Publications by authors named "Jan Aarseth"

42 Publications

Humoral immunity to SARS-CoV-2 mRNA vaccination in multiple sclerosis: the relevance of time since last rituximab infusion and first experience from sporadic revaccinations.

J Neurol Neurosurg Psychiatry 2021 Oct 20. Epub 2021 Oct 20.

Department of Neurology, Oslo University Hospital, Oslo, Norway.

Introduction: The effect of disease-modifying therapies (DMT) on vaccine responses is largely unknown. Understanding the development of protective immunity is of paramount importance to fight the COVID-19 pandemic.

Objective: To characterise humoral immunity after mRNA-COVID-19 vaccination of people with multiple sclerosis (pwMS).

Methods: All pwMS in Norway fully vaccinated against SARS-CoV-2 were invited to a national screening study. Humoral immunity was assessed by measuring anti-SARS-CoV-2 SPIKE RBD IgG response 3-12 weeks after full vaccination, and compared with healthy subjects.

Results: 528 pwMS and 627 healthy subjects were included. Reduced humoral immunity (anti-SARS-CoV-2 IgG <70 arbitrary units) was present in 82% and 80% of all pwMS treated with fingolimod and rituximab, respectively, while patients treated with other DMT showed similar rates as healthy subjects and untreated pwMS. We found a significant correlation between time since the last rituximab dose and the development of humoral immunity. Revaccination in two seronegative patients induced a weak antibody response.

Conclusions: Patients treated with fingolimod or rituximab should be informed about the risk of reduced humoral immunity and vaccinations should be timed carefully in rituximab patients. Our results identify the need for studies regarding the durability of vaccine responses, the role of cellular immunity and revaccinations.
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http://dx.doi.org/10.1136/jnnp-2021-327612DOI Listing
October 2021

Incidence of cancer in multiple sclerosis before and after the treatment era- a registry- based cohort study.

Mult Scler Relat Disord 2021 Oct 9;55:103209. Epub 2021 Aug 9.

Norwegian Multiple Sclerosis Competence Centre, Department of Neurology, Haukeland University Hospital, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway; Neuro-SysMed, Department of Neurology, Haukeland University Hospital, Bergen, Norway.

Background: Whether disease-modifying therapies (DMTs) influence cancer in multiple sclerosis (MS) is uncertain.

Objectives: Assess incidence of cancer diagnosis among Norwegian MS patients compared to the general population in 1953 to 1995 and 1996 to 2017-reflecting era before and after introduction of DMTs.

Methods: We performed a nationwide cohort study comprising 6949 MS patients and 37,922 controls, matched on age, sex and county. The cohort was linked to Norwegian Cancer Registry, Cause of Death Registry and National Educational database. We used Poisson regression to calculate incidence rate ratio (IRR) of cancer.

Results: During 1953-1995 MS patients had similar cancer frequency compared to controls (IRR: 1.11 (95% Confidence Intervals (CI): 0.90-1.37)), although MS patients had increased frequency of cancer in endocrine glands (IRR: 2.51 (1.27-4.93). During 1996-2017 we identified significant increased frequency of cancer among MS patients compared to controls (IRR: 1.38 (95% CI: 1.28-1.52): in brain (IRR: 1.97 (1.41-2.78)), meninges (IRR: 2.44 (1.54-3.77)), respiratory organs (IRR: 1.96 (1.49-2.63)). The excess cancer diagnosis was most frequent among MS patients ≥ 60 years of age (HR 1.30 (1.15-1.47)).

Conclusion: Incidence of cancer among MS patients compared to controls was higher in 1996 to 2017, corresponding in time to the introduction of DMT for MS. This was observed more frequently among MS patients older than 60 years of age.
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http://dx.doi.org/10.1016/j.msard.2021.103209DOI Listing
October 2021

Perinatal Depression and Anxiety in Women With Multiple Sclerosis: A Population-Based Cohort Study.

Neurology 2021 06 21;96(23):e2789-e2800. Epub 2021 Apr 21.

From the Departments of Clinical Medicine (K.E., Ø.F.T., K.-M.M., C.F.T., N.E.G., M.-H.B.) and Global Public Health and Primary Care (T.R.), University of Bergen; Neuro-SysMed (Ø.F.T., J.A., K.-M.M., T.R., S.W.), The Norwegian Multiple Sclerosis Registry and Biobank (J.A., S.W.), and The Norwegian Multiple Sclerosis Competence Centre (J.A., T.R.), Department of Neurology (K.E., S.W., N.E.G., M.-H.B.), Haukeland University Hospital, Bergen; Department of Neurology (H.Ø.F.), Telemark Hospital Trust, Skien; Department of Neurology (T.H.), Akershus University Hospital, Lørenskog; Institute of Clinical Medicine (T.H., C.S.), University of Oslo; Department of Neurology and The Norwegian National Advisory Unit on Tick-borne Diseases (Å.R.L.), Sørlandet Hospital, Kristiansand; Department of Neurology (J.S.W.), Møre og Romsdal Hospital Trust, Molde; Department of Neurology (N.Ø.), Nordland Hospital Trust, Bodø; Department of Neurology (C.S.), Vestre Viken Hospital Trust, Drammen; Department of Obstetrics and Gynecology (C.F.T.), Stavanger University Hospital; and Department of Neuromedicine and Movement Science (J.S.W.), Norwegian University of Science and Technology, Trondheim, Norway.

Objective: To assess the occurrence of perinatal depression and anxiety in women before and after diagnosis of multiple sclerosis (MS).

Methods: A total of 114,629 pregnant women were included in the Norwegian Mother, Father and Child Cohort study (1999-2008). We assessed depression and anxiety by questionnaires during and after pregnancy. Women with MS were identified from national health registries and hospital records and grouped into (1) MS diagnosed before pregnancy (n = 140) or MS diagnosed after pregnancy with (2) symptom onset before pregnancy (n = 98) or (3) symptom onset after pregnancy (n = 308). Thirty-five women were diagnosed with MS in the postpartum period. The reference group (n = 111,627) consisted of women without MS.

Results: Women with MS diagnosed before pregnancy had an adjusted odds ratio of 2.0 (95% confidence interval, 1.2-3.1) for depression in the third trimester. Risk factors were adverse socioeconomic factors and history of psychiatric disease and physical/sexual abuse. The risk of anxiety was not increased. Women diagnosed with MS in the postpartum period had especially high risk of postpartum depression. Women with MS symptom onset within 5 years after pregnancy had increased risk of both depression and anxiety during pregnancy, whereas women with more than 5 years until symptom onset did not.

Conclusion: Women diagnosed with MS have increased risk of perinatal depression. Women with MS symptom onset within 5 years after pregnancy have increased risk of both depression and anxiety during pregnancy.
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http://dx.doi.org/10.1212/WNL.0000000000012062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205461PMC
June 2021

Safety and efficacy of rituximab as first- and second line treatment in multiple sclerosis - A cohort study.

Mult Scler J Exp Transl Clin 2021 Jan-Mar;7(1):2055217320973049. Epub 2021 Jan 31.

Neuro-SysMed, Department of Neurology, Haukeland University Hospital, Bergen, Norway.

Background: Rituximab is increasingly used as off-label therapy in multiple sclerosis (MS). More data are needed on safety and efficacy of rituximab, particularly in cohorts of de novo patients and patients in early therapy escalation.

Objective: To investigate the safety and efficacy of off-label treatment with rituximab in an MS-cohort of predominantly de novo patients or as therapy escalation.

Methods: We retrieved safety and efficacy data from the Norwegian MS-registry and biobank for all MS-patients treated with rituximab at Haukeland University Hospital, Bergen, Norway, during a four year period.

Results: In the 365 MS-patients (320 relapsing-remitting MS (RRMS), 23 secondary progressive MS (SPMS), and 22 primary progressive MS (PPMS)), the overall annualized relapse rate (ARR) was 0.03 and annualized drug discontinuation rate (ADDR) was 0.05. NEDA-3 was achived in 79% of patients with available data (n=351). Sixty-one patients experienced infusion-related adverse events of which two were serious (CTCAE grade 3-4). Eighteen patients experienced serious non-infusion related adverse events, of which 16 were infections. Infections (n = 34; 9.3%, CTCAE grade 2-5), hypogammaglobulinemia (n = 19, 5.2%) and neutropenia (n = 16; 4.4%) were the most common non-infusion-related adverse events.

Conclusion: Rituximab was a safe and highly efficient disease modifying therapy in this cohort of MS-patients; however, infections and neutropenia need to be monitored.
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http://dx.doi.org/10.1177/2055217320973049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970692PMC
January 2021

High incidence and prevalence of MS in Møre and Romsdal County, Norway, 1950-2018.

Neurol Neuroimmunol Neuroinflamm 2020 05 26;7(3). Epub 2020 Mar 26.

From the Department of Neurology (J.S.W., R.M.), Møre og Romsdal Hospital Trust, Molde; Department of Neuromedicine and Movement Science (J.S.W.), Norwegian University of Science and Technology, Trondheim; Department of Neurology (J.H.A.), Haukeland University Hospital, The Norwegian Multiple Sclerosis Registry and Biobank, Bergen; Department of Neurology (K.-M.M.), Haukeland University Hospital, Neuro-SysMed; Department of Clinical Medicine (K.-M.M.), University of Bergen; and St. Olavs University Hospital and Norwegian University of Science and Technology (R.M.), Clinical Trial Unit Central Norway, Trondheim.

Objective: To determine prevalence and longitudinal trends in incidence of MS in Møre and Romsdal County, Western Norway, from 1950 to 2018.

Methods: Retrospective longitudinal population-based observational study. All patients diagnosed, or living, with MS in Møre and Romsdal were identified as incident or prevalent cases from local, regional, and national sources. We compiled the data in the Norwegian Multiple Sclerosis Registry and Biobank and used the aggregated data set to calculate incidence and prevalence rates using population measures obtained from Statistics Norway.

Results: On January 1, 2018, the estimated prevalence was 335.8 (95% CI, 314.1-358.5) per 100,000 inhabitants, with a female:male ratio of 2.3. From 1950 through 2017, we observed a considerable ( < 0.001) increase in average annual incidence rates from 2.1 (95% CI, 1.3-3.3) to 14.4 (95% CI, 11.9-17.3) per 100,000. From 2005 through 2017, the incidence among women increased from 17.1 (95% CI, 14.0-20.7) to 23.2 (95% CI, 18.7-28.5) per 100,000, whereas the incidence among men declined from 10.3 (95% CI, 7.9-13.2) to 5.9 (95% CI, 3.4-8.8) per 100,000.

Conclusion: Møre and Romsdal County in Western Norway has the highest prevalence of MS reported in Norway. The incidence has steadily increased since 1950, and during the latest 15 years, we observed opposing trends in sex-specific incidence rates.
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http://dx.doi.org/10.1212/NXI.0000000000000713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136041PMC
May 2020

Risk of cancer among multiple sclerosis patients, siblings, and population controls: A prospective cohort study.

Mult Scler 2020 10 1;26(12):1569-1580. Epub 2019 Oct 1.

Norwegian Multiple Sclerosis Competence Centre, Department of Neurology, Haukeland University Hospital, Bergen, Norway/Department of Clinical Medicine, University of Bergen, Bergen, Norway/Department of Neurology, Haukeland University Hospital, Bergen, Norway.

Background: Risk of cancer in multiple sclerosis (MS) patients compared to their siblings is unknown.

Objective: The objective was to prospectively investigate the risk of cancer among MS patients compared to siblings without MS and to population controls.

Methods: We retrieved data on MS patients born between 1930 and 1979 from the Norwegian Multiple Sclerosis Registry and population studies and on cancer diagnosis from the Cancer Registry of Norway. We used adjusted Cox proportional hazard regression to estimate cancer risk among 6883 MS patients, 8918 siblings without MS, and 37,919 population controls.

Results: During 65 years of follow-up, cancer risk among MS patients was higher than that among population controls (hazard ratio (HR) = 1.14, 95% confidence interval (CI): 1.05-1.23) in respiratory organs (HR = 1.66, 95% CI: 1.26-2.19), urinary organs (HR = 1.51, 95% CI: 1.12-2.04), and the central nervous system (HR = 1.52, 95% CI: 1.11-2. 09). Siblings had higher risk of hematological cancers compared with MS patients (HR = 1.82, 95% CI: 1.21-2.73) and population controls (HR = 1.72, 95% CI: 1.36-2.18).

Conclusion: MS patients were associated with increased risk of cancer compared to population controls. Siblings had increased risk of hematological cancer. This indicates that MS and hematological cancer could share a common etiology.
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http://dx.doi.org/10.1177/1352458519877244DOI Listing
October 2020

Antiepileptic and psychiatric medication in a nationwide cohort of patients with glioma WHO grade II-IV.

J Neurooncol 2018 Dec 23;140(3):739-748. Epub 2018 Nov 23.

Department of Neurology, Haukeland University Hospital, Jonas Lies vei 65, 5021, Bergen, Norway.

Introduction: Glioma is the most common intracranial primary brain tumor. Patients with glioma often suffer from epilepsy, anxiety and depression. Aims of this study were to identify risk factors for drug-treated anxiety and depression, and to determine the use of psychiatric medication in a national glioma cohort.

Methods: Data from the Cancer Registry of Norway on all persons diagnosed with glioma WHO grade II-IV 2004-2010 were linked with data from the Norwegian Prescription Database. Cox regression analysis was used to assess risk factors for drug-treated anxiety and depression. Standardized incidence ratios were calculated for psychiatric medication dispensed to glioma patients and compared to the general population.

Results: The glioma cohort consisted of 1056 males and 772 females. Of the 1828 patients, 565 had glioma grade II-III, and 1263 had grade IV. The patients with glioma grade II-III who were treated with levetiracetam had an increased risk for drug-treated anxiety compared to patients without levetiracetam; hazard ratio 2.8 (95% confidence interval 1.7-4.9). Female gender increased the risk for drug-treated anxiety compared to males in patients with glioma grade IV; hazard ratio 1.5 (95% confidence interval 1.2-2.0). Antidepressants were less frequently dispensed to patients with glioma grade II-III and epilepsy than to the general population.

Conclusions: Patients with glioma grade II-III on levetiracetam had an increased risk for drug-treated anxiety. The subgroup of patients with glioma grade II-III and epilepsy received less antidepressants than the general population.
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http://dx.doi.org/10.1007/s11060-018-03007-9DOI Listing
December 2018

Increased levels of cell-free mitochondrial DNA in the cerebrospinal fluid of patients with multiple sclerosis.

Mitochondrion 2017 05 23;34:32-35. Epub 2016 Dec 23.

Department of Neurology, Haukeland University Hospital, Bergen, Norway; Department of Clinical Medicine (K1), University of Bergen, Bergen, Norway. Electronic address:

Mitochondrial DNA (mtDNA) can act as damage-associated molecular pattern molecule (DAMP) and initiate an inflammatory response. We hypothesized that the concentration of mtDNA might reflect inflammatory activity in multiple sclerosis and investigated therefore levels of cell-free mitochondrial DNA in cerebrospinal fluid of patients with relapsing-remitting multiple sclerosis. Significantly higher levels of mtDNA were found in patients compared to controls and there was an inverse correlation between disease duration and mtDNA concentration. Our study suggests that mitochondria can be involved early in multiple sclerosis, but whether this is as an initiator of the inflammatory response or part of its maintenance is unclear. Further, our study suggests that changes in mtDNA may provide a novel marker for early disease activity.
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http://dx.doi.org/10.1016/j.mito.2016.12.003DOI Listing
May 2017

The influence of coping styles on long-term employment in multiple sclerosis: A prospective study.

Mult Scler 2017 Jun 6;23(7):1008-1017. Epub 2016 Sep 6.

KG Jebsen MS Research Centre, Institute of Clinical Medicine, University of Bergen, Bergen, Norway/Norwegian Multiple Sclerosis Registry and Biobank, Department of Neurology, Haukeland University Hospital, Bergen, Norway.

Background: The aim was to investigate predictive values of coping styles, clinical and demographic factors on time to unemployment in patients diagnosed with multiple sclerosis (MS) during 1998-2002 in Norway.

Method: All patients ( N = 108) diagnosed with MS 1998-2002 in Hordaland and Rogaland counties, Western Norway, were invited to participate in the long-term follow-up study in 2002. Baseline recordings included disability scoring (Expanded Disability Status Scale (EDSS)), fatigue (Fatigue Severity Scale (FSS)), depression (Beck Depression Inventory (BDI)), and questionnaire assessing coping (the Dispositional Coping Styles Scale (COPE)). Logistic regression analysis was used to identify factors associated with unemployed at baseline, and Cox regression analysis to identify factors at baseline associated with time to unemployment during follow-up.

Results: In all, 41 (44%) were employed at baseline. After 13 years follow-up in 2015, mean disease duration of 22 years, 16 (17%) were still employed. Median time from baseline to unemployment was 6 years (±5). Older age at diagnosis, female gender, and depression were associated with patients being unemployed at baseline. Female gender, long disease duration, and denial as avoidant coping strategy at baseline predicted shorter time to unemployment.

Conclusion: Avoidant coping style, female gender, and longer disease duration were associated with shorter time to unemployment. These factors should be considered when advising patients on MS and future employment.
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http://dx.doi.org/10.1177/1352458516667240DOI Listing
June 2017

Allelic imbalance of multiple sclerosis susceptibility genes IKZF3 and IQGAP1 in human peripheral blood.

BMC Genet 2016 Apr 14;17:59. Epub 2016 Apr 14.

Department of Neurology, Oslo University Hospital, Oslo, Norway.

Background: Multiple sclerosis is a chronic inflammatory, demyelinating disease of the central nervous system. Recent genome-wide studies have revealed more than 110 single nucleotide polymorphisms as associated with susceptibility to multiple sclerosis, but their functional contribution to disease development is mostly unknown.

Results: Consistent allelic imbalance was observed for rs907091 in IKZF3 and rs11609 in IQGAP1, which are in strong linkage disequilibrium with the multiple sclerosis associated single nucleotide polymorphisms rs12946510 and rs8042861, respectively. Using multiple sclerosis patients and healthy controls heterozygous for rs907091 and rs11609, we showed that the multiple sclerosis risk alleles at IKZF3 and IQGAP1 are expressed at higher levels as compared to the protective allele. Furthermore, individuals homozygous for the multiple sclerosis risk allele at IQGAP1 had a significantly higher total expression of IQGAP1 compared to individuals homozygous for the protective allele.

Conclusions: Our data indicate a possible regulatory role for the multiple sclerosis-associated IKZF3 and IQGAP1 variants. We suggest that such cis-acting mechanisms may contribute to the multiple sclerosis association of single nucleotide polymorphisms at IKZF3 and IQGAP1.
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http://dx.doi.org/10.1186/s12863-016-0367-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4832550PMC
April 2016

Genetic variants are major determinants of CSF antibody levels in multiple sclerosis.

Brain 2015 Mar 22;138(Pt 3):632-43. Epub 2015 Jan 22.

18 Danish Multiple Sclerosis Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Immunological hallmarks of multiple sclerosis include the production of antibodies in the central nervous system, expressed as presence of oligoclonal bands and/or an increased immunoglobulin G index-the level of immunoglobulin G in the cerebrospinal fluid compared to serum. However, the underlying differences between oligoclonal band-positive and -negative patients with multiple sclerosis and reasons for variability in immunoglobulin G index are not known. To identify genetic factors influencing the variation in the antibody levels in the cerebrospinal fluid in multiple sclerosis, we have performed a genome-wide association screen in patients collected from nine countries for two traits, presence or absence of oligoclonal bands (n = 3026) and immunoglobulin G index levels (n = 938), followed by a replication in 3891 additional patients. We replicate previously suggested association signals for oligoclonal band status in the major histocompatibility complex region for the rs9271640*A-rs6457617*G haplotype, correlated with HLA-DRB1*1501, and rs34083746*G, correlated with HLA-DQA1*0301 (P comparing two haplotypes = 8.88 × 10(-16)). Furthermore, we identify a novel association signal of rs9807334, near the ELAC1/SMAD4 genes, for oligoclonal band status (P = 8.45 × 10(-7)). The previously reported association of the immunoglobulin heavy chain locus with immunoglobulin G index reaches strong evidence for association in this data set (P = 3.79 × 10(-37)). We identify two novel associations in the major histocompatibility complex region with immunoglobulin G index: the rs9271640*A-rs6457617*G haplotype (P = 1.59 × 10(-22)), shared with oligoclonal band status, and an additional independent effect of rs6457617*G (P = 3.68 × 10(-6)). Variants identified in this study account for up to 2-fold differences in the odds of being oligoclonal band positive and 7.75% of the variation in immunoglobulin G index. Both traits are associated with clinical features of disease such as female gender, age at onset and severity. This is the largest study population so far investigated for the genetic influence on antibody levels in the cerebrospinal fluid in multiple sclerosis, including 6950 patients. We confirm that genetic factors underlie these antibody levels and identify both the major histocompatibility complex and immunoglobulin heavy chain region as major determinants.
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http://dx.doi.org/10.1093/brain/awu405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408440PMC
March 2015

Reply to comment: Month of birth and risk of multiple sclerosis: confounding and adjustments.

Ann Clin Transl Neurol 2014 May 10;1(5):376-7. Epub 2014 Apr 10.

Norwegian Multiple Sclerosis Competence Centre, Department of Neurology, Haukeland University Hospital Bergen, Norway ; Kristian Gerhard Jebsen Centre for MS Research, Department of Clinical Medicine, University of Bergen Bergen, Norway.

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http://dx.doi.org/10.1002/acn3.56DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4184690PMC
May 2014

Month of birth and risk of multiple sclerosis: confounding and adjustments.

Ann Clin Transl Neurol 2014 Feb 4;1(2):141-4. Epub 2014 Feb 4.

The Norwegian Multiple Sclerosis Competence Centre, Department of Neurology, Haukeland University Hospital Bergen, Norway ; Kristian Gerhard Jebsen Centre for MS-Research, Department of Clinical Medicine, University of Bergen Bergen, Norway.

A month of birth effect on multiple sclerosis (MS) risk has been reported from different countries. Recent critics have suggested that this finding is caused by confounding and that adequately adjusting for year and place of birth would markedly reduce this effect. All inhabitants in Norway are registered in the Norwegian Population Registry (Statistics Norway), making this an ideal area for performing adjusted analyses. Using the entire Norwegian population born between 1930 and 1979 (n = 2,899,260), we calculated the excess between observed and expected number of births for each month for 6649 Norwegian MS patients, 5711 mothers, 5247 fathers, and 8956 unaffected siblings. The analyses were adjusted for year of birth and place of birth according to the 19 counties in Norway. An unadjusted analysis revealed 13% fewer MS births than expected in February (P = 0.0015; Bonferroni corrected P = 0.018), 10% more in April (P = 0.0083; Bonferroni corrected P = 0.0996) and 15% more in December (P = 0.00058; Bonferroni corrected P = 0.007). Adjustments for both year and place of birth significantly altered our results for February and December, but even after these adjustments there were still 10% more MS births than expected in April (P = 0.00796; Bonferroni corrected P = 0.096). MS patients had a higher incidence of April births than their siblings (Fisher-exact test; P = 0.011), mothers (Fisher-exact test; P = 0.004), and fathers (Fisher-exact test; P = 0.011) without MS. Adjustments for confounding significantly affected our results. However, even after adjustments, there appears to be a persistent higher than expected frequency of April births in the MS population.
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http://dx.doi.org/10.1002/acn3.37DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4212485PMC
February 2014

Employment among patients with multiple sclerosis-a population study.

PLoS One 2014 23;9(7):e103317. Epub 2014 Jul 23.

Department of Neurology, Norwegian Multiple Sclerosis Competence Centre, Haukeland University Hospital (HUS), Bergen, Norway; Department of Clinical Medicine, KG Jebsen Center for MS research, University of Bergen, Bergen, Norway.

Objective: To investigate demographic and clinical factors associated with employment in MS.

Methods: The study included 213 (89.9%) of all MS patients in Sogn and Fjordane County, Western Norway at December 31st 2010. The patients underwent clinical evaluation, structured interviews and completed self-reported questionnaires. Demographic and clinical factors were compared between patients being employed versus patients being unemployed and according to disease course of MS. Logistic regression analysis was used to identify factors independently associated with current employment.

Results: After a mean disease duration of almost 19 years, 45% of the population was currently full-time or part- time employed. Patients with relapsing -remitting MS (RRMS) had higher employment rate than patients with secondary (SPMS) and primary progressive (PPMS). Higher educated MS patients with lower age at onset, shorter disease duration, less severe disability and less fatigue were most likely to be employed.

Conclusions: Nearly half of all MS patients were still employed after almost two decades of having MS. Lower age at onset, shorter disease duration, higher education, less fatigue and less disability were independently associated with current employment. These key clinical and demographic factors are important to understand the reasons to work ability in MS. The findings highlight the need for environmental adjustments at the workplace to accommodate individual 's needs in order to improve working ability among MS patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0103317PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4108421PMC
November 2015

Oligoclonal band phenotypes in MS differ in their HLA class II association, while specific KIR ligands at HLA class I show association to MS in general.

J Neuroimmunol 2014 Sep 6;274(1-2):174-9. Epub 2014 Jul 6.

Department of Neurology, Oslo University Hospital, Ullevål, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

Multiple sclerosis (MS) patients have been reported to have different HLA class II allele profiles depending on oligoclonal bands (OCBs) in the cerebrospinal fluid, but HLA class I alleles and killer cell immunoglobulin-like receptor (KIR) ligands have not been studied. We investigated the association of HLA alleles and KIR ligands according to OCB status in MS patients (n=3876). Specific KIR ligands were associated with patients when compared to controls (n=3148), supporting a role for NK cells in MS pathogenesis. HLA class I alleles and KIR ligands did not differ between OCB phenotypes, but HLA class II associations were convincingly replicated.
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http://dx.doi.org/10.1016/j.jneuroim.2014.06.024DOI Listing
September 2014

Immunotherapies influence the influenza vaccination response in multiple sclerosis patients: an explorative study.

Mult Scler 2014 07 16;20(8):1074-80. Epub 2014 Jan 16.

Norwegian Multiple Sclerosis Registry and Biobank, Department of Neurology, Haukeland University Hospital, Bergen, Norway KG Jebsen Centre for MS-Research, Department of Clinical Medicine, University of Bergen, Norway Norwegian Multiple Sclerosis Competence Centre, Department of Neurology, Haukeland University Hospital, Bergen, Norway.

Background: The immunogenicity of influenza vaccines in MS patients undergoing immunomodulatory treatment is not well studied.

Objectives: This explorative study investigated the influence of immunomodulatory treatment on MS patients receiving pandemic H1N1 (swine flu) vaccination in 2009 and seasonal influenza vaccination in 2010.

Methods: We investigated the immune response to pandemic H1N1 vaccination among 113 MS patients and 216 controls during the pandemic of 2009. We also investigated the serological response to seasonal influenza vaccination (2010 - 2011 season) among 49 vaccinated and 62 non-vaccinated MS patients, versus 73 controls. We evaluated these vaccine responses by haemagglutination inhibition assay.

Results: MS patients receiving immunomodulatory treatment had reduced protection (27.4%), compared to controls (43.5%) (p = 0.006), after pandemic H1N1 vaccination (2009). The rates of protection were not influenced by interferon beta treatment (44.4% protected), but were reduced among patients receiving glatiramer acetate (21.6%), natalizumab (23.5%), and mitoxantrone (0.0%). A similar pattern emerged after MS patients received a seasonal influenza vaccination in 2010.

Conclusions: These findings suggest that MS patients receiving immunomodulatory therapies other than interferon beta should be considered for a vaccine response analysis and perhaps be offered a second dose of the vaccine, in cases of insufficient protection.
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http://dx.doi.org/10.1177/1352458513513970DOI Listing
July 2014

Avidity of onconeural antibodies is of clinical relevance.

Cancer Immunol Immunother 2013 Aug 4;62(8):1393-6. Epub 2013 Jun 4.

Department of Neurology, Haukeland University Hospital, Jonas Lies vei 65, 5021, Bergen, Norway.

Onconeural antibodies are important in the detection of paraneoplastic neurological syndromes (PNS). The avidity of Hu, Yo, and CRMP5 antibodies from 100 patients was determined by immunoprecipitation (IP), and 13 of the Yo positive sera were also tested by surface plasmon resonance (SPR). There was a significant association between the results from IP and SPR. Yo antibodies had higher avidity than Hu and CRMP5 antibodies, and both high- and low-avidity antibodies were associated with tumors and PNS. High-avidity Yo antibodies were mainly associated with ovarian cancer, whereas high-avidity Hu and CRMP5 antibodies were mainly associated with small-cell lung cancer. Low-avidity CRMP5 and Yo antibodies were less often detected by a commercial line blot than high-avidity antibodies. The failure to detect low-avidity onconeural antibodies may result in under diagnosis of PNS.
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http://dx.doi.org/10.1007/s00262-013-1442-6DOI Listing
August 2013

Oligoclonal band status in Scandinavian multiple sclerosis patients is associated with specific genetic risk alleles.

PLoS One 2013 5;8(3):e58352. Epub 2013 Mar 5.

Department of Neurology, Oslo University Hospital, Ullevål, and Department of Medical Genetics, University of Oslo, Oslo, Norway.

The presence of oligoclonal bands (OCB) in cerebrospinal fluid (CSF) is a typical finding in multiple sclerosis (MS). We applied data from Norwegian, Swedish and Danish (i.e. Scandinavian) MS patients from a genome-wide association study (GWAS) to search for genetic differences in MS relating to OCB status. GWAS data was compared in 1367 OCB positive and 161 OCB negative Scandinavian MS patients, and nine of the most associated SNPs were genotyped for replication in 3403 Scandinavian MS patients. HLA-DRB1 genotypes were analyzed in a subset of the OCB positive (n = 2781) and OCB negative (n = 292) MS patients and compared to 890 healthy controls. Results from the genome-wide analyses showed that single nucleotide polymorphisms (SNPs) from the HLA complex and six other loci were associated to OCB status. In SNPs selected for replication, combined analyses showed genome-wide significant association for two SNPs in the HLA complex; rs3129871 (p = 5.7×10(-15)) and rs3817963 (p = 5.7×10(-10)) correlating with the HLA-DRB1*15 and the HLA-DRB1*04 alleles, respectively. We also found suggestive association to one SNP in the Calsyntenin-2 gene (p = 8.83×10(-7)). In HLA-DRB1 analyses HLA-DRB1*15∶01 was a stronger risk factor for OCB positive than OCB negative MS, whereas HLA-DRB1*04∶04 was associated with increased risk of OCB negative MS and reduced risk of OCB positive MS. Protective effects of HLA-DRB1*01∶01 and HLA-DRB1*07∶01 were detected in both groups. The groups were different with regard to age at onset (AAO), MS outcome measures and gender. This study confirms both shared and distinct genetic risk for MS subtypes in the Scandinavian population defined by OCB status and indicates different clinical characteristics between the groups. This suggests differences in disease mechanisms between OCB negative and OCB positive MS with implications for patient management, which need to be further studied.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0058352PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3589422PMC
December 2013

No evidence of association between mutant alleles of the CYP27B1 gene and multiple sclerosis.

Ann Neurol 2013 Mar 26;73(3):430-2. Epub 2013 Feb 26.

Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.

An association has previously been reported between susceptibility to multiple sclerosis and the rare mutant alleles of the CYP27B1 gene responsible for autosomal recessive vitamin D-dependent rickets type 1 (VDDR1). In an attempt to replicate this finding, we screened 495 multiplex families and 2,092 single affected families, together with 4,594 cases and 3,583 controls (a total of 17,073 individuals) but were unable to find any evidence supporting this putative association. Our data do not indicate that mutations responsible for VDDR1 influence the risk of developing multiple sclerosis.
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http://dx.doi.org/10.1002/ana.23833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3631291PMC
March 2013

Sex ratio of multiple sclerosis in persons born from 1930 to 1979 and its relation to latitude in Norway.

J Neurol 2013 Jun 6;260(6):1481-8. Epub 2013 Jan 6.

Centre for Clinical Research and Education, University Hospital of North Norway, 9038, Tromsø, Norway.

A remarkable increase in female to male ratio of multiple sclerosis (MS) is recognised in high incidence areas. Norway is a high-risk area for MS, spanning latitudes 58-71 °N. We studied whether the sex ratio has changed over time and whether it differs by clinical phenotype or by latitude. Population-based epidemiological data and data from the Norwegian MS Registry on patients born from 1930 to 1979 were combined in this study. Place of birth was retrieved from the Norwegian Population Registry and information on clinical subtypes was obtained from the Norwegian MS Registry. The female to male ratio ranged from 1.7 to 2.7 (median 2.0) in 5,469 patients born in Norway, and increased slightly by 5-year blocks of year of birth (p = 0.043). The sex ratio was 2.6:1 in 825 patients born 1970-1979, which is significantly higher than in those born 1930-1969 (p < 0.001). In patients with relapsing remitting onset, the sex ratio was 2.4:1, while it was 1.1:1 in those with primary progressive disease. The sex ratio did not differ between the south, the middle and the north of the country. The overall sex ratio of MS is strongly determined by cases with relapsing remitting onset. We did not observe the remarkable increase in sex ratios of MS reported from other high-risk areas. The high sex ratio in the youngest birth cohorts may change as an increasing proportion of cases in this age group is being diagnosed. Sex ratio was not associated with latitude.
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http://dx.doi.org/10.1007/s00415-012-6814-xDOI Listing
June 2013

Month of birth as a latitude-dependent risk factor for multiple sclerosis in Norway.

Mult Scler 2013 Jul 20;19(8):1028-34. Epub 2012 Dec 20.

Norwegian Multiple Sclerosis Competence Centre, Department of Neurology, Haukeland University Hospital, Bergen, Norway.

Objective: We aimed to determine if the risk of Multiple Sclerosis (MS) is associated with month of birth in Norway and to explore a possible latitudinal gradient.

Methods: All patients with MS born between 1930 and 1979 registered in the Norwegian MS Registry or ascertained in Norwegian prevalence studies were included (n = 6649). The latitude gradient was divided in Southern, Middle and Northern Norway, according to the estimated regional yearly mean vitamin D effective UV dose.

Results: Risk of MS was 11% higher for those born in April (p = 0.045), and 5% higher for those born in May (p = 0.229), 5% lower for those born in November (p = 0.302) and 12% lower for those born in February (p = 0.053) compared with the corresponding population, unaffected mothers and siblings. In Southern Norway the odds ratio of MS births in April and May was 1.05 (0.98-1.24), in Middle Norway 1.11 (0.97-1.27) and in Northern Norway 1.28 (1.0-1.63) compared with the other months.

Conclusions: This study confirms previous reports of increased MS births in spring and decreased MS births in the winter months. This could support the role of decreased sunlight exposure during pregnancy and vitamin D deficiency in prenatal life in MS.
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http://dx.doi.org/10.1177/1352458512471094DOI Listing
July 2013

Poor sleep in patients with multiple sclerosis.

PLoS One 2012 14;7(11):e49996. Epub 2012 Nov 14.

The Norwegian Multiple Sclerosis Competence Centre, Department of Neurology, Haukeland University Hospital, Bergen, Norway.

Background: Poor sleep is a frequent symptom in patients with multiple sclerosis (MS). Sleep may be influenced by MS-related symptoms and adverse effects from immunotherapy and symptomatic medications. We aimed to study the prevalence of poor sleep and the influence of socio-demographic and clinical factors on sleep quality in MS- patients.

Methods: A total of 90 MS patients and 108 sex-and age- matched controls were included in a questionnaire survey. Sleep complaints were evaluated by Pittsburgh Sleep Quality Index (PSQI) and a global PSQI score was used to separate good sleepers (≤ 5) from poor sleepers (>5). Excessive daytime sleepiness, the use of immunotherapy and antidepressant drugs, symptoms of pain, depression, fatigue and MS-specific health related quality of life were registered. Results were compared between patients and controls and between good and poor sleepers among MS patients.

Results: MS patients reported a higher mean global PSQI score than controls (8.6 vs. 6.3, p = 0.001), and 67.1% of the MS patients compared to 43.9% of the controls (p = 0.002) were poor sleepers. Pain (p = 0.02), fatigue (p = 0.001), depression (p = 0.01) and female gender (p = 0.04) were associated with sleep disturbance. Multivariate analyses showed that female gender (p = 0.02), use of immunotherapy (p = 005) and a high psychological burden of MS (p = 0.001) were associated with poor sleep among MS patients.

Conclusions: Poor sleep is common in patients with MS. Early identification and treatment of modifiable risk factors may improve sleep and quality of life in MS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0049996PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498191PMC
April 2013

Polymorphisms of the BDNF gene show neither association with multiple sclerosis susceptibility nor clinical course.

J Neuroimmunol 2012 Mar 15;244(1-2):107-10. Epub 2012 Feb 15.

Department of Neurology, Oslo University Hospital, Ullevål, N-0407 Oslo, Norway.

Brain-derived neurotrophic factor (BDNF) has been proposed a protective role in multiple sclerosis (MS) in several studies. The val(66)met polymorphism alters the function of the BDNF protein, and has along with rs56164415 previously been reported to be associated with MS. We genotyped BDNF SNPs val(66)met and rs56164415 in 2149 Norwegian MS patients and 2747 healthy controls. No association was found for any of the SNPs to disease susceptibility or any clinical or demographic parameters including sex, age at onset, disease course, disease severity and cognitive impairment.
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http://dx.doi.org/10.1016/j.jneuroim.2012.01.011DOI Listing
March 2012

Risk of MS is not associated with exposure to crude oil, but increases with low level of education.

Mult Scler 2011 Jul 22;17(7):780-7. Epub 2011 Feb 22.

Department of Public Health and Primary Health Care, University of Bergen, Norway.

Background: Offshore workers in the Norwegian upstream petroleum industry are exposed to a number of chemicals such as organic solvents, mineral oils and other hydrocarbons, possibly contributing to an increased risk of multiple sclerosis (MS).

Objective: To estimate the risk of MS in this population compared with the general working population in Norway, adjusting for education.

Methods: Using the Norwegian Registry of Employers and Employees we included all 27,900 offshore workers registered from 1981 to 2003 and 366,805 referents from the general working population matched by gender, age and community of residence. The cohort was linked to the Norwegian MS Registry and the Norwegian Education Registry.

Results: There was no increased risk of MS among the offshore workers. We found a marked and linear inverse relationship between level of education and the risk of MS in the total study population, with a rate ratio of 0.48 (95% CI, 0.53 to 0.88) for workers with a graduate degree compared to workers with elementary school only.

Conclusions: These findings do not support a major aetiological role of petroleum-based products, but rather point to smoking and other lifestyle factors related to the level of education as being important for the risk of MS.
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http://dx.doi.org/10.1177/1352458510397686DOI Listing
July 2011

Prevalence and incidence of multiple sclerosis in Oppland County: a cross-sectional population-based study in a landlocked county of Eastern Norway.

Acta Neurol Scand 2011 Oct 10;124(4):250-7. Epub 2010 Dec 10.

Department of Rehabilitation, Sykehuset Innlandet HF, Gjøvik, Norway.

OBJECTIVES - We report the prevalence and incidence rates of multiple sclerosis (MS) in Oppland County, Norway. METHODS - Records from all patients diagnosed with MS at the two Oppland County hospitals, Gjøvik and Lillehammer during 1989-2001 were evaluated. In addition, all general practitioners in Oppland County reported their patients into the study. RESULTS - The age-adjusted prevalence rate of definite MS was 174.4/ 100 000 on the prevalence day 1 January 2002. When the probable cases were included, the prevalence rate rose to 185.6/100 000. The highest prevalence rates were detected in the northern mountain areas, thus corroborating the results from previous local surveys 30-50 years ago. The prevalence of MS was statistically significantly associated with climatic, socioeconomic and geographic variables in the county. The age-adjusted incidence of definite and probable MS in Oppland County was 6.6/100 000 during 1989-1993 increasing to 7.6/100 000 during 1994-1998. DISCUSSION - We found the highest prevalence rates of MS ever reported in Norway. Our findings indicate a possible influence of environmental factors.
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http://dx.doi.org/10.1111/j.1600-0404.2010.01465.xDOI Listing
October 2011

Onconeural antibodies: improved detection and clinical correlations.

J Neuroimmunol 2011 Mar 19;232(1-2):166-70. Epub 2010 Nov 19.

Department of Neurology, Haukeland University Hospital, Bergen, Norway.

Onconeural antibodies are found in many patients with paraneoplastic neurological syndromes (PNS) and define the disease as paraneoplastic. The study describes the presence of onconeural antibodies and PNS in 555 patients with neurological symptoms and confirmed cancer within five years, and compares the diagnostic accuracy of different antibody assays (immunoprecipitation, immunofluorescence and immunoblot). Onconeural antibodies were found in 11.9% of the patients by immunoprecipitation, in 7.0% by immunofluorescence and in 6.3% by immunoblot. PNS were present in 81.8% of the cancer patients that were seropositive by immunoprecipitation. Immunofluorescence and immunoblot failed to detect onconeural antibodies in almost one third of the PNS cases.
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http://dx.doi.org/10.1016/j.jneuroim.2010.10.009DOI Listing
March 2011

How long can you keep working with benign multiple sclerosis?

J Neurol Neurosurg Psychiatry 2011 Jan 27;82(1):78-82. Epub 2010 Aug 27.

The Norwegian Multiple Sclerosis Competence Centre, Department of Neurology, Haukeland University Hospital, Bergen, Norway.

Objective: To study employment in benign multiple sclerosis (MS), the frequency of employment was analysed and the effect of early clinical and demographic factors on time to disability pension was evaluated in a population based MS cohort. The frequency of depression, cognitive function, fatigue and pain between benign and non-benign MS patients was compared, and their impact on employment in benign MS was studied.

Methods: All 188 patients alive, including 60 benign patients with onset of MS during 1976-1986 in Hordaland County, Western Norway, were interviewed and clinically examined in 2003. The Expanded Disability Status Scale (EDSS), depression (Beck Depression Inventory), cognitive function, fatigue, pain, year of disability pension, employment and type of occupation were registered. Benign MS was defined as an EDSS score ≤3.0 at least 10 years after disease onset.

Results: After a mean disease duration of 22.2 years, 32.4% of the cohort were still employed. A relapsing-remitting course, higher educational level and light physical work were significantly associated with longer time to disability pension in the general MS population. Thirty-nine (65.0%) benign MS patients were employed, independent of light or heavy physical work. Mild depressive symptoms were markedly associated with not being employed in benign MS (OR=7.3).

Conclusions: A relapsing-remitting course, higher educational level and light physical work significantly predicted longer time to disability pension in the total MS population. Among the benign MS patients, depressive symptoms, although mild, were strongly associated with not being employed.
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http://dx.doi.org/10.1136/jnnp.2010.210732DOI Listing
January 2011

Association to the Glypican-5 gene in multiple sclerosis.

J Neuroimmunol 2010 Sep 6;226(1-2):194-7. Epub 2010 Aug 6.

Department of Neurology, Oslo University Hospital, Ullevål, University of Oslo, Oslo, Norway.

Multiple sclerosis (MS) is an inflammatory, demyelinating disease affecting the central nervous system. MS-associated variants have been reported at both HLA and non-HLA loci, the latter including chromosome 13q31-32 and the Glypican-5 and Glypican-6 genes. In order to further explore the 13q31-32 region in MS, we genotyped 33 SNPs in 1355 Norwegian MS patients and 1446 Norwegian controls. An intronic SNP in the Glypican-5 gene (rs9523787) showed association with MS (p(corr)=0.006). Thus, this study supports that MS susceptibility at 13q31-32 may localize to the Glypican-5 gene, which should lead to further fine-mapping, replication and functional studies of this gene.
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http://dx.doi.org/10.1016/j.jneuroim.2010.07.003DOI Listing
September 2010

A rare variant of the TYK2 gene is confirmed to be associated with multiple sclerosis.

Eur J Hum Genet 2010 Apr 4;18(4):502-4. Epub 2009 Nov 4.

Department of Neurology, Oslo University Hospital, Ullevål, N-0407 Oslo, Norway.

A rare functional variant within the TYK2 gene (rs34536443) has been reported as protective in multiple sclerosis (MS) in recent studies. However, because of the low frequency of the minor allele (minor allele frequency=0.04), genome-wide significant association has been hard to establish. We genotyped 5429 Nordic MS cases and 6167 healthy controls for this TYK2 non-synonymous single-nucleotide polymorphism (ns-SNP), and combined the Nordic genotype data with raw genotypes from previous studies. The combined Nordic analysis showed significant association with MS (P=5 x 10(-4), odds ratio (OR) 0.78), and by mega-analysis of 10 642 MS patients, 10 620 controls and 2110 MS trios, the association at genome-wide significance level (P=5.08 x 10(-9), OR 0.77) was shown.
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http://dx.doi.org/10.1038/ejhg.2009.195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2987240PMC
April 2010

Interleukin-10 promoter polymorphisms in myasthenia gravis.

J Neuroimmunol 2009 May 18;210(1-2):63-6. Epub 2009 Mar 18.

Department of Clinical Medicine, University of Bergen, Norway.

Interleukin 10 (IL-10) is secreted by several hemopoietic cells and suppresses the Th1 mediated immune response, while stimulating B cell differentiation and the humoral immune response. IL-10 expression in Con A-stimulated peripheral blood mononuclear cells is related to three polymorphisms in the promoter region of the IL-10 gene; G/A at position -1082, T/C at position -819 and A/C at position -592. We analyzed the distribution of these IL-10 polymorphisms in 64 MG patients and 87 healthy blood donors to determine any influence on MG susceptibility. MG patients had a significantly higher frequency of the ACC/ACC haplotype (12.5% vs 3.4% in controls), as had the subgroups with late onset MG and thymomatous MG (20.0% and 21.4%, respectively). Early onset MG patients had a high frequency of the ATA/ATA haplotype (19.2% vs 3.4% in controls). Titin Ab-positive MG patients had high ACC/ACC (20.0%). This study indicates a direct link between IL-10 and MG pathogenesis, although the complex role of this multi-faceted cytokine in vivo is as yet not fully elucidated.
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http://dx.doi.org/10.1016/j.jneuroim.2009.02.009DOI Listing
May 2009
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