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

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

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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

Global DNA methylation changes in treated and untreated MS patients measured over time

Multiple sclerosis (MS) is an autoimmune, neurological disease. We investigated genome-wide DNA methylation profiles of CD4+ and CD8+ T cells from MS patients and healthy controls at baseline and a follow-up visit. Patients were all treatment-naïve at baseline, and either on treatment or remained untreated at the follow-up visit. MS patients show more changes in their T cell DNA methylation profiles as compared to healthy controls over time, with the most pronounced differences observed in the untreated MS patients. These findings underline the potential of DNA methylation as biomarkers in MS

Cognitive function in patients with neuroborreliosis: A prospective cohort study from the acute phase to 12 months post treatment

Background Long-term cognitive problems after neuroborreliosis treatment remain a subject of debate. We have previously shown that cognitive problems are not present in the acute phase of neuroborreliosis, although fatigue is common. The aim of this study was to re-assess the same patient cohort and evaluate long-term outcomes. Methods In this follow-up, we re-assessed 58 patients with well-characterized neuroborreliosis 12 months after completing treatment. The same protocol with eight subtests measuring attention and processing speed and the Fatigue Severity Scale (FSS) were used to compare the results from the acute phase to 12 months post treatment. Results We found no changes in attention or processing speed but a reduction in the level of fatigue (median score on FSS: 4.9 vs. 3.9, p < .001) from the acute phase to 12 months post treatment. Conclusion The patient group did not develop problems with attention or processing speed post treatment, while the level of fatigue decreased

Cognitive function in patients with neuroborreliosis: A prospective cohort study from the acute phase to 12 months post treatment

Background Long-term cognitive problems after neuroborreliosis treatment remain a subject of debate. We have previously shown that cognitive problems are not present in the acute phase of neuroborreliosis, although fatigue is common. The aim of this study was to re-assess the same patient cohort and evaluate long-term outcomes. Methods In this follow-up, we re-assessed 58 patients with well-characterized neuroborreliosis 12 months after completing treatment. The same protocol with eight subtests measuring attention and processing speed and the Fatigue Severity Scale (FSS) were used to compare the results from the acute phase to 12 months post treatment. Results We found no changes in attention or processing speed but a reduction in the level of fatigue (median score on FSS: 4.9 vs. 3.9, p < .001) from the acute phase to 12 months post treatment. Conclusion The patient group did not develop problems with attention or processing speed post treatment, while the level of fatigue decreased

Quantitative proteomics reveals protein dysregulation during T cell activation in multiple sclerosis patients compared to healthy controls

Background: Multiple sclerosis (MS) is an autoimmune, neurodegenerative disorder with a strong genetic component that acts in a complex interaction with environmental factors for disease development. CD4+ T cells are pivotal players in MS pathogenesis, where peripherally activated T cells migrate to the central nervous system leading to demyelination and axonal degeneration. Through a proteomic approach, we aim at identifying dysregulated pathways in activated T cells from MS patients as compared to healthy controls. Methods: CD4+ T cells were purified from peripheral blood from MS patients and healthy controls by magnetic separation. Cells were left unstimulated or stimulated in vitro through the TCR and costimulatory CD28 receptor for 24 h prior to sampling. Electrospray liquid chromatography-tandem mass spectrometry was used to measure protein abundances. Results: Upon T cell activation the abundance of 1801 proteins was changed. Among these proteins, we observed an enrichment of proteins expressed by MS-susceptibility genes. When comparing protein abundances in T cell samples from healthy controls and MS patients, 18 and 33 proteins were differentially expressed in unstimulated and stimulated CD4+ T cells, respectively. Moreover, 353 and 304 proteins were identified as proteins exclusively induced upon T cell activation in healthy controls and MS patients, respectively and dysregulation of the Nur77 pathway was observed only in samples from MS patients. Conclusions: Our study highlights the importance of CD4+ T cell activation for MS, as proteins that change in abundance upon T cell activation are enriched for proteins encoded by MS susceptibility genes. The results provide evidence for proteomic disturbances in T cell activation in MS, and pinpoint to dysregulation of the Nur77 pathway, a biological pathway known to limit aberrant effector T cell responses