Comparison of injective related reactions following ofatumumab and ocrelizumab in patients with multiple sclerosis: data from the European spontaneous reporting system.

Introduction: In 2021 ofatumumab, a recombinant human anti-CD20 monoclonal antibody (mAb) already authorized for the treatment of chronic lymphocytic leukemia, received the marketing approval for the treatment of relapsing forms of multiple sclerosis (MS). Differently from ocrelizumab, that is administered intravenously, ofatumumab if the first anti-CD20 mAb to be administered subcutaneously without a premedication. Methods and objectives: In this study we aimed to describe and compare the main characteristics of Individual Case Safety Reports (ICSRs) describing the occurrence of Injective Related Reactions (IRRs) following the treatment with ocrelizumab and ofatumumab reported in the Eudravigilance (EV) database during years 2021-2023. Results: A total of 860 ICSRs with either ofatumumab and ocrelizumab as suspected drug were retrieved from Eudravigilance, of which 51% associated with ofatumumab and 49% with ocrelizumab. The majority of patients who experienced IRRs following ocrelizumab belonged to the age group of 18-64 years (73%), while the age-group was mostly not specified (55%) in ICSRs reporting ofatumumab as suspected. The distribution of gender was almost similar in the two groups, with the majority of ICSRs related to female patients. "Pyrexia" was the Preferred Term (PT) most reported for ofatumumab, while "Infusion related reaction" were more frequently reported with ocrelizumab. Premedication drugs were reported in 148 ICSRs. Out of 89 ICSRs for which the Time to Event (TTE) was calculated, 74 reported IRRs that occurred the same day of the drug administration. Discussion: Based on the results of this study, although a risk of ofatumumab-induced IRRs cannot be excluded, it should be considered as manageable considering that the drug seems to be mostly associated with the occurrence of fever. Thus, it is important to continue to closely monitor the use of these in clinical practice to improve the knowledge on their long-term safety.

Deciphering the role of protein kinase A in the control of FoxP3 expression in regulatory T cells in health and autoimmunity.

The molecular mechanisms that govern differential T cell development from CD4+CD25-conventional T (Tconv) into CD4+CD25+ forkhead-box-P3+ (FoxP3+) inducible regulatory T (iTreg) cells remain unclear. Herein, we investigated the relative contribution of protein kinase A (PKA) in this process. Mechanistically, we found that PKA controlled the efficiency of human iTreg cell generation through the expression of different FoxP3 splicing variants containing or not the exon 2. We found that transient PKA inhibition reduced the recruitment of cAMP-responsive element-binding protein (CREB) on regulatory regions of the FoxP3 gene, a condition that is associated with an impaired acquisition of their suppressive capacity in vitro. To corroborate our findings in a human model of autoimmunity, we measured CREB phosphorylation and FoxP3 levels in iTreg cells from treatment-naïve relapsing-remitting (RR)-multiple sclerosis (MS) subjects. Interestingly, both phospho-CREB and FoxP3 induction directly correlated and were significantly reduced in RR-MS patients, suggesting a previously unknown mechanism involved in the induction and function of human iTreg cells.

Investigating the association between neoplasms and MOG antibody-associated disease.

Introduction: The association of myelin oligodendrocyte glycoprotein (MOG) antibody associated disease (MOGAD) and tumors has seldom been reported. We aim to investigate the occurrence of tumors in a cohort of patients with MOGAD and to describe their clinical features, in addition to previously reported cases. Methods: We retrospectively identified patients with MOGAD (i.e., compatible clinical phenotype and positive MOG antibodies analysed with a live cell-based assay) from 1/1/2015 to 1/1/2023 who had a neoplasm diagnosed within 2 years from MOGAD onset. Furthermore, we performed systematic review of literature to identify previously reported cases. Clinical, paraclinical and oncological findings were collected and reported as median (range) or number (percentage). Results: Two of 150 MOGAD patients (1%) had a concomitant neoplasm in our cohort. Fifteen additional cases were retrieved from literature. Median age was 39 (16-73) years-old, 12 patients were female. ADEM (n = 4;23.5%), encephalomyelitis (n = 3;17.6%), and monolateral optic neuritis (n = 2;11.8%) were the most frequent phenotypes. Median number of treatments was 1 (range 1-4), improvement was reported in 14/17 cases (82.4%). Oncological accompaniments were teratoma (n = 4), CNS (n = 3), melanoma (n = 2), lung (n = 2), hematological (n = 2), ovary (n = 1), breast (n = 1), gastrointestinal (n = 1), and thymic (n = 1) neoplasms. Median time from tumor diagnosis to MOGAD onset was 0 (range - 60 to 20) months. MOG expression in neoplastic tissue was reported in 2/4 patients. Median PNS-CARE score was 3 (range 0-7): 11 patients were classified as "non-PNS," 5 as "possible PNS," and 1 as "probable PNS." Discussion: Our study confirms that MOG is a low-risk antibody for paraneoplastic neurological syndromes and that the clinical presentation and oncological accompaniments are extremely variable. Most of these patients were classified as non-PNS, whereas only a minority was diagnosed with possible/probable PNS, frequently in association with ovarian teratoma. These findings support the notion that MOGAD is not a paraneoplastic disease.

A score that predicts aquaporin-4 IgG positivity in patients with longitudinally extensive transverse myelitis.

BACKGROUND AND PURPOSE: Longitudinally extensive transverse myelitis (LETM) associated with aquaporin-4 autoantibodies (AQP4-IgG) can cause severe disability. Early diagnosis and prompt treatment are critical to prevent relapses. A novel score is described based on clinical and neuroimaging characteristics that predicts AQP4-IgG positivity in patients with LETM. METHODS: Patients were enrolled both retrospectively and prospectively from multiple Italian centers. Clinical and neuroimaging characteristics of AQP4-IgG positive and negative patients were compared through univariate and multivariate analysis. RESULTS: Sixty-six patients were included. Twenty-seven (41%) were AQP4-IgG positive and median age at onset was 45.5 years (range 19-81, interquartile range 24). Female sex (odds ratio [OR] 17.9, 95% confidence interval [CI] 2.6-381.9; p = 0.014), tonic spasms (OR 45.6, 95% CI 3.1-2197; p = 0.017) and lesion hypointensity on T1-weighted images (OR 52.9, 95% CI 6.8-1375; p = 0.002) were independently associated with AQP4-IgG positivity. The AQP4-IgG positivity in myelitis (AIM) score predicted AQP4-IgG positivity with 85% sensitivity and 95% specificity. Positive and negative likelihood ratios were 16.6 and 0.2 respectively. The inter-rater and intra-rater agreement in the score application were both excellent. CONCLUSIONS: The AIM score predicts AQP4-IgG positivity with good sensitivity and specificity in patients with a first episode of LETM. The score may assist clinicians in early diagnosis and treatment of AQP4-IgG positive LETM.

Unmet needs and gaps in the identification of secondary progression in multiple sclerosis: a Southern Italy healthcare professionals' perspective.

OBJECTIVE: Multiple sclerosis (MS) is a chronic disease with different clinical courses and a tendency to worsening. The relapsing-remitting MS presents acute onset and relapses of neurological symptoms, followed by their remission. This form can convert to secondary progressive MS (SPMS) with irreversible neurological worsening and disability. The identification of signs, symptoms, markers of progression, and strategies to manage MS patients is mandatory to allow early identification of those at higher risk of conversion to SPMS, for prompt intervention to cope with the progression of the disease. METHODS: A panel of Italian experts from Southern Italy have reviewed the current knowledge on MS and its management and identified the crucial tools for SPMS recognition. RESULTS: More effective communication between patients and clinicians should be established, with the support of digital tools. Moreover, the improvement in the clinical use of biomarkers for progression (cellular structures and tissue organization, such as neurofilaments and chitinase 3-like 1, axonal and neurons density) and of instrumental analyses for recognition of whole-brain atrophy, chronic active lesions, spinal cord lesions and atrophy, and the improvement the combination of the Expanded Disability Status Scale and the evaluation of cognitive dysfunction are discussed. CONCLUSION: Given the availability of a pharmacological option, adequate education both for patients, regarding the evolution of the disease and the specific treatment, and for professionals, to allow more effective and sensitive communication and the best use of diagnostic and management tools, could represent a strategy to improve patient management and their quality of life.

Safety profile of SARS-CoV-2 vaccination in patients with antibody-mediated CNS disorders.

OBJECTIVES: In this retrospective multicenter study, we evaluated the safety of SARS-CoV-2 vaccination in patients harboring autoantibodies targeting neuronal surface and/or synaptic antigens. METHODS: From eight Italian Neurology Units, we included patients with: a) serum and/or CSF positivity for specific neuronal autoantibodies; b) a compatible neurological syndrome; and c) available follow-up ≥6 weeks after vaccination with any of the approved SARS-CoV-2 vaccines. Demographics, clinical data, and information regarding previous SARS-CoV-2 infection and vaccination were collected. Disease relapses were considered "post-infectious" or "post-vaccination" when occurring within 6 weeks from infection/vaccination. RESULTS: We included 66 patients; 7/66 (11%) had a previous history of SARS-CoV-2 infection and 1/7 (14%) had post-infection relapses. BNT162b2-Pfizer-BioNTec was administered in 55 cases (83.3%) and mRNA-1273-Moderna in 11 (16.7%). The median number of doses administered per patient was 2 (1-3) and >50% of patients did not experience side effects. Five patients (8%) had post-vaccination relapses (seizure 3/5); 4/5 improved after immunotherapy, while one did not receive immunotherapy and worsened. Patients with post-vaccination relapses had higher disability scores at vaccination (p = 0.025), a trend favoring Leucine-rich glioma-inactivated protein 1 LGI1 glutamic acid decarboxylase 65 (GAD65) antibodies (p =  0.054) and shorter time from last relapse (p = 0.057). DISCUSSION: Our data support the safety of SARS-CoV-2 vaccines in patients with neurological disorders associated with antibodies to neuronal and synaptic antigens.

PML risk is the main factor driving the choice of discontinuing natalizumab in a large multiple sclerosis population: results from an Italian multicenter retrospective study.

BACKGROUND: Natalizumab (NTZ) is an effective treatment for relapsing-remitting multiple sclerosis (RRMS). However, patients and physicians may consider discontinuing NTZ therapy due to safety or efficacy issues. The aim of our study was to evaluate the NTZ discontinuation rate and reasons of discontinuation in a large Italian population of RRMS patients. MATERIALS AND METHODS: The data were extracted from the Italian MS registry in May 2018 and were collected from 51,845 patients in 69 Italian multiple sclerosis centers. MS patients with at least one NTZ infusion in the period between June 1st 2012 to May 15th 2018 were included. Discontinuation rates at each time point were calculated. Reasons for NTZ discontinuation were classified as "lack of efficacy", "progressive multifocal leukoencephalopathy (PML) risk" or "other". RESULTS: Out of 51,845, 5151 patients, 3019 (58.6%) females, with a mean age of 43.6 ± 10.1 years (median 40), were analyzed. Out of 2037 (39.5%) who discontinued NTZ, a significantly higher percentage suspended NTZ because of PML risk compared to lack of efficacy [1682 (32.7% of 5151) vs 221 (4.3%), p < 0.001]; other reasons were identified for 99 (1.9%) patients. Patients discontinuing treatment were older, had longer disease duration and worse EDSS at the time of NTZ initiation and at last follow-up on NTZ treatment. The JCV index and EDSS at baseline were predictors for stopping therapy (HR 2.94, 95% CI 1.22-4.75; p = 0.02; HR 1.36, 95% CI 1.18-5.41; p = 0.04). CONCLUSIONS: Roughly 60% of MS patients stayed on NTZ treatment during the observation period. For those patients in whom NTZ discontinuation was required, it was mainly due to PML concerns.

Signals of pseudo-starvation unveil the amino acid transporter SLC7A11 as key determinant in the control of Treg cell proliferative potential.

Human CD4+CD25hiFOXP3+ regulatory T (Treg) cells are key players in the control of immunological self-tolerance and homeostasis. Here, we report that signals of pseudo-starvation reversed human Treg cell in vitro anergy through an integrated transcriptional response, pertaining to proliferation, metabolism, and transmembrane solute carrier transport. At the molecular level, the Treg cell proliferative response was dependent on the induction of the cystine/glutamate antiporter solute carrier (SLC)7A11, whose expression was controlled by the nuclear factor erythroid 2-related factor 2 (NRF2). SLC7A11 induction in Treg cells was impaired in subjects with relapsing-remitting multiple sclerosis (RRMS), an autoimmune disorder associated with reduced Treg cell proliferative capacity. Treatment of RRMS subjects with dimethyl fumarate (DMF) rescued SLC7A11 induction and fully recovered Treg cell expansion. These results suggest a previously unrecognized mechanism that may account for the progressive loss of Treg cells in autoimmunity and unveil SLC7A11 as major target for the rescue of Treg cell proliferation.

GAD65 autoimmunity after treatment with nivolumab: a multifocal presentation.

INTRODUCTION: Neurological disorders are considered rare complications of immune-checkpoint inhibitor. CASE DESCRIPTION: We report a 63-year-old man with recurrence of melanoma who presented epilepsy, limbic encephalitis, cerebellar ataxia, and stiff person syndrome soon after treatment with nivolumab, an immune-checkpoint inhibitor. On autoimmune screening, serum and CSF GAD65 were detected. Significant response to steroids and intravenous immunoglobulins were observed, but cancer recurred after nivolumab discontinuation in parallel with epileptic seizure and worsening of cognitive impairment and the patient died. DISCUSSION: This case expands the spectrum of GAD65-associated conditions induced by immune-checkpoint inhibitor and underlines treatment complexity when both neurological complications and tumour recurrence occur.

MRI activity and extended interval of Natalizumab dosing regimen: a multicentre Italian study.

BACKGROUND: To minimize the risk of Progressive Multifocal Leukoencephalopathy and rebound in JCV-positive multiple sclerosis (MS) patients after 24 natalizumab doses, it has been proposed to extend the administrations interval. The objective is to evaluate the EID efficacy on MRI activity compared with the standard interval dosing (SID). METHODS: Observational, multicentre, retrospective cohort study, starting from the 24th natalizumab infusion to the loss of follow-up or 2 years after baseline. Three hundred and sixteen patients were enrolled. The median dose interval (MDI) following the 24th infusion was 5 weeks, with a bimodal distribution (modes at 4 and 6 weeks). Patients were grouped into 2 categories according to the mean number of weeks between doses: <5 weeks, SID; ≥5 weeks, EID. RESULTS: One hundred and eighty-seven patients were in the SID group (MDI = 4.5 weeks) and 129 in the EID group (MDI 6.1 weeks). The risk to develop active lesions on MRI is similar in SID and EID groups during the 6 and 12 months after the 24th natalizumab infusion, respectively 4.27% (95% CI:0.84-7.70) vs 4.71% (95% CI:0.16-9.25%) [p = 0.89] and 8.50% (95% CI:4.05-12.95) vs 6.55% (95% CI:2.11-11.00%) [p = 0.56]. The EID regimen does not appear to increase the occurrence of MRI activity during follow-up. CONCLUSION: There is no evidence of the reduced efficacy of natalizumab in an EID setting regarding the MRI activity. This observation supports the need for a bigger randomized study to assess the need to change the standard of the natalizumab dosing schedule, to better manage JCV-positive patients.

Preliminary Results of the FASM Study, an On-Going Italian Active Pharmacovigilance Project.

BACKGROUND AND AIM: Disease-modifying therapies (DMTs) used in multiple sclerosis (MS) have distinct safety profiles. In this paper, we report preliminary results of an on-going pharmacovigilance project (the FASM study). RESULTS: Neurologists working at involved multiple sclerosis centers collected 272 Individual Case Safety Reports (ICSRs). Adverse drug reactions (ADRs) mainly occurred in adult patients and in a higher percentage of women compared to men. No difference was found in ADRs distribution by seriousness. The outcome was reported as favorable in 61% of ICSRs. Out of 272 ICSRs, almost 53% reported dimethyl fumarate, fingolimod and IFN beta 1a as suspected. These medications were commonly associated to the occurrence of ADRs related hematological, gastrointestinal, general, infective or cancer disorders. The median time to event (days) was 177 for dimethyl fumarate, 1058 for fingolimod and 413 for IFN beta 1a. The median time to event for the remaining suspected drugs was 226. CONCLUSION: We believe that our results, together with those that will be presented at the end of the study, may bring new knowledge concerning the safety profile of DMTs and their proper use. This will provide the opportunity to draw new recommendations both for neurologists and patients.

Epileptic seizures of suspected autoimmune origin: a multicentre retrospective study.

OBJECTIVE: To analyse autoantibody status in a well-defined European multicentre cohort of patients with epilepsy of unknown aetiology and to validate the recently proposed Antibody Prevalence in Epilepsy (APE2) and Response to ImmunoTherapy in Epilepsy (RITE2) scores. METHODS: We retrospectively collected clinical and paraclinical data of 92 patients referred to the Neurology Units of Verona and Salzburg between January 2014 and July 2019 with new-onset epilepsy, status epilepticus or chronic epilepsy of unknown aetiology. Fixed and live cell-based assays, tissue-based assays, immunoblot, and live rat hippocampal cell cultures were performed in paired serum/cerebrospinal fluid (CSF) to detect antineuronal and antiglial antibodies. The APE2 and RITE2 scores were then calculated and compared with clinical and laboratory data. RESULTS: Autoantibodies were detected in 29/92 patients (31.5%), with multiple positivity observed in 6/29 cases. The APE2 score (median 5, range 1-15) significantly correlated with antibody positivity (p=0.014), especially for the presence of neuropsychiatric symptoms (p<0.01), movement disorders (p<0.01), dysautonomia (p=0.03), faciobrachial dyskinesias (p=0.03) and cancer history (p<0.01). Status epilepticus was significantly more frequent in antibody-negative patients (p<0.01). Among the items of the RITE2 score, early initiation of immunotherapy correlated with a good treatment response (p=0.001), whereas a cancer history was significantly more common among non-responders (p<0.01). Persistence of neuropsychiatric symptoms and seizures correlated with antiepileptic maintenance after at least 1 year. CONCLUSIONS: This is the first study that independently validates the APE2 and RITE2 scores and includes the largest cohort of patients whose paired serum and CSF samples have been tested for autoantibodies possibly associated with autoimmune epilepsy.

Brain Radionecrosis After Adjuvant Radiation Therapy for a Primary Intracerebral Undifferentiated Sarcoma.

BACKGROUND: Primary intracranial sarcomas of the central nervous system are rare tumors. They mainly arise from intracranial mesenchymal tissue present in the meninges and can occur at any age. Sometimes osteosarcoma can involve the skull rather than long body bones. In this latter case it is the more common subtype. Surgery, when possible, is a mandatory option often associated with radiation therapy (RT) and chemotherapy. Brain radionecrosis (BRN) is commonly observed due to the growing use of radiosurgery and higher cumulative doses of radiation therapy. The combination of perfusion magnetic resonance imaging and 18fluoro-deoxy-glucose positron emission tomography can help to differentiate tumor progression from radiation injury. Steroids, anticoagulants, and bevacizumab usually control BRN. However, BRN can also have an unfavorable course. CASE DESCRIPTION: Here, we present a case of a 60-year-old male who underwent surgery for a brain tumor. The examination showed a primary undifferentiated high-grade sarcoma. Adjuvant RT was given with a total dose of 60 Gy. Six months later, the patient underwent a second surgery that revealed a BRN progressing despite different pharmacologic attempts. CONCLUSIONS: Primary intracranial sarcomas of the central nervous system are less prevalent among older adults with respect to the younger population. The use of RT alone or combined with chemotherapy is aimed at prolonging survival. However, it is not clearly defined if adjuvant treatments affect this parameter in older patients. RT should be carefully discussed owing to its potential severe neurologic toxicity. Indeed, a BRN can have a significant impact on quality of life and lead to death in certain cases.

Characteristics and treatment of Multiple Sclerosis-related trigeminal neuralgia: An Italian multi-centre study.

BACKGROUND: The prevalence of trigeminal neuralgia (TN) in Multiple Sclerosis (MS) patients is higher than in the general population and its management can be particularly challenging. Our aim is to describe the characteristics, treatment and prognostic factors of MS-related TN in a retrospective multicentre study. METHODS: Neurologists members of the RIREMS group (Rising Researchers in MS) enrolled MS patients with a TN diagnosis and filled out a spreadsheet comprising their clinical data. RESULTS: Population consisted of 298 patients. First-choice preventive treatments were carbamazepine and oxcarbazepine. A surgical procedure was performed in 81 (30%) patients, most commonly gamma knife stereotactic radiosurgery (37%), followed by microvascular decompression (22%) and radiofrequency thermocoagulation (21%); one third of patients underwent at least two procedures. Surgery was associated with higher disability, male sex and longer interval between MS and TN onset. Patients (77%) who stayed on at least one preventive medication at most recent follow-up, after a mean period of 8 years, had a higher disability compared to the untreated group. Furthermore, patients with higher disability at TN onset were less likely to discontinue their first preventive medication due to pain remission, had bilateral TN more frequently and underwent surgical interventions earlier. CONCLUSION: MS patients with a higher disability at TN onset and with a longer interval between MS and TN onset had differing clinical features and outcomes: pain was more frequently bilateral, surgery was more frequent and anticipated, and preventive medication discontinuation due to pain remission was less common.

Extending the Interval of Natalizumab Dosing: Is Efficacy Preserved?

Extending the natalizumab interval after the 24th administration could reduce the risk of progressive multifocal leukoencephalopathy (PML). The objective is to evaluate the noninferiority of the efficacy of an extended interval dosing (EID) compared with the standard interval dosing (SID) of natalizumab. It is an observational, multicenter (14 Italian centers), retrospective cohort study, starting from the 24th natalizumab infusion to the loss of follow-up or 2 years after baseline. Patients were grouped in 2 categories according to the mean number of weeks between doses: < 5 weeks, SID; ≥ 5 weeks, EID. Three hundred and sixty patients were enrolled. Median dose interval (MDI) following 24th infusion was 4.7 weeks, with a bimodal distribution (modes at 4 and 6 weeks). Two hundred and sixteen patients were in the SID group (MDI = 4.3 weeks) and 144 in the EID group (MDI 6.2 weeks). Annualized relapse rate was 0.060 (95% CI = 0.033-0.087) in the SID group and 0.039 (95% CI = 0.017-0.063) in the EID group. The non-inferiority of EID versus SID was satisfied. In conclusion, there is no evidence of a reduced efficacy of natalizumab in an EID setting. This observation confirms previous results and together with the emerging evidence of a reduced risk of PML associated to an EID, supports the need of a randomized study to assess the need to change the standard of the natalizumab dosing schedule.

THC/CBD oromucosal spray in patients with multiple sclerosis overactive bladder: a pilot prospective study.

Lower urinary tract dysfunctions (LUTDs) are commonly reported in multiple sclerosis (MS) patients and are mainly related to neurogenic overactive bladder (OAB). The aim of this observational study was to assess the effect of a tetrahydrocannabinol-cannabidiol (THC/CBD) oromucosal spray on resistant OAB by means of clinical and instrumental tools. Twenty-one MS patients were screened, and 15 cases have been evaluated. They underwent a specific clinical assessment (overactive bladder symptom score, OABSS) and a urodynamic assessment evaluating the maximal cystometric capacity (CCmax), bladder compliance (Qmax), maximum detrusor pressure (Pdet max), detrusor pressure at the first desire (Pdet first), bladder volume at the first desire (BVFD), leakage volume (LV), and post-void residual volume (PVR), before and after 4 weeks of THC/CBD administration. A complete neurological evaluation, including the assessment of their spasticity using the Modified Ashworth Scale (MAS) and the spasticity 0-10 numerical rating scale (NRS), was performed at the same times. Mobility was evaluated through the 25-ft walking-time test (T25-WT). The THC/CBD treatment successfully reduced the OAB symptoms (p = 0.001). Regarding the urodynamic findings after the end of treatment, PVR was significantly reduced (p = 0.016). Regarding the urodynamic findings after the end of treatment, PVR was significantly reduced (p = 0.016), while BVFD and CCmax were increased although the difference was not statistically significant. THC/CBD oromucosal spray has shown to be effective in improving overactive bladder symptoms in MS patients demonstrating a favorable impact on detrusor overactivity.

Glycolysis controls the induction of human regulatory T cells by modulating the expression of FOXP3 exon 2 splicing variants.

Human regulatory T cells (T(reg) cells) that develop from conventional T cells (T(conv) cells) following suboptimal stimulation via the T cell antigen receptor (TCR) (induced T(reg) cells (iT(reg) cells)) express the transcription factor Foxp3, are suppressive, and display an active proliferative and metabolic state. Here we found that the induction and suppressive function of iT(reg) cells tightly depended on glycolysis, which controlled Foxp3 splicing variants containing exon 2 (Foxp3-E2) through the glycolytic enzyme enolase-1. The Foxp3-E2-related suppressive activity of iT(reg) cells was altered in human autoimmune diseases, including multiple sclerosis and type 1 diabetes, and was associated with impaired glycolysis and signaling via interleukin 2. This link between glycolysis and Foxp3-E2 variants via enolase-1 shows a previously unknown mechanism for controlling the induction and function of T(reg) cells in health and in autoimmunity.