To Örebro University

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 4247 NTZ participants were included in the IMSE 1 study from August 2006 until March 2024 (71% female; mean age 36 years; 82% RMS; mean treatment duration 50 months). Since July 2021 498 patients have initiated treatment of which 468 had available data on administration. In this cohort, 181 (39%) initiated IV NTZ, of which 21 (12%) later switched to SC. 287 (61%) initiated treatment with SC NTZ of which 1 later switched to IV. The distribution between administration methods altered over time, where IV was more common in Q3 2021 (65%) and then successively dropped to 24% in Q1 2024.

The mean age at treatment start was 38 years (37 for IV and 38 for SC) and 67% (69% IV, 66% SC) were female.

Out of 468 participants, 273 (58%) later discontinued treatment. Discontinuation was significantly more common in the IV group (70%) compared with the SC group (51%) even though the percentage of patients positive for the John Cunningham virus (JCV+) and mean treatment duration in each group was similar.

The most common reason for discontinuation in both groups was JCV+ followed by “Other reason: unspecified”. Seven patients discontinued due to neutralizing NTZ antibodies; 7 from SC and 3 from IV.

Conclusion: The SC administration has become the preferred administration method for NTZ since its launch in the spring of 2021, with 61% of NTZ treatment initiations being administered using SC method. Significant differences in discontinuation rates between the two administration methods were seen. Longer observation periods will be needed to assess possible differences in tolerability and treatment adherence between the two administration modalities.

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 381 CladT exposed Persons with MS (PwMS) have been included in IMSE 10 since the launch of CladT in April 2018. In this cohort 89% remained with CladT while 41 patients (11%) discontinued treatment at any time after initiation. The most common reason for discontinuation was lack of effect (75.6%). All AEs reported to the Swedish Medical Products Agency will be shown.A total of 204 (54%) had CladT exposure for ⩾24 months of which 33 % being treatment naïve, 21% switched from Tysabri, 13 % from dimethyl fumarate and 19% from rituximab, prior CLadT treatment. In this cohort 90.6% remained with CladT after 24 months treatment.The ⩾24 months cohort demonstrated clinical stability with a non-significant trend for improvement in mean EDSS, 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 24month exposure.The IMSE 10 study is funded in a scientific collaboration agreement with Merck KGaA, Darmstadt Germany.

Introduction: Dimethyl fumarate (DMF) is an oral therapy for relapsing multiple sclerosis (RMS). DMF is included in the Swedish post-market surveillance study “Immunomodulation and Multiple Sclerosis Epidemiology” (IMSE).

Objectives/Aims: To assess the effectiveness and safety of DMF with focus on patients treated at least 72 months.

Methods: Descriptive data of Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Symbol Digit Modalities Test (SDMT), Multiple Sclerosis Impact Scale (MSIS-29) and Adverse Events (AEs) is obtained from the nationwide Swedish Neuro Registry (NeuroReg). Effectiveness measures were assessed using the paired samples T-test.

Results: 2843 DMF-treated patients were included between March 2014 and March 2024 with a mean treatment duration of 43 months and 72% of patients having discontinued treatment at least once. The main reasons for discontinuation were AEs (42%) and lack of effect (32%). 211 AEs were reported to the Medical Products Agency in Sweden of which 66 were serious. For both serious and non-serious AEs reported, gastrointestinal disorders were the most common (18% and 27%, respectively).

657 patients had continuous treatment for at least 72 months. This cohort had a mean age of 43 years and a mean treatment duration of 99 months. The majority (59%) had switched from interferon or glatiramer acetate and 31% were treatment naïve.

Significant improvements in mean values at 72 months of treatment compared to baseline were noted for MSSS and MSIS-29 Psychological (p<0.05). All other tests remained stable after 6 years of treatment. The Annual Relapse Rate (ARR) decreased significantly during treatment compared to one year prior to treatment start.

141 patients (21%) have discontinued DMF treatment in the 72-month cohort. The main reasons for discontinuation were lack of effect (38%), other reasons (25%) and AEs (18%).

Conclusion: DMF demonstrates clinical improvements and/or stability in patients treated ≥ 72 months. However, due to the high discontinuation rate there is an unavoidable selection bias. Continued follow up is needed to assess the effectiveness and safety of DMF over longer time periods in a real-world setting.

Introduction: ofatumumab is a human CD20 monoclonal antibody targeting B-cells and a small population of CD20+ T-cells. The treatment is administered once a month (after initial dosing) with subcutaneous injections for patients with Remitting Multiple Sclerosis (RMS). ofatumumab is included in the Swedish post-market surveillance study “Immunomodulation and Multiple Sclerosis Epidemiology substudy 12” (IMSE 12).

Objectives/Aims: To assess safety and effectiveness of ofatumumab with focus on 12 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), 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 111 ofatumumab exposed Persons with MS (PwMS) have been included in IMSE 12 since the launch in March 2021. In this cohort 93.7% remained with ofatumumab while 7 patients (6.3%) discontinued treatment at any time after initiation. The most common reasons for discontinuation were Adverse Event (unspecified, n=2) and Other Reasons (unspecified, n=2). All the AEs reported to the Swedish Medical Products Agency will be shown.In this cohort most PwMS (25.5 %) had switched from rituximab, 24.5% from natalizumab, 11.8% from dimethyl fumarate and 7.8% had been treatment naïve prior treatment with ofatumumab.51 patients have so far been treated with ofatumumab for ⩾12 months. The ⩾12month cohort demonstrated a non-significant trend for improvement in mean EDSS, MSSS, and a stable SDMT score compared with baseline. The mean annual relapse rate (ARR) decreased significantly (p<0.05) during first year of treatment (0.02) compared to the ARR (0.14) one-year prior treatment initiation.

Conclusion: PwMS exposed for ⩾12 months to ofatumumab display clinical stability and a tendency for improvement in EDSS, MSSS and SDMT compared with baseline. Longer observation times will be needed to assess the effectiveness and safety of ofatumumab beyond 12month exposure.

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 effectiveness of CladT with focus on age at treatment start. Two subgroups in the IMSE 10 study will be compared, below <45 or above ⩾ 45 years of age at treatment start.

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: By September 2023, a total of 313 CladT exposed Persons with MS (PwMS) have been included in IMSE 10 since the launch of CladT in April 2018. This cohort was divided into two subgroups, Below <45 (n=233) and Above ⩾45 (n=80) years of age at treatment start. The mean age was 33 and 51 years in the two subgroups, respectively.There were a higher proportion of SPMS (13%) in the older subgroup compared to the younger subgroup (1 %). The proportion of PwMS that discontinued their treatments was twice as high in the younger subgroup (13%) and the main cause of discontinuation was “Lack of effect” (81%) whereas for the older subgroup “other reasons” (40%) was the main cause of discontinuation.Both subgroups demonstrated clinical stability in mean EDSS that was kept stable during the first two treatment years. For both subgroups the mean annual relapse rate (ARR) decreased significantly (p<0.05) during the first two treatment years compare to the ARR one-year prior to cladribine treatment start. During the first year of treatment 5.7% of PwMS in the younger subgroup had new T2 lesions compared to 2.2% in the older subgroup (non-significant). During the second treatment year, 2.1 % of PwMS in the younger subgroup and, 0% of PwMS in the older subgroup had new T2 lesions (non-significant).

Conclusion: This data shows that PwMS below and above 45 years at treatment start exposed to CladT display clinical stability and a tendency for improvement compared with baseline in several of the investigated outcomes. The subgroup of PwMS with a treatment start above 45 years showed a tendency for less MRI activity compared to the subgroup below 45.

OBJECTIVE: To assess comparative effectiveness, safety, and tolerability of off-label rituximab, compared with frequently used therapies approved for multiple sclerosis (MS).

METHODS: A Swedish cohort study of persons with relapsing-remitting MS, age 18 to 75 years at inclusion and with a first therapy start or a first therapy switch between 2011 and 2018. Low-dose rituximab was compared with MS-approved therapies. Primary outcomes were proportions with 12 months confirmed disability worsening and change in MS Impact Scale-29 (MSIS-29) scores, respectively. Secondary endpoints included relapses, therapy discontinuation, and serious adverse events. Analyses used an intention-to-treat approach and were adjusted for demographics, MS features, and health characteristics.

RESULTS: We included 2,449 participants as first therapy start and 2,463 as first therapy switch. Proportions with disability worsening at 3 years were 9.1% for rituximab as first therapy and 5.1% after therapy switch, with no differences to MS-approved comparators. Worsening on rituximab was mostly independent of relapses. MSIS-29 with rituximab at 3 years improved by 1.3/8.4 points (physical/psychological) for first disease-modifying therapy (DMT) and 0.4/3.6 for DMT switch, and was mostly similar across therapies. Rituximab had lower relapse rates and higher therapy persistence in both groups. The rate of hospital-treated infections was higher with rituximab after a therapy switch, but not as a first therapy.

INTERPRETATION: This population-based real-world cohort study found low rates of disability progression, mostly independent of relapses, and without significant differences between rituximab and MS-approved comparators. Rituximab led to lower rates of inflammatory activity and higher treatment persistence, but was associated with an increased rate of serious infections. ANN NEUROL 2024.

Objectives/Aims: To address comparative effectiveness, safety, and tolerability of off-label rituximab, compared with frequently used therapies approved for relapsing-remitting multiple sclerosis.

Methods: A Swedish cohort study of persons with relapsing-remitting multiple sclerosis (RRMS), aged 18 to 75 years at inclusion, and with a first therapy start or a first therapy switch between 2011 and 2018 (Clinicaltrials.gov NCT03193866). Off-label low-dose rituximab (500 mg bi-annually) was compared with natalizumab (NTZ), dimethyl fumarate (DMF), interferons and glatiramer acetate in the first therapy group and NTZ, DMF, fingolimod and teriflunomide in the switch group, respectively. Primary outcomes were proportions with 12 months confirmed disability worsening and change in patient-reported multiple sclerosis impact scale-29. Secondary endpoints included relapses, therapy discontinuation, and serious adverse events. Analyses used an intention-to-treat (ITT) approach and were adjusted for demographics, RRMS disease features, and general health characteristics.

Results: We included 2,449 participants with a first therapy start and 2,463 after a first therapy switch. Proportions with disability worsening at 3 years were 9.1% for rituximab as first therapy and 5.1% after therapy switch, not significantly different from the MS-approved therapy comparators. Patient-reported scores were mostly stable, and similar across therapies. Among secondary endpoints, rituximab was superior regarding rate of annualized relapse rate (0.03 in both groups compared with 0.05 to 0.16 and 0.06 to 0.11 in comparator groups) and therapy persistence (89% in both groups compared with 17 to 46% and 38 to 54% in comparator groups). Incidence rate of hospital-treated infections was increased about two-fold with rituximab after a therapy switch, but not as a first therapy. Follow up data over five years and sub-group analyses will be included in the final presentation.

Conclusion: This large, population-based real-world cohort study found that overall disability progression rates were lower than previously described, without significant differences between rituximab and approved RRMS therapy comparators. Rituximab displayed higher treatment persistence and effectiveness in preventing relapses but was associated with an increased rate of serious infections. The ITT approach used means that therapy switching likely diluted potential underlying differences between therapies compared to if participants had remained longer on their initial treatment

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 for all patients included in the study.

Objectives/Aims: To investigate the proportion of patients, free of disease activity with a Cladribine treatment duration of at least 24 months.

Methods: CLADCOMS includes patients with RMS from eight academic neurology clinics in Sweden who started Cladribine treatment after 23rd of March 2018. Data is prospectively registered in the Swedish Neuroregistry using highly structured yearly follow-up. Descriptive data on relapses, MRI activity, and Patient Reported Outcome Measures were obtained from the registry.

Results: By December 2023, a total of 251 patients had been included in the CLADCOMS study. Over 58% (147 patients) of the included patients had a treatment duration with CladT for 24 months or longer. In previously treatment-naïve patients, 76.5% were relapse-free during the first 24 months of CladT treatment, and in previously natalalizumab-, dimethyl fumarate- and rituximab treated patients, relapse-free rates were 83%, 89% and 86.3%, respectively.Analysis of total B-cell lymphocyte count over time showed a significant (p<0.05) drop from baseline (0.29x109/L ±0.28) to year one (0.16x109/L ±0.13) and year two (0.14x109/L ±0.09). The proportion of CD19+/CD27+ memory B-cells dropped from 11.5% ±9.15% at baseline to 2.7% ±2.5% after the first year and to 2.4% ±2.0% after the second year of treatment. The proportions of CD19+ naïve B-cells raised over time from 61.8% ±17.8% at baseline to 79.2% ±16.2 after first year and 81.2% ±11.4 after second year of treatment.

Conclusion: CladT treatment showed clinical stability during the first two years regardless of previous treatment. The unique immune modulation helps to explain the durability of the effect 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.

Introduction: In the last years B-cell depleting therapies such as rituximab (RTX) have become commonplace in the therapeutic landscape of multiple sclerosis (MS), with this class of drugs showing high efficacy. Nevertheless, B-cell depleting therapies have been associated with a higher risk of bacterial infections compared to other disease modifying therapies.

Objectives/Aims: To report the frequency and type of antibiotic prescriptions during a 10-year period.

Methods: A retrospective cohort study was performed on MS-patients followed at Örebro University Hospital (Örebro, Sweden), having received at least one dose of RTX between 2011 and 2020. The number and types of prescribed antibiotic therapies were registered. Data collection was performed using the Swedish MS-registry and electronic patient files. We registered all prescriptions for antibacterial agents between the first dose of RTX administered and 12 months after the last dose, or until the study cut-off date of December 31, 2020, whichever came first.

Results: A total of 219 patients were included (213 with relapsing-remitting MS; mean age 40 years). The median Expanded Disability Status Scale was 2.0. Median disease duration was 36 months at the start of rituximab, median follow-up time was 43 months, and the median number of rituximab infusions was 6. A total of 415 antibiotic prescriptions were registered in this time period. The mean number of prescriptions per patient and year was 0.5. In the cohort, 115 (47%) of the patients did not receive an antibiotic prescription. The most common type of infection treated was urinary tract infections (UTI), followed by upper respiratory tract ones. The majority (83%) of patients who received antibiotic therapy for UTI were women. There were 16 patients (7%) that required long duration of treatment with antibiotics and 15 (7%) of the study population were hospitalized for infections.

Conclusion: Prescription of antibiotics is frequent among MS-patients treated with RTX, occurring in approximately half of this patient population. UTI is the most common cause of antibiotic treatment.

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.