Abstract Background Neuromyelitis optica spectrum disorders (NMOSD) are associated with a high burden of depression, pain, and physical disability, all of which significantly impair quality of life. At the same time, discussions on the cost-effectiveness of treatment strategies are gaining importance. However, it is not yet known whether specific symptom burdens are particularly cost-driving. This study aims to provide a comprehensive cost analysis considering depression and pain to optimise future healthcare strategies. Methods This prospective cross-sectional multicentre study was conducted at twelve centres of the Neuromyelitis Optica Study Group (NEMOS). Over a three-year period, 115 NMOSD patients were recruited. Disease-related costs, pain, and depression were assessed using standardised questionnaires. A generalised linear model analysis and graphical sub-cost analysis were performed to identify key cost drivers. The robustness of our findings was confirmed using two independent depression rating scales. Results In our sample of 115 patients, 77% suffered from chronic pain with a median pain intensity of 4.0 on the numeric rating scale (NRS). Moreover, 56% of patients reported depressive symptoms. In multivariate regression analysis, depression emerged as a significant predictor of total costs (p < 0.001) alongside the EDSS score (p < 0.001) and age (p = 0.004). In contrast, pain was not significantly influencing total costs (p = 0.057), despite being reported by the majority of patients. Graphical analyses highlighted informal costs as the main cost driver in patients with increasing depressive symptoms. Conclusions Depressive symptoms are not only common in NMOSD patients but also represent a major cost driver alongside neurological disability. Addressing these symptoms is essential for optimal patient care and may help reduce the socioeconomic burden.

Background:B-cell depleting therapies (BCDT), including ocrelizumab, ofatumumab, and ublituximab, are highly effective disease-modifying therapies for multiple sclerosis (MS). Several case reports have raised concerns about new-onset or exacerbation of psoriasis under BCDT. Objectives:This article aims to analyze clinical characteristics, treatment courses, and outcomes of MS patients who developed or experienced worsening of psoriasis during BCDT. Design:This retrospective, multicenter analysis included patients from four German university hospitals (Düsseldorf, Hannover, Bochum, Giessen). Methods:We retrospectively screened 3228 MS patients under BCDT between 2020 and 2024 for development of psoriasis or an exacerbation of a known psoriasis. Clinical data, including Expanded Disability Status Scale, Psoriasis Area and Severity Index scores, treatment regimens, and comorbidities, were analyzed. Results:Among 3228 patients treated with BCDT, 7 developed new-onset psoriasis and 10 showed exacerbation of preexisting psoriasis. The median time to psoriasis onset or worsening was 13 months (3-83 months) under continuous treatment with BCDT. Topical therapies were effective in most cases, but a change of MS treatment or initiation of psoriasis-specific immunotherapies, including the interleukin-17A-antibody secukinumab, was required in four patients. Conclusion:Psoriasis onset or worsening during BCDT is rare. While most cases are manageable with standard psoriasis treatments, severe cases may necessitate therapy adjustments. The potential immunological interplay between MS and psoriasis treatment warrants further investigation.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system with distinct subtypes, relapsing MS (RMS) and primary progressive MS (PPMS), which differ in clinical course and underlying immunopathology. Cytokines are pleiotropic mediators of inflammatory and regenerative processes and are considered important contributors to the pathophysiology of MS. Ocrelizumab, a CD20-targeting monoclonal antibody, is approved for the treatment of patients with RMS and PPMS, yet its effects on circulating cytokines and neurotrophic factors remain incompletely understood. In this prospective observational study, 84 patients with MS (57 RMS, 27 PPMS) were analyzed regarding demographic data, disease activity and serum cytokine profiles before and 6 months after the start of ocrelizumab therapy. Baseline analyses revealed distinct cytokine signatures between patients with RMS and PPMS, with higher levels of several proinflammatory cytokines and chemokines in patients with RMS. Following ocrelizumab treatment, divergent cytokine profiles between patients with RMS and PPMS were partially attenuated, with significant modulation of Th1-associated chemokines and an increase in brain-derived neurotrophic factor (BDNF) observed in patients with RMS. In contrast, cytokine signatures in patients with PPMS remained largely unaffected by ocrelizumab treatment. Patients with RMS with disease activity during the first 6 months of ocrelizumab treatment showed a significant increase in different chemokines compared to baseline compared with patients without disease activity or those with PPMS. Our findings support divergent immunological mechanisms in RMS and PPMS, with a stronger cytokine-driven pathology and more pronounced immunomodulatory effects of ocrelizumab on the cytokine profile in patients with RMS.

BACKGROUND:Studies on interrater agreement in MRI analysis for patients experiencing a first clinical episode suggestive of multiple sclerosis (MS) are limited and outdated. This study aimed to evaluate interrater agreement for lesion identification in the brain, optic nerve, and spinal cord, and to assess variability in applying the 2017 and 2024 McDonald criteria. METHODS:Seventy-eight patients underwent a standardized multisequence 3 Tesla MRI of the brain, optic nerves, and spinal cord, analyzed by three readers with varying expertise. Lesions were categorized based on location according to McDonald criteria. Interrater variability was measured using Cohen's κ for pairwise reader comparisons and Fleiss κ for overall agreement. RESULTS:Interrater agreement ranged from slight to fair for total lesion count and moderate to substantial for lesion presence. The highest agreement occurred for spinal cord lesions (κ = 0.84), periventricular T2 lesions (κ = 0.70), and gadolinium-enhancing brain lesions (κ = 0.75). Classification agreement based on diagnostic criteria was substantial between the 2017 and 2024 McDonald criteria revisions (κ = 0.65). CONCLUSIONS:Despite advanced standardized imaging protocols at 3 T, interrater agreement regarding lesion counts does not improve substantially. However, agreement in classifying lesions according to diagnostic criteria is consistent between the 2017 and 2024 criteria.

Cerebrospinal fluid (CSF) specific oligoclonal bands (OCB) are a key diagnostic marker in multiple sclerosis (MS). Recent studies suggest that OCB reduction may reflect treatment efficacy and propose it as a potential endpoint in trials with chimeric antigen receptor (CAR) T-cell therapy. However, the prognostic value of baseline OCB count remains unclear. This study analyzed data from 454 persons (314 had MS, 140 clinically isolated syndrome). OCB analysis was performed by isoelectric focusing in polyacrylamide gel, followed by silver staining. The correlation of the number of OCBs with clinical and paraclinical parameters as well as follow-up outcomes was evaluated. Our results showed that in OCB positive persons with MS, the median number of CSF specific bands was 19. No significant correlation was found between OCB count and age, sex, initial EDSS, or MRI lesion load. OCB count also did not predict relapse risk or EDSS progression. However, strong correlations were observed with intrathecal synthesis of IgG and kappa free light chains. Therefore, our conclusion is that OCB count does not reflect clinical disease activity at diagnosis nor predict clinical progression within the observed median follow-up period of 9 months. Whether a decrease in OCB count indicates reduced humoral immune response in the CNS under certain therapies remains unclear and requires further prospective studies.

BACKGROUND:The optimal strategy after discontinuation of B-cell depleting therapies like ocrelizumab in people with multiple sclerosis (pwMS) remains uncertain, particularly regarding delayed disease reactivation, disability progression and required treatment duration before cessation. METHODS:In this prospective two-centre observational cohort study with propensity score-matched (PSM) analysis, we evaluated recurrence of disease activity and disability worsening after ocrelizumab discontinuation. PwMS fulfilling the 2017 McDonald criteria were enrolled between January 2018 and December 2023 at two German MS centres. Participants received ocrelizumab for ≥12 months with no inflammatory activity in the preceding 12 months. Of 655 eligible patients (continuers, n=578; discontinuers, n=77), 290 were included after 4:1 PSM. The primary exposure was discontinuation, mainly due to infection concerns during COVID-19 (81%) or hypogammaglobulinaemia (16%). Main outcomes were time to combined inflammatory activity (CIA) and progression independent of relapse activity (PIRA). Receiver operating characteristic (ROC) identified optimal treatment duration. RESULTS:After median follow-up of 28.5 months, there was no significant difference in CIA risk between groups (HR: 0.91, 95% CI 0.08 to 10.79) or for PIRA (HR: 4.8, 95% CI 0.38 to 60.2). Beyond 24 months after discontinuation, disease activity remained stable, with a numerical rise that did not reach statistical significance. ROC analysis suggested no further reduction of activity beyond 29-30 months of therapy, but increasing reactivation risk after >32 months off-treatment. CONCLUSIONS:For stable pwMS, ocrelizumab discontinuation after about 30 months on-treatment appears safe short-term, though vigilant monitoring is warranted beyond 2 years off-treatment due to potential delayed reactivation.

Hereditary transthyretin (ATTRv) amyloidosis is a rare, progressive multisystem disease caused by pathogenic variants in the transthyretin (TTR) gene. ATTRv-associated Polyneuropathy (ATTRv-PN) manifests in a length-dependent sensorimotor and autonomic pattern, commonly accompanied by cardiomyopathy. In recent years, clinical trials have introduced two classes of disease modifying treatments (DMT), TTR stabilizers and gene silencers. Across populations and outcome parameters, all trials share one result disease progression was significantly slowed and patients’ span and quality of life substantially improved compared to placebo, even though a function once lost would not be retrieved. This expert consensus paper provides recommendations for the treatment of ATTRv-PN in Germany and was jointly developed by experts from the German Society of Amyloid Diseases (DGAK) and the German Neurological Society (DGN). In addition to evidence from pivotal clinical trials, the recommendations incorporate benefit assessments of the German Federal Joint Committee (G-BA). For first-line treatment, the DGAK/DGN recommends one of the two second-generation TTR gene-silencing agents, vutrisiran or eplontersen, for most patients with symptomatic ATTRv-PN. For patients showing even minor signs of disease progression under a TTR stabilizer, the authors recommend immediate switch to a gene silencer. Evidence is limited for or against switching between silencers or combining different agents. Informed patient participation is crucial upon initiation and adaptation of DMT. For central nervous system (CNS) involvement, none of the approved agents sufficiently crosses the blood-brain barrier. Aligned with that, there are no observed or expected CNS side effects of any of the DMTs. In the future, next-generation RNA-interference therapies, gene-editing approaches, and amyloid-depleting antibodies are expected to further expand therapeutic options.

BACKGROUND AND OBJECTIVES:Biologically informative markers like glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) may help predict confirmed disability worsening (CDW) in multiple sclerosis (MS). However, data on the prognostic value of their blood concentrations in progressive MS (PMS) are limited, and there are substantial discrepancies in the published literature. This international collaboration uses individual participant data to define the prognostic value of serum GFAP and NfL in people with PMS (pwPMS). METHODS:Data were collected from BioMS-eu network centres and collaborating cohorts. pwPMS with primary progressive MS (PPMS) or secondary progressive MS (SPMS) with at least one GFAP value and at least three follow-up expanded disability status scale (EDSS) scores were included. The prognostic value of serum GFAP and NfL age- and sex-adjusted Z-scores for future CDW was evaluated using Cox regression models, accounting for sex, age, baseline disease duration and EDSS, and dominant treatment during follow-up. RESULTS:1058 participants and 7530 encounters were included (median age 53 years (IQR: 44 to 59), 57% female, follow-up 4.6 years (2.9 to 8.4)) with median baseline GFAP of 0.74 (-0.10 to 1.55) and NfL of 0.64 (-0.36 to 1.51). 723 CDW events were recorded. Each GFAP Z-score increase was associated with ~10% higher CDW risk (adjusted HR (aHR) 1.107 (1.001 to 1.225), p=0.049). Results were mainly driven by SPMS participants (n=613, aHR 1.242 (1.073 to 1.438), p=0.004). Higher NfL Z-scores predicted CDW only in PPMS participants (1.236 (1.092 to 1.399), p=0.001). CONCLUSIONS:GFAP was a prognostic indicator for future CDW in pwPMS, especially in pwSPMS. On the other hand, NfL was predictive of CDW only in pwPPMS.

A wide variety of immunomodulatory therapies are already available for the treatment of multiple sclerosis (MS). Through fundamental insights from basic research with a gain of knowledge in the pathological processes underlying MS, the exploration of additional medical compounds within clinical trials has been ignited. Emerging novel medications with innovative mechanisms of action are being introduced. Those mechanisms of action include a broad therapeutic spectrum of substances targeting various protein kinases, some of which could also be used for the treatment of other autoimmune-mediated diseases. The advancement of new compounds could therefore enable a more personalized approach in treating MS, taking into consideration patients' co-existing autoimmune-mediated diseases. In this review, we discuss potential compounds targeting protein kinases, currently under investigation in clinical trials for various autoimmune diseases that could become viable treatment options for MS and comorbid autoimmune conditions in the future.

Kappa free light chains (KFLC), a byproduct of immunoglobulin (Ig) synthesis by B-lineage cells, can serve as an indicator for inflammatory activity. In multiple sclerosis (MS), especially the intrathecal KFLC production has gained increasing importance as a biomarker for central nervous system (CNS) inflammation and was included into the proposed 2024 revision of the McDonald criteria. In contrast, studies investigating the significance of KFLC in serum and the effects of disease-modifying therapies (DMT) on KFLC serum concentration in MS are rare. The aim of the present work was to investigate the impact of B cell depletion with ocrelizumab on KFLC concentrations in serum of MS patients and the ability of serum KFLC to monitor disease activity. 50 MS patients were included in the present study– 38 with the diagnosis of relapsing MS (RMS) and 12 with diagnosis of primary-progressive MS (PPMS) -, who were treated with ocrelizumab for two years. Serum concentrations of albumin, immunoglobulins and KFLC as well as lymphocyte subsets were determined at baseline and after two years. Serum Ig and KFLC concentrations were found to be significantly lower after two years of ocrelizumab treatment (mean serum concentrations: KFLC: 9.5 mg/l vs. 7.8 mg/l, p = 0.0003; IgG: 9 g/l vs. 8 g/l, p = 0.0002; IgA: 2 g/l vs. 1.8 g/l, p = 0.0010; IgM: 1.8 g/l vs. 0.7 g/l, p < 0.0001). Serum KFLC concentration did not correlate with clinical and paraclinical parameters of disease activity. Treatment with ocrelizumab reduces serum KFLC concentration in MS patients. However, serum KFLC concentration is not able to predict disease activity in these MS patients.

Hereditary transthyretin (ATTRv) amyloidosis is a progressive multisystem disorder, mainly characterized by cardiac dysfunction and polyneuropathy. Due to its rarity and heterogeneous presentation, diagnosis is often delayed, which has a direct impact on the initiation of treatment and, therefore, span and quality of life. To facilitate early disease recognition, we aimed to develop and validate a new screening tool for early identification of ATTRv amyloidosis with polyneuropathy (AmyloScan®). Potential disease characteristics were identified via literature screening, interviews and detailed examination of ATTRv amyloidosis patients (n = 10) and controls (CIDP: chronic inflammatory demyelinating polyneuropathy, n = 15; diabetic polyneuropathy, n = 15) using validated questionnaires, and autonomic and sensory testing. The preliminary AmyloScan® was developed and validated in patients with polyneuropathy caused by ATTRv amyloidosis (n = 21), CIDP (n = 19), or others (n = 43). By sensitivity and discriminant analyses, we determined the most characteristic item combinations for ATTRv amyloidosis. Cut-off values were defined by Receiver Operator Curves. The final AmyloScan® includes 12 questions and two sensory bedside tests. All items require simple yes/no answers, resulting in a total score of 0–14 points and two cut-off values: A value of ≥ 4 indicates an increased chance (sensitivity: 95.2

Transthyretin (TTR) amyloidosis manifests in two distinct forms: hereditary (ATTRv) and wild-type transthyretin amyloidosis (ATTRwt). Despite being one of the commonest manifestations in ATTRv amyloidosis, the presence of polyneuropathy has long been underestimated in ATTRwt patients. This prospective study enrolled 72 patients with ATTRv (n = 11) and ATTRwt (n = 61) amyloidosis. Our standardized protocol included a detailed patient history, clinical and electrophysiological examinations, assessment of unrelated neuropathy risk factors and predefined red flags for ATTRv amyloidosis, as well as serum neurofilament light chain concentrations (NfL). We found signs of polyneuropathy in all ATTRv patients and a vast majority of ATTRwt patients (84%). Predefined red flag symptom clusters were prevalent in both subgroups, indicating significant overlap, however gastrointestinal symptoms were more frequent in ATTRv amyloidosis (p = 0.008), while carpal tunnel syndrome was less common (p = 0.015) compared to ATTRwt amyloidosis. The groups differed in severity of polyneuropathy, with ATTRv patients demonstrating more pronounced subjective limitations, greater clinical disability, marked nerve conduction abnormalities, and higher serum NfL concentrations (p = 0.011). Our findings underscore a high prevalence of polyneuropathy in patients with transthyretin amyloidosis, irrespective of its origin. Differences in the severity of polyneuropathy as well as in red flags indicate different underlying mechanisms of damage.

Objective:This study analyzed clinical characteristics, attack recovery and long-term disability accumulation in late-onset (LO ≥ 50 years at onset) versus early-onset (EO < 50 years) NMOSD. Methods:This multicenter cohort study included demographic and clinical data from 446 NMOSD patients collected from 35 German Neuromyelitis Optica Study Group (NEMOS) centers. Time to disability milestones was estimated through Kaplan-Meier analysis and Cox proportional hazard regression models adjusted for sex, year of onset, immunotherapy exposure and antibody status. Generalized estimating equations (GEE) were used to compare attack outcomes. Results:Of the 446 NMOSD patients analyzed (83.4% female, 85.4% AQP4-IgG-positive, median age at disease onset = 43 years), 153 had a late-onset (34.3%). AQP4-IgG+ prevalence was higher in LO- than in EO-NMOSD (94.1% vs. 80.9%, p<0.001). Optic neuritis at onset was more frequent in EO-NMOSD (27.4% vs. 42.6%, p<0.002), whereas myelitis was more common in LO-NMOSD (58.4% vs. 37.9%, p<0.001). Both groups had similar annualized attack rates (AAR, 0.51 vs. 0.54, p=0.352), but attack recovery was poorer (complete remission in 15.6% vs. 27.4%, p<0.001) and relapse-associated worsening (RAW) was higher in LO-NMOSD (RAW: 3 vs. 0.5, p<0.001). Long-term immunotherapy use was comparable. LO-NMOSD exhibited faster progression to disability endpoints (EDSS 4: HR = 2.64, 95% CI=1.81-3.84). Interpretation:LO-NMOSD patients presented more often with myelitis, experienced worse attack outcomes and faster disability accumulation, despite comparable AAR, acute attack treatment and long-term treatment regimens. Accordingly, therapeutic strategies for attack and prophylactic treatment in LO-NMOSD have to be improved.

Background:Right ventricular-pulmonary arterial (RV-PA) uncoupling in cardiac amyloidosis (CA) has been underexplored, with focus mainly on tricuspid annular plane systolic excursion (TAPSE)/pulmonary artery systolic pressure (PASP). This study aims to evaluate the association of various echocardiographic surrogates of RV-PA coupling with outcomes in cardiac transthyretin (ATTR-CA) and light-chain (AL-CA) amyloidosis. Methods:We analyzed RV-PA coupling in patients diagnosed with ATTR-CA and AL-CA at our center between 2014 and 2023. RV-PA coupling was assessed using TAPSE/PASP, fractional area change (FAC)/PASP, and RV free wall strain (RVFWS)/PASP. The primary endpoint was all-cause mortality. Results:A total of 120 patients (86% ATTR-CA, 14% AL-CA) were included in the study (median age 77 years, 88% male). During a median follow-up period of 23 (IQR: 15-34) months, the primary endpoint occurred in 25 patients (21%). The study population was stratified based on the ROC-derived TAPSE/PASP cutoff of <0.30 mm/mmHg, demonstrating RV-PA uncoupling. Lower RV-PA coupling surrogates were independently associated with higher mortality (HR per +0.1 unit: TAPSE/PASP, 0.74, 95% CI: 0.59-0.93, p = 0.011; FAC/PASP, 0.87, 0.77-0.98, p = 0.018; RVFWS/PASP, 0.78, 0.63-0.97, p = 0.024). TAPSE/PASP demonstrated the strongest prognostic discrimination (AUC: 0.79, bootstrapped 95% CI: 0.66-0.91), compared with FAC/PASP (AUC: 0.75, 0.58-0.91) and RVFWS/PASP (AUC: 0.72, 0.52-0.87). Conclusions:RV-PA uncoupling may be linked to a higher risk of all-cause mortality in CA. TAPSE/PASP outperformed numerically FAC/PASP and RVFWS/PASP in predicting long-term survival, although it did not clearly outperform established RV function parameters.

Optic neuritis is a frequent initial presentation of multiple sclerosis (MS). It has been suggested that optic nerve lesions on magnetic resonance imaging (MRI) should be considered as an additional lesion location for the demonstration of dissemination in space (DIS) in diagnostic criteria for MS. However, the potential value of optic nerve lesion(s) in MS diagnostic criteria has not yet been sufficiently investigated. We prospectively included 79 patients presenting with the first clinical event suggestive of MS. All patients underwent neurological work-up, visual-evoked potential (VEP) testing, cerebrospinal fluid (CSF) analysis and contrast-enhanced MRI of the brain, spinal cord and optic nerves (ON). Patients were classified results according to the McDonald 2017 criteria, the MAGNIMS criteria and alternative criteria considering ON imaging findings for both DIS and dissemination in time (DIT). 69 patients (87

Since 2018 subcutaneous immunoglobulin (SCIg) has been approved for the maintenance treatment of chronic inflammatory demyelinating polyneuropathy (CIDP). However, comprehensive real-world data for long-term SCIg treatment are scarce for CIDP and especially for other immune-mediated neuropathies such as multifocal motor neuropathy (MMN). In this observational study, 62 patients with CIDP and 13 with MMN were analyzed. Patients had been receiving regular intravenous immunoglobulin (IVIg) and transitioned to an equivalent weekly dose of SCIg. A comprehensive set of biographical, clinical, and paraclinical data were compared between the time of the switch and after 12 months. Subcutaneous administration was continued by 84