2. The intraclass correlation coefficient measured at three different site levels were good (0.7943, 0.7509) to moderate (0.5701). Conclusions Almost one-quarter of our healthy population had an ultrasound cross-sectional area ulnar nerve more than 8 mm2 and few more than 10 mm2. A cut-off of ultrasound cross-sectional area ulnar nerve measurement more than 10 mm2 could be considered as pathological. No abnormal elbow ulnar nerve vascularization has been seen. This is the first step towards normal B-mode ulnar nerve values at the elbow to further detect pathological US findings as ulnar nerve entrapment.

CD5 is constitutively expressed on T cells and a subset of mature normal and leukemic B cells in patients with chronic lymphocytic leukemia (CLL). Important functional properties are associated with CD5 expression in B cells, including signal transducer and activator of transcription 3 activation, IL-10 production and the promotion of B-lymphocyte survival and transformation. However, the pathway(s) by which CD5 influences the biology of B cells and its dependence on B-cell receptor (BCR) co-signaling remain unknown. In this study, we show that CD5 expression activates a number of important signaling pathways, including Erk1/2, leading to IL-10 production through a novel pathway independent of BCR engagement. This pathway is dependent on extracellular calcium (Ca2+) entry facilitated by upregulation of the transient receptor potential channel 1 (TRPC1) protein. We also show that Erk1/2 activation in a subgroup of CLL patients is associated with TRPC1 overexpression. In this subgroup of CLL patients, small inhibitory RNA (siRNA) for CD5 reduces TRPC1 expression. Furthermore, siRNAs for CD5 or for TRPC1 inhibit IL-10 production. These findings provide new insights into the role of CD5 in B-cell biology in health and disease and could pave the way for new treatment strategies for patients with B-CLL.

Patients with multiple myeloma are generally older and vary in fitness levels, which may influence the clinical benefit of treatment. Patients from the large, phase 3 FIRST trial in newly diagnosed multiple myeloma (NDMM) were retrospectively investigated to determine outcomes based on frailty using scores for age, Charlson Comorbidity Index (CCI), and Eastern Cooperative Oncology Group performance status (ECOG PS), instead of the EQ-5D quality-of-life questionnaire, as previously reported. ECOG PS (n = 1618) was investigated in frailty groups: frail (49%) and nonfrail (51%). Frail patients experienced worse progression-free and overall survival vs nonfrail patients. Prognostic assessment was improved when combining frailty and International Staging System stage (I/II vs III). Frail patients had a higher risk of developing grade 3/4 treatment-emergent adverse events. Treatment effects observed in the FIRST trial were confirmed per frailty group and per frailty and ISS group. The use of this ECOG PS–containing frailty scale as a predictive measure of clinical outcomes in patients with transplant-ineligible NDMM is supported by data from the FIRST trial. This score, based on age, CCI, and ECOG PS, can be easily replicated and may help design future myeloma studies in frail or nonfrail elderly patients., SCOPUS: ar.j, info:eu-repo/semantics/published

International audience; Chronic lymphocytic leukemia (CLL) is the most common type of leukemia and the anti-CD20 monoclonal antibody, rituximab, represents the therapeutic gold standard for more than 2 decades in this pathology, when used in combination with chemotherapy. However, some patients experience treatment resistance or rapid relapses, and in particular, those harboring a 17p/TP53 deletion (del(17p)). This resistance could be explained by a chemo-resistance, but it could also result from the direct impact of del(17p) on the pharmacokinetics of rituximab, which represents the aim of the present study. Accordingly, 44 CLL patients were included in the study, and among them 9 presented a del(17p). Next, a total of 233 rituximab sera were selected for a pharmacokinetic study and analyzed in a two-compartment model showing important differences when del(17p) CLL patients were compared with non-del(17p) patients treated with rituximab and chemotherapy: (1) clearance of rituximab was faster; (2) central volume of rituximab distribution V1 (peripheral blood) was reduced while peripheral volume V2 (lymphoid organs and tissues) was increased; and (3) the rate of rituximab elimination (Kout) was faster. In contrast, the group with a better prognosis harboring isolated del(13q) presented a slower rate of elimination (Kout). Pharmacokinetic parameters were independent from the other factors tested such as age, sex, chemotherapy regimen (fludarabine/cyclophosphamide versus bendamustine), IGHV mutational status, and FCGR3A 158VF status. In conclusion, this study provides an additional argument to consider that del(17p) is effective not only to control chemoresistance but also monoclonal antibody activity, based on higher rituximab turnover.

Objective To describe the disease course of patients with early arthritis without rheumatoid factor (RF) and anti-citrullinated protein auto-antibodies (ACPA) in an inception cohort. To determine baseline predictors of fulfilling 2010 ACR/EULAR criteria for rheumatoid arthritis (RA) for these patients within 3 years. Method Patients included in the multicenter ESPOIR cohort were compared at baseline and 3 years by whether they were negative for RF and ACPA (“seronegative”) or positive for RF and/or ACPA (“seropositive”). Univariate analysis was used to determine the association between baseline variables in seronegative patients and RA classification. Stepwise multiple logistic regression was used to identify predictors of RA classification within 3 years, estimating odds ratios (ORs). Results Among 354 seronegative patients, 224/340 with available data (65.9%) fulfilled RA classification at baseline and 189/233 (81.1%) at 3 years. As compared with seropositive patients, seronegative patients had lower DAS28 (p = 0.002) and lower modified total Sharp score (mTSS; p = 0.026) at baseline; DAS28 remission was similar (p = 0.634), but radiographic progression rate was lower in seronegative patients (p

The work described has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement No. 115565, the resources for which are composed of a financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and the European Federation of Pharmaceutical Industries and Associations (EFPIA) companies'in-kind contribution. We thank all the members of PRECISESADS Consortium and INSERM U1227 for their effort in the sample recruitment, distribution and assessment of the samples used in this study. We are grateful to Dr Wesley H Brooks (Tampa, USA) for editorial assistance and to Valerie Le Troadec for secretarial assistance., High amount of polyclonal free light chains (FLC) are reported in systemic autoimmune diseases (SAD) and we took advantage of the PRECISESADS study to better characterize them. Serum FLC levels were explored in 1979 patients with SAD (RA, SLE, SjS, Scl, APS, UCTD, MCTD) and 614 healthy controls. Information regarding clinical parameters, disease activity, medications, autoantibodies (Ab) and the interferon α and/or γ scores were recorded. Among SAD patients, 28.4% had raised total FLC (from 12% in RA to 30% in SLE and APS) with a normal kappa/ lambda ratio. Total FLC levels were significantly higher in SAD with inflammation, active disease in SLE and SjS, and an impaired pulmonary functional capacity in SSc, while independent from kidney impairment, infection, cancer and treatment. Total FLC concentrations were positively correlated among the 10/17 (58.8%) autoantibodies (Ab) tested with anti-RNA binding protein Ab (SSB, SSA-52/60 kDa, Sm, U1-RNP), anti-dsDNA/nucleosome Ab, rheumatoid factor and negatively correlated with complement fractions C3/C4. Finally, examination of interferon (IFN) expression as a potential driver of FLC overexpression was tested showing an elevated level of total FLC among patients with a high IFNα and IFNγ Kirou's score, a strong IFN modular score, and the detection in the sera of B-cell IFN dependent factors, such as TNF-R1/TNFRSF1A and CXCL10/IP10. In conclusion, an elevated level of FLC, in association with a strong IFN signature, defines a subgroup of SAD patients, including those without renal affectation, characterized by increased disease activity, autoreactivity, and complement reduction., Innovative Medicines Initiative Joint Undertaking 115565, European Commission FP7/2007-2013, European Federation of Pharmaceutical Industries and Associations (EFPIA), Institut National de la Sante et de la Recherche Medicale (Inserm), European Commission U1227

The anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are a heterogeneous group of rare syndromes characterized by necrotizing inflammation of small and medium-sized blood vessels and the presence of ANCAs. Several clinicopathological classification systems exist that aim to define homogeneous groups among patients with AAV, the main syndromes being microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) and eosinophilic GPA (EGPA). Two main types of ANCA can be detected in patients with AAV. These ANCAs are defined according to their autoantigen target, namely leukocyte proteinase 3 (PR3) and myeloperoxidase (MPO). Patients with GPA are predominantly PR3-ANCA-positive, whereas those with MPA are predominantly MPO-ANCA-positive, although ANCA specificity overlaps only partially with these clinical syndromes. Accumulating evidence suggests that ANCA specificity could be better than clinical diagnosis for defining homogeneous groups of patients, as PR3-ANCA and MPO-ANCA are associated with different genetic backgrounds and epidemiology. ANCA specificity affects the phenotype of clinical disease, as well as the patient's initial response to remission-inducing therapy, relapse risk and long-term prognosis. Thus, the classification of AAV by ANCA specificity rather than by clinical diagnosis could convey clinically useful information at the time of diagnosis.

RhuG-CSF reduces the duration of neutropenia induced by chemotherapies. The most frequent drug used for this indication is filgrastim (initially Neupogen®-AMGEN SA). Filgrastim biosimilars have bee...

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International audience; To evaluate the effects of infectious episodes at early stages of rheumatoid arthritis (eRA) development, 59 untreated eRA patients, 77 first-degree relatives, from a longitudinal Tatarstan women cohort, were included, and compared to 67 healthy women without rheumatoid arthritis (RA) in their family history. At inclusion, informations were collected regarding both the type and incidence of infectious symptom episodes in the preceding year, and granulocyte reactive oxygen species (ROS) were studied at the basal level and after stimulation with serum-treated zymosan (STZ). In the eRA group, clinical [disease activity score (DAS28), health assessment questionnaire] and biological parameters associated with inflammation (erythrocyte sedimentation rate, C-reactive protein) or with RA [rheumatoid factor, anticyclic citrullinated peptide (anti-CCP2) antibodies] were evaluated. An elevated incidence of infection events in the previous year characterized the eRA and relative groups. In addition, a history of herpes simplex virus (HSV) episodes was associated with disease activity, while an elevated incidence of anti-CCP2 autoantibody characterized eRA patients with a history of viral upper respiratory tract infection symptoms (V-URI). Granulocyte ROS activity in eRA patients was quantitatively [STZ peak and its area under the curve (AUC)] and qualitatively (STZ time of peak) altered, positively correlated with disease activity, and parameters were associated with viral symptoms including HSV exacerbation/recurrence, and V-URI. In conclusion, our study provides arguments to consider a history of increased viral infection symptoms in RA at the early stage and such involvement needs to be studied further.

International audience; Maintenance of self-tolerance of auto-reactive lymphocytes is a fundamental mechanism to prevent the onset of autoimmune diseases. Deciphering the mechanisms involved in the deregulations leading to tolerance disruption and autoimmunity is still a major area of interest to identify new therapeutic targets and options. Ca(2+) signaling plays a major role in B cell normal development and is therefore finely tuned by B cell receptor (BCR)-dependent and independent pathways. Developmental changes in the characteristics of BCR-dependent Ca(2+) signals as well as the modulation of basal intracellular concentration ([Ca(2+)]i) contribute strongly to self-tolerance maintaining mechanisms responsible for the physical or functional elimination of autoreactive B cells such as clonal deletion, receptor editing, and anergy. Implication of Ca(2+) signals in B tolerance mechanisms mainly occurs through the specific activation of transcriptional programs depending on the amplitude, shape, and duration of Ca(2+) signals. A large number of studies reported Ca(2+) signaling defects in autoimmune pathology such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and primary Sjӧgren's syndrome (pSS). However, the precise nature of the molecular events responsible for these deregulations is not fully understood. Moreover, the demonstration of a direct correlation between Ca(2+) signaling defects and tolerance disruption is still lacking. The recent identification of proteins involved in B cell Ca(2+) signals such as ORAI, stromal interaction molecule and transient receptor potential is opening new horizons for understanding Ca(2+) signaling defects observed in autoimmune diseases and for proposing potentially new therapeutic solutions. This review aims to present an overview of the developmental evolution of BCR dependent Ca(2+) signaling and to place this signaling pathway in the context of mechanisms involved in tolerance maintenance and breakdown.

Among the large spectrum of autoantibodies (Ab) detected in systemic lupus erythematosus (SLE), anti-dsDNA Ab have been used to diagnose and assess disease activity for more than 60 years. Anti-dsDNA Ab are often associated with anti-nucleosome Ab, and in clinical practice combining both is helpful for diagnosis, prognosis, and as biomarkers to monitor response to treatment, especially when using drugs that target B cells and Ab production. In general, the association of anti-dsDNA Ab plus anti-nucleosome Ab is linked with disease flares and can indicate lupus nephritis. Moreover and since anti-nucleosome Ab have higher sensitivity and specificity than anti-dsDNA Ab, the former is a useful marker in SLE patients negative for anti-dsDNA Ab and in the diagnosis of certain types of drug-induced lupus.

Mechanims of peripheral tolerance include molecular controls and the presence of regulatory lymphocytes. Regulatory T lymphocytes (Tregs) correspond to different sub-populations of T cells that control immune responses due to the production of cytokines, such as IL-10 and with direct cell-to-cell contacts. Tregs targets are antigen presenting cells, such as dendritic cells, effector CD4(+) and CD8(+) lymphocytes but also effector antibody-producing B lymphocytes. Regulatory B lymphocytes (Bregs) have been more recently described and likely represent different sub-populations of B cells that control the development of autoimmune and inflammatory diseases due to the production of IL-10 and using intercellular contacts. Bregs targets encompass all the cells involved in the immune responses which are thus under a dual control by regulatory lymphocytes. Development and efficient activity of Tregs appear dependent of Bregs for a better regulation of autoimmune reactions, of anti-infectious reactions, but also of anti-tumor reactions.

To the Editor: We read with interest in The Journal of Rheumatology the article by Kang, et al , “High Incidence of Arterial and Venous Thrombosis in Antineutrophil Cytoplasmic Antibody-associated Vasculitis,”1 which reported a dramatically high incidence of arterial (ATE) and venous thrombosis events (VTE) in a hospital-based cohort of patients with antineutrophil cytoplasmic antibody–associated vasculitis (AAV). The study generally supports the previously reported increased risk of ATE and VTE in patients affected by AAV2–8, but has a number of inaccuracies and methodological issues that inflate the incidence rates of ATE and VTE. First, the authors compared clinical and laboratory features at baseline between groups defined by events that occurred during the followup (ATE vs no ATE, and VTE vs no VTE, Table 1 and … Address correspondence to Dr. D. Cornec, CHU Brest, Rheumatology, Boulevard Tanguy Prigent, Brest, 29609, France. E-mail: divi.cornec{at}chu-brest.fr

International audience; Granulocyte-colony stimulating factors (G-CSFs) enhance bone marrow (BM) recovery after autologous stem cell transplant (ASCT) in patients with lymphoma and myeloma. Few publications exist that discuss the use of filgrastim biosimilars after ASCT. We conducted a single-center retrospective study in patients with lymphoma and myeloma treated at Brest Hospital to assess the cost reductions related to and the efficiency and safety of filgrastim biosimilars. We identified 65 patients with lymphoma or myeloma treated with filgrastim biosimilars for ASCT and compared 19 parameters of these patients, including BM recovery, side effects, infectious complications and treatment costs, with published historical data on a cohort of 50 patients treated with classic filgrastim. We observed a significant reduction of G-CSF costs in both groups but did not observe a change in total hospitalization costs (representing less than 2% of the costs) between groups. Additionally, we did not observe differences between the two groups in BM recovery, infectious complications, side effects or the other studied parameters. In this retrospective study, the absence of differences between groups after ASCT in lymphoma and myeloma led us to believe that these drugs could be safely and effectively used for such indications without a significant impact on hospitalization costs. A prospective study should be conducted to confirm our results.

International audience; Chitin is a ubiquitous polysaccharide in fungi, insects, allergens, and parasites that is released at sites of infection. Its role in the generation of tissue inflammation, however, is not fully understood. We hypothesized that chitin is an important adjuvant for adaptive immunity. Mice were injected with a solution of ovalbumin and chitin. We used in vivo and ex vivo/in vitro approaches to characterize the ability of chitin fragments to foster adaptive immune responses against ovalbumin and compared these responses to those induced by aluminum hydroxide (alum). In vivo, ovalbumin challenge caused an eosinophil-rich pulmonary inflammatory response, Th2 cytokine elaboration, IgE induction, and mucus metaplasia in mice that had been sensitized with ovalbumin plus chitin or ovalbumin plus alum. Toll-like receptor-2, MyD88, and IL-17A played critical roles in the chitin-induced responses, and MyD88 and IL-17A played critical roles in the alum-induced responses. In vitro, CD4(+) T cells from mice sensitized with ovalbumin plus chitin were incubated with ovalbumin-stimulated bone marrow-derived dendritic cells. In these experiments, CD4(+) T-cell proliferation, IL-5, IL-13, IFN-γ, and IL-17A production were appreciated. Toll-like receptor-2, MyD88, and IL-17A played critical roles in these in vitro adjuvant properties of chitin. TLR-2 was required for cell proliferation, whereas IL-17 and TLR-2 were required for cytokine elaboration. IL-17A also inhibited the generation of adaptive Th1 responses. These studies demonstrate that chitin is a potent multifaceted adjuvant that induces adaptive Th2, Th1, and Th17 immune responses. They also demonstrate that the adjuvant properties of chitin are mediated by a pathway(s) that involves and is regulated by TLR-2, MyD88, and IL-17A.

Importance of the field: Sjogren's syndrome (SS) is an autoimmune epithelitis. This exocrinopathy is frequently associated with extraglandular complications, and the patients are at risk of developing B cell lymphoma. Given the lack of disease-modifying drugs, and the fact that SS is a quintessential B-cell mediated disease, attention has recently been focused on biotherapies.Areas covered in this review: Despite negative grounds, TNF-α antagonists have been tested in the disease, and proven not be efficient. However, B-cell depleting therapy using anti-CD20 antibodies such as rituximab, which is a chimeric mAb, has shown promise in the field, while anti-CD22 mAb seems to be less active.What the reader will gain: New treatments against the B-cell activating factor of the TNF family are about to be tested, or replaced by receptor immunoglobulin decay protein.Take home message: B-cell depleting therapies seem promising in SS, but no data are, thus far, available on treatments targeting B-cell activating fac...

International audience; Sjögren's syndrome (SS) or autoimmune epithelitis is characterized by focal lymphocytic infiltrates surrounding the tubular epithelium of exocrine glands and by overactivity of the B-cell population. Although T cells were long considered the main effectors in SS, recent findings indicating a key role for B cells have prompted studies of treatments designed to deplete the B-cell population. Among molecules that can be targeted to achieve B-cell depletion, CD20 and CD22 are surface antigens expressed specifically by B lymphocytes; and the cytokine B-cell-activating factor belonging to the TNF family (BAFF) is a TNF receptor ligand involved in B-cell differentiation, survival, and activation. The aim of this review is to discuss the clinical outcomes of SS patients treated with B-cell depletion.

International audience; Intensive treatments like autologous blood stem cell transplantations are standard consolidation treatments for lymphoma and myeloma in young people. The upper age limit for these procedures is constantly increasing. Instead of studying the impact of aging on harvesting peripheral blood stem cells (PBSC), we performed a retrospective study to explore the feasibility of collecting stem cells from patients older than 65 years and compared the efficacy to harvest in younger patients. During a period of 7 years, we identified 108 patients with myeloma or lymphoma who were older than 65 years who underwent PBSC collection. Only eight patients failed to produce a successful harvest. The majority of patients only needed one apheresis (71%). There was a median number of 5.3 x 10(6) CD34+ cells/kg. Our study demonstrated that older patients can also undergo PBSC harvests similar to younger patients.

International audience; Dysbaric osteonecrosis (DON) is an avascular bone necrosis seen in divers and compressed-air workers. It continues to be a significant occupational hazard that has important medical and social consequences for professional divers. The prevalence of DON varied between 0% and 70.6% in professional divers in the literature. This paper seeks to describe the distribution of the lesions, the diagnosis and the prognosis of individuals affected by DON referred to a French occupational disease center. We led a retrospective study by searching for cases of DON in the medical files of divers seen in our occupational disease center between 2001 and 2014. 332 professional divers consulted in our center between 2001 and 2014.Clinical, radiological and pathological data were collected to report about the cases. We report two cases of DON in divers. The first case is a left femoral head lesion in a 38-year-old man who underwent a total hip arthroplasty. Histopathological examination of the native femoral head confirmed the diagnosis of DON. The second case of DON concerns the humeral heads in a 52-year-old man. The treatment was conservative in this second case. In both cases the patients have been declared definitely medically unfit to dive and were financially compensated. Conclusion: The prognosis of DON raises the question of the ability among employees whose rehabilitation is difficult.

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International audience; Objectives: To explore beliefs and apprehensions about disease and its treatment in patients with rheumatoid arthritis and spondyloarthritis. Methods: 25 patients with rheumatoid arthritis and 25 with spondyloarthritis participated in semi-structured interviews about their disease and its treatment. The interviews were performed by trained interviewers in participants' homes. The interviews were recorded and the main themes identified by content analysis. Results: Patients differentiated between the underlying cause of the disease, which was most frequently identified as a hereditary or individual predisposition. In patients with rheumatoid arthritis, the most frequently cited triggering factor for disease onset was a psychological factor or life-event, whereas patients with spondyloarthritis tended to focus more on an intrinsic vulnerability to disease. Stress and overexertion were considered important triggering factors for exacerbations, and relaxation techniques were frequently cited strategies to manage exacerbations. The unpredictability of the disease course was a common source of anxiety. Beliefs about the disease and apprehensions about the future tended to evolve over the course of the disease, as did treatment expectations. Conclusions: Patients with rheumatoid arthritis and spondyloarthritis hold a core set of beliefs and apprehensions that reflect their level of information about their disease and are not necessarily appropriate. The physician can initiate discussion of these beliefs in order to dispel misconceptions, align treatment expectations, provide reassurance to the patient and readjust disease management. Such a dialogue would help improve standards of care in these chronic and incapacitating diseases.

Objectives hamstring strain injuries are the most common sports-related muscle injuries and one of the main causes of missed sporting events. Hypothesis clinical findings reflecting hamstring injury severity at presentation predict time to sports resumption. Design cohort study (prognosis); Level of evidence, 2. Methods five sports medicine specialists at four sports medicine centers prospectively evaluated 120 athletes within 5 days of acute hamstring injury. Patients were interviewed and asked to evaluate their worst pain on a visual analog scale (VAS). Four physical criteria were assessed at baseline: bruising, tenderness to palpation, pain upon isometric contraction, and pain upon passive straightening. The same standardized rehabilitation protocol was used in all patients. A standardized telephone interview was conducted 45 days after the injury to determine the time to-full recovery (≤40 days or >40 days). Results by univariate analysis, clinical criteria associated with a full recovery time >40 days were VAS pain score greater than 6, popping sound injury, pain during everyday activities for more than 3 days, bruising, and greater than 15° motion-range limitation. By multivariate analysis, only VAS pain score and pain during everyday activities were significantly associated with time to recovery >40 days (53% sensitivity, 95% specificity). Conclusion the initial examination provides valuable information that can be used to predict the time to full recovery after acute hamstring injuries in athletes.

International audience; The B cell-activating factor of the tumor-necrosis factor family (BAFF) plays a dominant role in the B cell homeostasis. By rescuing autoreactive B cells, excessive BAFF favors the development of autoimmune diseases. Given the numbers of variants of this B cell-specific cytokine, caution must be exercized when determining its serum level. Alternate splice isoforms, such as Δ3 BAFF and Δ4 BAFF, have been identified. They raise the possibility that their overproduction impact the synthesis of full-length BAFF.

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International audience; Although not exclusive, mounting evidence supports the fact that DNA methylation at CpG dinucleotides controls B-cell development and the progressive eliminati or inactivation of autoreactive B cell. Indeed, the expression of different B ce specific factors, including Pax5, rearrangement of the B-cell receptor (BCR) and cytokine production are tightly controlled by DNA methylation. Among normal B cells, the autoreactive CD5+ B cell sub-population presents a reduced capacity to methylate its DNA that leads to the expression of normally repressed genes, such as the human endogenous retrovirus (HERV). In systemic lupus erythematosus (SLE) patients, the archetype ofautoimmune disease, autoreactive B cells are characterized by their inability to induce DNA methylation that prolongs their survival. Finally, treating B cells with demethylating drugs increased their autoreactivity. Altogether this suggests that a deeper comprehension ofDNA methylation in B cells may offer opportunities to develop new therapeutics to control autoreactive B cells.

International audience; Systemic lupus erythematosus (SLE) disease is an autoimmune disease of unknown aetiology that affects predominantly women of child bearing age. Since previous studies, including ours, have demonstrated that CD4+ T cells and B cells from SLE patients are defective in their ability to methylate their DNA upon antigen stimulation, the aim of this study was to investigate whether DNA demethylation affects the transcription of HRES-1 in B cells. HRES-1 is the prototype of Human Endogenous Retrovirus (HERV) overexpressed in SLE. We have observed that SLE B cells were characterized by their incapacity to methylate the HRES-1 promoter, both in unstimulated and in anti-IgM stimulated B cells. In turn, HRES-1/p28 expression was increased in SLE B cells after B cell receptor engagement, but not in controls. In SLE B cells the Erk/DNMT1 pathway was defective. In addition, blocking the autocrine-loop of IL-6 in SLE B cells with an anti-IL-6 receptor monoclonal antibody restores DNA methylation and control of HRES-1/p28 expression became effective. As a consequence, a better understanding of HERV dysregulation in SLE reinforces our comprehension of the disease and opens new therapeutic perspectives.

Objective Primary Sjogren's syndrome (SS) is a complex disorder, in part due to B cell abnormalities. Although anti–B cell therapy is promising in primary SS, no treatment has yet been demonstrated to modify the disease course. This open-label study was undertaken to evaluate the efficacy of rituximab in primary SS and to investigate whether expression of specific genes is associated with efficacy of this treatment. Methods Fifteen patients with primary SS were treated in an open-label trial. Salivary gland biopsy specimens were obtained, and total RNA was extracted and amplified. Microarray analysis with the Affymetrix Human Genome U133 Plus 2.0 Array was used to analyze >54,000 transcripts, and potential pathways were identified. Results With gene expression data obtained before treatment, patients could be correctly classified in terms of whether they would be responders or nonresponders to rituximab. Gene pathway analysis demonstrated that the B cell signaling pathway was the most profoundly differentially expressed before treatment in the responders compared with nonresponders. Subclassification of patients based on the level of infiltration also demonstrated differential expression of genes belonging to the interferon (IFN) pathway between responders and nonresponders. Furthermore, unsupervised analysis based on gene expression modification before and after treatment allowed identification of 8 genes that were differentially expressed between responders and nonresponders, with the difference remaining significant after Bonferroni correction. Conclusion Our results demonstrate the ability to elaborate a set of genes predictive of rituximab efficacy and highlight the importance of studying the differential expression of B cell and IFN pathway signaling molecules in relation to the response to anti-CD20 treatment. A randomized controlled study is currently ongoing to confirm these results.

Recent advances in epigenetics have enhanced our knowledge of how environmental factors (UV radiation, drugs, infections, etc.) contribute to the development of autoimmune diseases (AID) in genetically predisposed individuals. Studies conducted in monozygotic twins discordant for AID and spontaneous autoimmune animal models have highlighted the importance of DNA methylation changes and histone modifications. Alterations in the epigenetic pattern seem to be cell specific, as CD4+ T cells and B cells are dysregulated in systemic lupus erythematosus, synovial fibroblasts in rheumatoid arthritis and cerebral cells in multiple sclerosis. With regard to lymphocytes, the control of tolerance is affected, leading to the development of autoreactive cells. Other epigenetic processes, such as the newly described miRNAs, and post-translational protein modifications may also be suspected. Altogether, a conceptual revolution is in progress, in AID, with potential new therapeutic strategies targeting epigenetic patterns.

International audience; Sjögren's syndrome (SS) is a chronic autoimmune epithelitis, and several lines of experiments indicate that multifactorial factors contribute to salivary gland epithelial cells (SGEC) dysfunctions including a combination of environmental factors, lymphocytic infiltrations, genetic predispositions as well as epigenetic defects. Such statement is reinforced by the observation that global DNA methylation (5MeCyt) is altered in minor salivary glands from pSS patients and that such defect is associated cytokeratin 19 (KRT19) overexpression. An epigenetic deregulation of the KRT19 gene was further tested by treating the human salivary gland (HSG) cell line with the DNA demethylating agent 5-azacytidin, and with the histone acetylase inhibitor trichostatin A. Blocking DNA methylation, but not histone acetylation, with 5-azacytidin was associated with KRT19 overexpression at both transcriptional and protein level. Next, analysis of the CpG genome-wide methylome array in the KTR19 locus from long term cultured SGEC obtained from 8 pSS patients revealed a more reduced DNA methylation level in those patients with defective global DNA methylation. Altogether, our data, therefore, suggest that alteration of DNA methylation in SGEC may contribute to pSS pathophysiology in part by controlling the expression of KRT19.

International audience; The recently recognized importance of B cells in systemic lupus erythematosus (SLE) raises the question as to whether those expressing CD5 predominate over the remaining B lymphocytes in the pathophysiology of this disease. Owing to their B B-cell receptor (BCR) polyspecificity, autoantibody production has been originally ascribed to CD5-positive B1 lymphocytes. Instead, it has since been established that high-affinity autoantibodies derive from CD5-negative B2 cells. Even worse, in the light of current findings, CD5-positive B cells have been considered to play a paradoxical role in preventing, rather than inducing, autoimmunity. In this context, there is evidence that the membrane expression of CD5 is regulated, and, to this end, a genetic mechanism has been described, based on the selection between exon 1A (E1A) and exon 1B (E1B). The full-length protein variant, encoded by E1A-cd5, translocates the phosphatase SHP-1 to the vicinity of the BCR, raises its threshold, and thereby limits the response of autoreactive B cells. In contrast, the truncated variant, encoded by E1B-cd5, remains in the cytoplasm, along with SHP1. Normally, EIB E1B is silenced by methylation and its product degraded in the proteosomes. Hence, a defect in the DNA methyl transfer favors the development of SLE, by preventing the effects of SHP-1.

To analyse the frequency and characterise the systemic presentation of primary Sjögren's syndrome (SS) out of the ESSDAI classification in a large international, multi-ethnic cohort of patients.The Big Data Sjögren Project Consortium is an international, multicentre registry based on world-wide data-sharing and cooperative merging of pre-existing clinical SS databases from leading centres in clinical research in SS from the five continents. A list of 26 organ-by-organ systemic features not currently included in the ESSDAI classification was defined according to previous studies; these features were retrospectively recorded.Information about non-ESSDAI features was available in 6331 patients [5,917 female, mean age at diagnosis 52 years, mainly White (86.3%)]. A total of 1641 (26%) patients had at least one of the ESSDAI systemic features. Cardiovascular manifestations were the most frequent organ-specific group of non-ESSDAI features reported in our patients (17% of the total cohort), with Raynaud's phenomenon being reported in 15%. Patients with systemic disease due to non-ESSDAI features had a lower frequency of dry mouth (90.7% vs. 94.1%, p0.001) and positive minor salivary gland biopsy (86.7% vs. 89%, p=0.033), a higher frequency of anti-Ro/SSA (74.7% vs. 68.7%, p0.001), anti-La/SSB antibodies (44.5% vs. 40.4%, p=0.004), ANA (82.7% vs. 79.5%, p=0.006), low C3 levels (17.4% vs. 9.7%, p0.001), low C4 levels (14.4% vs. 9.6%, p0.001), and positive serum cryoglobulins (8.6% vs. 5.5%, p=0.001). Systemic activity measured by the ESSDAI, clinESSDAI and DAS was higher in patients with systemic disease out of the ESSDAI in comparison with those without these features (p0.001 for all comparisons).More than a quarter of patients with primary SS may have systemic manifestations not currently included in the ESSDAI classification, with a wide variety of cardiovascular, digestive, pulmonary, neurological, ocular, ENT (ear, nose, and throat), cutaneous and urological features that increase the scope of the systemic phenotype of the disease. However, the individual frequency of each of these non-ESSDAI features was very low, except for Raynaud's phenomenon.

International audience; Autoimmunity is believed to develop when genetically predisposed individuals encounter epigenetic modifications in response to environmental factors. Recent advances in the understanding of epigenetic mechanisms, their contribution to the immune function, and to the development of autoimmunity are presented in this special issue of Clinical Reviews in Allergy and Immunology. Potential new therapeutic strategies and biomarkers are also addressed.