Publications by authors named "Caroline Pot"

39 Publications

Recurrence of disease activity after fingolimod discontinuation in older patients previously stable on treatment.

Mult Scler Relat Disord 2021 Mar 21;51:102918. Epub 2021 Mar 21.

Division of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital, Lausanne, Switzerland. Electronic address:

Background: Discontinuing fingolimod (FTY) in older patients is a growing concern with little evidence supporting the decision to pursue treatment and reasonable doubt for disease reactivation after withdrawal.

Objective: To estimate the incidence of recurrence of disease activity (RDA) and rebound after FTY withdrawal in patients older than 50 years.

Methods: Retrospective analysis of all MS patients in our clinic who discontinued FTY after at least 6 months of treatment, according to disease activity on FTY and age at discontinuation. RDA was defined as the occurrence of either clinical and/or MRI activity in the 6 months after FTY withdrawal and rebound when the levels of disease activity surpassed pretreatment activity.

Results: From the 128 patients who discontinued FTY since 2011, up to 35.2% of patients experienced evidence of disease activity and 12.5% had a rebound. The incidence of both RDA and rebound was not different among individuals who had persistent disease activity on FTY to those who stopped FTY for other reasons than inefficacy (RDA: 25.5% vs 20.5%, p = 0.353 rebound: 14.5% vs 11%, p = 0.596). Negative predictive factors for RDA were younger age at disease onset (p = 0.036), highly active disease at baseline (p = 0.003) and previous treatment with NTZ (p = 0.013). Older age at FTY discontinuation did not reduce the risk of RDA in patients previously stable on treatment (OR 0.972, 95% CI 0.871-1.085, p = 0.613), although the incidence of RDA/rebound was half less in the older patients (36.5% in the <50 vs 19% in the ≥50 year-old, p = 0.174) and none of the patients over 60 experienced RDA.

Conclusion: Although there is a tendency for a lower risk of disease reactivation in the older patients, the incidence of RDA, and even rebound, is not negligible between the age of 50 and 60 years, even in patients with previously stable MS on FTY.
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http://dx.doi.org/10.1016/j.msard.2021.102918DOI Listing
March 2021

Comparison of non-parametric T relaxometry methods for myelin water quantification.

Med Image Anal 2021 04 8;69:101959. Epub 2021 Jan 8.

Computer Science Department, University of Verona, Verona, Italy.

Multi-component T relaxometry allows probing tissue microstructure by assessing compartment-specific T relaxation times and water fractions, including the myelin water fraction. Non-negative least squares (NNLS) with zero-order Tikhonov regularization is the conventional method for estimating smooth T distributions. Despite the improved estimation provided by this method compared to non-regularized NNLS, the solution is still sensitive to the underlying noise and the regularization weight. This is especially relevant for clinically achievable signal-to-noise ratios. In the literature of inverse problems, various well-established approaches to promote smooth solutions, including first-order and second-order Tikhonov regularization, and different criteria for estimating the regularization weight have been proposed, such as L-curve, Generalized Cross-Validation, and Chi-square residual fitting. However, quantitative comparisons between the available reconstruction methods for computing the T distribution, and between different approaches for selecting the optimal regularization weight, are lacking. In this study, we implemented and evaluated ten reconstruction algorithms, resulting from the individual combinations of three penalty terms with three criteria to estimate the regularization weight, plus non-regularized NNLS. Their performance was evaluated both in simulated data and real brain MRI data acquired from healthy volunteers through a scan-rescan repeatability analysis. Our findings demonstrate the need for regularization. As a result of this work, we provide a list of recommendations for selecting the optimal reconstruction algorithms based on the acquired data. Moreover, the implemented methods were packaged in a freely distributed toolbox to promote reproducible research, and to facilitate further research and the use of this promising quantitative technique in clinical practice.
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http://dx.doi.org/10.1016/j.media.2021.101959DOI Listing
April 2021

An IL-27-Driven Transcriptional Network Identifies Regulators of IL-10 Expression across T Helper Cell Subsets.

Cell Rep 2020 11;33(8):108433

Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address:

Interleukin-27 (IL-27) is an immunoregulatory cytokine that suppresses inflammation through multiple mechanisms, including induction of IL-10, but the transcriptional network mediating its diverse functions remains unclear. Combining temporal RNA profiling with computational algorithms, we predict 79 transcription factors induced by IL-27 in T cells. We validate 11 known and discover 5 positive (Cebpb, Fosl2, Tbx21, Hlx, and Atf3) and 2 negative (Irf9 and Irf8) Il10 regulators, generating an experimentally refined regulatory network for Il10. We report two central regulators, Prdm1 and Maf, that cooperatively drive the expression of signature genes induced by IL-27 in type 1 regulatory T cells, mediate IL-10 expression in all T helper cells, and determine the regulatory phenotype of colonic Foxp3 regulatory T cells. Prdm1/Maf double-knockout mice develop spontaneous colitis, phenocopying ll10-deficient mice. Our work provides insights into IL-27-driven transcriptional networks and identifies two shared Il10 regulators that orchestrate immunoregulatory programs across T helper cell subsets.
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http://dx.doi.org/10.1016/j.celrep.2020.108433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771052PMC
November 2020

The oxysterol receptor GPR183 in inflammatory bowel diseases.

Br J Pharmacol 2020 Nov 4. Epub 2020 Nov 4.

Institute of Molecular Medicine, RWTH Aachen University, Aachen, Germany.

Immune cell trafficking is an important mechanism for the pathogenesis of inflammatory bowel disease (IBD). The oxysterol receptor GPR183 and its ligands, dihydroxylated oxysterols, can mediate positioning of immune cells including innate lymphoid cells. GPR183 has been mapped to an IBD risk locus, however another gene, Ubac2 is encoded on the reverse strand and associated with Behçet's disease, therefore the role of GPR183 as a genetic risk factor requires validation. GPR183 and production of its oxysterol ligands are up-regulated in human IBD and murine colitis. Gpr183 inactivation reduced severity of colitis in group 3 innate lymphoid cells-dependent colitis and in IL-10 colitis but not in dextran sodium sulphate colitis. Irrespectively, Gpr183 knockout strongly reduced accumulation of intestinal lymphoid tissue in health and all colitis models. In conclusion, genetic, translational and experimental studies implicate GPR183 in IBD pathogenesis and GPR183-dependent cell migration might be a therapeutic drug target for IBD.
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http://dx.doi.org/10.1111/bph.15311DOI Listing
November 2020

Paramagnetic Rim Lesions are Specific to Multiple Sclerosis: An International Multicenter 3T MRI Study.

Ann Neurol 2020 11 9;88(5):1034-1042. Epub 2020 Sep 9.

Department of Neurology, Johns Hopkins University, Baltimore, MD.

In multiple sclerosis (MS), a subset of chronic active white matter lesions are identifiable on magnetic resonance imaging by their paramagnetic rims, and increasing evidence supports their association with severity of clinical disease. We studied their potential role in differential diagnosis, screening an international multicenter clinical research-based sample of 438 individuals affected by different neurological conditions (MS, other inflammatory, infectious, and non-inflammatory conditions). Paramagnetic rim lesions, rare in other neurological conditions (52% of MS vs 7% of non-MS cases), yielded high specificity (93%) in differentiating MS from non-MS. Future prospective multicenter studies should validate their role as a diagnostic biomarker. ANN NEUROL 2020;88:1034-1042.
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http://dx.doi.org/10.1002/ana.25877DOI Listing
November 2020

The central vein sign in multiple sclerosis patients with vascular comorbidities.

Mult Scler 2020 Aug 4:1352458520943785. Epub 2020 Aug 4.

Department of Neurology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium/Department of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland/Department of Neurology, Cliniques universitaires Saint Luc, Université Catholique de Louvain, Brussels, Belgium.

Background: The central vein sign (CVS) is an imaging biomarker able to differentiate multiple sclerosis (MS) from other conditions causing similar appearance lesions on magnetic resonance imaging (MRI), including cerebral small vessel disease (CSVD). However, the impact of vascular risk factors (VRFs) for CSVD on the percentage of CVS positive (CVS) lesions in MS has never been evaluated.

Objective: To investigate the association between different VRFs and the percentage of CVS lesions in MS.

Methods: In 50 MS patients, 3T brain MRIs (including high-resolution 3-dimensional T2*-weighted images) were analyzed for the presence of the CVS and MRI markers of CSVD. A backward stepwise regression model was used to predict the combined predictive effect of VRF (i.e. age, hypertension, diabetes, obesity, ever-smoking, and hypercholesterolemia) and MRI markers of CSVD on the CVS.

Results: The median frequency of CVS lesions was 71% (range: 35%-100%). In univariate analysis, age ( < 0.0001), hypertension ( < 0.001), diabetes ( < 0.01), obesity ( < 0.01), smoking ( < 0.05), and the presence of enlarged-perivascular-spaces on MRI ( < 0.005) were all associated with a lower percentage of CVS lesions. The stepwise regression model showed that age and arterial hypertension were both associated with the percentage of CVS lesions in MS (adjusted  = 0.46;  < 0.0001 and  = 0.01, respectively).

Conclusion: The proportion of CVS lesions significantly decreases in older and hypertensive MS patients. Although this study was conducted in patients with an already established MS diagnosis, the diagnostic yield of the previously proposed 35% CVS proportion-based diagnostic threshold appears to be not affected. Overall these results suggest that the presence of VRF for CSVD should be taken into account during the CVS assessment.
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http://dx.doi.org/10.1177/1352458520943785DOI Listing
August 2020

Neurologie et COVID-19.

Rev Med Suisse 2020 May;16(692):947-949

Service de Neurologie, Hôpital du Valais, 1950 Sion.

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May 2020

60/30: 60% of the Morbidity-Associated Multiple Sclerosis Disease Burden Comes From the 30% of Persons With Higher Impairments.

Front Neurol 2020 6;11:156. Epub 2020 Mar 6.

Department of Epidemiology, Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland.

Multiple sclerosis (MS) is the most common chronic, non-traumatic, neurologic disease in young adults. While approximate values of the disease burden of MS are known, individual drivers are unknown. To estimate the age-, sex-, and disease severity-specific contributions to the disease burden of MS. We estimated the disease burden of MS using disability-adjusted life years (DALYs) following the Global Burden of Disease study (GBD) methodology. The data sources consisted of the Swiss MS Registry, a recent prevalence estimation, and the Swiss mortality registry. The disease burden of MS in Switzerland in 2016 was 6,938 DALYs (95%-interval: 6,018-7,955), which corresponds to 97 DALYs per 100,000 adult inhabitants. Morbidity contributed 59% of the disease burden. While persons in an asymptomatic (EDSS-proxy 0) and mild (EDSS-proxy >0-3.5) disease stage represent 68.4% of the population, they make up 39.8% of the MS-specific morbidity. The remaining 60.2% of the MS-specific morbidity stems from the 31.6% of persons in a moderate (EDSS-proxy 4-6.5) or severe (EDSS-proxy ≥7) disease stage. Morbidity has a larger influence on the disease burden of MS than mortality and is shared in a ratio of 2:3 between persons in an asymptomatic/mild and moderate/severe disease stage in Switzerland. Interventions to reduce severity worsening in combination with tailored, symptomatic treatments are important future paths to lower the disease burden of MS.
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http://dx.doi.org/10.3389/fneur.2020.00156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068809PMC
March 2020

Rôle de la nutrition et de la flore intestinale dans les maladies autoimmunes - Que sait-on vraiment ? Représentation et connaissances scientifiques.

Authors:
Caroline Pot

Rev Med Suisse 2020 Jan;16(679):184-185

Service de neurologie, Département des neurosciences cliniques, CHUV et Université de Lausanne, 1011 Lausanne.

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January 2020

Intercellular Adhesion Molecule-1 (ICAM-1) and ICAM-2 Differentially Contribute to Peripheral Activation and CNS Entry of Autoaggressive Th1 and Th17 Cells in Experimental Autoimmune Encephalomyelitis.

Front Immunol 2019 14;10:3056. Epub 2020 Jan 14.

Theodor Kocher Institute, University of Bern, Bern, Switzerland.

In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), myelin-specific T cells are activated in the periphery and differentiate in T helper (Th) 1 and Th17 effector cells, which cross the blood-brain barrier (BBB) to reach the central nervous system (CNS), where they induce neuroinflammation. Here, we explored the role of intercellular adhesion molecule-1 (ICAM-1) and ICAM-2 in the activation of naïve myelin-specific T cells and in the subsequent migration of differentiated encephalitogenic Th1 and Th17 cells across the BBB and . While on antigen-presenting cells ICAM-1, but not ICAM-2 was required for the activation of naïve CD4 T cells, endothelial ICAM-1 and ICAM-2 mediated both Th1 and Th17 cell migration across the BBB. ICAM-1/-2-deficient mice developed ameliorated typical and atypical EAE transferred by encephalitogenic Th1 and Th17 cells, respectively. Our study underscores important yet cell-specific contributions for ICAM-1 and ICAM-2 in EAE pathogenesis.
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http://dx.doi.org/10.3389/fimmu.2019.03056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6970977PMC
November 2020

Disrupting Myelin-Specific Th17 Cell Gut Homing Confers Protection in an Adoptive Transfer Experimental Autoimmune Encephalomyelitis.

Cell Rep 2019 Oct;29(2):378-390.e4

Laboratories of Neuroimmunology, Neuroscience Research Center and Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Chemin des Boveresses 155, 1066 Epalinges, Switzerland. Electronic address:

Multiple sclerosis (MS) is a common autoimmune disease of the CNS. Although an association between MS and inflammatory bowel diseases is observed, the link connecting intestinal immune responses and neuroinflammation remains unclear. Here we show that encephalitogenic Th17 cells infiltrate the colonic lamina propria before neurological symptom development in two murine MS models, active and adoptive transfer experimental autoimmune encephalomyelitis (EAE). Specifically targeting Th17 cell intestinal homing by blocking the α4β7-integrin and its ligand MAdCAM-1 pathway impairs T cell migration to the large intestine and dampens EAE severity in the Th17 cell adoptive transfer model. Mechanistically, myelin-specific Th17 cells proliferate in the colon and affect gut microbiota composition. The beneficial effect of blocking the α4β7-integrin and its ligand MAdCAM-1 pathway on EAE is interdependent with gut microbiota. Those results show that disrupting myelin-specific Th17 cell trafficking to the large intestine harnesses neuroinflammation and suggests that the gut environment and microbiota catalyze the encephalitogenic properties of Th17 cells.
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http://dx.doi.org/10.1016/j.celrep.2019.09.002DOI Listing
October 2019

Oxysterols in Autoimmunity.

Int J Mol Sci 2019 Sep 12;20(18). Epub 2019 Sep 12.

Laboratories of Neuroimmunology, Neuroscience Research Center and Division of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital and Lausanne University, Chemin des Boveresses 155, 1066 Epalinges, Switzerland.

Cholesterol is a member of the sterol family that plays essential roles in biological processes, including cell membrane stability and myelin formation. Cholesterol can be metabolized into several molecules including bile acids, hormones, and oxysterols. Studies from the last few decades have demonstrated that oxysterols are not only active metabolites but are further involved in the modulation of immune responses. Liver X Receptors (LXRs), nuclear receptors for oxysterols, are important for cholesterol homeostasis and regulation of inflammatory response but are still poorly characterized during autoimmune diseases. Here we review the current knowledge about the role of oxysterols during autoimmune conditions and focus on the implication of LXR-dependent and LXR-independent pathways. We further highlight the importance of these pathways in particular during central nervous system (CNS) autoimmunity and inflammatory bowel diseases (IBD) in both experimental models and human studies. Finally, we discuss our vision about future applications and research on oxysterols related to autoimmunity.
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http://dx.doi.org/10.3390/ijms20184522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770630PMC
September 2019

The "central vein sign" in patients with diagnostic "red flags" for multiple sclerosis: A prospective multicenter 3T study.

Mult Scler 2020 04 19;26(4):421-432. Epub 2019 Sep 19.

Department of Neurology, Center of Clinical Neurosciences, Lausanne University Hospital, Lausanne, Switzerland.

Background: The central vein sign (CVS) has been shown to help in the differential diagnosis of multiple sclerosis (MS), but most prior studies are retrospective.

Objectives: To prospectively assess the diagnostic predictive value of the CVS in diagnostically difficult cases.

Methods: In this prospective multicenter study, 51 patients with suspected MS who had clinical, imaging, or laboratory "red flags" (i.e. features atypical for MS) underwent 3T fluid-attenuated inversion recovery (FLAIR*) magnetic resonance imaging (MRI) for CVS assessment. After the diagnostic work-up, expert clinicians blinded to the results of the CVS assessment came to a clinical diagnosis. The value of the CVS to prospectively predict an MS diagnosis was assessed.

Results: Of the 39 patients who received a clinical diagnosis by the end of the study, 27 had MS and 12 received a non-MS diagnosis that included systemic lupus erythematosus, sarcoidosis, migraine, Sjögren disease, SPG4-spastic-paraparesis, neuromyelitis optica, and Susac syndrome. The percentage of perivenular lesions was higher in MS (median = 86%) compared to non-MS (median = 21%;  < 0.0001) patients. A 40% perivenular lesion cutoff was associated with 97% accuracy and a 96% positive/100% negative predictive value.

Conclusion: The CVS detected on 3T FLAIR* images can accurately predict an MS diagnosis in patients suspected to have MS, but with atypical clinical, laboratory, and imaging features.
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http://dx.doi.org/10.1177/1352458519876031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080603PMC
April 2020

How do patients enter the healthcare system after the first onset of multiple sclerosis symptoms? The influence of setting and physician specialty on speed of diagnosis.

Mult Scler 2020 04 18;26(4):489-500. Epub 2019 Jan 18.

Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland.

Background: Diagnosing multiple sclerosis (MS) early is crucial to avoid future disability. However, potentially preventable delays in the diagnostic cascade from contact with a physician to definite diagnosis still occur and their causes are still unclear.

Objective: To identify the possible causes of delays in the diagnostic process.

Methods: We analyzed the data of the Swiss MS Registry. With logistic regression, we modeled the time from the first contact to the first consultation (contact-to-evaluation time, ⩽1 month/>1 month) and the evaluation-to-diagnosis time (⩽6 months/>6 months). Potential factors were health system characteristics, sociodemographic variables, first symptoms, and MS type.

Results: We included 522 participants. Mostly, general practitioners (67%) were contacted first, without delaying the diagnosis. In contrast, first symptoms and MS type were the major contributors to delays: gait problems were associated with longer contact-to-evaluation times, depression as a concomitant symptom with longer evaluation-to-diagnosis times, and having primary progressive MS prolonged both phases. In addition, living in mountainous areas was associated with longer contact-to-evaluation times, whereas diagnosis after 2000 was associated with faster diagnoses.

Conclusion: For a quicker diagnosis, awareness of MS as a differential diagnosis of gait disorders and the co-occurrence of depression at onset should be raised, and these symptoms should be attentively followed.
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http://dx.doi.org/10.1177/1352458518823955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140343PMC
April 2020

The EBI2-oxysterol axis promotes the development of intestinal lymphoid structures and colitis.

Mucosal Immunol 2019 05 11;12(3):733-745. Epub 2019 Feb 11.

Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

The gene encoding for Epstein-Barr virus-induced G-protein-coupled receptor 2 (EBI2) is a risk gene for inflammatory bowel disease (IBD). Together with its oxysterol ligand 7α,25-dihydroxycholesterol, EBI2 mediates migration and differentiation of immune cells. However, the role of EBI2 in the colonic immune system remains insufficiently studied. We found increased mRNA expression of EBI2 and oxysterol-synthesizing enzymes (CH25H, CYP7B1) in the inflamed colon of patients with ulcerative colitis and mice with acute or chronic dextran sulfate sodium (DSS) colitis. Accordingly, we detected elevated levels of 25-hydroxylated oxysterols, including 7α,25-dihydroxycholesterol in mice with acute colonic inflammation. Knockout of EBI2 or CH25H did not affect severity of DSS colitis; however, inflammation was decreased in male EBI2 mice in the IL-10 colitis model. The colonic immune system comprises mucosal lymphoid structures, which accumulate upon chronic inflammation in IL-10-deficient mice and in chronic DSS colitis. However, EBI2 mice formed significantly less colonic lymphoid structures at baseline and showed defects in inflammation-induced accumulation of lymphoid structures. In summary, we report induction of the EBI2-7α,25-dihydroxycholesterol axis in colitis and a role of EBI2 for the accumulation of lymphoid tissue during homeostasis and inflammation. These data implicate the EBI2-7α,25-dihydroxycholesterol axis in IBD pathogenesis.
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http://dx.doi.org/10.1038/s41385-019-0140-xDOI Listing
May 2019

Factors associated with time from first-symptoms to diagnosis and treatment initiation of Multiple Sclerosis in Switzerland.

Mult Scler J Exp Transl Clin 2018 Oct-Dec;4(4):2055217318814562. Epub 2018 Dec 6.

Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Switzerland.

Background: Recent studies emphasise the importance of timely diagnosis and early initiation of disease-modifying treatment in the long-term prognosis of multiple sclerosis.

Objectives: The objective of this study was to investigate factors associated with extended time to diagnosis and time to disease-modifying treatment initiation in the Swiss Multiple Sclerosis Registry.

Methods: We used retrospective data (diagnoses 1996-2017) of the survey-based Swiss Multiple Sclerosis Registry and fitted logistic regression models (extended time to diagnosis ≥2 years from first symptoms, extended time to disease-modifying treatment initiation ≥1 year from diagnosis) with demographic and a priori defined variables.

Results: Our study, based on 996 persons with multiple sclerosis, suggests that 40% had an extended time to diagnosis, and extended time to disease-modifying treatment initiation was seen in 23%. Factors associated with extended time to diagnosis were primary progressive multiple sclerosis (odds ratio (OR) 5.09 (3.12-8.49)), diagnosis setting outside of hospital (neurologist (private practice) OR 1.54 (1.16-2.05)) and more uncommon first symptoms (per additional symptom OR 1.17 (1.06-1.30)). Older age at onset (per additional 5 years OR 0.84 (0.78-0.90)) and gait problems (OR 0.65 (0.47-0.89)) or paresthesia (OR 0.72 (0.54-0.95)) as first symptoms were associated with shorter time to diagnosis. Extended time to disease-modifying treatment initiation was associated with older age at diagnosis (per additional 5 years OR 1.18 (1.09-1.29)). In more recent years, time to diagnosis and time to disease-modifying treatment initiation tended to be shorter.

Conclusions: Even in recent periods, substantial and partially systematic variation regarding time to diagnosis and time to disease-modifying treatment initiation remains. With the emerging paradigm of early treatment, the residual variation should be monitored carefully.
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http://dx.doi.org/10.1177/2055217318814562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6293378PMC
December 2018

Patterns of care for Multiple Sclerosis in a setting of universal care access: A cross-sectional study.

Mult Scler Relat Disord 2019 Feb 2;28:17-25. Epub 2018 Dec 2.

Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Hirschengraben 84, 8001 Zurich, Switzerland. Electronic address:

Background: Current guidelines recommend regular neurological MS care in persons diagnosed with MS, but little is known about implementation of this recommendation or potential access barriers. This study examined disease-specific and sociodemographic differences between MS patients in Neurological Care (NeC), General Practitioner Care (GPC), or no Physician Care (NoPC) to identify group differences and characteristics that may suggest care access barriers.

Methods: Patient-reported data were analyzed from 1038 Swiss Multiple Sclerosis Registry participants by means of multivariable regression to identify systematic differences across the three care groups. Assessments included comprehensive data on clinical, sociodemographic, and geographic factors.

Results: 89% reported being in regular care by a neurologist (56% in private practices, 44% in hospitals), 5% were in GPC, and 6% reported No Physician Care (NoPC). Compared with the NeC group, patients not seeing a neurologist included two subgroups, one consisting of persons with a primary progressive MS (PPMS) and/or an extended MS history. The second subgroup included persons with a recent MS diagnosis within the last 2 years. Within the NeC group, the patients seen in private practices were of older age and more frequently female compared to those at clinics, but no differences were detected with regard to disability status, MS type, or treatment patterns.

Conclusions: Access to neurological care is high in Switzerland. Given the emerging paradigm for early treatment and new drugs for progressive MS, regular neurology visits should be promoted among patient groups currently less in neurological care such as persons with PPMS or recently diagnosed.
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http://dx.doi.org/10.1016/j.msard.2018.11.033DOI Listing
February 2019

The Swiss Multiple Sclerosis Registry (SMSR): study protocol of a participatory, nationwide registry to promote epidemiological and patient-centered MS research.

BMC Neurol 2018 Aug 13;18(1):111. Epub 2018 Aug 13.

Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Hirschengraben 84, CH-8001, Zurich, Switzerland.

Background: Multiple sclerosis (MS) is one of the most frequently observed neurological conditions in Switzerland, but data sources for country-wide epidemiological trend monitoring are lacking. Moreover, while clinical and laboratory MS research are generally well established, there is a gap in patient-centered MS research to inform care management, or treatment decisions and policy making not only in Switzerland but worldwide.

Methods: In light of these research gaps, the Swiss Multiple Sclerosis Society initiated and funded the Swiss Multiple Sclerosis Registry (SMSR) an open-ended, longitudinal and prospective, nationwide, patient-centered study. The SMSR recruits adult persons with a suspected or confirmed MS diagnosis who reside or receive care in Switzerland. The SMSR has established a governance structure with clear rules and guidelines. It follows a citizen-science approach with direct involvement of persons with MS (PwMS), who contribute actively to registry development, operations, and research. Main scientific goals entail the study of MS epidemiology in Switzerland, health care access and provision, as well as life circumstances and wellbeing of persons with MS. The innovative study design ("layer model") offers several participation options with different time commitments. Data collection is by means of regular surveys and medical record abstraction. Survey participation is offered in different modes (web, paper & pencil) and in the three main national languages (German, French, Italian). Participants also receive regular data feedbacks for personal use and self-monitoring, contextualized in the whole population of study participants. Data feedbacks are also used to solicit data corrections of key variables from participants.

Discussion: The SMSR combines the advantages of traditional and novel research methods in medical research and has recruited over 1600 PwMS in its first year. The future-oriented design and technology will enable a response not only to future technological innovations and research trends, but also to challenges in health care provision for MS.

Trial Registration: ClinicalTrials.gov   NCT02980640 ; December 6, 2016; retrospectively registered.
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http://dx.doi.org/10.1186/s12883-018-1118-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6088400PMC
August 2018

The disease burden of Multiple Sclerosis from the individual and population perspective: Which symptoms matter most?

Mult Scler Relat Disord 2018 Oct 21;25:112-121. Epub 2018 Jul 21.

Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland. Electronic address:

Background: MS symptoms affect many functional domains. Knowing the specific impact of symptoms on health-related quality of life (HRQoL) is vital for successful disease and symptom management in MS. We aimed at investigating how specific MS symptoms contribute to the disease burden in individuals and from a population perspective.

Methods: We included 855 Swiss Multiple Sclerosis Registry participants with a relapsing-remitting form (RRMS) or a progressive form (PMS). HRQoL was measured with the EuroQol 5-Dimension EQ-5D-index and EQ-Visual Analogue Scale (EQ-VAS) on 0-100% scales. Their associations with 20 symptoms, socio-demographic and clinical information were explored in median regression models, stratified by RRMS and PMS.

Results: We included 611 participants with RRMS and 244 with PMS. In RRMS, gait (-6.5%) and balance problems (-5.1%) had the largest EQ-5D-index reductions, and were also important at the population level (frequencies 45% and 52%). Fatigue, depression, and spasticity (frequencies 74.1%, 31%, 38%) also contributed to the population disease burden. In PMS, spasticity, paralysis, and bowel problems had the largest impact on EQ-5D-index, both at the individual and population levels. The largest impact on EQ-VAS at population level was associated in RRMS with balance problems, depression, dizziness, and spasticity, while in PMS with weakness, pain, and paralysis.

Conclusions: While HRQoL at population level is most affected by balance problems, spasticity, and depression in RRMS, the biggest HRQoL losses in PMS are caused by spasticity, paralysis, weakness, and pain. Many symptoms with the largest effects in individuals substantially contribute to the population disease burden.
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http://dx.doi.org/10.1016/j.msard.2018.07.013DOI Listing
October 2018

IL-27-Induced Type 1 Regulatory T-Cells Produce Oxysterols that Constrain IL-10 Production.

Front Immunol 2017 25;8:1184. Epub 2017 Sep 25.

Laboratories of Neuroimmunology, Division of Neurology and Neuroscience Research Center, Department of Clinical Neurosciences, Lausanne University Hospital, Lausanne, Switzerland.

The behaviors of lymphocytes, including CD4 T helper cells, are controlled on many levels by internal metabolic properties. Lipid metabolites have recently been ascribed a novel function as immune response modulators and perturbation of steroids pathways modulates inflammation and potentially promotes a variety of diseases. However, the impact of lipid metabolism on autoimmune disease development and lymphocyte biology is still largely unraveled. In this line, oxysterols, oxidized forms of cholesterol, have pleiotropic roles on the immune response aside from their involvements in lipid metabolism. The oxysterols 25-hydroxycholesterol (25-OHC) and 7α,25-dihydroxycholesterol (7α,25-OHC) regulate antiviral immunity and immune cell chemotaxis. However, their physiological effects on adaptive immune response in particular on various subset CD4 T lymphocytes are largely unknown. Here, we assessed oxysterol levels in subset of CD4 T cells and demonstrated that 25-OHC and transcript levels of its synthesizing enzyme, cholesterol 25-hydroxylase, were specifically increased in IL-27-induced type 1 regulatory T (T1) cells. We further showed that 25-OHC acts as a negative regulator of T1 cells in particular of IL-10 secretion liver X receptor signaling. Not only do these findings unravel molecular mechanisms accounting for IL-27 signaling but also they highlight oxysterols as pro-inflammatory mediators that dampens regulatory T cell responses and thus unleash a pro-inflammatory response.
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http://dx.doi.org/10.3389/fimmu.2017.01184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622150PMC
September 2017

Increased interleukin-27 cytokine expression in the central nervous system of multiple sclerosis patients.

J Neuroinflammation 2017 07 24;14(1):144. Epub 2017 Jul 24.

Department of Pathology and Immunology, Geneva University Hospital and University of Geneva, 1211, Geneva 4, Switzerland.

Background: Multiple sclerosis (MS) is an autoimmune disorder characterized by chronic inflammation, demyelination, and neuronal damage. During autoimmunity, cytokines are important mediators of the inflammation. In this line, interleukin-27 (IL-27) modulates inflammation and can be produced directly at inflammatory sites such as in the joints during rheumatoid arthritis or in the central nervous system (CNS) during MS. While in animal models of MS, treatment with IL-27 decreases the disease severity, its role in humans is not clearly established and it is not known if IL-27 could be detected in the cerebrospinal fluid (CSF) of MS patients.

Methods: In this study, we measured IL-27 levels using a quantitative enzyme-linked immunosorbent assay in CSF of patients with relapsing remitting multiple sclerosis (RRMS), isolated optic neuritis (ON) and non-inflammatory neurological disease (NIND) as well as in the sera of healthy donors (HD) and RRMS patients undergoing different disease modifying treatments. We further confirmed by immunohistology of patient biopsies the identity of IL-27 producing cells in the brain of active MS lesions.

Results: We observed that IL-27 levels are increased in the CSF but not in the sera of RRMS compared to HD. We confirmed that IL-27 is expressed in active MS plaques by astrocytes of MS patients.

Conclusions: Our results point toward a local secretion of IL-27 in the CNS that is increased during autoimmune processes. We propose that local production of IL-27 could sign the induction of a regulatory response that promotes inflammation's resolution. The effect of new immunomodulatory therapies on cerebral IL-27 production could be used to understand the biology of IL-27 in MS disease.
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http://dx.doi.org/10.1186/s12974-017-0919-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5525372PMC
July 2017

EBI2 Expression and Function: Robust in Memory Lymphocytes and Increased by Natalizumab in Multiple Sclerosis.

Cell Rep 2017 01;18(1):213-224

Laboratories of Neuroimmunology, Neuroscience Research Center, Department of Clinical Neurosciences, Lausanne University Hospital, Chemin des Boveresses 155, 1066 Epalinges, Switzerland; Department of Pathology and Immunology, Geneva University Medical Center, Rue Michel-Servet 1, 1211 Geneva 4, Switzerland; Division of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital, Rue du Bugnon 46, 1011 Lausanne, Switzerland. Electronic address:

The interaction between oxysterols and the G protein-coupled receptor Epstein-Barr virus-induced gene 2 (EBI2) fine-tunes immune cell migration, a mechanism efficiently targeted by several disease-modifying treatments developed to treat multiple sclerosis (MS), such as natalizumab. We previously showed that memory CD4 T lymphocytes migrate specifically in response to 7α,25-dihydroxycholesterol (7α,25-OHC) via EBI2 in the MS murine model experimental autoimmune encephalomyelitis. However, the EBI2 expression profile in human lymphocytes in both healthy and MS donors is unknown. Here, we characterize EBI2 biology in human lymphocytes. We observed that EBI2 is functionally expressed on memory CD4 T cells and is enhanced under natalizumab treatment. These data suggest a significant role for EBI2 in human CD4 T cell migration, notably in patients with MS. Better knowledge of EBI2 involvement in autoimmunity may therefore lead to an improved understanding of the physiopathology of MS.
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http://dx.doi.org/10.1016/j.celrep.2016.12.006DOI Listing
January 2017

The Swiss Multiple Sclerosis Cohort-Study (SMSC): A Prospective Swiss Wide Investigation of Key Phases in Disease Evolution and New Treatment Options.

PLoS One 2016 31;11(3):e0152347. Epub 2016 Mar 31.

Neurology, Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, Basel, Switzerland.

The mechanisms leading to disability and the long-term efficacy and safety of disease modifying drugs (DMDs) in multiple sclerosis (MS) are unclear. We aimed at building a prospective cohort of MS patients with standardized collection of demographic, clinical, MRI data and body fluids that can be used to develop prognostic indicators and biomarkers of disease evolution and therapeutic response. The Swiss MS Cohort (SMSC) is a prospective observational study performed across seven Swiss MS centers including patients with MS, clinically isolated syndrome (CIS), radiologically isolated syndrome or neuromyelitis optica. Neurological and radiological assessments and biological samples are collected every 6-12 months. We recruited 872 patients (clinically isolated syndrome [CIS] 5.5%, relapsing-remitting MS [RRMS] 85.8%, primary progressive MS [PPMS] 3.5%, secondary progressive MS [SPMS] 5.2%) between June 2012 and July 2015. We performed 2,286 visits (median follow-up 398 days) and collected 2,274 serum, plasma and blood samples, 152 cerebrospinal fluid samples and 1,276 brain MRI scans. 158 relapses occurred and expanded disability status scale (EDSS) scores increased in PPMS, SPMS and RRMS patients experiencing relapses. Most RRMS patients were treated with fingolimod (33.4%), natalizumab (24.5%) or injectable DMDs (13.6%). The SMSC will provide relevant information regarding DMDs efficacy and safety and will serve as a comprehensive infrastructure available for nested research projects.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0152347PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4816556PMC
August 2016

IL-27 Induces Th17 Differentiation in the Absence of STAT1 Signaling.

J Immunol 2015 Nov 25;195(9):4144-53. Epub 2015 Sep 25.

Department of Pathology and Immunology, Geneva University Hospital, 1211 Geneva 4, Switzerland; Division of Neurology, Department of Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland

It is known that differentiation of Th17 cells is promoted by activation of STAT3 and inhibited by activation of STAT1. Although both transcription factors are activated by several cytokines, including IL-6, IL-21, and IL-27, each of these cytokines has a very different effect on Th17 differentiation, ranging from strong induction (IL-6) to strong inhibition (IL-27). To determine the molecular basis for these differences, we measured STAT3 and STAT1 activation profiles for IL-6, IL-21, and IL-27, as well as for cytokine pairs over time. We found that the ratio of activated STAT3/activated STAT1 is crucial in determining whether cytokines promote or inhibit Th17 differentiation. IL-6 and IL-21 induced p-STAT3/p-STAT1 ratios > 1, leading to the promotion of Th17 differentiation, whereas IL-27 or IL-6+IL-27 induced p-STAT3/p-STAT1 ratios < 1, resulting in inhibition of Th17 differentiation. Consistent with these findings, we show that IL-27 induces sufficient p-STAT3 to promote Th17 differentiation in the absence of STAT1. Furthermore, IL-27-induced STAT1-deficient T cells were indistinguishable from bona fide highly proinflammatory Th17 cells because they induced severe experimental autoimmune encephalomyelitis upon adoptive transfer. Our results suggest that the ratio of p-STAT3/p-STAT1 induced by a cytokine or cytokine pairs can be used to predict whether they induce a competent Th17-differentiation program.
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http://dx.doi.org/10.4049/jimmunol.1302246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4610870PMC
November 2015

Ag-presenting CpG-activated pDCs prime Th17 cells that induce tumor regression.

Cancer Res 2014 Nov 24;74(22):6430-40. Epub 2014 Sep 24.

Department of Pathology and Immunology, University of Geneva Medical School, Geneva, Switzerland.

Plasmacytoid dendritic cells (pDC) rapidly and massively produce type I IFN and other inflammatory cytokines in response to foreign nucleic acids, thereby indirectly influencing T-cell responses. Moreover, antigen (Ag)-presenting pDCs directly regulate T-cell differentiation. Depending on the immune environment, pDCs exhibit either tolerogenic or immunogenic properties. Here, we show that CpG-activated pDCs promote efficient Th17 differentiation. Indeed, Th17 responses are defective in mice selectively lacking MHCII on pDCs upon antigenic challenge. Importantly, in those mice, the frequency of Th17 cells infiltrating solid tumors is impaired. As a result, the recruitment of infiltrating leukocytes in tumors, including tumor-specific cytotoxic T lymphocytes (CTL), is altered and results in increased tumor growth. Importantly, following immunization with tumor Ag and CpG-B, MHCII-restricted Ag presentation by pDCs promotes the differentiation of antitumor Th17 cells that induce intratumor CTL recruitment and subsequent regression of established tumors. Our results highlight a new role for Ag presenting activated pDCs in promoting the development of Th17 cells and impacting on antitumor immunity.
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http://dx.doi.org/10.1158/0008-5472.CAN-14-1149DOI Listing
November 2014

Metallothioneins negatively regulate IL-27-induced type 1 regulatory T-cell differentiation.

Proc Natl Acad Sci U S A 2013 May 29;110(19):7802-7. Epub 2013 Apr 29.

Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

IL-27-induced type 1 regulatory T (Tr1) cells suppress autoimmunity by producing IL-10. Signal transducer and activator of transcription (STAT) 1 and STAT3 have been described as key transcription factors that promote IL-10 secretion from Tr1 cells induced by IL-27. However, the molecular pathways for negatively regulating Tr1 cell differentiation remain elusive. Here, we show that IL-27 induces metallothioneins (MTs) that in turn prevent Tr1 cell development. MT expression leads to the reduction of STAT1 and STAT3 phosphorylation under Tr1 differentiation condition, resulting in impaired IL-10 production. Accordingly, Tr1 cells derived from MT-deficient mice showed an increased ability to produce IL-10 and potently suppress experimental autoimmune encephalomyelitis upon adoptive transfer. Moreover, activation of STAT1 and/or STAT3 can overcome the suppression of IL-10 by MTs, indicating a dynamic balance between STATs and MTs in regulating IL-10 during Tr1 cell differentiation.
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http://dx.doi.org/10.1073/pnas.1211776110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3651423PMC
May 2013

SOCS3 transactivation by PPARγ prevents IL-17-driven cancer growth.

Cancer Res 2013 Jun 25;73(12):3578-90. Epub 2013 Apr 25.

Institut National de la Santé et de la Recherche Medicale (INSERM), U866, France.

Activation of the transcription factor PPARγ by the n-3 fatty acid docosahexaenoic acid (DHA) is implicated in controlling proinflammatory cytokine secretion, but the intracellular signaling pathways engaged by PPARγ are incompletely characterized. Here, we identify the adapter-encoding gene SOCS3 as a critical transcriptional target of PPARγ. SOCS3 promoter binding and gene transactivation by PPARγ was associated with a repression in differentiation of proinflammatory T-helper (TH)17 cells. Accordingly, TH17 cells induced in vitro displayed increased SOCS3 expression and diminished capacity to produce interleukin (IL)-17 following activation of PPARγ by DHA. Furthermore, naïve CD4 T cells derived from mice fed a DHA-enriched diet displayed less capability to differentiate into TH17 cells. In two different mouse models of cancer, DHA prevented tumor outgrowth and angiogenesis in an IL-17-dependent manner. Altogether, our results uncover a novel molecular pathway by which PPARγ-induced SOCS3 expression prevents IL-17-mediated cancer growth.
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http://dx.doi.org/10.1158/0008-5472.CAN-12-4018DOI Listing
June 2013

Nogo-A downregulation improves insulin secretion in mice.

Diabetes 2013 May 28;62(5):1443-52. Epub 2012 Dec 28.

Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland.

Type 2 diabetes (T2D) is characterized by β-cell dysfunction and the subsequent depletion of insulin production, usually in a context of increased peripheral insulin resistance. T2D patients are routinely treated with oral antidiabetic agents such as sulfonylureas or dipeptidyl peptidase-4 antagonists, which promote glucose- and incretin-dependent insulin secretion, respectively. Interestingly, insulin secretion may also be induced by neural stimulation. Here we report the expression of Nogo-A in β-cells. Nogo-A is a membrane protein that inhibits neurite outgrowth and cell migration in the central nervous system. We observed that Nogo-A-deficient mice display improved insulin secretion and glucose clearance. This was associated with a stronger parasympathetic input and higher sensitivity of β-cells to the cholinergic analog carbachol. Insulin secretion was also improved in diabetic db/db mice treated with neutralizing antibody against Nogo-A. Together, these findings suggest that promoting the vagal stimulation of insulin secretion through the selective inhibition of Nogo-A could be a novel therapeutic approach in T2D.
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http://dx.doi.org/10.2337/db12-0949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3636604PMC
May 2013

Aryl hydrocarbon receptor controls regulatory CD4+ T cell function.

Authors:
Caroline Pot

Swiss Med Wkly 2012 31;142:w13592. Epub 2012 May 31.

Division of Neurology, Geneva University Hospital and Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.

The ligand activated transcription factor aryl hydrocarbon receptor (AhR) has been studied for many decades in toxicology as the ligand for the environmental contaminant dioxin. However, AhR has recently emerged as a critical physiological regulator of immune responses affecting both innate and adaptive systems, and several AhR ligands with different pharmacological profiles have recently been studied. The current review discusses new insights into the role of AhR signalling and AhR ligands on the regulation of the immune system, with a focus on regulatory T cells which maintain immune tolerance. Notably, AhR is expressed and modulates the development of two induced regulatory CD4+ T cell subsets, the forkhead box P3-positive (Foxp3+) regulatory T cells (iTreg) and the IL-10-secreting type 1 regulatory T (T(R)1) cells, through different signalling pathways. We will finally discuss how AhR ligands could be exploited to alleviate human autoimmune diseases. Clearly, drugs targeted against AhR should promote the development of new strategies to fight against autoimmune diseases.
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http://dx.doi.org/10.4414/smw.2012.13592DOI Listing
October 2012