Background Fatigue is a common symptom in people with multiple sclerosis (pwMS) with severe implications. A self-guided, internet-based intervention to reduce fatigue in MS, based on cognitive behavioral therapy (CBT), is approved as a digital health application (DiGA) in the German healthcare system. However, real-world evidence for efficacy is lacking. Methods Of the 165 patients screened for fatigue using the Fatigue Scale for Motor and Cognitive Functions (FSMC), 129 were diagnosed with fatigue (FSMC ≥ 43) and enrolled. Patients with fatigue were randomized 1:1 to either a 12-week CBT-based online intervention (elevida, a CE-certified, self-guided DiGA for the management of MS-related fatigue; n = 64) or a psychoeducation arm (n = 65). After 12 weeks, patients in the psychoeducation group could cross-over to the CBT-based online intervention group. The primary outcome was FSMC-change. Results The 12-week follow-up showed a reduction in FSMC in the primary CBT-based online intervention group (repeated measures ANOVA: F(1,48) = 10.99, p = 0.002), as well as the crossover-group (repeated measures ANOVA: F(1,15) = 5.81, p = 0.029). However, between-group analyses did not demonstrate superiority of the CBT-based online intervention over psychoeducation (mean difference 1.8 points, 95% CI −2.0 to 5.6; p = 0.35). Conclusion Our results highlight CBT-based online interventions as promising supportive tools for managing cognitive fatigue in pwMS.

Neurologists frequently encounter multiple sclerosis (MS) patients with coexisting autoimmune disorders such as psoriasis (PsO). The evolving landscape of immunotherapies has made treatment decisions more complex, yet also opened opportunities for therapies targeting shared immunopathogenic mechanisms. However, evidence for this patient group remains limited to case reports and small series. In this multicenter observational study, 420 MS patients were screened, identifying 38 with PsO. These were compared with MS-only patients regarding demographics, disease course, Expanded Disability Status Scale (EDSS), and disease-modifying therapy (DMT) use. DMT histories, reasons for discontinuation, and adverse events were analyzed. Logistic regression assessed PsO and MS worsening, using dimethyl fumarate (DMF) as reference. MS/PsO patients were older at diagnosis (37.6 vs. 33.0 years). EDSS and disease course showed no statistically significant differences. DMF was most frequently used (68%), with low rates of PsO (8%) and MS worsening (15%). PsO worsening was common under teriflunomide (75%), interferons (38%), and sphingosine-1-phosphate (S1P) modulators (40%). Logistic regression suggested higher odds under teriflunomide (OR = 16.5, p = 0.028), interferons (OR = 16.5, p = 0.004), and S1P-modulators (OR = 8.25, p = 0.047). Anti-CD20 therapies (OR = 2.75, p = 0.257) and natalizumab (OR = 1.83, p = 0.635) showed non-significant trends. Interleukin-17 (IL-17) inhibitors were well tolerated, with >50% stable in both conditions and no significant MS worsening (OR = 1.67, p = 0.546). IL-17 inhibitors and DMF showed a favorable tolerability in MS/PsO. Teriflunomide, interferons, and S1P-modulators frequently exacerbate PsO. CD20 therapies and natalizumab remain effective for MS but may worsen PsO; IL-17-based combinations appear promising in highly active disease.

The choroid plexus (CP), a key regulator of cerebrospinal fluid production and immune cell trafficking, is increasingly recognized as a potential magnetic resonance imaging (MRI) biomarker in multiple sclerosis (MS). Serum neurofilament light chain (sNfL) serves as a sensitive blood-based indicator of neuroaxonal injury. We investigate the prognostic value of CP volume and its longitudinal change for neurodegeneration, defined by sNfL levels and disability progression. In a prospective, multicenter, longitudinal study, 891 people with MS undergo high-resolution 3T MRI, sNfL measurement, and clinical assessment over 6 years; 434 meet criteria for inclusion. CP volume correlates with sNfL after adjustment for demographic, clinical, treatment, and imaging variables. In a 2-year MRI subcohort (n = 209), CP enlargement likewise associates with sNfL. High CP volume confers a 1.8-fold increased risk of disability worsening and a 2.7-fold increased risk of progression independent of relapse activity. These findings identify CP imaging as a promising non-invasive biomarker of neuroaxonal loss and relapse-free progression.

Although B cell depletion slows disability accrual in people with multiple sclerosis (pwMS), the role of B cells in MS-associated neuronal injury remains elusive. B cells release cytokines such as lymphotoxin-α (LTα), and this proinflammatory protein is also present in the cerebrospinal fluid (CSF) and meninges of pwMS. B cell-specific ablation of LTα alleviates disease severity in a preclinical model of MS. To further study the impact of B cell-derived cytokines on neuronal function, we performed patch-clamp recordings on human iPSC-derived neurons. Coculture with proinflammatory human B cells led to depolarization and aberrant firing. Pretreatment of proinflammatory B cells with a Bruton's tyrosine kinase inhibitor (BTKi), reported in patients to beneficially affect disability progression even in the absence of inflammatory relapse activity, prevented neuronal impairment and inhibited LTα release from B cells. Blocking LTα, tumor necrosis factor receptor 1 (TNFR1), or receptor-interacting protein kinase 1 or 3 also prevented neuronal impairment, but blocking TNFα or LTβ had no such effect. Neuronal impairment was reversible by BTKi or blockage of LTα, and this reversibility was dependent on the activity of acid sphingomyelinase. In pwMS, LTα correlated with elevated neurofilament light chain (NfL) abundance in CSF, and anti-CD20 B cell-depletion therapy led to a reduction in circulating LTα, supporting the role of B cells as a regulator for LTα. These findings highlight the negative impact of B cell-derived LTα on neurons and suggest potential treatment avenues for MS-associated neuronal injury.

Background:With the development of highly effective disease-modifying treatments, vaccinations are becoming increasingly important in people with neurological autoimmune diseases. However, questions regarding the safety and efficacy of vaccinations under immunotherapy remain. Objective:To provide recommendations on types and timing of vaccinations for people with neuroimmunological diseases under different immunotherapies. Design:Our study presents a German evidence-based expert consensus on vaccination under immunotherapies in neurological autoimmune diseases. Methods:Based on literature research, a consortium of experts evaluated the quality of evidence, integrated clinical experience, and responded to a questionnaire determining an agreement (>75%) on statements concerning vaccination upon immune therapies in neuroimmunological diseases. Results:The specific humoral and cellular response to vaccination can be compromised under alemtuzumab, azathioprine, cladribine, cyclophosphamide, CD19/CD20 antibodies (inebilizumab, ocrelizumab, ofatumumab, rituximab, ublituximab), dimethyl fumarate/diroximel fumarate, FcRn inhibitors (efgartigimod, rozanolixizumab), complement C5 inhibitors (eculizumab, ravulizumab, zilucoplan), interleukin-6 receptor antibodies (tocilizumab, satralizumab), intravenous immunoglobulins, long-term steroid administration, methotrexate, mitoxantrone, mycophenolate mofetil, tacrolimus, teriflunomide, tumor necrosis factor-α blockers, and sphingosine-1-phosphate receptor modulators (fingolimod, ozanimod, ponesimod, siponimod), as well as after autologous stem cell transplantation. The lymphocyte count can have an influence here. Overall, it is generally advisable to complete vaccination before starting immunotherapy. However, in the case of an active inflammatory disease course with possible irreversible neurological deficits, a delay in therapy initiation until immunization has been completed cannot be justified. The application of live vaccines is contraindicated for most therapies and is only recommended after a strict risk-benefit assessment. Conclusion:Vaccinations are necessary for individuals on immunotherapy to reduce the risk of infections and the associated risk of worsening neurological autoimmune diseases. However, the humoral and cellular vaccination response may be impaired under immunotherapy necessitating close monitoring. Here, we provide applicable recommendations to optimize immunization for individuals receiving immunotherapy due to a neurological autoimmune disease.

ObjectiveEstablishing biomarkers to predict multiple sclerosis (MS) disability accrual has been challenging using a single biomarker approach, likely due to the complex interplay of neuroinflammation and neurodegeneration. Here, we aimed to investigate the prognostic value of single and multimodal biomarker combinations to predict four-year disability progression in patients with MS.MethodsIn total, 111 MS patients were followed up for four years to track disability accumulation based on the Expanded Disability Status Scale (EDSS). Three clinically relevant modalities (MRI, OCT and blood serum) served as sources of potential predictors for disease worsening. Two key measures from each modality were determined and related to subsequent disability progression: lesion volume (LV), gray matter volume (GMV), retinal nerve fiber layer, ganglion cell-inner plexiform layer, serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein. First, receiver operator characteristic (ROC) analyses were performed to identify the discriminative power of individual biomarkers and their combinations. Second, we applied structural equation modeling (SEM) to the single biomarkers in order to determine their causal inter-relationships.ResultsBaseline GMV on its own allowed identification of subsequent EDSS progression based on ROC analysis. All other individual baseline biomarkers were unable to discriminate between progressive and non-progressive patients on their own. When comparing all possible biomarker combinations, the tripartite combination of MRI, OCT and blood biomarkers achieved the highest discriminative accuracy. Finally, predictive causal modeling identified that LV mediates significant parts of the effect of GMV and sNfL on disability progression.ConclusionMultimodal biomarkers, i.e. different major surrogates for pathology derived from MRI, OCT and blood, inform about different parts of the disease pathology leading to clinical progression.

OBJECTIVE:We examined the impact of the rs10191329 genetic risk variant on neuroaxonal damage as measured by serum neurofilament light chain (sNfL) levels, and disability progression in people with multiple sclerosis (pwMS). METHODS:In a cohort of pwMS (n = 740), 658 participants were prospectively monitored every 2 years for less than a decade while 82 of 740 pwMS were monitored retrospectively for up to 40 years. We investigated associations between rs10191329 variants and clinical outcome, including Expanded Disability Status Scale (EDSS), disability accrual (defined by EDSS-increase of at least 1.5 for patients starting at EDSS 0, at least 1.0 EDSS-points for patients with an initial EDSS between 1 and 4.5 and at least 0.5 points for patients starting with an EDSS equal or greater than 5) and progression to secondary progressive MS (SPMS). Clinical outcomes were analyzed using Kaplan-Meier and Cox proportional hazards analyses. Disability accumulation over time was depicted using a generalized mixed-effect model. Single-molecule array was used to assess sNfL levels. RESULTS:Homozygous, heterozygous, and non-carriers of the rs10191329 risk variant displayed comparable sNfL levels indicating similar neuroaxonal damage at the time of diagnosis. Importantly, in homozygous carriers we found highest sNfL levels in follow-up visits preceding elevated disease progression later in the disease course, a steeper increase in overall disability measures and higher probability of SPMS development. INTERPRETATION:These findings highlight how genetic variants may serve as new biomarkers for disease progression and can be used for personalized medicine and risk assessment in MS. ANN NEUROL 2025;97:596-605.

Immunomodulatory and immunosuppressive therapy is needed in people with a chronic neuroinflammatory disease of the central nervous system such as multiple sclerosis (MS). Therefore, MS requires monitoring for and preventing against infectious diseases like SARS-CoV-2. Vaccination and anti-viral treatments are, in particular, recommended for elderly people and people at risk of a severe course of infection and of MS. Here, we asked whether repetitive infection or vaccination influenced responses upon receiving high efficacy treatments, namely sphingosine-1-phosphate receptor modulator (S1P) or anti-CD20 B cell antibody (anti-CD20) treatments. We performed a prospective real-world study of people with MS (pwMS) under S1P or anti-CD20 with repetitive exposure to the SARS-CoV-2 virus or vaccine. The measurement of anti-SARS-CoV-2 antibody titres was performed by two independent immunoassays after initial immunisation and after booster vaccination or infection. Other laboratory and clinical parameters were included in the analysis of influencing factors. As secondary outcomes, lymphocyte and immunoglobulin levels were observed longitudinally under intravenous and subcutaneous anti-CD20 treatment. In a long-term real-world cohort of 201 pwMS, we found that despite lymphopenia upon S1P drugs, the SARS-CoV-2 immunisation response increased both in selective and non-selective S1P (100% and 88% seroconversion, respectively), whereas those under anti-CD20 therapies merely exhibited a slight long-term increase in antibody titres (52% seroconversion). The latter was independent of immunoglobulin or total lymphocyte levels, which mostly remained stable. If the individual was immunised prior to therapy initiation, their levels of SARS-CoV-2 antibodies remained high under treatment. PwMS under non-selective S1P benefit from repetitive vaccination. The risk of an insufficient vaccination response mirrored by lower SARS-CoV-2 antibodies remains in pwMS receiving anti-CD20 treatment, even after repetitive exposure to the vaccine or virus. Due to the compromised vaccination response in CD20-depleting drugs, prompt antiviral treatment might be necessary.

Background As B cell-depleting therapies in multiple sclerosis (MS) have gained significant importance in the last several years, their long-term safety profile is of considerable clinical interest. Late-onset neutropenia (LON) is a rare, but potentially severe, adverse event that was first described in patients with rheumatic disorders under therapy with rituximab. Ofatumumab was approved in 2021 for the treatment of relapsing-remitting multiple sclerosis (RRMS). Neutropenia occurred in 0.2% of patients in clinical phase 3 trials, and to date, no cases of LON have been reported under ofatumumab treatment. Methods Here, we report a case of repetitive symptomatic LON under ocrelizumab as well as ofatumumab treatment. Additionally, we review the literature on rare occurrences of LON in patients with MS, neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) undergoing B cell-depleting therapies, including rituximab, ocrelizumab, ofatumumab, inebilizumab, and ublituximab. Findings In our case, the patient presented with repetitive symptomatic LON under ocrelizumab as well as ofatumumab treatment leading to febrile infections, subsequent use of antibiotics, and application of granulocyte-colony-stimulating factor. After repetitive episodes of LON under both B cell-depleting strategies, cladribine was subsequently initiated. A nine-month follow-up showed a normal neutrophil count and no evidence of disease activity. Conclusions This case highlights the significance of symptomatic late-onset blood count changes under both ocrelizumab and ofatumumab and emphasizes the importance of continuous monitoring of the differential blood count under B cell-depleting treatment. Funding This study was supported by the Deutsche Forschungsgemeinschaft (DFG; SFB CRC-TR-128 to F.Z., V.F., and S.B..; SFB 1080 and SFB CRC-1292 to F.Z..; and SFB/TRR 355 to S.B.) and the Hermann and Lilly Schilling Foundation (to S.B.).

Background: Interferon-beta (IFN-β) still plays a fundamental role in immunomodulation of people with multiple sclerosis (MS) with low disease activity and in clinically isolated syndrome (CIS). In 2014, pegylated (PEG) interferon was licensed by the European Medicines Agency (EMA) for relapsing-remitting MS (RRMS), enabling a lower dosing frequency. Objectives: Our retrospective study compares laboratory findings and adverse events between subcutaneous (sc.) PEG-IFN-β-1a and IFN-β-1a in RRMS and CIS patients. Design: Patients with CIS or RRMS fulfilling the revised McDonald criteria from 2017 visiting the neurology department of the University Medical Center of the Johannes Gutenberg University Mainz from 2010 to 2019 and treated with sc. PEG-IFN-β-1a or sc. IFN-β-1a ( n = 202) were screened for eligibility. Patients who underwent regular laboratory controls in-house were included in our analysis ( n = 128). Methods: We evaluate disease progression through clinical examination, relapse history, and magnetic resonance imaging (MRI) disease activity (gadolinium-enhancing or new T2 lesions). Relevant laboratory findings such as leukopenia (leukocyte count < 3.5/nl) and neutropenia (neutrophil count <43% of lymphocytes or <1500/µl) were assessed. Telephone interviews evaluated the side effects of the respective medication. A subgroup of patients was analyzed regarding neutrophil quantities and qualities. Results: Patients treated with sc. PEG-IFN-β-1a had significantly lower leukocyte counts ( p = 0.046) and higher incidences of leukopenia ( p = 0.006) and neutropenia ( p = 0.03) compared to sc. IFN-β-1a. Clinical and MRI disease activity showed no significant differences, but people treated with sc. PEG-IFN-β-1a reported more common adverse events such as joint/muscle pain, injection-site reaction, and infections. No serious adverse events were reported. Conclusion: Treatment with sc. PEG-IFN-β-1a compared to unpegylated sc. IFN-β resulted in a significantly greater reduction in leukocyte and neutrophil levels with a higher incidence of side effects. We suggest mandatory monitoring of differential blood counts before and during treatment.

Anti-CD20 therapy to deplete B cells is highly efficacious in preventing new white matter lesions in patients with relapsing-remitting multiple sclerosis (RRMS), but its protective capacity against gray matter injury and axonal damage is unclear. In a passive experimental autoimmune encephalomyelitis (EAE) model whereby T H 17 cells promote brain leptomeningeal immune cell aggregates, we found that anti-CD20 treatment effectively spared myelin content and prevented myeloid cell activation, oxidative damage, and mitochondrial stress in the subpial gray matter. Anti-CD20 treatment increased B cell survival factor (BAFF) in the serum, cerebrospinal fluid, and leptomeninges of mice with EAE. Although anti-CD20 prevented gray matter demyelination, axonal loss, and neuronal atrophy, co-treatment with anti-BAFF abrogated these benefits. Consistent with the murine studies, we observed that elevated BAFF concentrations after anti-CD20 treatment in patients with RRMS were associated with better clinical outcomes. Moreover, BAFF promoted survival of human neurons in vitro. Together, our data demonstrate that BAFF exerts beneficial functions in MS and EAE in the context of anti-CD20 treatment.

BackgroundCombination treatment with BRAF/MEK inhibitors favorably impact progression-free survival in malignant melanoma. However, it may cause paradoxical activation of the MAPK/ERK pathway in immune cells without BRAF mutation, which may lead to over activation of the immune system, especially in patients with pre-existing autoimmune conditions. In this case report, treatment of malignant melanoma with BRAF/MEK inhibitors was associated with radiological disease exacerbation of pre-existing multiple sclerosis (MS).Case presentationA 47-year-old patient with pre-existing MS was diagnosed with malignant melanoma in June 2020. Anti-tumor treatment was initiated with a combination therapy of BRAF inhibitor dabrafenib and MEK inhibitor trametinib. In February 2022, the patient presented at our neurological clinic after routine MRI revealed exacerbation of radiological MS disease activity with ten new and gadolinium-enhancing lesions, and concomitant high levels of neurofilament light chain (NfL) in serum, a marker for axonal damage. In-depth analysis of immune cells in both peripheral blood and cerebrospinal fluid was performed by multi-color flow cytometry. After treatment with the B cell-depleting antibody ocrelizumab, MS disease stability was obtained and anti-tumor medication could be continued.ConclusionsImmunomodulatory treatment in cancer patients is highly effective from an oncological point of view, but may be associated with autoimmune side effects. This is of special importance in patients with pre-existing autoimmune diseases, as reflected by our case of MS disease reactivation under treatment with BRAF/MEK inhibitors. In our case, sequential modulation of immune cell subsets by B cell depletion, associated with marked shifts in B and T cell subsets, allowed for stabilization of disease and continuation of anti-tumor treatment.