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| 2. |
- Forsberg, Linda, et al.
(author)
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A comparison of administration and discontinuation of Natalizuamb in Sweden over time for patients treated with either sucutaneous (SC) or intravenous (IV) administration methods since July 2021
- 2023
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In: Multiple Sclerosis Journal. - : Sage Publications. - 1352-4585 .- 1477-0970. ; 29:Suppl. 3, s. 617-617
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Journal article (other academic/artistic)abstract
- Introduction: Natalizumab (NTZ) is a highly effective disease modulatory treatment for relapsing multiple sclerosis (RMS) originally launched as an intravenous (IV) therapy in Sweden in August 2006. A new subcutaneous (SC) administration method for NTZ was launched in April 2021.Objectives/Aims: To investigate how the administration of NTZ has evolved in Sweden since the introduction of SC NTZ in 2021, and to explore potential differences in treatment discontinuation patterns between the SC or IV administration modalities.Methods: Descriptive data will be presented from the “Immunomodulation and Multiple Sclerosis Epidemiology Study” (IMSE 1) study cohort. Data is collected from the nationwide Swedish Neuro Registry (NeuroReg). The drug survival is assessed using the Kaplan Meier one-year drug survival curve and Breslow Wilcoxon test of equality distribution.Results: A total of 4011 NTZ participants were included in the IMSE 1 study from August 2006 until March 2023 (72% female; mean age 36 years; 80% RRMS; mean treatment duration 49 months), including 295 since July 2021, of which 264 had available data on method of administration. In this cohort, 109 (41%) initiated IV NTZ, of which 16 (15%) later switched to SC administration, and 155 (59%) initiated treatment with SC NTZ. The distribution between administration methods altered over time, where IV was more common in Q3 2021 (70%) and then successively dropped to 31% in Q1 2023.The mean age at treatment start was 36 years (35 for IV and 37 for SC) and 69% (70% IV, 68% SC) were female.Out of 264 participants, 73 (28%) later discontinued treatment. Discontinuation was numerically more common in the IV group compared with the SC group, but differences in the one-year drug survival rate did not reach statistical significance.The most common reason for discontinuation in the IV group was “other reason; unspecified” followed by positive JC-virus serology (JCV+). In the SC group JCV+ was the most common reason for discontinuation. Four patients discontinued due to neutralizing NTZ antibodies; 2 in each group.Conclusion: The SC administration has become the preferred administration method for NTZ since its launch in the spring of 2021, with 59% of NTZ treatment initiations being administered using SC method. We did not find significant differences in discontinuation rates between the two administration methods. Longer observation periods will be needed to assess possible differences in tolerability and treatment adherence between the two administration modalities.
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| 3. |
- Forsberg, Linda, et al.
(author)
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Improved clinical outcomes in patients treated with Natalizumab for at least 11 years - Real-world data from a Swedish national post-marketing surveillance study (IMSE 1)
- 2023
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In: Multiple Sclerosis Journal. - : Sage Publications. - 1352-4585 .- 1477-0970. ; 29:Suppl. 3, s. 965-966
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Journal article (other academic/artistic)abstract
- Introduction: Natalizumab (NTZ) is a highly effective disease modulatory treatment for relapsing multiple sclerosis (RMS). Post-marketing surveillance is important to evaluate the long-term safety and effectiveness in a real-world setting. To this end the “Immunomodulation and Multiple Sclerosis Epidemiology Study” (IMSE 1) was initiated upon launch of NTZ in Sweden (Aug 2006).Objectives/Aims: To follow-up the long-term effectiveness and safety of NTZ in a real-world setting.Methods: Adverse events (AEs), Serious AEs (SAEs), John Cunningham virus status (JCV) and clinical effectiveness measures; Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Symbol Digit Modalities Test (SDMT) and Multiple Sclerosis Impact Scale (MSIS-29) data were collected from the nationwide Swedish Neuro Registry (NeuroReg). Effectiveness measures were assessed using the Wilcoxon Signed Rank Test.Results: A total of 4011 NTZ patients were included in the IMSE 1 study from August 2006 until March 2023 (72% female; mean age 36 years; 80% RRMS; mean treatment duration 52 months) and 249 had been treated for at least 132 months. Of the 132-month cohort, 75% were female, the mean age was 36 years, 88% had RRMS, and the mean treatment duration was 160 months. The majority were treated with interferons and glatiramer acetate prior to NTZ (68%), where 30% (74/249) discontinued NTZ treatment; 43% (32/74) due to being JCV positive (JCV+), with a mean JCV index of 1.1±0.9 (n=66). Annualized relapse rates dropped from 0.40 in the year before treatment start to 0.04 during treatment, where 68% were entirely free of relapses and 21% had only 1 relapse during the entire treatment period (17% missing data). All clinical effectiveness measures, except EDSS showed statistically significant improvement between baseline and 132 months (p<0.05).From the entire IMSE1 cohort (N=4011), 132 SAEs have been reported to the Swedish MPA, including 9 cases (2 fatal) of progressive multifocal leukoencephalopathy (PML) of which 8 occurred between 2008 and 2012, and one in 2018.Conclusion: NTZ is generally well tolerated and displays sustained effectiveness regarding cognitive, physical and psychological measures, as well as relapse-control. Introduction of JCV testing has led to fewer treated JCV+ patients, likely explaining a drastically reduced incidence of PML.
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| 4. |
- Jons, Daniel, et al.
(author)
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Epstein-Barr virus seroreactivity, putative autoimmunity and axonal injury in pre-symptomatic multiple sclerosis
- 2023
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In: Multiple Sclerosis Journal. - : Sage Publications. - 1352-4585 .- 1477-0970. ; 29:Suppl. 3, s. 39-40
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Journal article (other academic/artistic)abstract
- Introduction: Multiple sclerosis (MS) and presymptomatic axonal injury appears to develop only after an Epstein-Barr virus (EBV) infection. Anoctamin2 (ANO2), a chloride channel expressed in glial cells and neurons, was identified as a possible MS autoantigen. We here examine serum neurofilament (sNfL), a comprehensive EBV seroreactivity and antibodies against ANO2 in pre-symptomatic MS.Objectives/Aims: To study whether the appearance of EBV seroreactivity in the pre-symptomatic phase of MS precedes cumulating MS-induced neuroaxonal damage and whether it is associated with an incipient autoreactivity against a reported MS autoantigen (ANO2).Methods: We performed a case-control study with presymptomatic serum samples identified through cross-linkage of the Swedish MS register and Swedish biobanks. We assayed serum antibodies against EBV nuclear antigen 1 (EBNA1), viral capsid antigen p18 (VCAp18), EBV glycoprotein 350 (gp350), anoctamin 2 (ANO2), and serum neurofilament light (sNfL) in 669 pre-MS cases and matched controls.Results: EBNA1 seroreactivity increased in the pre-MS group from 20–15 years before MS onset, followed by gp350 seroreactivity (p=0.001–0.002, 15–10 years before onset). This appeared before the elevation of sNfL in EBV seropositive pre-MS cases (p=8⋅10-5, 10–5 years before onset). No significant sNfL increase was observed in the EBV seronegative group (p=0.95). Pre-MS cases with the highest sNfL levels cumulated in the EBV seropositive group (p=0.038). ANO2 seropositivity appeared virtually only in the EBNA1 seropositive group, in 16.7 % of EBNA1 seropositive pre-MS samples and in 10.0 % of corresponding controls (p=0.001). Combined EBNA1 and ANO2 seropositivity showed a higher association with subsequent MS than EBNA1 independent of ANO2 (p=0.002–0.028). In the EBNA1 seropositive stratum, ANO2 seropositivity was associated with 26% higher sNfL.Conclusion: In presymptomatic MS an antibody response against EBV, associated with ANO2 autoimmunity, was detectable before elevated sNfL, which cumulated in the EBV seropositive group. ANO2 seropositivity was associated with higher sNfL. An increase in ANO2 seroreactivity did not appear until after EBV seroconversion, limited to a subgroup of the EBV seropositive stratum. Thus, this specific cross-reaction could contribute to MS pathogenesis in a subgroup. This further implicates EBV in the pathogenesis of MS.
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| 5. |
- Larsson, Veronica, et al.
(author)
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CLADCOMS- CLADribine tablets long-term Control Of MS - a post-marketing investigator driven study
- 2023
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In: Multiple Sclerosis Journal. - : Sage Publications. - 1352-4585 .- 1477-0970. ; 29:Suppl. 3, s. 968-969
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Journal article (other academic/artistic)abstract
- Introduction: Cladribine is a deoxyadenosine analogue prodrug that induces immune reconstitution by selectively targeting B- and T-lymphocytes. Cladribine tablets (CladT) are administered in two courses, 12 months apart, for patients with relapsing multiple sclerosis (RMS). Post-marketing surveillance is important for evaluation of long-term safety and effectiveness in a real-world setting. CLADCOMS (CLADribine tablets long-term Control Of MS) is a post-marketing investigator driven study. Here we report two year prospectively obtained data on the first 100 patients included in the study until April 2021.Objectives/Aims: To investigate number of patients free of disease activity until April 2023 among the first 100 RMS patients included.Methods: CLADCOMS includes patients with RMS from eight academic neurology clinics of Sweden starting Cladribine treatment after 23rd of March 2018. Data was prospectively registered in the Swedish Neuroregistry using highly structured yearly follow-up routines. Descriptive data on relapses, MRI activity, and Patient Reported Outcome Measures from the first 100 patient included in the study were obtained from the registry.Results: By April 2023, 206 patients were included in the CLADCOMS study. In April 2021 the first 100 patients had entered the study including 30% treatment naïve, 26% switched from natalizumab, 10% from dimethyl fumarate and 7% from rituximab. After the first two years after treatment initiation 87% were relapse free. MRI-activity during the first two years after treatment initiation will be analyzed.Analysis of CD19+ B-cells counts over time showed a significant drop from baseline before first dose (0.38x109/L ±0.68) to year one (0.15x109/L ±0.12) and year two (0.13x109/L ±0.09). The proportion of memory B-cells dropped from 11.8% ±9.33% at baseline to 3.0% ±2.8% after the first year and to 2.6% ±2.4% after the second year of treatment. The proportions of naïve B-cells raised over time from 61% ±18.3% at baseline to 76.8% ±18.7 year one and 78.6% ±12.3 after two years of treatment.Conclusion: CladT treatment demonstrates clinical stability during the first two years after treatment initiation. The unique immune depletion helps to explain the durability of effects of Cladribine. However, continued follow-up is needed to assess the effectiveness and safety of treatment with Cladribine to investigate time to disease re-activation after full treatment.
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| 6. |
- Larsson, Veronica, et al.
(author)
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Clinical Effectiveness and Safety of Cladribine Tablets for Patients Treated at least 24 Months in the Swedish post-market surveillance study "Immunomodulation and Multiple Sclerosis Epidemiology 10"(IMSE 10)
- 2023
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In: Multiple Sclerosis Journal. - : Sage Publications. - 1352-4585 .- 1477-0970. ; 29:Suppl. 3, s. 616-616
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Journal article (other academic/artistic)abstract
- Introduction: Cladribine is a deoxyadenosine analogue prodrug targeting proliferating B- and T-lymphocytes. Cladribine tablets (CladT) are administered in two courses, 12 months apart, for patients with remitting multiple sclerosis (RMS). CladT is included in the Swedish post-market surveillance study “Immunomodulation and Multiple Sclerosis Epidemiology substudy 10” (IMSE 10).Objectives/Aims: To assess safety and effectiveness of CladT with focus on 24 months treatment outcomes.Methods: Data on Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Symbol Digit Modalities Test (SDMT), Multiple Sclerosis Impact Scale (MSIS-29), European Quality of Life -5 Dimensions Test (EQ-5D), Visual Analog Scale (VAS) scores, and relapses and Adverse Events (AEs) were collected from the nationwide Swedish Neuro Registry (NeuroReg). Effectiveness measures and relapse rates were assessed using Wilcoxon Signed Rank Test.Results: A total of 287 CladT exposed Persons with MS (PwMS) have been included in IMSE 10 since the launch of CladT in April 2018. In this cohort 90.6% remained with CladT while 27 patients (9%) discontinued treatment at any time after initiation. The most common reason for discontinuation was lack of effect (78%). A total of 24 AEs were reported to the Swedish Medical Products Agency, of which 10 were serious. The most common AE reported were infection and infestation.A total of 137 patients had CladT exposure for ⩾24 months of which 30 % being treatment naïve, 19% switched from Tysabri, 10 % from dimethyl fumarate and 7% from rituximab, prior CLadT treatment. In this cohort 91.9% remained with CladT. The ⩾24 months’ cohort demonstrated clinical stability with a non-significant trend for improvement in mean MSSS, SDMT, MSIS-29 Psychological/Physical scores compared with baseline. All other outcomes remained stable. The mean annual relapse rate (ARR) decreased significantly (p<0.05) during all treatment years compared to the ARR one-year prior treatment.Lymphocyte levels decreased from a mean of 1.9 x 109/L at treatment start to 1.11 x 109/L at 12 Months and 0.87 x 109/L at 24 months of treatment.Conclusion: Most PwMS exposed for ⩾24 months to CladT display clinical stability and a tendency for improvement compared with baseline in several of the investigated outcomes. Longer observation times will be needed to assess the effectiveness and safety of CladT beyond 24 month exposure.
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| 7. |
- Manouchehrinia, A., et al.
(author)
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Comparative effectiveness of natalizumab on cognition in multiple sclerosis: A cohort study
- 2023
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In: Multiple Sclerosis Journal. - : SAGE Publications. - 1352-4585 .- 1477-0970. ; 29:4-5, s. 628-636
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Journal article (peer-reviewed)abstract
- Background: Cognitive impairment occurs in 40%-70% of persons with multiple sclerosis (MS). Objective: To examine the effectiveness of natalizumab compared with other disease-modifying treatments (DMTs) on improving cognition as measured by the Symbol Digit Modalities Test (SDMT). Methods: Data were collected as part of Swedish nationwide phase IV surveillance studies (2007-2020). An increase in SDMT score by > 10% of the difference between maximum score possible (110) and the baseline value was defined as cognitive improvement. The likelihood of improvement was compared between natalizumab-treated individuals and individuals treated with other DMTs using mixed effect logistic regression. Trend in odds of improvement was investigated using slope analyses. Results: We included 2100 persons with relapsing-remitting MS treated with natalizumab and 2622 persons treated with other DMTs. At 6 months, 45% reached improvement. The natalizumab group showed largest odds of improvement during follow-up (odds ratio: 2.3, 95% confidence interval (CI): 1.5-3.5). The odds of improvement increased by 7% (95% CI: 6-7) per month of natalizumab treatment. The equivalent estimate was 4% (95% CI: 2-5) for other monoclonal antibodies and nonsignificant for oral or platform therapies. Conclusion: Treatment with natalizumab or other monoclonal antibodies is associated with a significantly faster likelihood of cognitive improvement than platform or oral DMTs.
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| 8. |
- Montgomery, Scott, 1961-
(author)
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What Types of Infection Are Implicated in MS Pathogenesis?
- 2023
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In: Multiple Sclerosis Journal. - : Sage Publications. - 1352-4585 .- 1477-0970. ; 29:Suppl. 2, s. 11-11
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Journal article (other academic/artistic)abstract
- Background: Severe acute infections are implicated in MS aetiology. Adolescence may represent a period of heightened susceptibility, with several years of asymptomatic/prodromal disease activity before an MS diagnosis. Infections may also be associated with MS exacerbations or severity.Objectives: To assess if hospital-treated infections during adolescence or earlier childhood are associated with MS risk. To determine if SARS-CoV-2 infection in people with MS resulted in increased risk of subsequent hospital admission for MS.Methods: Swedish registers provided information on 2,422,969 people born between 1970 and 1994 (with follow-up to 2014). The association of hospital-treated infections before age 20 years with MS risk was assessed using Cox regression. Registers also provided information on all Swedish residents with MS in December 2019 (n=20,237), with follow-up to September 2022. Cox regression assessed whether SARS-CoV-2 infections (modelled as time-dependent covariates) were associated with hospital admission for MS, with adjustment including for number of hospital admissions since 2015 prior to infection and Charlson comorbidity index.Results: Some, but not all, serious bacterial or viral infections in adolescence but not earlier childhood, were associated raised risk of MS after age 20 years (median age at diagnosis 29.7 years), including respiratory infections, with an adjusted hazard ratio (and 95% confidence interval) of 1.54 (1.30-1.83). The association with respiratory infections was not explained by prior infectious mononucleosis, which was also associated with MS risk: 3.19 (2.29-4.46) Among those with MS in 2019, hospital admission for SARS-CoV-2 infection was associated with increased risk of subsequent admission for MS (typically >50 days later): 2.06 (1.18, 3.60), most notably among women.Conclusion: Severe respiratory infections in adolescence are associated with increased MS diagnosis risk, often more than 10 years later. SARS-CoV-2 treated in hospital is associated with increased risk of hospital admission for MS, particularly among women. It is plausible that the pandemic will have short- and long-term consequences for MS risk, as well as MS severity or exacerbations.
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