SARS-CoV-2 messenger RNA vaccination in healthy individuals generates immune protection against COVID-19. However, little is known about SARS-CoV-2 mRNA vaccine-induced responses in immunosuppressed ...patients. We investigated induction of antigen-specific antibody, B cell and T cell responses longitudinally in patients with multiple sclerosis (MS) on anti-CD20 antibody monotherapy (n = 20) compared with healthy controls (n = 10) after BNT162b2 or mRNA-1273 mRNA vaccination. Treatment with anti-CD20 monoclonal antibody (aCD20) significantly reduced spike-specific and receptor-binding domain (RBD)-specific antibody and memory B cell responses in most patients, an effect ameliorated with longer duration from last aCD20 treatment and extent of B cell reconstitution. By contrast, all patients with MS treated with aCD20 generated antigen-specific CD4 and CD8 T cell responses after vaccination. Treatment with aCD20 skewed responses, compromising circulating follicular helper T (T
) cell responses and augmenting CD8 T cell induction, while preserving type 1 helper T (T
1) cell priming. Patients with MS treated with aCD20 lacking anti-RBD IgG had the most severe defect in circulating T
responses and more robust CD8 T cell responses. These data define the nature of the SARS-CoV-2 vaccine-induced immune landscape in aCD20-treated patients and provide insights into coordinated mRNA vaccine-induced immune responses in humans. Our findings have implications for clinical decision-making and public health policy for immunosuppressed patients including those treated with aCD20.
In patients with multiple sclerosis (MS), activation of immune cells and breakdown of the blood-brain barrier (BBB) lead to demyelination and axon injury. Although repairing damage to neurons is not ...possible, immunomodulating therapies can reduce the inflammatory processes that lead to demyelination. Interferon-beta (IFN-beta) is a polypeptide, normally produced by fibroblasts, that has antiviral and antiproliferative effects. Binding of IFN-beta to its receptor induces a complex transcriptional response. In immune cells (the most likely target of IFN-beta's therapeutic effect in MS), IFN-beta reduces antigen presentation and T-cell proliferation, alters cytokine and matrix metalloproteinase (MMP) expression, and restores suppressor function. Therapeutic forms of IFN-beta can be produced in bacterial expression systems (IFN-beta1b) or in mammalian cells (IFN-beta1a). These forms have some differences in their amino acid sequence and posttranslational modifications, but the transcriptional response to IFN- beta1b and IFN-beta1a appears to be similar, if not indistinguishable. However, the biological response and the clinical effect do vary with changes in the dosing frequency of IFN-beta. In clinical trials, IFN-beta1a IM administered weekly elicits a transient biological response compared to IFN-beta1b administered SC every other day or IFN-beta1a (administered SC three times per week). Comparative clinical trials suggest that the differences in the biological response are clinically meaningful: more frequent IFN-beta administration produces superior clinical responses.
White matter of the brain has been demonstrated to have multiple relaxation components. Among them, the short transverse relaxation time component (T2<40ms; T2⁎<25ms at 3T) has been suggested to ...originate from myelin water whereas long transverse relaxation time components have been associated with axonal and/or interstitial water. In myelin water imaging, T2 or T2⁎ signal decay is measured to estimate myelin water fraction based on T2 or T2⁎ differences among the water components. This method has been demonstrated to be sensitive to demyelination in the brain but suffers from low SNR and image artifacts originating from ill-conditioned multi-exponential fitting. In this study, a novel approach that selectively acquires short transverse relaxation time signal is proposed. The method utilizes a double inversion RF pair to suppress a range of long T1 signal. This suppression leaves short T2⁎ signal, which has been suggested to have short T1, as the primary source of the image. The experimental results confirm that after suppression of long T1 signals, the image is dominated by short T2⁎ in the range of myelin water, allowing us to directly visualize the short transverse relaxation time component in the brain. Compared to conventional myelin water imaging, this new method of direct visualization of short relaxation time component (ViSTa) provides high quality images. When applied to multiple sclerosis patients, chronic lesions show significantly reduced signal intensity in ViSTa images suggesting sensitivity to demyelination.
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•A new approach that selectively acquire short T2⁎ is demonstrated.•Signal characteristics suggest that the primary signal is from myelin water.•MS lesions show signal reduction demonstrating sensitivity to demyelination.
Multiple sclerosis update Markowitz, Clyde E
The American journal of managed care,
11/2013, Letnik:
19, Številka:
16 Suppl
Journal Article
Recenzirano
Multiple sclerosis (MS) is a chronic but incurable disease of the central nervous system (CNS) that is often diagnosed in the second or third decade of life. It is more common among women than men, ...significantly impairs patient quality of life, and is associated with substantial costs to patients, healthcare systems, and society. Of the approximately 2.3 million individuals worldwide that have MS, more than 400,000 reside in the United States. Although the etiology of MS is not completely understood, a great deal of evidence suggests a complex relationship between environmental and genetic factors. The pathophysiology of MS involves an aberrant attack by the host immune system on oligodendrocytes, which synthesize and maintain myelin sheaths in the CNS. There are 4 identified disease courses in MS, and approximately 85% of people with MS present with relapsing-remitting MS, which is characterized by discrete acute attacks followed by periods of remission. Signs and symptoms of MS are dependent on the demyelinated area(s) of the CNS and often involve sensory disturbances, limb weakness, fatigue, and increased body temperature. The criteria for a diagnosis of MS include evidence of damage in at least 2 separate areas of the CNS, evidence that the damage occurred at different time points, and the ruling out of other possible diagnoses. Diseasemodifying drugs (DMDs) that reduce the frequency of relapses, development of brain lesions, and progression of disability are the standard of care for relapsing forms of MS, and the use of DMDs should be initiated as early as possible.
Objective
Cross‐sectional studies of optical coherence tomography (OCT) show that retinal nerve fiber layer (RNFL) thickness is reduced in multiple sclerosis (MS) and correlates with visual function. ...We determined how longitudinal changes in RNFL thickness relate to visual loss. We also examined patterns of RNFL thinning over time in MS eyes with and without a prior history of acute optic neuritis (ON).
Methods
Patients underwent OCT measurement of RNFL thickness at baseline and at 6‐month intervals during a mean follow‐up of 18 months at 3 centers. Low‐contrast letter acuity (2.5%, 1.25% contrast) and visual acuity (VA) were assessed.
Results
Among 299 patients (593 eyes) with ≥6 months follow‐up, eyes with visual loss showed greater RNFL thinning compared to eyes with stable vision (low‐contrast acuity, 2.5%: p < 0.001; VA: p = 0.005). RNFL thinning increased over time, with average losses of 2.9μm at 2 to 3 years and 6.1μm at 3 to 4.5 years (p < 0.001 vs 0.5–1‐year follow‐up interval). These patterns were observed for eyes with or without prior history of ON. Proportions of eyes with RNFL loss greater than test‐retest variability (≥6.6μm) increased from 11% at 0 to 1 year to 44% at 3 to 4.5 years (p < 0.001).
Interpretation
Progressive RNFL thinning occurs as a function of time in some patients with MS, even in the absence of ON, and is associated with clinically significant visual loss. These findings are consistent with subclinical axonal loss in the anterior visual pathway in MS, and support the use of OCT and low‐contrast acuity as methods to evaluate the effectiveness of putative neuroprotection protocols. ANN NEUROL 2010;67:749–760
Current disease-modifying treatments in multiple sclerosis (MS) are partially effective in reducing relapses and slowing disease progression, but these treatments do not restore function and are ...effective mainly in relapsing forms of MS. Unmet needs in MS include treatments for progressive forms of MS, agents with improved efficacy and safety profiles and that comprehensively manage MS symptoms, and medications with neuroprotective or remyelinating properties. Some adverse effects of disease-modifying agents could be reduced if medications are developed with more specific treatment targets, and research into the pathogenesis of MS may lead to agents that could restore myelin or protect nerves from inflammation.
To examine the relation of visual function to retinal nerve fiber layer (RNFL) thickness as a structural biomarker for axonal loss in multiple sclerosis (MS), and to compare RNFL thickness among MS ...eyes with a history of acute optic neuritis (MS ON eyes), MS eyes without an optic neuritis history (MS non-ON eyes), and disease-free control eyes.
Cross-sectional study.
Patients with MS (n = 90; 180 eyes) and disease-free controls (n = 36; 72 eyes).
Retinal never fiber layer thickness was measured using optical coherence tomography (OCT; fast RNFL thickness software protocol). Vision testing was performed for each eye and binocularly before OCT scanning using measures previously shown to capture dysfunction in MS patients: (1) low-contrast letter acuity (Sloan charts, 2.5% and 1.25% contrast levels at 2 m) and (2) contrast sensitivity (Pelli-Robson chart at 1 m). Visual acuity (retroilluminated Early Treatment Diabetic Retinopathy charts at 3.2 m) was also measured, and protocol refractions were performed.
Retinal nerve fiber layer thickness measured by OCT, and visual function test results.
Although median Snellen acuity equivalents were better than 20/20 in both groups, RNFL thickness was reduced significantly among eyes of MS patients (92 mum) versus controls (105 mum) (P<0.001) and particularly was reduced in MS ON eyes (85 mum; P<0.001; accounting for age and adjusting for within-patient intereye correlations). Lower visual function scores were associated with reduced average overall RNFL thickness in MS eyes; for every 1-line decrease in low-contrast letter acuity or contrast sensitivity score, the mean RNFL thickness decreased by 4 mum.
Scores for low-contrast letter acuity and contrast sensitivity correlate well with RNFL thickness as a structural biomarker, supporting validity for these visual function tests as secondary clinical outcome measures for MS trials. These results also suggest a role for ocular imaging techniques such as OCT in trials that examine neuroprotective and other disease-modifying therapies. Although eyes with a history of acute optic neuritis demonstrate the greatest reductions in RNFL thickness, MS non-ON eyes have less RNFL thickness than controls, suggesting the occurrence of chronic axonal loss separate from acute attacks in MS patients.
Multiple sclerosis (MS) is an immune-mediated neurological disorder, and up to 50% of patients experience depression. We investigated how white matter network disruption is related to depression in ...MS.
Using electronic health records, 380 participants with MS were identified. Depressed individuals (MS+Depression group; n = 232) included persons who had an ICD-10 depression diagnosis, had a prescription for antidepressant medication, or screened positive via Patient Health Questionnaire (PHQ)-2 or PHQ-9. Age- and sex-matched nondepressed individuals with MS (MS-Depression group; n = 148) included persons who had no prior depression diagnosis, had no psychiatric medication prescriptions, and were asymptomatic on PHQ-2 or PHQ-9. Research-quality 3T structural magnetic resonance imaging was obtained as part of routine care. We first evaluated whether lesions were preferentially located within the depression network compared with other brain regions. Next, we examined if MS+Depression patients had greater lesion burden and if this was driven by lesions in the depression network. Primary outcome measures were the burden of lesions (e.g., impacted fascicles) within a network and across the brain.
MS lesions preferentially affected fascicles within versus outside the depression network (β = 0.09, 95% CI = 0.08 to 0.10, p < .001). MS+Depression patients had more lesion burden (β = 0.06, 95% CI = 0.01 to 0.10, p = .015); this was driven by lesions within the depression network (β = 0.02, 95% CI = 0.003 to 0.040, p = .020).
We demonstrated that lesion location and burden may contribute to depression comorbidity in MS. MS lesions disproportionately impacted fascicles in the depression network. MS+Depression patients had more disease than MS-Depression patients, which was driven by disease within the depression network. Future studies relating lesion location to personalized depression interventions are warranted.
Four sphingosine 1‐phosphate (S1P) receptor modulators (fingolimod, ozanimod, ponesimod, and siponimod) are approved by the US Food and Drug Administration for the treatment of multiple sclerosis. ...This review summarizes efficacy and safety data on these S1P receptor modulators, with an emphasis on similarities and differences. Efficacy data from the pivotal clinical trials are generally similar for the four agents. However, because no head‐to‐head clinical studies were conducted, direct efficacy comparisons cannot be made. Based on the adverse event profile of S1P receptor modulators, continued and regular monitoring of patients during treatment will be instructive. Notably, the authors recommend paying attention to the cardiac monitoring guidelines for these drugs, and when indicated screening for macular edema and cutaneous malignancies before starting treatment. To obtain the best outcome, clinicians should choose the drug based on disease type, history, and concomitant medications for each patient. Real‐world data should help to determine whether there are meaningful differences in efficacy or side effects between these agents.
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