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Grut, V., Biström, M., Salzer, J., Stridh, P., Jons, D., Gustafsson, R., . . . Sundström, P. (2024). Human herpesvirus 6A and axonal injury before the clinical onset of multiple sclerosis. Brain, 147(1), 177-185
Open this publication in new window or tab >>Human herpesvirus 6A and axonal injury before the clinical onset of multiple sclerosis
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2024 (English)In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 147, no 1, p. 177-185Article in journal (Refereed) Published
Abstract [en]

Recent research indicates that multiple sclerosis is preceded by a prodromal phase with elevated levels of serum neurofilament light chain (sNfL), a marker of axonal injury. The effect of environmental risk factors on the extent of axonal injury during this prodrome is unknown. Human herpesvirus 6A (HHV-6A) is associated with an increased risk of developing multiple sclerosis. The objective of this study was to determine if HHV-6A serostatus is associated with the level of sNfL in the multiple sclerosis prodrome, which would support a causative role of HHV-6A.

A nested case-control study was performed by crosslinking multiple sclerosis registries with Swedish biobanks. Individuals with biobank samples collected before the clinical onset of multiple sclerosis were included as cases. Controls without multiple sclerosis were randomly selected, matched for biobank, sex, sampling date and age. Serostatus of HHV-6A and Epstein-Barr virus was analysed with a bead-based multiplex assay. The concentration of sNfL was analysed with single molecule array technology. The association between HHV-6A serology and sNfL was assessed by stratified t-tests and linear regressions, adjusted for Epstein-Barr virus serostatus and sampling age. Within-pair ratios of HHV-6A seroreactivity and sNfL were calculated for each case and its matched control. To assess the temporal relationship between HHV-6A antibodies and sNfL, these ratios were plotted against the time to the clinical onset of multiple sclerosis and compared using locally estimated scatterplot smoothing regressions with 95% confidence intervals (CI).

Samples from 519 matched case-control pairs were included. In cases, seropositivity of HHV-6A was significantly associated with the level of sNfL (+11%, 95% CI 0.2-24%, P = 0.045) and most pronounced in the younger half of the cases (+24%, 95% CI 6-45%, P = 0.007). No such associations were observed among the controls. Increasing seroreactivity against HHV-6A was detectable before the rise of sNfL (significant within-pair ratios from 13.6 years versus 6.6 years before the clinical onset of multiple sclerosis).

In this study, we describe the association between HHV-6A antibodies and the degree of axonal injury in the multiple sclerosis prodrome. The findings indicate that elevated HHV-6A antibodies both precede and are associated with a higher degree of axonal injury, supporting the hypothesis that HHV-6A infection may contribute to multiple sclerosis development in a proportion of cases.

Place, publisher, year, edition, pages
Oxford University Press, 2024
Keywords
axonal injury, Epstein-Barr virus, human herpesvirus 6-A, multiple sclerosis, neurofilament light chain
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-219831 (URN)10.1093/brain/awad374 (DOI)001129461500001 ()37930324 (PubMedID)2-s2.0-85181761078 (Scopus ID)
Funder
Swedish Research Council, 2015-02419Visare NorrRegion Jämtland Härjedalen, JLL-967380The Swedish Brain FoundationEU, Horizon 2020, 733161Swedish Research Council, 2017-00915Swedish Research Council, 2022-00732
Available from: 2024-01-22 Created: 2024-01-22 Last updated: 2024-01-22Bibliographically approved
Gröning, R., Dernstedt, A., Ahlm, C., Normark, J., Sundström, P. & Forsell, M. N. E. (2023). Immune response to SARS-CoV-2 mRNA vaccination in multiple sclerosis patients after rituximab treatment interruption. Frontiers in Immunology, 14, Article ID 1219560.
Open this publication in new window or tab >>Immune response to SARS-CoV-2 mRNA vaccination in multiple sclerosis patients after rituximab treatment interruption
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2023 (English)In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, article id 1219560Article in journal (Refereed) Published
Abstract [en]

Peripheral B cell depletion via anti-CD20 treatment is a highly effective disease-modifying treatment for reducing new relapses in multiple sclerosis (MS) patients. A drawback of rituximab (RTX) and other anti-CD20 antibodies is a poor immune response to vaccination. While this can be mitigated by treatment interruption of at least six months prior to vaccination, the timing to resume treatment while maintaining subsequent vaccine responses remains undetermined. Here, we characterized SARS-CoV-2 S-directed antibody and B cell responses throughout three BNT162b2 mRNA vaccine doses in RTX-treated MS patients, with the first two doses given during treatment interruption. We examined B-cell mediated immune responses in blood samples from patients with RTX-treated MS throughout three BNT162b2 vaccine doses, compared to an age- and sex-matched healthy control group. The first vaccine dose was given 1.3 years (median) after the last RTX infusion, the second dose one month after the first, and the third dose four weeks after treatment re-initiation. We analyzed SARS-CoV-2 S-directed antibody levels using enzyme-linked immunosorbent assay (ELISA), and the neutralization capacity of patient serum against SARS-CoV-2 S-pseudotyped lentivirus using luciferase reporter assay. In addition, we assessed switched memory (CD19+CD20+CD27+IgD-), unswitched memory (CD19+CD20+CD27+IgD+), naïve (CD19+CD20+CD27-IgD+), and double negative (DN, CD19+CD20+CD27-IgD-) B cell frequencies, as well as their SARS-CoV-2 S-specific (CoV+) and Decay Accelerating Factor-negative (DAF-) subpopulations, using flow cytometry. After two vaccine doses, S-binding antibody levels and neutralization capacity in SARS-CoV-2-naïve MS patients were comparable to vaccinated healthy controls, albeit with greater variation. Higher antibody response levels and CoV+-DN B cell frequencies after the second vaccine dose were predictive of a boost effect after the third dose, even after re-initiation of rituximab treatment. MS patients also exhibited lower frequencies of DAF- memory B cells, a suggested proxy for germinal centre activity, than control individuals. S-binding antibody levels in RTX-treated MS patients after two vaccine doses could help determine which individuals would need to move up their next vaccine booster dose or postpone their next RTX infusion. Our findings also offer first indications on the potential importance of antigenic stimulation of DN B cells and long-term impairment of germinal centre activity in rituximab-treated MS patients.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2023
Keywords
B cell immunology, COVID-19, multiple sclerosis, rituximab, vaccination
National Category
Infectious Medicine Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-212992 (URN)10.3389/fimmu.2023.1219560 (DOI)37575257 (PubMedID)2-s2.0-85167514064 (Scopus ID)
Funder
Region Västerbotten, RV-969133Swedish Research Council, 2020-0625Swedish Research Council, 2021-04665Knut and Alice Wallenberg Foundation, VA-2021-0018Knut and Alice Wallenberg Foundation, VA-2022-0008Science for Life Laboratory, SciLifeLab
Available from: 2023-08-18 Created: 2023-08-18 Last updated: 2024-01-17Bibliographically approved
Jons, D., Grut, V., Bergström, T., Zetterberg, H., Biström, M., Gunnarsson, M., . . . Andersen, O. (2023). Seroreactivity against lytic, latent and possible cross-reactive EBV antigens appears on average 10 years before MS induced preclinical neuroaxonal damage. Journal of Neurology, Neurosurgery and Psychiatry, Article ID 331868.
Open this publication in new window or tab >>Seroreactivity against lytic, latent and possible cross-reactive EBV antigens appears on average 10 years before MS induced preclinical neuroaxonal damage
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2023 (English)In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, article id 331868Article in journal (Refereed) Epub ahead of print
Abstract [en]

Background: Multiple sclerosis (MS) and presymptomatic axonal injury appear to develop only after an Epstein-Barr virus (EBV) infection. This association remains to be confirmed across a broad preclinical time range, for lytic and latent EBV seroreactivity, and for potential cross-reacting antigens.

Methods: We performed a case-control study with 669 individual serum samples obtained before clinical MS onset, identified through cross-linkage with the Swedish MS register. We assayed antibodies against EBV nuclear antigen 1 (EBNA1), viral capsid antigen p18, glycoprotein 350 (gp350), the potential cross-reacting protein anoctamin 2 (ANO2) and the level of sNfL, a marker of axonal injury.

Results: EBNA1 (latency) seroreactivity increased in the pre-MS group, at 15-20 years before clinical MS onset, followed by gp350 (lytic) seroreactivity (p=0.001-0.009), ANO2 seropositivity appeared shortly after EBNA1-seropositivity in 16.7% of pre-MS cases and 10.0% of controls (p=0.001). With an average lag of almost a decade after EBV, sNfL gradually increased, mainly in the increasing subgroup of seropositive pre-MS cases (p=8.10-5 compared with non-MS controls). Seropositive pre-MS cases reached higher sNfL levels than seronegative pre-MS (p=0.038). In the EBNA1-seropositive pre-MS group, ANO2 seropositive cases had 26% higher sNfL level (p=0.0026).

Conclusions: Seroreactivity against latent and lytic EBV antigens, and in a subset ANO2, was detectable on average a decade before the appearance of a gradually increasing axonal injury occurring in the last decade before the onset of clinical MS. These findings strengthen the hypothesis of latent EBV involvement in the pathogenesis of MS.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2023
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-215746 (URN)10.1136/jnnp-2023-331868 (DOI)001085444600001 ()37802637 (PubMedID)2-s2.0-85174051593 (Scopus ID)
Funder
Visare NorrRegion Jämtland HärjedalenSwedish Research Council, 2018-02532EU, European Research Council, 681712EU, European Research Council, 101053962Familjen Erling-Perssons StiftelseStiftelsen Gamla TjänarinnorThe Swedish Brain Foundation, FO2019-0228EU, Horizon 2020Swedish Research Council, 2017-00915The Swedish Brain Foundation, FO2017-0243NIH (National Institutes of Health), 1R01AG068398-01Knut and Alice Wallenberg FoundationEU, Horizon 2020, 733161Swedish Research Council, 2020-01638
Available from: 2023-11-02 Created: 2023-11-02 Last updated: 2024-01-09
Jons, D., Zetterberg, H., Biström, M., Alonso-Magdalena, L., Gunnarsson, M., Vrethem, M., . . . Andersen, O. (2022). Axonal injury in asymptomatic individuals preceding onset of multiple sclerosis. Annals of Clinical and Translational Neurology, 9(6), 882-887
Open this publication in new window or tab >>Axonal injury in asymptomatic individuals preceding onset of multiple sclerosis
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2022 (English)In: Annals of Clinical and Translational Neurology, E-ISSN 2328-9503, Vol. 9, no 6, p. 882-887Article in journal (Refereed) Published
Abstract [en]

Axonal loss is the main cause of irreversible disability in multiple sclerosis (MS). Serum neurofilament light (sNfL) is a biomarker of axonal disintegration. In this nested case–control study, blood samples from 519 presymptomatic persons (age range 4–39 years) who later received an MS diagnosis showed higher sNfL concentrations than 519 matched controls (p < 0.0001), noticeable at least 10 years before clinical MS onset. Mean values for pre-MS and control groups were 9.6 pg/mL versus 7.4 pg/mL 0–5 years before onset, and 6.4 pg/mL versus 5.8 pg/mL 5–10 years before onset. These results support that axonal injury occurs early in MS pathogenesis.

Place, publisher, year, edition, pages
John Wiley & Sons, 2022
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:umu:diva-194907 (URN)10.1002/acn3.51568 (DOI)000789844900001 ()35502756 (PubMedID)2-s2.0-85129266300 (Scopus ID)
Funder
Swedish Research Council, 2018-0253EU, European Research Council, 681712Familjen Erling-Perssons StiftelseStiftelsen Gamla TjänarinnorThe Swedish Brain Foundation, FO2019-022EU, Horizon 2020Swedish Research Council, 2017-00915The Swedish Brain Foundation, FO2017-0243
Available from: 2022-06-01 Created: 2022-06-01 Last updated: 2023-03-24Bibliographically approved
Tedeholm, H., Piehl, F., Lycke, J., Link, J., Stawiarz, L., Burman, J., . . . Andersen, O. (2022). Effectiveness of first generation disease-modifying therapy to prevent conversion to secondary progressive multiple sclerosis. Multiple Sclerosis and Related Disorders, 68, Article ID 104220.
Open this publication in new window or tab >>Effectiveness of first generation disease-modifying therapy to prevent conversion to secondary progressive multiple sclerosis
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2022 (English)In: Multiple Sclerosis and Related Disorders, ISSN 2211-0348, E-ISSN 2211-0356, Vol. 68, article id 104220Article in journal (Refereed) Published
Abstract [en]

Background: The use of disease-modifying therapies (DMTs) in multiple sclerosis (MS) has been associated with reduced relapse rates and accumulation of disability. However, studies examining impact of DMT on risk of transition to secondary progressive MS (SPMS) leveraging population-based nationwide data are still rare. Here, we determine the population incidence of conversion to SPMS using two consecutive nation-wide cohorts, one immediately before and one after the introduction of DMT in Sweden.

Methods: We included two consecutive population cohorts of relapsing-remitting MS (RRMS) from the Swedish national MS register for the periods 1975–1994 (n = 2161), before DMT availability, and 1995–2011 (n = 3510), in which DMTs, mainly first generation DMT (injectables), became available and eventually were used by 70% of patients. We explored the risk of transition to SPMS as a calendar year function encompassing the two cohorts. In addition, we determined the incidence of transition to SPMS through age strata below and above 50 years in untreated and treated patient subgroups.

Results: The risk of conversion to SPMS (adjusted for current age, current time since onset, calendar year and sex) was significantly lower in the second compared with the first population cohort (hazard ratio 0.58; CI 0.48, 0.70). The risk of SPMS conversion per calendar year decreased by 2.6% annually (p < 0.001) after 1995. The risk of SPMS conversion increased with age until age 50. Thereafter, it was unchanged or decreased among those with early MS onset age (<35 years), but continued to increase with onset at higher age, with similar trends in treated and untreated subgroups.

Conclusion: The incidence of SPMS conversion significantly decreased at the population level after introduction of first generation DMTs by 1995. DMT efficiency was confirmed by a downward turn of the annual trajectory of the risk of SPMS conversion after 1995. An onset age determined pattern of variable SPMS incidence in higher age appeared in both treated and untreated strata. While first generation DMT delayed conversion to SPMS, their long-term effect was only moderate.

Place, publisher, year, edition, pages
Elsevier, 2022
Keywords
Annual incidence, Disease-modifying therapy, Multiple sclerosis, Observational study, Secondary progression
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-200572 (URN)10.1016/j.msard.2022.104220 (DOI)000881824300005 ()36242804 (PubMedID)2-s2.0-85139846258 (Scopus ID)
Funder
Region Västra Götaland
Available from: 2022-10-31 Created: 2022-10-31 Last updated: 2023-09-05Bibliographically approved
Piehl, F., Eriksson-Dufva, A., Budzianowska, A., Feresiadou, A., Hansson, W., Hietala, M. A., . . . Frisell, T. (2022). Efficacy and safety of rituximab for new-onset generalized myasthenia gravis: the RINOMAX randomized clinical trial. JAMA Neurology, 79(11), 1105-1112
Open this publication in new window or tab >>Efficacy and safety of rituximab for new-onset generalized myasthenia gravis: the RINOMAX randomized clinical trial
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2022 (English)In: JAMA Neurology, ISSN 2168-6149, E-ISSN 2168-6157, Vol. 79, no 11, p. 1105-1112Article in journal (Refereed) Published
Abstract [en]

IMPORTANCE: Rituximab is a third-line option for refractory generalized myasthenia gravis (MG) based on empirical evidence, but its effect in new-onset disease is unknown.

OBJECTIVE: To investigate the efficacy and safety of rituximab compared with placebo as an add-on to standard of care for MG.

DESIGN, SETTING, AND PARTICIPANTS: This randomized, double-blind, placebo-controlled study took place throughout 48 weeks at 7 regional clinics in Sweden. Key inclusion criteria were age older than 18 years, onset of generalized symptoms within 12 months or less, and a Quantitative Myasthenia Gravis (QMG) score of 6 or more. Patients were screened from October 20, 2016, to March 2, 2020. Key exclusion criteria included pure ocular MG, suspected thymoma, previous thymectomy, and prior noncorticosteroid immunosuppressants or high doses of corticosteroids.

INTERVENTIONS: Participants were randomized 1:1 without stratification to a single intravenous infusion of 500 mg of rituximab or matching placebo.

MAIN OUTCOMES AND MEASURES: Minimal disease manifestations at 16 weeks defined as a QMG score of 4 or less with prednisolone, 10 mg or less daily, and no rescue treatment.

RESULTS: Of 87 potentially eligible patients, 25 were randomized to rituximab (mean [SD] age, 67.4 [13.4] years; 7 [28%] female) and 22 to placebo (mean [SD] age, 58 [18.6] years; 7 [32%] female). Compared with placebo, a greater proportion with rituximab met the primary end point; 71% (17 of 24) in the rituximab group vs 29% (6 of 21) in the placebo group (Fisher exact test P = .007; probability ratio, 2.48 [95% CI, 1.20-5.11]). Secondary end points, comparing changes in Myasthenia Gravis Activities of Daily Living and Myasthenia Gravis Quality of Life at 16 weeks with QMG at 24 weeks did not differ between groups with censoring for rescue treatment (per-protocol analysis) but were in favor of active treatment when rescue treatment was taken into account by worst rank imputation (post hoc analysis). Rescue treatments were also more frequent in the placebo arm (rituximab: 1 [4%]; placebo, 8 [36%]). One patient in the placebo arm had a myocardial infarction with cardiac arrest and 1 patient in the active arm experienced a fatal cardiac event.

CONCLUSIONS AND RELEVANCE: A single dose of 500 mg of rituximab was associated with greater probability of minimal MG manifestations and reduced need of rescue medications compared with placebo. Further studies are needed to address long-term benefit-risk balance with this treatment.

Place, publisher, year, edition, pages
American Medical Association (AMA), 2022
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-203265 (URN)10.1001/jamaneurol.2022.2887 (DOI)000857176500002 ()36121672 (PubMedID)2-s2.0-85138398348 (Scopus ID)
Funder
Swedish Research Council, 2015-00887Swedish Research Council, 2020-02700
Available from: 2023-01-17 Created: 2023-01-17 Last updated: 2023-03-24Bibliographically approved
Grut, V., Biström, M., Salzer, J., Stridh, P., Lindam, A., Alonso-Magdalena, L., . . . Sundström, P. (2022). Free vitamin D3 index and vitamin D-binding protein in multiple sclerosis: A presymptomatic case-control study. European Journal of Neurology, 29(8), 2335-2342
Open this publication in new window or tab >>Free vitamin D3 index and vitamin D-binding protein in multiple sclerosis: A presymptomatic case-control study
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2022 (English)In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 29, no 8, p. 2335-2342Article in journal (Refereed) Published
Abstract [en]

BACKGROUND AND PURPOSE: High levels of 25-hydroxyvitamin D3 (25[OH]D3 ) are associated with a lower risk for multiple sclerosis (MS). The bioavailability of 25(OH)D3 is regulated by its main plasma carrier, vitamin D-binding protein (DBP). Free 25(OH)D3 can be estimated by also measuring DBP concentration. In addition, DBP has immunomodulatory functions that may independently affect MS pathogenesis. No previous studies have assessed free 25(OH)D3 or DBP in presymptomatically collected samples. This study was undertaken to assess free 25(OH)D3 and DBP as risk factors for MS.

METHODS: A nested case-control study was performed with presymptomatic serum samples identified through cross-linkage of MS registries and Swedish biobanks. Concentration of 25(OH)D3 was measured with liquid chromatography and DBP levels with sandwich immunoassay. Free 25(OH)D3 was approximated as free vitamin D3 index: (25[OH]D3 /DBP) × 103 . MS risk was analyzed by conditional logistic regression, calculating odds ratios (ORs) with 95% confidence intervals (CIs).

RESULTS: Serum samples from 660 pairs of matched cases and controls were included. At <20 years of age, high levels of free vitamin D3 index were associated with a lower risk of MS (highest vs. lowest quintile: OR = 0.37, 95% CI = 0.15-0.91, p for trend across quintiles = 0.04). At age 30-39 years, high levels of DBP were associated with a lower MS risk (highest vs. lowest quintile: OR = 0.36, 95% CI = 0.15-0.85, p for trend = 0.02).

CONCLUSIONS: These findings support the hypothesis that high levels of free 25(OH)D3 at a young age reduce the risk of MS later in life. They also implicate a role for DBP in MS etiology.

Place, publisher, year, edition, pages
John Wiley & Sons, 2022
Keywords
case-control studies, multiple sclerosis, vitamin D, vitamin D-binding protein
National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:umu:diva-202379 (URN)10.1111/ene.15407 (DOI)000805801300001 ()35582958 (PubMedID)2-s2.0-85131168703 (Scopus ID)
Funder
Region Jämtland Härjedalen, JLL-939768Visare NorrSwedish Research Council, 2015-02419
Available from: 2023-01-09 Created: 2023-01-09 Last updated: 2023-05-25Bibliographically approved
Alonso-Magdalena, L., Zia, E., Carmona I Codina, O., Pessah-Rasmussen, H. & Sundström, P. (2022). Incidence and prevalence of multiple sclerosis in Malmö, southern Sweden. Multiple Sclerosis International, Article ID 5464370.
Open this publication in new window or tab >>Incidence and prevalence of multiple sclerosis in Malmö, southern Sweden
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2022 (English)In: Multiple Sclerosis International, ISSN 2090-2654, E-ISSN 2090-2662, article id 5464370Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: To estimate the incidence and prevalence of multiple sclerosis (MS) in Malmö municipality in southwestern Sweden.

MATERIALS AND METHODS: Multiple sources were used in the case identification process. Case ascertainment was assessed by medical chart review including examinations such as magnetic resonance imaging, cerebrospinal fluid analyses, and relevant laboratory tests. Cases were classified according to the 2010 McDonald's diagnostic criteria. Onset-adjusted prevalence and a definition of onset symptoms were applied.

RESULTS: The crude incidence of MS in 2001-2010 in Malmö municipality was 5.3/100,000 (95% confidence interval (CI): 4.5 to 6.2). There was a relapsing onset in 90.5% of cases. The female to male ratio was 1.8. The onset-adjusted prevalence for Dec 2010 was 133/100,000 (95% CI, 120 to 146) with a female to male ratio of 2.1.

CONCLUSIONS: This is the first population-based epidemiological study in Skåne, the most southwestern part of Sweden showing a high incidence and prevalence. We found a lower incidence than expected according to previous nationwide figures, probably due to methodological differences between the studies. Our findings support the presence of a north-south gradient of MS prevalence in Sweden.

Place, publisher, year, edition, pages
Hindawi Publishing Corporation, 2022
National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:umu:diva-202380 (URN)10.1155/2022/5464370 (DOI)000778436300001 ()35345609 (PubMedID)
Available from: 2023-01-09 Created: 2023-01-09 Last updated: 2023-01-10Bibliographically approved
Svenningsson, A., Frisell, T., Burman, J., Salzer, J., Fink, K., Hallberg, S., . . . Lycke, J. (2022). Safety and efficacy of rituximab versus dimethyl fumarate in patients with relapsing-remitting multiple sclerosis or clinically isolated syndrome in Sweden: a rater-blinded, phase 3, randomised controlled trial. Lancet Neurology, 21(8), 693-703
Open this publication in new window or tab >>Safety and efficacy of rituximab versus dimethyl fumarate in patients with relapsing-remitting multiple sclerosis or clinically isolated syndrome in Sweden: a rater-blinded, phase 3, randomised controlled trial
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2022 (English)In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 21, no 8, p. 693-703Article in journal (Refereed) Published
Abstract [en]

Background: B-cell depleting therapies are highly efficacious in relapsing-remitting multiple sclerosis but one such therapy, rituximab, is not approved for multiple sclerosis and no phase 3 trial data are available. We therefore examined the safety and efficacy of rituximab compared with dimethyl fumarate in patients with relapsing-remitting multiple sclerosis to obtain data that might allow inclusion of rituximab in treatment guidelines.

Methods: RIFUND-MS was a multicentre, rater-blinded, active-comparator, phase 3, randomised controlled trial done at 17 Swedish university and community hospitals. Key inclusion criteria for participants were: age 18–50 years; relapsing-remitting multiple sclerosis or clinically isolated syndrome according to prevailing McDonald criteria; 10 years or less since diagnosis; untreated or only exposed to interferons or glatiramer acetate; and with clinical or neuroradiological disease activity in the past year. Patients were automatically randomly assigned (1:1) by the treating physician using a randomisation module in the Swedish multiple sclerosis registry, without stratification, to oral dimethyl fumarate 240 mg twice daily or to intravenous rituximab 1000 mg followed by 500 mg every 6 months. Relapse evaluation, Expanded Disability Status Scale rating, and assessment of MRI scans were done by examining physicians and radiologists masked to treatment allocation. The primary outcome was the proportion of patients with at least one relapse (defined as subacute onset of new or worsening neurological symptoms compatible with multiple sclerosis with a duration of more than 24 h and preceded by at least 30 days of clinical stability), assessed in an intention-to-treat analysis using log-binomial regression with robust standard errors. This trial is registered at ClinicalTrials.gov, NCT02746744.

Findings: Between July 1, 2016, and Dec 18, 2018, 322 patients were screened for eligibility, 200 of whom were randomly assigned to a treatment group (100 assigned to rituximab and 100 assigned to dimethyl fumarate). The last patient completed 24-month follow-up on April 21, 2021. 98 patients in the rituximab group and 97 patients in the dimethyl fumarate group were eligible for the primary outcome analysis. Three (3%) patients in the rituximab group and 16 (16%) patients in the dimethyl fumarate group had a protocol-defined relapse during the trial, corresponding to a risk ratio of 0·19 (95% CI 0·06–0·62; p=0·0060). Infusion reactions (105 events [40·9 per 100 patient-years]) in the rituximab group and gastrointestinal reactions (65 events [47·4 per 100 patient-years]) and flush (65 events [47·4 per 100 patient-years]) in the dimethyl fumarate group were the most prevalent adverse events. There were no safety concerns.

Interpretation: RIFUND-MS provides evidence that rituximab given as 1000 mg followed by 500 mg every 6 months is superior to dimethyl fumarate in preventing relapses over 24 months in patients with early relapsing-remitting multiple sclerosis. Health economic and long-term safety studies of rituximab in patients with multiple sclerosis are needed. 

Place, publisher, year, edition, pages
Elsevier, 2022
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-198292 (URN)10.1016/S1474-4422(22)00209-5 (DOI)000855325100016 ()35841908 (PubMedID)2-s2.0-85134346933 (Scopus ID)
Funder
Swedish Research Council
Available from: 2022-08-01 Created: 2022-08-01 Last updated: 2023-09-05Bibliographically approved
Grut, V., Biström, M., Salzer, J., Stridh, P., Lindam, A., Alonso-Magdalena, L., . . . Sundström, P. (2022). Systemic inflammation and risk of multiple sclerosis: a presymptomatic case-control study. Multiple Sclerosis Journal, Experimental, Translational and Clinical, 8(4), 1-4
Open this publication in new window or tab >>Systemic inflammation and risk of multiple sclerosis: a presymptomatic case-control study
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2022 (English)In: Multiple Sclerosis Journal, Experimental, Translational and Clinical, E-ISSN 2055-2173, Vol. 8, no 4, p. 1-4Article in journal (Refereed) Published
Abstract [en]

Background: C-reactive protein (CRP) is a marker of systemic inflammation. Increased levels of CRP in young persons have been suggested to decrease the risk of multiple sclerosis (MS).

Objectives: To assess CRP as a risk factor for MS.

Methods: Levels of CRP were measured with a high-sensitive immunoassay in biobank samples from 837 individuals who later developed MS and 984 matched controls. The risk of developing MS was analysed by conditional logistic regression on z-scored CRP values.

Results: Levels of CRP were not associated with MS risk.

Conclusions: We found no association between CRP levels and risk of MS development.

Place, publisher, year, edition, pages
Sage Publications, 2022
Keywords
C-reactive protein, Case-control studies, multiple sclerosis, systemic inflammation
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:umu:diva-201466 (URN)10.1177/20552173221139768 (DOI)000927944400001 ()2-s2.0-85142702455 (Scopus ID)
Funder
Swedish Research Council, 2015-02419Visare Norr, 940405Region Jämtland Härjedalen, JLL-939768
Available from: 2022-12-06 Created: 2022-12-06 Last updated: 2023-09-05Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-3552-1861

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