Cortical morphology predicts placebo response in multiple sclerosis

Despite significant insights into the neural mechanisms of acute placebo responses, less is known about longer-term placebo responses, such as those seen in clinical trials, or their interactions with brain disease. We examined brain correlates of placebo responses in a randomized trial of a then controversial and now disproved endovascular treatment for multiple sclerosis. Patients received either balloon or sham extracranial venoplasty and were followed for 48 weeks. Venoplasty had no therapeutic effect, but a subset of both venoplasty- and sham-treated patients reported a transient improvement in health-related quality of life, suggesting a placebo response. Placebo responders did not differ from non-responders in total MRI T2 lesion load, count or location, nor were there differences in normalized brain volume, regional grey or white matter volume or cortical thickness (CT). However, responders had higher lesion activity. Graph theoretical analysis of CT covariance showed that non-responders had a more small-world-like CT architecture. In non-responders, lesion load was inversely associated with CT in somatosensory, motor and association areas, precuneus, and insula, primarily in the right hemisphere. In responders, lesion load was unrelated to CT. The neuropathological process in MS may produce in some a cortical configuration less capable of generating sustained placebo responses.

Clinical Predictors of Neurogenic Lower Urinary Tract Dysfunction in Persons with Multiple Sclerosis

Background: Multiple sclerosis patients often develop neurogenic lower urinary tract dysfunction with a potential risk of upper urinary tract damage. Diagnostic tools are urodynamics, bladder diary, uroflowmetry, and post-void residual, but recommendations for their use are controversial. Objective: We aimed to identify clinical parameters indicative of neurogenic lower urinary tract dysfunction in multiple sclerosis patients. Methods: 207 patients were prospectively assessed independent of the presence of lower urinary tract symptoms. We analyzed Expanded Disability Status Scale scores, uroflowmetry, post-void residual, rate of urinary tract infections, standardized voiding frequency, and voided volume in correlation with urodynamic findings. Results: We found a significant correlation between post-void residual (odds ratio (OR) 4.17, confidence interval (CI) 1.20–22.46), urinary tract infection rate (OR 3.91, CI 1.13–21.0), voided volume (OR 4.53, CI 1.85–11.99), increased standardized voiding frequency (OR 7.40, CI 2.15–39.66), and urodynamic findings indicative of neurogenic lower urinary tract dysfunction. Expanded Disability Status Scale shows no correlation. Those parameters (except post-void residual) are also associated with reduced bladder compliance, as potential risk for kidney damage. Conclusion: Therefore, bladder diary and urinary tract infection rate should be routinely assessed to identify patients who require urodynamics.

Diagnostic Value of JC Polyomavirus Viruria, Viremia, Serostatus and microRNA Expression in Multiple Sclerosis Patients Undergoing Immunosuppressive Treatment

Markers of JC polyomavirus (JCPyV) activity can be used to evaluate the risk of progressive multifocal leukoencephalopathy (PML) in treated multiple sclerosis (MS) patients. The presence of JCPyV DNA and microRNA (miR-J1-5p), the anti-JCV index and the sequence of the non-coding control region (NCCR) in urine and plasma were determined in 42 MS subjects before treatment (T0), 6 months (T6) and 12 months (T12) after natalizumab, ocrelizumab, fingolimod or dimethyl-fumarate administration and in 25 healthy controls (HC). The number of MS patients with viruria increased from 43% at T0 to 100% at T12, whereas it remained similar for the HC group (35–40%). Viremia first occurred 6 months after treatment in MS patients and increased after 12 months, whereas it was absent in HC. The viral load in urine and plasma from the MS cohort increased over time, mostly pronounced in natalizumab-treated patients, whereas it persisted in HC. The archetypal NCCR was detected in all positive urine, whereas mutations were observed in plasma-derived NCCRs resulting in a more neurotropic variant. The prevalence and miR-J1-5p copy number in MS urine and plasma dropped after treatment, whereas they remained similar in HC specimens. Viruria and miR-J1-5p expression did not correlate with anti-JCV index. In conclusion, analyzing JCPyV DNA and miR-J1-5p levels may allow monitoring JCPyV activity and predicting MS patients at risk of developing PML.

Cellular and humoral immunity to SARS-CoV-2 infection in multiple sclerosis patients on ocrelizumab and other disease-modifying therapies: a multi-ethnic observational study

Objective: To determine the impact of MS disease-modifying therapies (DMTs) on the development of cellular and humoral immunity to SARS-CoV-2 infection. Methods: MS patients aged 18-60 were evaluated for anti-nucleocapsid and anti-Spike RBD antibody with electro-chemiluminescence immunoassay; antibody responses to Spike protein, RBD, N-terminal domain with multiepitope bead-based immunoassays (MBI); live virus immunofluorescence-based microneutralization assay; T-cell responses to SARS-CoV-2 Spike using TruCulture ELISA; and IL-2 and IFNγ ; ELISpot assays. Assay results were compared by DMT class. Spearman correlation and multivariate analyses were performed to examine associations between immunologic responses and infection severity. Results: Between 1/6/2021 and 7/21/2021, 389 MS patients were recruited (mean age 40.3 years; 74% female; 62% non-White). Most common DMTs were ocrelizumab (OCR) - 40%; natalizumab - 17%, Sphingosine 1-phosphate receptor (S1P) modulators -12%; and 15% untreated. 177 patients (46%) had laboratory evidence of SARS-CoV-2 infection; 130 had symptomatic infection, 47 - asymptomatic. Antibody responses were markedly attenuated in OCR compared to other groups (p≤0.0001). T-cell responses (IFNγ) were decreased in S1P (p=0.03), increased in natalizumab (p<0.001), and similar in other DMTs, including OCR. Cellular and humoral responses were moderately correlated in both OCR (r=0.45, p=0.0002) and non-OCR (r=0.64, p<0.0001). Immune responses did not differ by race/ethnicity. COVID-19 clinical course was mostly non-severe and similar across DMTs; 7% (9/130) were hospitalized. Interpretation: DMTs had differential effects on humoral and cellular immune responses to SARS-CoV-2 infection. Immune responses did not correlate with COVID-19 clinical severity in this relatively young and non-disabled group of MS patients.

Neurological update: treatment escalation in multiple sclerosis patients refractory to fingolimod—potentials and risks of subsequent highly active agents

A critical issue in the management of relapsing MS (RMS) is the discontinuation of disease-modifying treatments (DMT) due to lack of efficacy, intolerability or impending risks. With new therapeutic agents introduced into the treatment of RMS, immediate- and long-term consequences of sequential drug use, as well as the effect of the sequence in which the drugs are given, are unclear but may affect efficacy, adverse events, and long-term immunocompetence. In the absence of clinical studies specifically addressing these concerns, observations from clinical practice are of particular value in guiding current management algorithms. Prompted by a study published by Ferraro et al. in this journal, we set out to provide an overview of the published real-world evidence on the effectiveness and safety of switching from fingolimod to another DMT in patients with active RMS. Seventeen publications reporting relevant information were identified. The literature suggests that immune cell depletion induced by alemtuzumab or ocrelizumab is associated with an increased risk of relapse and worsening disability in patients switching from fingolimod compared to patients switching from other therapeutic agents. However, the evidence reported for natalizumab and cladribine is inconclusive. While shortening of the washout period may limit early disease reactivation after fingolimod discontinuation, there is no strong evidence that the duration of the washout period or the absolute lymphocyte count at baseline are predictors of attenuated long-term efficacy. Further real-world studies are required to better understand outcomes among patients who are under-represented in controlled trials.

Thrombotic Thrombocytopenic Purpura in Interferon Beta-1a-Treated Patient Diagnosed with Relapsing-Remitting Multiple Sclerosis: A Case Report

Background: Secondary thrombotic thrombocytopenic purpura (TTP) due to interferon beta-1a intramuscular (im) treatment is an uncommon adverse effect with only a few cases in multiple sclerosis patients reported worldwide. TTP together with haemolytic uremic syndrome (HUS) are classic forms of thrombotic microangiopathy, characterized by small-vessel platelet micro-thrombi that manifest clinically in a similar manner. Most common signs and symptoms include bruises and ecchymosis, neurologic symptoms and renal impairment. Interferon beta-1a represents one of the first-line therapies for relapsing-remitting multiple sclerosis due to its accessibility and efficacy. Case presentation: A 36-year-old woman who was previously diagnosed with relapsing-remitting multiple sclerosis had received weekly intramuscular injections with beta-interferon-1a (Avonex 30 mcg). After 9 months of treatment, she presented bruises and ecchymosis on her limbs and torso, epistaxis, gingival bleeding aggravated within 48 h and a persistent headache that was non-responsive to common analgesics. Haematology tests revealed typical results for thrombotic microangiopathy, including severe thrombocytopenia (4000/mm3) and microangiopathic haemolytic anaemia with frequent schistocytes on the peripheral blood smear. Once the beta-interferon administration was ceased and upon the initiation of methylprednisolone, the symptoms remitted. Conclusions: In this case study, we portrayed the particular association between the remission phase of multiple sclerosis and the violent onset of interferon-induced thrombotic thrombocytopenic purpura.

Dysregulated B cell differentiation towards antibody-secreting cells in neuromyelitis optica spectrum disorder

Background Anti-aquaporin 4 (AQP4) antibody (AQP4-Ab) is involved in the pathogenesis of neuromyelitis optica spectrum disorder (NMOSD). However, the mechanism involved in AQP4-Ab production remains unclear. Methods We analyzed the immunophenotypes of patients with NMOSD and other neuroinflammatory diseases as well as healthy controls (HC) using flow cytometry. Transcriptome analysis of B cell subsets obtained from NMOSD patients and HCs was performed. The differentiation capacity of B cell subsets into antibody-secreting cells was analyzed. Results The frequencies of switched memory B (SMB) cells and plasmablasts were increased and that of naïve B cells was decreased in NMOSD patients compared with relapsing–remitting multiple sclerosis patients and HC. SMB cells from NMOSD patients had an enhanced potential to differentiate into antibody-secreting cells when cocultured with T peripheral helper cells. Transcriptome analysis revealed that the profiles of B cell lineage transcription factors in NMOSD were skewed towards antibody-secreting cells and that IL-2 signaling was upregulated, particularly in naïve B cells. Naïve B cells expressing CD25, a receptor of IL-2, were increased in NMOSD patients and had a higher potential to differentiate into antibody-secreting cells, suggesting CD25+ naïve B cells are committed to differentiate into antibody-secreting cells. Conclusions To the best of our knowledge, this is the first study to demonstrate that B cells in NMOSD patients are abnormally skewed towards antibody-secreting cells at the transcriptome level during the early differentiation phase, and that IL-2 might participate in this pathogenic process. Our study indicates that CD25+ naïve B cells are a novel candidate precursor of antibody-secreting cells in autoimmune diseases.

Worse Physical Disability Is Associated With the Expression of PD-1 on Inflammatory T-Cells in Multiple Sclerosis Patients With Older Appearing Brains

Background: Magnetic Resonance Imaging (MRI) analysis method “brain-age” paradigm could offer an intuitive prognostic metric (brain-predicted age difference: brain-PAD) for disability in Multiple Sclerosis (MS), reflecting structural brain health adjusted for aging. Equally, cellular senescence has been reported in MS using T-cell biomarker CD8+CD57+.Objective: Here we explored links between MRI-derived brain-age and blood-derived cellular senescence. We examined the value of combining brain-PAD with CD8+CD57+(ILT2+PD-1+) T-cells when predicting disability score in MS and considered whether age-related biological mechanisms drive disability.Methods: Brain-age analysis was applied to T1-weighted MRI images. Disability was assessed and peripheral blood was examined for CD8+CD57+ T-cell phenotypes. Linear regression models were used, adjusted for sex, age and normalized brain volume.Results: We included 179 mainly relapsing-remitting MS patients. A high brain-PAD was associated with high physical disability (mean brain-PAD = +6.54 [5.12–7.95]). CD8+CD57+(ILT2+PD-1+) T-cell frequency was neither associated with disability nor with brain-PAD. Physical disability was predicted by the interaction between brain-PAD and CD8+CD57+ILT2+PD-1+ T-cell frequency (AR2 = 0.196), yet without improvement compared to brain-PAD alone (AR2 = 0.206; AICc = 1.8).Conclusion: Higher frequency of CD8+CD57+ILT2+PD-1+ T-cells in the peripheral blood in patients with an older appearing brain was associated with worse disability scores, suggesting a role of these cells in the development of disability in MS patients with poorer brain health.