Implementering av Legemiddelinnkjøpsamarbeid (LIS)-anbefalinger ved multippel sklerose

Bakgrunn: De siste 18 årene har et økende antall kostbare immunmodulerende medikamenter blitt tilgjengelig i Norge for bruk ved multippel sklerose (MS). De regionale helseforetakene (RHFene) inngikk i 2007 en avtale vedrørende legemiddelinnkjøpsamarbeid (LIS). LIS-MS spesialistgruppen gir anbefalinger for preparatvalg ved oppstart eller endring av behandling ut fra kostnadsberegninger basert på godkjente indikasjoner og nasjonale retningslinjer for behandling av MS. Laveste gjennomsnittlige behandlingskostnad gir grunnlag for preparatvalg. RHFene har vedtatt å benytte LIS-anbefalingene som instruks i egne helseforetak. Avvik fra anbefalingene skal begrunnes og dokumenteres i pasientenes journal. Denne oppgaven hadde som mål å belyse hvordan LIS-anbefalingene for MS-behandling er blitt implementert de siste årene ved en av Norges største MS-klinikker. Dernest ønsket vi å studere implikasjoner av LIS-anbefalingene for pasientene og spesialisthelsetjenesten og diskutere dette i et klinisk samt et helsepolitisk perspektiv. Metode: I kvalitets-registeret over MS-pasienter ved nevrologisk avdeling ved på Oslo universitetssykehus (OUS), identifiserte vi 174 MS-pasienter som startet med immunmodulerende førstelinje MS-behandling for første gang i perioden januar 2011-september 2014. Data ble innhentet ved gjennomgang av pasientenes journaler. Kliniske parametere, data om medikamentbruk, bivirkninger og seponerings-årsaker ble analysert med deskriptiv statistikk. Tid til medikamentbytte første, andre, tredje og fjerde gang for de mest brukte medikamentene ble sammenlignet ved deskriptive analyser og i Kaplan-Meier levetidsanalyser og Log Rank test. Resultater: Mer enn halvparten (55,2 %) av pasientene startet behandling med Extavia® eller Betaferon® (interferon β-1b), slik LIS-MS spesialistgruppen har anbefalt i studieperioden. Copaxone® (glatirameracetat) var det første MS-medikamentet som ble brukt blant 33,3 % av pasientene, og mindre andeler av pasientene startet med andre preparater. Medikament-valget var begrunnet i journalen, slik retningslinjen sier. I løpet av studieperioden sluttet 59 % av de som startet med Extavia® og 80 % av de som starter med Betaferon® med disse medikamentene. I overkant av 50 % sluttet med det alternative førstelinje medikamentet Copaxone®. Det var ingen signifikant forskjell i behandlingslengden mellom Extavia®, Betaferon® og Copaxone®, som gjennomsnittlig var mellom 18 og 24 måneder. Pasientene hadde hyppig kjente bivirkninger av alle tre behandlingene. Det hyppigste var influensa-symptomer ved Extavia® og Betaferon® (55 %) og reaksjoner på injeksjonsstedet ved Copaxone (53 %). Tilsvarende ble behandlingen avbrutt på grunn av influensa-symptomer i 13 % av tilfellene og på grunn av reaksjoner på innstikks-stedet hos 14 %. Attakker eller endringer på MRI-bilder førte til seponering hos 23 % av pasientene, likt fordelt i disse to behandlingsgruppene. Ønske om å bruke et annet medikament ble angitt som seponeringsårsak hos 22 %, uavhengig av bivirkninger. Tilsammen byttet 64 % av pasientene medikament i løpet av studieperioden minst en gang. Det var også mange pasienter som startet med andre typer medikamenter i løpet av studieperioden (n=229), og de fleste av disse (81,2 %) startet med tablett-behandlinger. Konklusjon: Studien bekrefter at MS-klinikken på OUS har implementert MS-LIS-anbefalingene, i og med at den største andelen av pasientene startet med Extavia®- eller Betaferon®-injeksjoner. En relativt stor andel begynte med det alternative førstelinje-medikamentet Copaxone®. Medikamentvalgene var begrunnet i journalene, slik instruksen tilsier. Pasientene hadde hyppig kjente bivirkninger av disse tre medikamentene. Flertallet sluttet eller skiftet til andre medikamenter i løpet av observasjonsperioden, delvis på grunn av bivirkninger, terapi-svikt eller ønske om å bruke et annet preparat. Man bør derfor vurdere å inkludere kostnader for pasienter og helsevesen ved medikamentbytter i kostnadsanalysene ved LIS-anbefalinger ved MS. En økende andel pasienter startet med perorale medikamenter ved medikament-skiftet, parallelt med at disse kom på det norske markedet. Dette gir støtte til den endrede praksisen som ble innført ved LIS-anbefalingen for 2015, der tablett-behandling med Aubagio® likestilles med injeksjonsbehandling med Extavia®, til tross for at tablett-behandlingen er nesten dobbelt så dyr. Studien støtter også argumenter for større grad av persontilpassede medikamentvalg. Resultater av den pågående fullstendige metodevurderingen vedrørende bruk av legemidler ved MS i Norge vil være avgjørende for fremtidige LIS-anbefalinger for MS-behandling

Quantitative proteomic analyses of CD4+ and CD8+ T cells reveal differentially expressed proteins in multiple sclerosis patients and healthy controls

Background Multiple sclerosis (MS) is an autoimmune, neuroinflammatory disease, with an unclear etiology. However, T cells play a central role in the pathogenesis by crossing the blood–brain-barrier, leading to inflammation of the central nervous system and demyelination of the protective sheath surrounding the nerve fibers. MS has a complex inheritance pattern, and several studies indicate that gene interactions with environmental factors contribute to disease onset. Methods In the current study, we evaluated T cell dysregulation at the protein level using electrospray liquid chromatography–tandem mass spectrometry to get novel insights into immune-cell processes in MS. We have analyzed the proteomic profiles of CD4+ and CD8+ T cells purified from whole blood from 13 newly diagnosed, treatment-naive female patients with relapsing–remitting MS and 14 age- and sex-matched healthy controls. Results An overall higher protein abundance was observed in both CD4+ and CD8+ T cells from MS patients when compared to healthy controls. The differentially expressed proteins were enriched for T-cell specific activation pathways, especially CTLA4 and CD28 signaling in CD4+ T cells. When selectively analyzing proteins expressed from the genes most proximal to > 200 non-HLA MS susceptibility polymorphisms, we observed differential expression of eight proteins in T cells between MS patients and healthy controls, and there was a correlation between the genotype at three MS genetic risk loci and protein expressed from proximal genes. Conclusion Our study provides evidence for proteomic differences in T cells from relapsing–remitting MS patients compared to healthy controls and also identifies dysregulation of proteins encoded from MS susceptibility genes.publishedVersio

Assessment of cognitive function, structural brain changes and fatigue 6 months after treatment of neuroborreliosis

publishedVersionPaid Open Acces

The Effect of Smoking on Long-term Gray Matter Atrophy and Clinical Disability in Patients with Relapsing-Remitting Multiple Sclerosis

The relationship between smoking, long-term brain atrophy, and clinical disability in patients with multiple sclerosis (MS) is unclear. Here, we assessed long-term effects of smoking by evaluating MRI and clinical outcome measures after 10 years in smoking and nonsmoking patients with relapsing-remitting MS (RRMS).publishedVersio

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

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. This article is made freely available for use in accordance with BMJ’s website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.publishedVersio

Serum neurofilament as a predictor of 10-year grey matter atrophy and clinical disability in multiple sclerosis: a longitudinal study

Background The predictive value of serum neurofilament light chain (sNfL) on long-term prognosis in multiple sclerosis (MS) is still unclear. Objective Investigate the relation between sNfL levels over a 2-year period in patients with relapsing-remitting MS, and clinical disability and grey matter (GM) atrophy after 10 years. Methods 85 patients, originally enrolled in a multicentre, randomised trial of ω−3 fatty acids, participated in a 10-year follow-up visit. sNfL levels were measured by Simoa quarterly until month 12, and then at month 24. The appearance of new gadolinium-enhancing (Gd+) lesions was assessed monthly between baseline and month 9, and then at months 12 and 24. At the 10-year follow-up visit, brain atrophy measures were obtained using FreeSurfer. Results Higher mean sNfL levels during early periods of active inflammation (Gd+ lesions present or recently present) predicted lower total (β=−0.399, p=0.040) and deep (β=−0.556, p=0.010) GM volume, lower mean cortical thickness (β=−0.581, p=0.010) and higher T2 lesion count (β=0.498, p=0.018). Of the clinical outcomes, higher inflammatory sNfL levels were associated with higher disability measured by the dominant hand Nine-Hole Peg Test (β=0.593, p=0.004). Mean sNfL levels during periods of remission (no Gd+ lesions present or recently present) did not predict GM atrophy or disability progression. Conclusion Higher sNfL levels during periods of active inflammation predicted more GM atrophy and specific aspects of clinical disability 10 years later. The findings suggest that subsequent long-term GM atrophy is mainly due to neuroaxonal degradation within new lesions.publishedVersio

Fourteen sequence variants that associate with multiple sclerosis discovered by meta-analysis informed by genetic correlations

A meta-analysis of publicly available summary statistics on multiple sclerosis combined with three Nordic multiple sclerosis cohorts (21,079 cases, 371,198 controls) revealed seven sequence variants associating with multiple sclerosis, not reported previously. Using polygenic risk scores based on public summary statistics of variants outside the major histocompatibility complex region we quantified genetic overlap between common autoimmune diseases in Icelanders and identified disease clusters characterized by autoantibody presence/absence. As multiple sclerosis-polygenic risk scores captures the risk of primary biliary cirrhosis and vice versa (P = 1.6 x 10(-7), 4.3 x 10(-9)) we used primary biliary cirrhosis as a proxy-phenotype for multiple sclerosis, the idea being that variants conferring risk of primary biliary cirrhosis have a prior probability of conferring risk of multiple sclerosis. We tested 255 variants forming the primary biliary cirrhosis-polygenic risk score and found seven multiple sclerosis-associating variants not correlated with any previously established multiple sclerosis variants. Most of the variants discovered are close to or within immune-related genes. One is a low-frequency missense variant in TYK2, another is a missense variant in MTHFR that reduces the function of the encoded enzyme affecting methionine metabolism, reported to be dysregulated in multiple sclerosis brain.publishedVersio

Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk

Multiple sclerosis is a complex neurological disease, with 3c20% of risk heritability attributable to common genetic variants, including >230 identified by genome-wide association studies. Multiple strands of evidence suggest that much of the remaining heritability is also due to additive effects of common variants rather than epistasis between these variants or mutations exclusive to individual families. Here, we show in 68,379 cases and controls that up to 5% of this heritability is explained by low-frequency variation in gene coding sequence. We identify four novel genes driving MS risk independently of common-variant signals, highlighting key pathogenic roles for regulatory T cell homeostasis and regulation, IFN\u3b3 biology, and NF\u3baB signaling. As low-frequency variants do not show substantial linkage disequilibrium with other variants, and as coding variants are more interpretable and experimentally tractable than non-coding variation, our discoveries constitute a rich resource for dissecting the pathobiology of MS. In a large multi-cohort study, unexplained heritability for multiple sclerosis is detected in low-frequency coding variants that are missed by GWAS analyses, further underscoring the role of immune genes in MS pathology

Assessing genome-wide significance for the detection of differentially methylated regions

DNA methylation plays an important role in human health and disease, and methods for the identification of differently methylated regions are of increasing interest. There is currently a lack of statistical methods which properly address multiple testing, i.e. control genome-wide significance for differentially methylated regions. We introduce a scan statistic (DMRScan), which overcomes these limitations. We benchmark DMRScan against two well established methods (bumphunter, DMRcate), using a simulation study based on real methylation data. An implementation of DMRScan is available from Bioconductor. Our method has higher power than alternative methods across different simulation scenarios, particularly for small effect sizes. DMRScan exhibits greater flexibility in statistical modeling and can be used with more complex designs than current methods. DMRScan is the first dynamic approach which properly addresses the multiple-testing challenges for the identification of differently methylated regions. DMRScan outperformed alternative methods in terms of power, while keeping the false discovery rate controlled

Assessing the Power of Exome Chips

Genotyping chips for rare and low-frequent variants have recently gained popularity with the introduction of exome chips, but the utility of these chips remains unclear. These chips were designed using exome sequencing data from mainly American-European individuals, enriched for a narrow set of common diseases. In addition, it is well-known that the statistical power of detecting associations with rare and low-frequent variants is much lower compared to studies exclusively involving common variants. We developed a simulation program adaptable to any exome chip design to empirically evaluate the power of the exome chips. We implemented the main properties of the Illumina HumanExome BeadChip array. The simulated data sets were used to assess the power of exome chip based studies for varying effect sizes and causal variant scenarios. We applied two widely-used statistical approaches for rare and low-frequency variants, which collapse the variants into genetic regions or genes. Under optimal conditions, we found that a sample size between 20,000 to 30,000 individuals were needed in order to detect modest effect sizes (0.5% 1%) with 80% power. For small effect sizes (PAR <0.5%), 60,000–100,000 individuals were needed in the presence of non-causal variants. In conclusion, we found that at least tens of thousands of individuals are necessary to detect modest effects under optimal conditions. In addition, when using rare variant chips on cohorts or diseases they were not originally designed for, the identification of associated variants or genes will be even more challenging