Propionic acid (PA), a microbial-derived short-chain fatty acid, contributes to intestinal barrier integrity, systemic immune regulation, and neuronal function. Individuals with multiple sclerosis show reduced PA levels, and open-label data have suggested beneficial immunomodulatory and clinical effects of supplementation. The Multiple sclerosis And DisAbility Improvement (MADAI) trial was a randomized, double-blind, placebo-controlled, single-centre, phase 2b study designed to evaluate the efficacy and safety of PA as an add-on therapy in adults with clinically stable multiple sclerosis. Between April 5 and 29 May 2024, 101 adults (64% women; mean age 45 years) were randomly assigned in a 2:1 ratio to receive PA 500 mg twice daily or matching placebo for 90 days. The primary outcome was the change in serum neurofilament light chain (sNfL) concentration, a biomarker of neuroaxonal damage, adjusted for age, body mass index, creatinine, and baseline sNfL. Secondary outcomes included physical and cognitive performance measures and patient-reported outcomes, including fatigue and quality of life scores. sNfL levels were significantly reduced in the PA group {-17.9%; from 9.77 pg/ml [95% confidence interval (CI) 9.00 to 10.60] to 8.02 pg/ml (95% CI 7.36 to 8.73); mean difference 1.75 pg/ml (95% CI 0.9 to 2.6); P = 0.000025}, while no significant change was observed in the placebo group. The adjusted mean difference in sNfL levels between the PA and placebo groups at follow-up was 0.91 pg/ml (95% CI 0.02 to 1.79; P = 0.045). Reductions in sNfL were also observed among participants in the PA arm receiving moderate-to-high efficacy disease-modifying therapies (n = 41; P = 0.0001), including those on anti-CD20 treatment (n = 27; P = 0.0005). There was a trend towards improvement in motor fatigue in the PA group. No serious adverse events related to the study medication occurred. PA supplementation was well tolerated and associated with significant reductions in sNfL, suggesting attenuation of neuroaxonal injury in multiple sclerosis. These findings support further evaluation of PA as an add-on treatment in larger, long-term studies.

OBJECTIVES:Optimizing brain health is increasingly recommended for patients with multiple sclerosis (MS). We investigated associations between modifiable lifestyle and metabolic factors with physical and cognitive performance in 101 MS patients. METHODS:In this prospective, cross-sectional, exploratory study, we assessed smoking, alcohol consumption, body mass index (BMI), lipid profiles (high-density lipoprotein, HDL; low-density lipoprotein, LDL; triglycerides), and vitamin levels (vitamin D, vitamin B12, and folic acid). Associations with upper limb function (Nine-Hole Peg Test, 9HPT), lower limb function (10-meter walking test; balance board), cognitive performance (Symbol Digit Modalities Test, SDMT), and employment (weekly working hours) were examined. RESULTS:Many patients showed potential for metabolic improvement, with abnormal levels observed in LDL (57%), triglycerides (27%), vitamin D (14%), vitamin B12 (7%), and folic acid (19%). Elevated BMI was found in 41% and 24% reported smoking. Pack-years were negatively associated with performance in the 10-meter walking test (r=-0.59, 95% CI: -0.81 to -0.23, p=0.003), and a higher BMI was linked to poorer balance (r=0.21, 95% CI: 0.01-0.4, p=0.042), while higher HDL levels correlated with preserved upper limb function (r=-0.21, 95% CI: -0.39 to -0.01, p=0.04). No consistent correlations were observed regarding vitamins. Performance in the SDMT and the 10-meter walking test were associated with unemployment. CONCLUSIONS:Many MS patients exhibit dyslipidemia and obesity, highlighting the need for targeted interventions to enhance neurological resilience. Our cross-sectional analysis indicates that smoking, low HDL, and higher BMI may have adverse clinical effects in MS.

OBJECTIVE:To describe long-term outcomes after anti-CD20 discontinuation in selected patients with secondary progressive multiple sclerosis (SPMS) who remained without subsequent disease-modifying therapy (DMT). METHODS:We retrospectively analyzed data from four centers in Austria and Switzerland. Inclusion criteria were SPMS, ≥ 2 anti-CD20 cycles, discontinuation without subsequent DMT, and ≥ 36 months follow-up. The primary endpoint was time to first confirmed Expanded Disability Status Scale (EDSS) worsening, defined as a ≥ 0.5-point increase after discontinuation documented at a subsequent routine visit. Secondary endpoints were relapses, MRI activity, and severe infections. No continuation cohort was available. RESULTS:Fifty-five patients were included (61% female). Mean age at anti-CD20 start was 53.5 ± 6.6 years, disease duration 19.3 ± 10.1 years, treatment duration 32.8 ± 16.1 months, and post-discontinuation follow-up 55.1 ± 14.1 months. Mean EDSS increased from 5.9 ± 1.3 before anti CD20, to 6.3 ± 1.3 at discontinuation and 6.9 ± 1.2 at last follow-up. Confirmed EDSS worsening occurred in 31 patients (56%). Hazard analysis suggested an exploratory late increase between 48 and 60 months (p = 0.043) based on small numbers at risk. Relapses occurred in 6 patients (10.9%), MRI activity in 4/35 (11%), and severe infections in 17 (31%). CONCLUSIONS:In this selected SPMS cohort, focal inflammatory activity was uncommon, whereas confirmed EDSS worsening accumulated over long-term follow-up. Because inclusion required ≥ 36 months untreated follow-up, early disease activity may have been underestimated, and apparent stability may have been overestimated. Findings are descriptive and hypothesis-generating and do not establish safety or optimal timing of anti-CD20 discontinuation.

Over the past two decades, anti-CD20 monoclonal antibodies have become a cornerstone in the management of B cell malignancies and autoimmune diseases, including multiple sclerosis (MS). Although their ability to induce profound depletion of peripheral B cells is well established, the broader spectrum of their immunomodulatory actions remains incompletely understood. This gap is clinically relevant, as treatment responses in MS do not consistently correlate with peripheral B cell counts. Moreover, tissue-resident B cells, particularly those within the central nervous system (CNS) and secondary lymphoid organs, as well as long-lived plasma cells, are largely unaffected by anti-CD20 therapy. These observations underscore the need to elucidate additional mechanisms contributing to therapeutic efficacy, including effects in antibody-mediated disorders such as neuromyelitis optica spectrum disorder (NMOSD). In this review, we focus on preclinical and clinical evidence concerning the effects of anti-CD20 therapies on soluble immunological mediators—cytokines, chemokines, and adhesion molecules—across MS. Emerging data suggest anti-CD20 treatments may restore the balance between pro-inflammatory and regulatory pathways, indirectly modulating other immune cell populations. However, available studies are constrained by small sample sizes, heterogeneous methods, and variable patient populations. Future systematic investigations are needed to clarify mechanisms of action, guide rational combination therapies, improve understanding of treatment response and side effects, and deepen insights into the underlying disease itself.

BackgroundThe reversible splenial lesion syndrome is frequently associated with systemic and central nervous system infections. Whether an infection associated with the occurrence of the reversible splenial lesion syndrome could play a role in the later development of multiple sclerosis is unknown.MethodsCase Report.ResultsA 27-year-old woman developed an infection-related reversible splenial lesion syndrome. Diagnostic findings did not establish a specific type of infection, but revealed evidence for a potential disposition towards autoimmunity. 32 months after the initial presentation, new clinical and radiological manifestations developed that led to a diagnosis of multiple sclerosis.ConclusionsIn susceptible individuals, infectious disease processes involving the central nervous system, such as described in this case, might be a factor in the pathogenesis of multiple sclerosis. More research on the prodromal stage of multiple sclerosis is needed to better understand the relationship between infections and autoimmunity.

BACKGROUND:Mobile health (mHealth) technology can support therapy adherence and self-management of people with multiple sclerosis (MS), but mHealth solutions tailored for the Austrian context are currently lacking. OBJECTIVES:This study aimed to evaluate usability, user experience and user acceptance of the Swiss "MS Active App" in an Austrian setting, and to identify transferable requirements and design implications. METHODS:Nine people with MS used the MS Active App for one week as part of their individual physiotherapy and occupational therapy. Data collection included standardised questionnaires, a user diary, qualitative interviews with patients, and focus group discussions with therapists. RESULTS:People with MS and their therapists rated the usability, user experience and user acceptance of the app as overall good. Qualitative accounts included a number of specific suggested improvements from which transferable requirements and design implications may be derived. CONCLUSION:The MS Active App offers a potentially suitable mHealth solution for people with MS in Austria, but several suggested improvements should be considered prior to implementation in practice.

Given the financial constraints in public healthcare, we investigated the monthly out-of-pocket expenses for non-pharmacological treatments among individuals with multiple sclerosis (MS), a chronic neurological disorder that primarily affects individuals of working age. This cross-sectional study employed an online questionnaire to evaluate the expenses and utilization of non-pharmacological treatments, as well as the weekly working hours among 104 individuals with relapsing-remitting MS (RRMS, 79%), secondary progressive MS (SPMS, 12%), and primary progressive MS (PPMS, 10%). Non-pharmacological treatments were used by 82% of participants (vitamin D (43%), physiotherapy (31%), massage (21%), magnesium (19%)). The average monthly out-of-pocket expenses were 136 EUR (SD ± 218) and significantly higher among individuals with PPMS (337 EUR SD ± 354) compared to RRMS (110 EUR SD ± 195; p = 0.01). The average weekly working hours were 26 and significantly lower among individuals with PPMS (11 h/week, SD ± 16; p = 0.008) and SPMS (13 h/week, SD ± 16; p = 0.001) compared to the RRMS cohort (30 h/week, SD ± 15). Working hours were not related to individual monthly costs. This study reveals substantial expenses incurred by individuals with MS in Austria, particularly those with PPMS, highlighting the willingness to actively participate in their disease management. Physicians should be aware of the financial resources and inform about available evidence on non-pharmacological treatment approaches.

OBJECTIVE:To investigate the impact of transition interval length when switching from natalizumab (NTZ) to anti-CD20 monoclonal antibodies (antiCD20) on recurrent disease activity and safety in relapsing multiple sclerosis (RMS). METHODS:Aggregating data from 8 MS centres in Austria, Switzerland, and Germany, we included RMS patients who (i) continuously received NTZ for ≥3 months, (ii) were switched to antiCD20, and (iii) had ≥12 months follow-up after switch. The primary endpoint was occurrence of relapse after switch, secondary endpoints included severe infections (CTCAE grade ≥3). RESULTS:Overall, 139 RMS patients were included (70.5% females, mean age at switch 38.8 years [SD 9.7], mean disease duration at switch 11.3 years [SD 6.2], median duration on NTZ 4.4 years [range: 0.3-16.4], median transition interval 58 days [0-180]). Relapse occurred in 18 patients (12.9%) after NTZ discontinuation. Of those, 11 (61.1%) patients relapsed during the transition interval. No patient with a transition interval below 30 days experienced a relapse, compared to 11.1% and 16.1% with transition intervals of 30-44 days and ≥ 45 days, respectively. In multivariable Cox regression, a transition interval ≥ 45 days predicted a 4.73-fold increased risk of relapse. Over approximately 4 years of follow-up, six severe infections were reported without any noticeable effect of transition interval length. No PML occurred. CONCLUSIONS:Switching from NTZ to antiCD20 is generally both effective and safe. Keeping the transition interval below 30 days provides the optimal balance between preventing recurrent disease activity and ensuring safety.

Intrathecal immunoglobulin A (IgA) synthesis in multiple sclerosis (MS) has long earned little attention, despite a potential significance in disease pathogenesis and prognosis. The presence of IgA-positive plasma cells in MS lesions and along damaged axons suggests a role in disease pathogenesis. Available clinical evidence about a potential positive or negative prognostic role is scarce and inconclusive. Recent observations, however, highlight the migration of immune regulatory IgA-producing plasma cells from the gut to the central nervous system (CNS) in experimental autoimmune encephalitis models. A connection between intrathecal IgA synthesis and the gut–brain axis in MS was further corroborated by the discovery of gut microbiota-specific IgA+ B cells in human CNS during relapse. In this review, we summarize current evidence on the occurrence and immunopathology of intrathecal IgA synthesis in MS, explore its biological implications, and address methodological challenges regarding the detection of IgA as a major limitation and possible source of inconsistencies in clinical studies. By synthesizing these diverse lines of evidence, we highlight the importance of further research and the need for standardized detection methods to clarify the role of IgA in MS pathogenesis, disease progression, and as potential biomarker.

Background: Cladribine (CLAD), an immune reconstitution therapy for active multiple sclerosis (MS), can reduce intrathecal antibody production. Objectives: In this study, we investigated the long-term impact of oral CLAD on protective antibody levels, essential for preventing infections and immune defense. Design: Observational long-term study including a cohort of 15 CLAD-treated MS patients. Methods: We longitudinally studied the humoral immunity to seven common pathogens (measles, mumps, varicella-zoster virus, diphtheria and tetanus toxin, rubella, hepatitis B virus (HBV)) and absolute immunoglobulin G (IgG) levels prior to CLAD treatment (baseline, BL; 12/2017–03/2020) and after an average of 73 months (long-term) follow-up to explore the impact on pre-existing IgG. At long-term, we assessed IgG response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to evaluate potential inhibitory effects on the formation of new immunity. Results: We found no CLAD associated loss of humoral immunity over up to 7 years. Pathogen-specific IgG antibodies were present in 60%–100% and 67%–100% of patients at BL and long-term, respectively. We found no decline in absolute IgG levels 73 months after starting CLAD treatment. Patients who received subsequent anti-CD20 treatment had significantly lower SARS-CoV-2 antibody levels ( p = 0.011) compared to the rest of the cohort, which developed adequate anti-SARS-CoV-2 IgG. One patient had a clinically silent tick-borne encephalitis (TBE) infection mounting appropriate IgG and IgM. No severe COVID-19 cases occurred, and no new safety concerns were identified. Conclusion: These long-term data suggest that CLAD treatment does not impact preexisting humoral immunity or antibody production toward novel antigens. Our results support the positive long-term safety profile of the drug.

INTRODUCTION:Sphingosine-1-phosphate receptor (S1PR) modulators are effective therapies for multiple sclerosis (MS) that block lymphocyte egress from secondary lymphoid organs. This migration inhibition carries the risk of reduced infection-control as reported for the non-selective S1PR modulator, fingolimod. CXCL13:CXCR5-associated immune activities play a key role in protective antibody-based immunity but are also linked to inflammation in MS. Utilizing the ongoing SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic, we aimed to determine whether selective S1PR modulation with ozanimod acts on the CXCL13:CXCR5 axis for modulating MS activity and whether this impacts anti-viral immune responses. METHODS:This 1-year observational study included 20 patients with MS receiving ozanimod and 10 healthy probands. CXCR5+ T cells, B cells, serum CXCL13, anti-SARS-CoV-2 serostatus, and SARS-CoV-2-spike protein (ProtS)-reactive T cell responses were measured at 3-month intervals. RESULTS:CXCR5+ T and B cell frequencies and serum CXCL13, but not anti-SARS-CoV-2 responses, declined after ozanimod initiation. Anti-SARS-CoV-2 antibody and ProtS-reactive T cell responses peaked after recall vaccinations and break-through infections. Notably, ProtS-reactive T cell frequencies shifted from CD4+ to CD8+ T cell responses in patients treated with ozanimod compared to controls. CONCLUSION:Selective S1P receptor modulation with ozanimod affects the CXCL13:CXCR5 axis by reducing circulating CXCR5+ lymphocytes and serum CXCL13, which may contribute to reduce meningeal inflammation in MS. Moreover, the anti-SARS-CoV-2 immune defense appeared to be preserved during treatment with SARS-CoV-2-reactive CD8+ T cells, possibly compensating the lack of CD4+ T cell responses. Our immunological data may well apply to other viral infections and underscore the favorable safety and efficacy profile of ozanimod.

Background and purposeThis study was undertaken to raise awareness of a role of B cells in immune checkpoint inhibitor (ICI)-associated neurological immune-related adverse events (nirAE).MethodsA systematic literature review was made, with case observations of a melanoma and a non-small cell lung cancer (NSCLC) patient who developed ICI-associated nirAE with cerebrospinal fluid (CSF) findings indicating B cell involvement.ResultsTwo patients receiving ipilimumab/nivolumab for melanoma and chemotherapy/pembrolizumab for NSCLC developed nirAE in the form of myocarditis/myositis/myasthenia gravis overlap syndrome (triple M) and cerebellitis plus longitudinal transverse myelitis (c-LETM), respectively. Intrathecal inflammation with chemokine C-X-C motif ligand (CXCL13) elevation was present in both patients; the triple M case had acetylcholine receptor antibodies, antititin reactivity, altered CD4/CD8 T cell ratio in blood, and depressed programmed death-1 (PD-1) expression on CSF T cells; the c-LETM case showed intrathecal antibody production and plasma cells. Both patients insufficiently responded to first-line treatment. The NSCLC case improved upon administration of B cell-depleting therapy with rituximab, whereas the melanoma patient died before escalation therapy was initiated. Literature research revealed one additional ICI-associated LETM case with intrathecal CXCL13 elevation, three cases with ICI-associated aquaporin-4 antibody neuromyelitis spectrum disorder, and evidence of B cell-mediated toxicity based on antibody-mediated immune pathologies in ICI-associated immune-related adverse events.ConclusionsThe case observations highlight the plethora of uncertainties in diagnosis and treatment of ICI-associated nirAE, exemplify the heterogeneity of immune mechanisms involved, and suggest a role of B cells, which may be underdiagnosed. Intrathecal CXCL13 may serve as a biomarker of B cell involvement in nirAE, supported by intrathecal immunoglobulin synthesis, presence of plasma cells, and/or recruitment of cognate immune cells.

Background/Objectives: diagnosis of Lyme neuroborreliosis (LNB) relies on medical history, clinical findings, and detection of pathogen-specific antibodies in the blood and cerebrospinal fluid (CSF). The chemoattractant CXCL13 serves as an additional marker for LNB acuity. During the diagnostic workup, cytomorphological examination of immune cells in CSF provides early insights. Lympho-monocytic pleocytosis with plasma cells and activated lymphocytes is usually described as a typical feature of LNB. In contrast we frequently observe a cytological cell picture featuring neutrophilic granulocytes as well as activated mononuclear cells and plasma cells in patients with LNB, which we refer to as a mixed cell picture. We, hence, investigated the presence of granulocytes to determine their role as typical findings associated with LNB. Methods: we conducted a retrospective analysis of CSF cytology in patients diagnosed with definite LNB at the Department of Neurology, Christian Doppler Medical Centre, Salzburg between 2015 and 2021. CSF results of patients with more than 10 erythrocytes/µL were excluded to avoid the presence of granulocytes due to artificial blood contamination. Additionally, CXCL13 levels were recorded, where available. Results: a total of 75 patients (42 female; 56%) met the diagnostic criteria of definite LNB. Cytology revealed the presence of granulocytes in the CSF of 91% of the patients (68/75). CXCL13 elevation was found to be significantly associated with the presence of granulocytes in CSF (p = 0.0025, or 1.009 (95% CI: 1.003–1.016). Conclusions: we confirm a mixed cell picture with granulocytes, activated mononuclear cells and plasma cells being a typical finding in the CSF cytology of LNB. The association between granulocytes and elevated CXCL13 suggests that their presence is a specific feature of the acute, untreated phase of LNB.

Abstract BACKGROUND Neurological immune-related adverse events (nirAE) can occur following cancer treatment with immune checkpoint inhibitors (ICI). Mainly attributed to autoreactive T-cells, nirAE usually respond to first line therapy with high-dose steroids (GC). Severe or fatal outcomes are rare & most frequently reported in clinically overlapping syndromes with accumulating evidence of B cell autoimmunity. MATERIAL AND METHODS We present 2 patients who developed grade 3-4 nirAE with evidence suggestive for B cell involvement. RESULTS Case 1: A 75y female with metastatic melanoma developed double vision & general weakness 2 weeks after the 1st cycle of ipilimumab & nivolumab. Diagnostic workup showed pleocytosis (27 cells/µl) with elevated CXCL13 (316 pg/ml) in cerebrospinal fluid (CSF). Increases of creatine kinase, troponin T, elevated levels of anti-acetylcholine receptor antibodies & positive anti-titin antibodies led to the diagnosis of myocarditis & myositis/myasthenia gravis overlap syndrome. The patient received pulsed high-dose GC with tapering. CSF flow cytometry revealed intrathecal recruitment of CXCL13-responsive B cell helper T cells of a predominant inflammatory phenotype & a highly increased pathological CD4/CD8 T cell ratio in peripheral blood. Clinically non-responding to GC, the patient received additional therapy with immunoglobulins (IVIG). 2 weeks later she was readmitted due to generalized myopathy with dropped head & received a second cycle of high-dose GC since she refused plasmapheresis. Further escalation with rituximab could not be realized because the patient rapidly deteriorated & deceased. Case 2: A 75y female with metastatic invasive enteric adenocarcinoma of the lung developed gait ataxia & ataxia of the lower limbs 5 months after pembrolizumab therapy. CSF analysis showed a pleocytosis (248 cells/µl) with plasma cells, pronounced CXCL13 elevation (>488 pg/ml) & positive screening for anti-neuronal cerebellar antibodies, suggesting ICI-mediated cerebellitis. The patient received high-dose GC & IVIG for 5 days each, was discharged but readmitted 5 months later due to subacute onset of spastic paraparesis. Magnetic resonance imaging of the spine revealed thoracic myelopathy & CSF showed mild pleocytosis (5 cells/µl), intrathecal immunoglobulin synthesis & mild CXCL13 elevation (33 pg/ml). The patient completed a second cycle of steroids followed by rituximab targeting B-cell involvement & currently 4 months later is clinically stable. CONCLUSION Intrathecal CXCL13 may serve as diagnostic tool of B cell involvement, here supported by intrathecal immunoglobulin synthesis, presence of plasma cells and/or severely altered immune cell compositions. Early treatment escalation with B cell depleting agents such as rituximab may help prevent fatal clinical courses.

People with multiple sclerosis (pwMS) have an increased risk of infection. As disease-modifying therapies (DMTs) and other treatments may interact with the immune system, there may be concerns about vaccine efficacy and safety. Therefore, it is important to evaluate possible interactions between DMTs and vaccines. The fumarates, dimethyl fumarate, diroximel fumarate, and monomethyl fumarate, are approved for the treatment of relapsing multiple sclerosis. This review assesses the evidence on vaccine response in pwMS treated with fumarates, with a particular focus on COVID-19 vaccines. Treatment with fumarates does not appear to result in blunting of humoral responses to vaccination; for COVID-19 vaccines, particularly RNA-based vaccines, evidence indicates antibody responses similar to those of healthy recipients. While data on the effect of fumarates on T-cell responses are limited, they do not indicate any significant blunting. COVID-19 vaccines impart a similar degree of protection against severe COVID-19 infection for pwMS on fumarates as in the general population. Adverse reactions following vaccination are generally consistent with those observed in the wider population; no additional safety signals have emerged in those on fumarates. Additionally, no increase in relapse has been observed in pwMS following vaccination. In pwMS receiving fumarates, vaccination is generally safe and elicits protective immune responses.

Serum neurofilament light chain (sNfL) is an intensely investigated biomarker in multiple sclerosis (MS). The aim of this study was to explore the impact of cladribine (CLAD) on sNfL and the potential of sNfL as a predictor of long-term treatment response. Data were gathered from a prospective, real-world CLAD cohort. We measured sNfL at baseline (BL-sNfL) and 12 months (12Mo-sNfL) after CLAD start by SIMOA. Clinical and radiological assessments determined fulfilment of “no evidence of disease activity” (NEDA-3). We evaluated BL-sNfL, 12M-sNfL and BL/12M sNfL ratio (sNfL-ratio) as predictors for treatment response. We followed 14 patients for a median of 41.5 months (range 24.0–50.0). NEDA-3 was fulfilled by 71%, 57% and 36% for a period of 12, 24 and 36 months, respectively. We observed clinical relapses in four (29%), MRI activity in six (43%) and EDSS progression in five (36%) patients. CLAD significantly reduced sNfL (BL-sNfL: mean 24.7 pg/mL (SD ± 23.8); 12Mo-sNfL: mean 8.8 pg/mL (SD ± 6.2); p = 0.0008). We found no correlation between BL-sNfL, 12Mo-sNfL and ratio-sNfL and the time until loss of NEDA-3, the occurrence of relapses, MRI activity, EDSS progression, treatment switch or sustained NEDA-3. We corroborate that CLAD decreases neuroaxonal damage in MS patients as determined by sNfL. However, sNfL at baseline and at 12 months failed to predict clinical and radiological treatment response in our real-world cohort. Long-term sNfL assessments in larger studies are essential to explore the predictive utility of sNfL in patients treated with immune reconstitution therapies.

Therapeutic plasma exchange (TPE) is used for drug-resistant neuroimmunological disorders, but its mechanism of action remains poorly understood. We therefore prospectively explored changes in soluble, humoral, and cellular immune components associated with TPE. We included ten patients with neurological autoimmune disorders that underwent TPE and assessed a panel of clinically relevant pathogen-specific antibodies, total serum immunoglobulin (Ig) levels, interleukin-6 (IL-6, pg/mL), C-reactive protein (CRP, mg/dL), procalcitonin (PCT, µg/L) and major lymphocyte subpopulations (cells/µL). Blood was collected prior to TPE (pre-TPE, baseline), immediately after TPE (post-TPE), as well as five weeks (follow-up1) and 130 days (follow-up2) following TPE. Pathogen-specific antibody levels were reduced by −86% (p < 0.05) post-TPE and recovered to 55% (follow-up1) and 101% (follow-up2). Ig subclasses were reduced by −70–89% (p < 0.0001) post-TPE with subsequent complete (IgM/IgA) and incomplete (IgG) recovery throughout the follow-ups. Mean IL-6 and CRP concentrations increased by a factor of 3–4 at post-TPE (p > 0.05) while PCT remained unaffected. We found no alterations in B- and T-cell populations. No adverse events related to TPE occurred. TPE induced a profound but transient reduction in circulating antibodies, while the investigated soluble immune components were not washed out. Future studies should explore the effects of TPE on particular cytokines and assess inflammatory lymphocyte lineages to illuminate the mode of action of TPE beyond autoantibody removal.

Anti-CD20 therapies decrease the humoral response to SARS-CoV-2 immunization. We aimed to determine the extent of the humoral response to SARS-CoV-2 antigens in correlation with peripheral B-cell dynamics among patients with central nervous system inflammatory disorders treated with anti-CD20 medications. We retrospectively included patients receiving anti-CD20 therapy after antigen contact who were divided into responders (>7 binding antibody units (BAU)/mL) and non-responders (<7 BAU/mL). In participants with first antigen contact prior to therapy, we investigated the recall response elicited once under treatment. We included 80 patients (responders n = 34, non-responders n = 37, recall cohort n = 9). The B-cell counts among responders were significantly higher compared to non-responders (mean 1012 cells/µL ± SD 105 vs. mean 17 cells/µL ± SD 47; p < 0.001). Despite very low B-cell counts (mean 9 cells/µL ± SD 20), humoral response was preserved among the recall cohort (mean 1653 BAU/mL ± SD 2250.1) and did not differ significantly from responders (mean 735 BAU/mL ± SD 1529.9; p = 0.14). Our data suggest that peripheral B cells are required to generate antibodies to neo-antigens but not for a recall response during anti-CD20 therapy. Evaluation of B-cell counts and pre-existing SARS-CoV-2 antibodies might serve as biomarkers for estimating the immune competence to mount a humoral response to SARS-CoV-2 antigens.

Cerebrospinal fluid (CSF) has recently experienced a revival in diagnostics and research. However, little progress has been made regarding CSF cell analysis. For almost a century, CSF cell count and cytomorphological examination have been central diagnostic parameters, with CSF pleocytosis as a hallmark finding of neuroinflammation and cytology offering valuable clues regarding infectious, autoimmune, and malignant aetiologies. A great deal of information, however, remains unattended as modern immune phenotyping technologies have not yet been broadly incorporated into routine CSF analysis. This is a serious deficit considering the central role of CSF cells as effectors in central nervous system (CNS) immune defence and autoimmune CNS processes, and the diagnostic challenges posed by clinically overlapping infectious and immune-mediated CNS diseases. Here, we summarize historical, specimen-intrinsic, methodological, and technical issues determining the state-of-the-art diagnostics of CSF cells and outline future perspectives for this underutilized window into meningeal and CNS immunity.