Case Report: Balancing immune responses - multiple sclerosis disease exacerbation under BRAF/MEK treatment for malignant melanoma.

Background: Combination 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 presentation: A 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. Conclusions: Immunomodulatory 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.

Implications of immunometabolism for smouldering MS pathology and therapy.

Clinical symptom worsening in patients with multiple sclerosis (MS) is driven by inflammation compartmentalized within the CNS, which results in chronic neuronal damage owing to insufficient repair mechanisms. The term 'smouldering inflammation' summarizes the biological aspects underlying this chronic, non-relapsing and immune-mediated mechanism of disease progression. Smouldering inflammation is likely to be shaped and sustained by local factors in the CNS that account for the persistence of this inflammatory response and explain why current treatments for MS do not sufficiently target this process. Local factors that affect the metabolic properties of glial cells and neurons include cytokines, pH value, lactate levels and nutrient availability. This Review summarizes current knowledge of the local inflammatory microenvironment in smouldering inflammation and how it interacts with the metabolism of tissue-resident immune cells, thereby promoting inflammatory niches within the CNS. The discussion highlights environmental and lifestyle factors that are increasingly recognized as capable of altering immune cell metabolism and potentially responsible for smouldering pathology in the CNS. Currently approved MS therapies that target metabolic pathways are also discussed, along with their potential for preventing the processes that contribute to smouldering inflammation and thereby to progressive neurodegenerative damage in MS.

Impact of extended interval dosing of ocrelizumab on immunoglobulin levels in multiple sclerosis.

BACKGROUND: Long-term B cell depletion with ocrelizumab in multiple sclerosis (MS) is associated with severe side effects such as hypogammaglobulinemia and infections. Our study therefore aimed to assess immunoglobulin levels under treatment with ocrelizumab and implement an extended interval dosing (EID) scheme. METHODS: Immunoglobulin levels of 51 patients with ≥24 months of treatment with ocrelizumab were analyzed. After ≥4 treatment cycles, patients chose to either continue on the standard interval dosing (SID) regimen (n = 14) or, in the case of clinically and radiologically stable disease, switch to B cell-adapted EID (n = 12, next dose at CD19+ B cells >1% of peripheral blood lymphocytes). FINDINGS: Levels of immunoglobulin M (IgM) declined rapidly under ocrelizumab treatment. Risk factors for IgM and IgA hypogammaglobulinemia were lower levels at baseline and more previous disease-modifying therapies. B cell-adapted EID of ocrelizumab increased the mean time until next infusion from 27.3 to 46.1 weeks. Ig levels declined significantly in the SID group over 12 months but not in the EID group. Previously stable patients remained stable under EID as measured by expanded disability status scale (EDSS), neurofilament light chain, timed 25-foot walk (T25-FW), 9-hole peg test (9-HPT), symbol digit modalities test (SDMT), and multiple sclerosis impact scale (MSIS-29). CONCLUSIONS: In our pilot study, B cell-adapted EID of ocrelizumab prevented the decline of Ig levels without affecting disease activity in previously stable patients with MS. Based on these findings, we propose a new algorithm for long-term ocrelizumab treatment. FUNDING: This study was supported by the Deutsche Forschungsgemeinschaft (SFB CRC-TR-128, SFB 1080, and SFB CRC-1292) and the Hertie Foundation.

Comparative effectiveness of natalizumab versus ocrelizumab in multiple sclerosis: a real-world propensity score-matched study.

Background: For treatment of relapsing-remitting multiple sclerosis (RRMS), a broad range of disease-modifying therapies (DMT) is available. However, few comparative effectiveness studies between different drugs have been performed. Objectives: This study aimed to compare the efficacy and treatment continuation of natalizumab and ocrelizumab in a real-world cohort of patients with relapsing-remitting multiple sclerosis (RRMS) from two German university hospitals. Methods: We performed a retrospective analysis of RRMS patients who initiated treatment with natalizumab or ocrelizumab between January 2016 and April 2019 at the German university hospitals of Mainz and Düsseldorf. Bayesian propensity score matching was conducted to correct for differences in baseline characteristics. Our primary outcome was no evidence of disease activity [NEDA-3: no relapses, no confirmed disability progression, and no magnetic resonance imaging (MRI) activity] and its subcomponents. Secondary outcomes included measurement of neurofilament light chain (NfL) in serum, analysis of premature discontinuation, and evidence of rebound activity in patients switching from natalizumab to ocrelizumab. Results: We identified 63 patients starting treatment with natalizumab and 76 patients starting with ocrelizumab. Binary logistic regression showed that treatment with natalizumab or a higher number of relapses in the previous year were independently associated with a higher risk for relapses. Patients receiving natalizumab had a higher probability of premature discontinuation of therapy (p = 0.002). After propensity score matching of the two treatment arms, 55 patients remained per group. NEDA-3 after 30 months of follow-up was reached by 53.1% in the ocrelizumab group and 36.1% in the natalizumab group (p = 0.177). Ocrelizumab was superior to natalizumab concerning the occurrence of relapses in log-rank test (p = 0.019). NfL levels in serum were low under both treatments. Patients who switched from natalizumab to ocrelizumab showed no increased rebound activity. Discussion: This study provides class IV evidence that treatment of RRMS patients with ocrelizumab and natalizumab show comparable effectiveness in combined endpoints, while ocrelizumab might be more effective in preventing the occurrence of relapses.

Evaluation of Age-Dependent Immune Signatures in Patients With Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: In MS, an age-related decline in disease activity and a decreased efficacy of disease-modifying treatment have been linked to immunosenescence, a state of cellular dysfunction associated with chronic inflammation. METHODS: To evaluate age-related immunologic alterations in MS, we compared immune signatures in peripheral blood (PB) and CSF by flow cytometry in patients with relapsing-remitting (RR) (PB n = 38; CSF n = 51) and primary progressive (PP) MS (PB n = 40; CSF n = 36) and respective controls (PB n = 40; CSF n = 85). RESULTS: Analysis revealed significant age-related changes in blood immune cell composition, especially in the CD8 T-cell compartment of healthy donors (HDs) and patients with MS. However, HDs displayed a strong age-dependent decline in the expression of the immunoregulatory molecules KLRG1, LAG3, and CTLA-4 on memory CD8 T cells, whereas this age-dependent reduction was completely abrogated in patients with MS. An age-dependent increase in the expression of the costimulatory molecule CD226 on memory CD8 T cells was absent in patients with MS. CD226 expression correlated with disability in younger (≤50 years) patients with MS. CSF analysis revealed a significant age-dependent decline in various immune cell populations in PPMS but not RRMS, suggesting a differential effect of aging on the intrathecal compartment in PPMS. DISCUSSION: Our data illustrate that aging in MS is associated with a dysbalance between costimulatory and immunoregulatory signals provided by CD8 T cells favoring a proinflammatory phenotype and, more importantly, a pattern of premature immune aging in the CD8 T-cell compartment of young patients with MS with potential implications for disease severity.

Ocrelizumab Extended Interval Dosing in Multiple Sclerosis in Times of COVID-19.

OBJECTIVE: To evaluate the clinical consequences of extended interval dosing (EID) of ocrelizumab in relapsing-remitting multiple sclerosis (RRMS) during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: In our retrospective, multicenter cohort study, we compared patients with RRMS on EID (defined as ≥4-week delay of dose interval) with a control group on standard interval dosing (SID) at the same period (January to December 2020). RESULTS: Three hundred eighteen patients with RRMS were longitudinally evaluated in 5 German centers. One hundred sixteen patients received ocrelizumab on EID (median delay [interquartile range 8.68 [5.09-13.07] weeks). Three months after the last ocrelizumab infusion, 182 (90.1%) patients following SID and 105 (90.5%) EID patients remained relapse free (p = 0.903). Three-month confirmed progression of disability was observed in 18 SID patients (8.9%) and 11 EID patients (9.5%, p = 0.433). MRI progression was documented in 9 SID patients (4.5%) and 8 EID patients (6.9%) at 3-month follow-up (p = 0.232). Multivariate logistic regression showed no association between treatment regimen and no evidence of disease activity status at follow-up (OR: 1.266 [95% CI: 0.695-2.305]; p = 0.441). Clinical stability was accompanied by persistent peripheral CD19+ B-cell depletion in both groups (SID vs EID: 82.6% vs 83.3%, p = 0.463). Disease activity in our cohort was not associated with CD19+ B-cell repopulation. CONCLUSION: Our data support EID of ocrelizumab as potential risk mitigation strategy in times of the COVID-19 pandemic. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with RRMS, an EID of at least 4 weeks does not diminish effectiveness of ocrelizumab.

Supplementary medication in multiple sclerosis: Real-world experience and potential interference with neurofilament light chain measurement.

BACKGROUND: As vitamins and dietary supplements are obtainable without prescription, treating physicians often ignore their intake by patients with multiple sclerosis (MS) and may therefore miss potential adverse effects and interactions. OBJECTIVE: We aimed to assess the spectrum and intake frequency of supplementary medication in a cohort of MS patients and to analyse the effect of biotin intake on measurement of serum neurofilament light chain (sNfL), an emerging marker of disease activity. METHODS: MS patients visiting our neurology outpatient clinic completed a questionnaire on their past or present use of vitamins or dietary supplements. In addition, the impact of two different doses of biotin (10 and 300 mg/day) on sNfL was studied in healthy volunteers. RESULTS: Of 186 patients, 72.6% reported taking over-the-counter vitamins or dietary supplements currently or previously. Most frequently used was vitamin D (60.0%), followed by biotin. Female patients and patients with primary progressive MS tended to use supplements more frequently. Biotin intake did not interfere with sNfL measurement by single molecule array (Simoa). CONCLUSIONS: The use of vitamins and dietary supplements is frequent among patients with MS. Thus, treating physicians should be aware of the pitfalls of supplementary treatment and educate their patients accordingly.

Ocrelizumab initiation in patients with MS: A multicenter observational study.

OBJECTIVE: To provide first real-world experience on patients with MS treated with the B cell-depleting antibody ocrelizumab. METHODS: We retrospectively collected data of patients who had received at least 1 treatment cycle (2 infusions) of ocrelizumab at 3 large neurology centers. Patients' characteristics including premedication, clinical disease course, and documented side effects were analyzed. RESULTS: We could identify 210 patients (125 women, mean age ± SD, 42.1 ± 11.4 years) who had received ocrelizumab with a mean disease duration of 7.3 years and a median Expanded Disability Status Scale score of 3.75 (interquartile range 2.5-5.5; range 0-8). Twenty-six percent of these patients had a primary progressive MS (PPMS), whereas 74% had a relapsing-remitting (RRMS) or active secondary progressive (aSPMS) disease course. Twenty-four percent of all patients were treatment naive, whereas 76% had received immune therapies before. After ocrelizumab initiation (median follow-up was 200 days, range 30-1,674 days), 13% of patients with RRMS/aSPMS experienced a relapse (accounting for an annualized relapse rate of 0.17, 95% CI 0.10-0.24), and 5% of all patients with MS experienced a 12-week confirmed disability progression. Treatment was generally well tolerated, albeit only short-term side effects were recorded, including direct infusion-related reactions and mild infections. CONCLUSIONS: We provide class IV evidence that treatment with ocrelizumab can stabilize naive and pretreated patients, indicating that ocrelizumab is an option following potent MS drugs such as natalizumab and fingolimod. Further studies are warranted to confirm these findings and to reveal safety concerns in the longer-term follow-up. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with MS, ocrelizumab can stabilize both treatment-naive and previously treated patients.

MOG encephalomyelitis: distinct clinical, MRI and CSF features in patients with longitudinal extensive transverse myelitis as first clinical presentation.

BACKGROUND: Based on clinical, immunological and histopathological evidence, MOG-IgG-associated encephalomyelitis (MOG-EM) has emerged as a distinct disease entity different from multiple sclerosis (MS) and aquaporin-4-antibody-positive neuromyelitis optica spectrum disorder (NMOSD). MOG-EM is associated with a broader clinical phenotype including optic neuritis, myelitis, brainstem lesions and acute disseminated encephalomyelitis with a substantial clinical and radiological overlap to other demyelinating CNS disorders. OBJECTIVE: To evaluate common clinical, MRI and CSF findings, as well as therapy responses in patients with longitudinal extensive transverse myelitis (LETM) as initial clinical presentation of MOG-EM. METHODS: After excluding patients with a known diagnosis of MS, we identified 153 patients with myelitis of which 7 fulfilled the inclusion criteria and were investigated for MRI, CSF and clinical parameters. RESULTS: Patients with LETM as first clinical presentation of MOG-EM display similar characteristics, namely a lack of gadolinium-enhancement in spinal cord MRI, marked pleocytosis, negative oligoclonal bands, a previous history of infections/vaccinations and response to antibody-depleting treatments for acute attacks and long-term treatment. CONCLUSIONS: We identify common pathological findings in patients with LETM as first clinical presentation of MOG-EM which distinguishes it from other forms of LETM and should lead to testing for MOG-IgG in these cases.

ß1-Integrin- and KV1.3 channel-dependent signaling stimulates glutamate release from Th17 cells.

Although the impact of Th17 cells on autoimmunity is undisputable, their pathogenic effector mechanism is still enigmatic. We discovered soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) complex proteins in Th17 cells that enable a vesicular glutamate release pathway that induces local intracytoplasmic calcium release and subsequent damage in neurons. This pathway is glutamine dependent and triggered by binding of ß1-integrin to vascular cell adhesion molecule 1 (VCAM-1) on neurons in the inflammatory context. Glutamate secretion could be blocked by inhibiting either glutaminase or KV1.3 channels, which are known to be linked to integrin expression and highly expressed on stimulated T cells. Although KV1.3 is not expressed in CNS tissue, intrathecal administration of a KV1.3 channel blocker or a glutaminase inhibitor ameliorated disability in experimental neuroinflammation. In humans, T cells from patients with multiple sclerosis secreted higher levels of glutamate, and cerebrospinal fluid glutamine levels were increased. Altogether, our findings demonstrate that ß1-integrin- and KV1.3 channel-dependent signaling stimulates glutamate release from Th17 cells upon direct cell-cell contact between Th17 cells and neurons.

Immunoneuropsychiatry - novel perspectives on brain disorders.

Immune processes have a vital role in CNS homeostasis, resilience and brain reserve. Our cognitive and social abilities rely on a highly sensitive and fine-tuned equilibrium of immune responses that involve both innate and adaptive immunity. Autoimmunity, chronic inflammation, infection and psychosocial stress can tip the scales towards disruption of higher-order networks. However, not only classical neuroinflammatory diseases, such as multiple sclerosis and autoimmune encephalitis, are caused by immune dysregulation that affects CNS function. Recent insight indicates that similar processes are involved in psychiatric diseases such as schizophrenia, autism spectrum disorder, bipolar disorder and depression. Pathways that are common to these disorders include microglial activation, pro-inflammatory cytokines, molecular mimicry, anti-neuronal autoantibodies, self-reactive T cells and disturbance of the blood-brain barrier. These discoveries challenge our traditional classification of neurological and psychiatric diseases. New clinical paths are required to identify subgroups of neuropsychiatric disorders that are phenotypically distinct but pathogenically related and to pave the way for mechanism-based immune treatments. Combined expertise from neurologists and psychiatrists will foster translation of these paths into clinical practice. The aim of this Review is to highlight outstanding findings that have transformed our understanding of neuropsychiatric diseases and to suggest new diagnostic and therapeutic criteria for the emerging field of immunoneuropsychiatry.