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IMPORTANCE: Understanding the association between clinically defined relapses and radiological activity in multiple sclerosis (MS) is essential for patient treatment and therapeutic development. OBJECTIVE: To investigate clinical events identified as relapses but not associated with new T2 lesions or gadolinium-enhanced T1 lesions on brain and spinal cord magnetic resonance imaging (MRI). DESIGN, SETTING, AND PARTICIPANTS: This multicenter observational cohort study was conducted between January 2015 and June 2023. Data were extracted on June 8, 2023, from the French MS registry. All clinical events reported as relapses in patients with relapsing-remitting MS were included if brain and spinal cord MRI was performed within 12 and 24 months before the event, respectively, and 50 days thereafter with gadolinium injection. EXPOSURES: Events were classified as relapses with active MRI (RAM) if a new T2 lesion or gadolinium-enhanced T1 lesion appeared on brain or spinal cord MRI or as acute clinical events with stable MRI (ACES) otherwise. MAIN OUTCOMES AND MEASURES: Factors associated with ACES were investigated; patients with ACES and RAM were compared regarding Expanded Disability Status Scale (EDSS) course, relapse rate, confirmed disability accrual (CDA), relapse-associated worsening (RAW), progression independent of relapse activity (PIRA), and transition to secondary progressive (SP) MS, and ACES and RAM rates under each disease-modifying therapy (DMT) were estimated. RESULTS: Among 31 885 clinical events, 637 in 608 patients (493 [77.4%] female; mean [SD] age, 35.8 [10.7] years) were included. ACES accounted for 166 (26.1%) events and were more likely in patients receiving highly effective DMTs, those with longer disease duration (odds ratio [OR], 1.04; 95% CI, 1.01-1.07), or those presenting with fatigue (OR, 2.14; 95% CI, 1.15-3.96). ACES were associated with significant EDSS score increases, lower than those found for RAM. Before the index event, patients with ACES experienced significantly higher rates of relapse (relative rate [RR], 1.21; 95% CI, 1.01-1.46), CDA (hazard ratio [HR], 1.54; 95% CI, 1.13-2.11), and RAW (HR, 1.72; 95% CI, 1.20-2.45). Patients with ACES were at significantly greater risk of SP transition (HR, 2.58; 95% CI, 1.02-6.51). Although RAM rate decreased with DMTs according to their expected efficacy, ACES rate was stable across DMTs. CONCLUSIONS AND RELEVANCE: The findings in this study introduce the concept of ACES in MS, which accounted for one-fourth of clinical events identified as relapses.

IMPORTANCE: A recent randomized clinical trial concluded that discontinuing medium-efficacy therapy might be a reasonable option for older patients with nonactive multiple sclerosis (MS), but there is a lack of data on discontinuing high-efficacy therapy (HET). In younger patients, the discontinuation of natalizumab and fingolimod is associated with a risk of rebound of disease activity. OBJECTIVE: To determine whether discontinuing HET in patients 50 years and older with nonactive MS is associated with an increased risk of relapse compared with continuing HET. DESIGN, SETTING, AND PARTICIPANTS: This observational cohort study used data from 38 referral centers from the French MS registry (Observatoire Français de la Sclérose en Plaques [OFSEP] database). Among 84704 patients in the database, data were extracted for 1857 patients 50 years and older with relapsing-remitting MS treated by HET and with no relapse or magnetic resonance imaging activity for at least 2 years. After verification of the medical records, 1620 patients were classified as having discontinued HET or having remained taking treatment and were matched 1:1 using a dynamic propensity score (including age, sex, disease phenotype, disability, treatment of interest, and time since last inflammatory activity). Patients were included from February 2008 to November 2021, with a mean (SD) follow-up of 5.1 (2.9) years. Data were extracted in June 2022. EXPOSURES: Natalizumab, fingolimod, rituximab, and ocrelizumab. MAIN OUTCOMES AND MEASURES: Time to first relapse. RESULTS: Of 1620 included patients, 1175 (72.5%) were female, and the mean (SD) age was 54.7 (4.8) years. Among the 1452 in the HET continuation group and 168 in the HET discontinuation group, 154 patients in each group were matched using propensity scores (mean [SD] age, 57.7 [5.5] years; mean [SD] delay since the last inflammatory activity, 5.6 [3.8] years; mean [SD] follow-up duration after propensity score matching, 2.5 [2.1] years). Time to first relapse was significantly reduced in the HET discontinuation group compared with the HET continuation group (hazard ratio, 4.1; 95% CI, 2.0-8.5; P < .001) but differed between HETs, with a hazard ratio of 7.2 (95% CI, 2.1-24.5; P = .001) for natalizumab, 4.5 (95% CI, 1.3-15.5; P = .02) for fingolimod, and 1.1 (95% CI, 0.3-4.8; P = .85) for anti-CD20 therapy. CONCLUSION AND RELEVANCE: As in younger patients, in patients 50 years and older with nonactive MS, the risk of relapse increased significantly after stopping HETs that impact immune cell trafficking (natalizumab and fingolimod). There was no significant increase in risk after stopping HETs that deplete B-cells (anti-CD20 therapy). This result may inform decisions about stopping HETs in clinical practice.

IMPORTANCE: Moderately effective therapies (METs) have been the main treatment in pediatric-onset multiple sclerosis (POMS) for years. Despite the expanding use of highly effective therapies (HETs), treatment strategies for POMS still lack consensus. OBJECTIVE: To assess the real-world association of HET as an index treatment compared with MET with disease activity. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective cohort study conducted from January 1, 2010, to December 8, 2022, until the last recorded visit. The median follow-up was 5.8 years. A total of 36 French MS centers participated in the Observatoire Français de la Sclérose en Plaques (OFSEP) cohort. Of the total participants in OFSEP, only treatment-naive children with relapsing-remitting POMS who received a first HET or MET before adulthood and at least 1 follow-up clinical visit were included in the study. All eligible participants were included in the study, and none declined to participate. EXPOSURE: HET or MET at treatment initiation. MAIN OUTCOMES AND MEASURES: The primary outcome was the time to first relapse after treatment. Secondary outcomes were annualized relapse rate (ARR), magnetic resonance imaging (MRI) activity, time to Expanded Disability Status Scale (EDSS) progression, tertiary education attainment, and treatment safety/tolerability. An adapted statistical method was used to model the logarithm of event rate by penalized splines of time, allowing adjustment for effects of covariates that is sensitive to nonlinearity and interactions. RESULTS: Of the 3841 children (5.2% of 74 367 total participants in OFSEP), 530 patients (mean [SD] age, 16.0 [1.8] years; 364 female [68.7%]) were included in the study. In study patients, both treatment strategies were associated with a reduced risk of first relapse within the first 2 years. HET dampened disease activity with a 54% reduction in first relapse risk (adjusted hazard ratio [HR], 0.46; 95% CI, 0.31-0.67; P < .001) sustained over 5 years, confirmed on MRI activity (adjusted odds ratio [OR], 0.34; 95% CI, 0.18-0.66; P = .001), and with a better tolerability pattern than MET. The risk of discontinuation at 2 years was 6 times higher with MET (HR, 5.97; 95% CI, 2.92-12.20). The primary reasons for treatment discontinuation were lack of efficacy and intolerance. Index treatment was not associated with EDSS progression or tertiary education attainment (adjusted OR, 0.51; 95% CI, 0.24-1.10; P = .09). CONCLUSIONS AND RELEVANCE: Results of this cohort study suggest that compared with MET, initial HET in POMS was associated with a reduction in the risk of first relapse with an optimal outcome within the first 2 years and was associated with a lower rate of treatment switching and a better midterm tolerance in children. These findings suggest prioritizing initial HET in POMS, although long-term safety studies are needed.

The pathogenic role of terminally differentiated effector memory (TEMRA) CD8+T cells has been implicated in kidney transplant failure. The authors showed that humoral rejection of kidney allografts is associated with an accumulation of cytolytic TEMRA CD8+T cells in blood and in kidney graft biopsies. They demonstrated that TEMRA CD8+T cells from kidney transplant recipients exhibit enhanced migratory properties compared with effector memory CD8+T cells and that the chemokine CXCL12 not only promotes migration of TEMRA CD8+T cells toward nonlymphoid organs but also triggers a purinergic P2X4 receptor–dependent proinflammatory response. They also found that agents aimed at potential TEMRA CD8+T cell–specific targets inhibited the migration of TEMRA CD8+T cells from kidney transplant recipients, suggesting a possible strategy in treating kidney transplant failure.

L’accumulation du handicap au cours de la Sclérose en plaques (SEP) est liée à 2 mécanismes inflammatoires présents dès les phases précoces de la maladie : l’inflammation périphérique et centrale.

En lien avec l’évolution des prises en soins, tysathome vise à valider le traitement par natalizumab en hospitalisation à domicile pour les patients vivant avec une sclérose en plaques.

La corrélation entre les poussées définies cliniquement et l’activité radiologique dans la sclérose en plaques (SEP) n’a été que très peu étudiée.

Les réponses thérapeutiques des patients atteints de sclérose en plaques (SEP) sont hétérogènes. Les technologies du numérique pourraient permettre d’évaluer les patients tout en visualisant les données de patients similaires.

IMPORTANCE: Risk factors associated with the severity of coronavirus disease 2019 (COVID-19) in patients with multiple sclerosis (MS) are unknown. Disease-modifying therapies (DMTs) may modify the risk of developing a severe COVID-19 infection, beside identified risk factors such as age and comorbidities. OBJECTIVE: To describe the clinical characteristics and outcomes in patients with MS and COVID-19 and identify factors associated with COVID-19 severity. DESIGN, SETTING, AND PARTICIPANTS: The Covisep registry is a multicenter, retrospective, observational cohort study conducted in MS expert centers and general hospitals and with neurologists collaborating with MS expert centers and members of the Société Francophone de la Sclérose en Plaques. The study included patients with MS presenting with a confirmed or highly suspected diagnosis of COVID-19 between March 1, 2020, and May 21, 2020. EXPOSURES: COVID-19 diagnosed with a polymerase chain reaction test on a nasopharyngeal swab, thoracic computed tomography, or typical symptoms. MAIN OUTCOMES AND MEASURES: The main outcome was COVID-19 severity assessed on a 7-point ordinal scale (ranging from 1 [not hospitalized with no limitations on activities] to 7 [death]) with a cutoff at 3 (hospitalized and not requiring supplemental oxygen). We collected demographics, neurological history, Expanded Disability Severity Scale score (EDSS; ranging from 0 to 10, with cutoffs at 3 and 6), comorbidities, COVID-19 characteristics, and outcomes. Univariate and multivariate logistic regression models were used to estimate the association of collected variables with COVID-19 outcomes. RESULTS: A total of 347 patients (mean [SD] age, 44.6 [12.8] years, 249 women; mean [SD] disease duration, 13.5 [10.0] years) were analyzed. Seventy-three patients (21.0%) had a COVID-19 severity score of 3 or more, and 12 patients (3.5%) died of COVID-19. The median EDSS was 2.0 (range, 0-9.5), and 284 patients (81.8%) were receiving DMT. There was a higher proportion of patients with a COVID-19 severity score of 3 or more among patients with no DMT relative to patients receiving DMTs (46.0% vs 15.5%; P < .001). Multivariate logistic regression models determined that age (odds ratio per 10 years: 1.9 [95% CI, 1.4-2.5]), EDSS (OR for EDSS ≥6, 6.3 [95% CI. 2.8-14.4]), and obesity (OR, 3.0 [95% CI, 1.0-8.7]) were independent risk factors for a COVID-19 severity score of 3 or more (indicating hospitalization or higher severity). The EDSS was associated with the highest variability of COVID-19 severe outcome (R2, 0.2), followed by age (R2, 0.06) and obesity (R2, 0.01). CONCLUSIONS AND RELEVANCE: In this registry-based cohort study of patients with MS, age, EDSS, and obesity were independent risk factors for severe COVID-19; there was no association found between DMTs exposure and COVID-19 severity. The identification of these risk factors should provide the rationale for an individual strategy regarding clinical management of patients with MS during the COVID-19 pandemic.

The ideal treatment for multiple sclerosis (MS) would target both the neuroinflammatory component of the disease (peripheral and central) and its neurodegenerative component, via modulation of a ubiquitous and pleiotropic common target. Sphingosine-1-phosphate (S1P), a product of sphingosine metabolism, regulates many biological functions (including cell proliferation and survival, cell migration, the immune response and cardiovascular function) via five subtypes of receptor. These receptors are expressed in all types of brain cells where they modulate a number of processes involved in neuronal plasticity, including myelination, neurogenesis and neuroprotection. This profile has aroused interest in modulation of S1P function as a therapeutic target in many brain diseases, particularly those in which the immune system plays a role in the development of brain lesions. Fingolimod, a S1P receptor modulator, exerts its beneficial effects in MS through its anti-inflammatory and anti-neurodegenerative effects. This review discusses recent evidence indicating that fingolimod may target both the inflammatory and neurodegenerative components of the disease process in MS.

IMPORTANCE: Risk of developing progressive multifocal leukoencephalopathy (PML) is the major barrier to using natalizumab for patients with multiple sclerosis (MS). To date, the association of risk stratification with PML incidence has not been evaluated. OBJECTIVE: To describe the temporal evolution of PML incidence in France before and after introduction of risk minimization recommendations in 2013. DESIGN, SETTING, AND PARTICIPANTS: This observational study used data in the MS registry OFSEP (Observatoire Français de la Sclérose en Plaques) collected between April 15, 2007, and December 31, 2016, by participating MS expert centers and MS-dedicated networks of neurologists in France. Patients with an MS diagnosis according to current criteria, regardless of age, were eligible, and those exposed to at least 1 natalizumab infusion (n = 6318) were included in the at-risk population. A questionnaire was sent to all centers, asking for a description of their practice regarding PML risk stratification. Data were analyzed in July 2018. EXPOSURES: Time from the first natalizumab infusion to the occurrence of PML, natalizumab discontinuation plus 6 months, or the last clinical evaluation. MAIN OUTCOMES AND MEASURES: Incidence was the number of PML cases reported relative to the person-years exposed to natalizumab. A Poisson regression model for the 2007 to 2016 period estimated the annual variation in incidence and incidence rate ratio (IRR), adjusted for sex and age at treatment initiation and stratified by period (2007-2013 and 2013-2016). RESULTS: In total, 6318 patients were exposed to natalizumab during the study period, of whom 4682 (74.1%) were female, with a mean (SD [range]) age at MS onset of 28.5 (9.1 [1.1-72.4]) years; 45 confirmed incident cases of PML were diagnosed in 22 414 person-years of exposure. The crude incidence rate for the whole 2007 to 2016 period was 2.00 (95% CI, 1.46-2.69) per 1000 patient-years. Incidence significantly increased by 45.3% (IRR, 1.45; 95% CI, 1.15-1.83; P = .001) each year before 2013 and decreased by 23.0% (IRR, 0.77; 95% CI, 0.61-0.97; P = .03) each year from 2013 to 2016. CONCLUSIONS AND RELEVANCE: The results of this study suggest, for the first time, a decrease in natalizumab-associated PML incidence since 2013 in France that may be associated with a generalized use of John Cunningham virus serologic test results; this finding appears to support the continuation and reinforcement of educational activities and risk-minimization strategies in the management of disease-modifying therapies for multiple sclerosis.

Today's medicine strives to be personalized, preventive, predictive and participatory. This implies to have access to multimodal data to better characterize patients groups and to combine clinical and imaging data with high-quality biological samples. Collecting such data is one of the objectives of the Observatoire français de la sclérose en plaques (OFSEP), the French MS registry. On December 2022, the OFSEP biocollection includes 4,888 patients with scientific characteristics and about 90,000 samples. Thanks to its richness, this biocollection open for the scientific community, contributes to address unmet needs in MS through identification of multiomics determinants of MS activity, progression and secondary effects.

Microglia and astrocytes modulate inflammation and neurodegeneration in the central nervous system (CNS)1–3. Microglia modulate pro-inflammatory and neurotoxic activities in astrocytes, but the mechanisms involved are not completely understood4,5. Here we report that TGFα and VEGF-B produced by microglia regulate the pathogenic activities of astrocytes in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. Microglia-derived TGFα acts via the ErbB1 receptor in astrocytes to limit their pathogenic activities and EAE development. Conversely, microglial VEGF-B triggers FLT-1 signalling in astrocytes and worsens EAE. VEGF-B and TGFα also participate in the microglial control of human astrocytes. Furthermore, expression of TGFα and VEGF-B in CD14+cells correlates with the multiple sclerosis lesion stage. Finally, metabolites of dietary tryptophan produced by the commensal flora control microglial activation and TGFα and VEGF-B production, modulating the transcriptional program of astrocytes and CNS inflammation through a mechanism mediated by the aryl hydrocarbon receptor. In summary, we identified positive and negative regulators that mediate the microglial control of astrocytes. Moreover, these findings define a pathway through which microbial metabolites limit pathogenic activities of microglia and astrocytes, and suppress CNS inflammation. This pathway may guide new therapies for multiple sclerosis and other neurological disorders. TGFα and VEGF-B produced by microglia regulate astrocyte function in the experimental autoimmune encephalomyelitis model of multiple sclerosis.

Les maladies associées aux anticorps anti-MOG (MOGAD) débutent fréquemment chez des femmes qui sont en âge de procréer. L’impact de la grossesse et du post-partum sur la maladie est, à ce jour, inconnu.

Les évolutions et les réponses thérapeutiques dans la sclérose en plaques (SEP) étant hétérogènes, évaluer les patients au regard d’un sous-groupe en population est une forme de médecine de précision.

Flashes of light or phosphenes are the sensation of light without light actually entering the eye. This phenomenon can be evoked by stimulation of the retina or the visual cortex of the brain and can appear unilaterally or bilaterally. From an ophthalmologic perspective, phosphenes can arise from photoreceptor induction by mechanical,1,2inflammatory,3or vascular4stimuli. Therefore, it is necessary to determine the origin of phosphenes for further management. We encountered a patient who reported having phosphenes while moving his eyes laterally. We performed various ophthalmologic imaging studies to identify the origin of these phosphenes.

In Multiple Sclerosis (MS) women, therapeutic management for pregnancy planning and during pregnancy still represents a challenge regarding timing of disease-modifying therapies (DMT) stop, risk of disease reactivation and potential fetal toxicity. The objective of this study was to describe disease activity during pregnancy and postpartum depending on treatment status before conception in women with MS.

•PRO-MSACTIVE evaluated ocrelizumab in patients with active RMS.•This phase IV study tended to mimic current clinical practice.•Disease activity was assessed by clinical and/or imaging features.•Efficacy and safety profile of ocrelizumab is confirmed in a pragmatic setting.•PRO data allowed a better understanding of MS impact on patients’ lives.

•No guidelines available for treatment of asymptomatic bacteriuria before immunosuppression in MS.•A survey of clinical practice in case of ASB before immunosuppression was performed in France.•A great variability in Diagnostic and therapeutic procedures was found.•There is no consensus among MS neurologists to detect and treat ASB before Immunosuppression.

Reactivation of Multiple Sclerosis (MS) activity has been described after fingolimod cessation. Because of its contra indication during pregnancy, switch towards lower efficacy treatments are frequent in MS patients with childbearing desire but expose them to a risk of disease reactivation.

High doses of intravenous methylprednisolone are recommended to treat relapses in patients with multiple sclerosis, but can be inconvenient and expensive. We aimed to assess whether oral administration of high-dose methylprednisolone was non-inferior to intravenous administration.

Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS). With growing evidence for environmental and genetic factors, MS is now accepted as an autoimmune disease. This complex disease seems to implicate various cell types in both innate and adaptive compartments. Here, we discuss recent advances in the immunological field of MS research.

Obstructive sleep apnea (OSA) has been associated with hypertension, which is one of the intermediary mechanisms leading to increased cardiovascular morbidity. This study aimed at evaluating the effects of a combination of continuous positive airway pressure (CPAP) and telemedicine support on blood pressure (BP) reduction in high cardiovascular risk OSA patients.

L’étude de phase IV PRO-MSACTIVE (NCT03589105) évalue l’efficacité, la tolérance et l’impact d’ocrelizumab (OCR) sur les résultats rapportés par les patients (PROs) dans la sclérose en plaques récurrente (SEP-R) active.

Lors d’une persistance d’activité résiduelle sous fingolimod (FNG) chez des patients SEP récurrent rémittent (RR), la stratégie thérapeutique actuelle est basée sur un switch vers le natalizumab (NTZ) ou les anti-CD20.

Significant alterations in the transmigration capacity of peripheral blood T‐lymphocytes found as a feature in multiple sclerosis. Mechanisms of T lymphocyte trafficking in the brain remain unclear in MS. We hypothesized that MS is associated with increased CD4+ and CD8+ T lymphocyte trafficking across the BBB. To test this hypothesis, we calculated the frequency of PSGL‐1+/CD4+ and PSGL‐1+CD8+ or LFA‐1+/CD4+/CD8+ T cells in the PBMC of 27 patients with a RR‐MS (21 untreated and six IFN‐β‐treated) and 18 HI. Next, we measured their ex vivo TR across resting and TNF‐α‐activated human BBB‐derived hCMEC/D3 endothelial layers under static conditions. The frequency of PSGL‐1+CD4+ T lymphocytes was significantly higher in treated or untreated MS patients than HI. Furthermore, resting hCMEC/D3 TR of CD4+ lymphocytes (purified or in PBMC) from treated or untreated MS patients were significantly higher than those of HI and associated with significant enrichments of CD4+PSGL+ or CD4+PSGL‐1+CD45RO+ T cells in their transmigrating fractions. The TR of CD4+ and CD8+ from MS patients across TNF‐α‐activated hCMEC/D3 were also significantly higher than that observed in HI. Resting hCMEC/D3 transmigration was blocked significantly by anti‐PSGL‐1/anti‐LFA‐1 in all groups, and anti‐VLA‐4 inhibited transmigration of MS T cells specifically. Purified PSGL‐1‐negative CD4+ lymphocytes transmigrated resting hCMEC/D3 with <10% of transmigrating cells re‐expressing PSGL‐1, suggesting PSGL‐1‐independent transmigration mechanisms. The frequency of PSGL‐1 was unchanged in CD8+ cells from MS patients, whereas CD8+LFA‐1highwere reduced significantly in IFN‐β‐treated patients specifically. Collectively, MS is associated with an expanding pool of PSGL‐1+CD4+ T lymphocytes able to transmigrate the BBB endothelium in vitro and possibly contributing to brain pathology.

BACKGROUND Acute demyelinating encephalomyelitis (ADEM) is characterized by a severe inflammatory attack, frequently secondary to infectious events or vaccinations. To date, no clear criteria exist for ADEM, and the risk of subsequent evolution to multiple sclerosis (MS) remains unknown. OBJECTIVE To evaluate the risk of evolution to MS after a first episode of ADEM. DESIGN Observational, retrospective case study. SETTING Thirteen French MS centers. PATIENTS We retrospectively studied 60 patients with ADEM who were older than 15 years with no history suggestive of an inflammatory event who presented to MS centers from January 1, 1995, through December 31, 2005. We excluded 6 patients with multiphasic ADEM because this is a rare condition and somewhat difficult to classify. After a mean follow-up of 3.1 years (range, 1-10 years), the remaining 54 patients were then classified into 2 groups: monophasic ADEM (ADEM group) (n = 35) and clinically definite MS (MS group) (n = 19). MAIN OUTCOME MEASURES Clinical, laboratory, magnetic resonance imaging, and follow-up data were evaluated for each group. RESULTS Patients in the ADEM group more frequently had atypical symptoms of MS (26 of 35 [74%]) than patients with MS (8 of 19 [42%]) (P = .02). Oligoclonal bands were more frequently observed in the MS group (16 of 19 [84%]) than in the ADEM group (7 of 35 [20%]) (P &lt;.001). Patients in the ADEM group more frequently had gray matter involvement (21 of 35 [60%]) than those in the MS group (2 of 19 [11%]) (P &lt;.001). On the basis of these results, we consider that the presence of any 2 of the following 3 criteria could be used to differentiate patients with ADEM from those with MS in our cohort: atypical clinical symptoms for MS, absence of oligoclonal bands, and gray matter involvement. On this basis, 29 of the 35 patients in the ADEM group (83%) and 18 of the 19 patients in the MS group (95%) were classified in the appropriate category. CONCLUSIONS Our study found some differences concerning the risk of evolution to clinically definite MS after a first demyelinating episode suggestive of ADEM. These findings led us to propose criteria that should now be tested in a larger, prospective cohort study.Arch Neurol. 2007;64:(10)938-944--

Une comparaison des données de vraie vie de l’interféron bêta-1a sous-cutané 22/44μg (IFNβ-1a) et du tériflunomide (TFN) peut permettre de mieux comprendre les avantages de ces deux traitements.

L’arsenal thérapeutique s’est enrichi dans le traitement des formes actives de sclérose en plaques (SEP), mais très peu d’études comparent les molécules de manière prospective.

Most kidney transplant recipients who discontinue immunosuppression reject their graft. Nevertheless, a small number do not, suggesting that allogeneic tolerance state (referred to operational tolerance) is achievable in humans. So far, however, the rarity of such patients has limited their study. Because operational tolerance could be linked to anergy, ignorance or to an active regulatory mechanism, we analyzed the blood T-cell repertoire usage of these patients. We report on comparison of T-cell selection in drug-free operationally tolerant kidney recipients (or with minimal immunosuppression), recipients with stable graft function, chronic rejection and healthy individuals. The blood T cells of operationally tolerant patients display two major characteristics: an unexpected strongly altered T-cell receptor (TCR) Vβ usage and high TCR transcript accumulation in selected T cells. The cytokine transcriptional patterns of sorted T cells with altered TCR usage show no accumulation of cytokine transcripts (IL10, IL2, IL13, IFN-γ), suggesting a state of hyporesponsiveness in these patients. Identification of such a potential surrogate pattern of operational toler-ance in transplant recipients under life-long immuno-suppression may provide a new basis and rationale for exploration of tolerance state. However, these data ob-tained in a limited number of patients require further confirmation on larger series.

Most kidney transplant recipients who discontinue immunosuppression reject their graft. Nevertheless, a small number do not, suggesting that allogeneic tolerance state (referred to operational tolerance) is achievable in humans. So far, however, the rarity of such patients has limited their study. Because operational tolerance could be linked to anergy, ignorance or to an active regulatory mechanism, we analyzed the blood T-cell repertoire usage of these patients. We report on comparison of T-cell selection in drug-free operationally tolerant kidney recipients (or with minimal immunosuppression), recipients with stable graft function, chronic rejection and healthy individuals. The blood T cells of operationally tolerant patients display two major characteristics: an unexpected strongly altered T-cell receptor (TCR) Vβ usage and high TCR transcript accumulation in selected T cells. The cytokine transcriptional patterns of sorted T cells with altered TCR usage show no accumulation of cytokine transcripts (IL10, IL2, IL13, IFN-γ), suggesting a state of hyporesponsiveness in these patients. Identification of such a potential surrogate pattern of operational tolerance in transplant recipients under life-long immunosuppression may provide a new basis and rationale for exploration of tolerance state. However, these data obtained in a limited number of patients require further confirmation on larger series.

Multiple sclerosis is an inflammatory demyelinating disease of the CNS associated with T cells autoreactive for myelin components. In this study, we analysed the T‐cell receptor (TCR) usage of the variable β (Vβ) chain transcriptome in the blood of multiple sclerosis patients at various stages of the disease using a global and quantitative comparison of the complementarity‐determining region 3 length distribution (CDR3‐LD) of transcripts of the 26 Vβ genes. We investigated 35 patients: 12 with a high risk of multiple sclerosis, 10 with clinically definite multiple sclerosis, 13 with a relapsing–remitting worsening and active multiple sclerosis and 13 healthy individuals. Cells bearing the TCR transcripts with altered CDR3‐LD were sorted and studied for CD4 or CD8 phenotype, cytokine transcript accumulation and response to human myelin basic protein (MBP). We show that patients from all the groups have a significantly skewed blood T‐cell repertoire. Vβ transcriptome patterns were more altered in patients from the clinically definite multiple sclerosis group and the worsening and active multiple sclerosis group than in the high risk group. The T cells sorted from Vβ families with altered CDR3‐LD concerned both CD4 and CD8 T cells, with a more pronounced skewing in the CD8 compartment. These cells displayed a significantly increased level of interferon‐γ, interleukin‐2 and tumour necrosis factor‐α transcripts compared with their counterparts from the healthy individual group. Furthermore, using interferon‐γ enzyme‐linked immunospot (ELISPOT) assays, T cells from four out of seven altered Vβ families tested from multiple sclerosis patients responded to human MBP, whereas no response was observed with human albumin or with altered Vβ families from healthy individuals. Our data support the concept of an early autoimmune component in the disease and emphasize the possible involvement of CD8‐positive T cells in multiple sclerosis.