Background and objectives:Black and Hispanic people with MS (pMS) have been found to have different disease courses and/or worse outcomes associated with MS compared to White pMS. They are also more likely to be negatively impacted by social determinants of health, further worsening disparities in outcomes. As these disparities may affect treatment response, non-White pMS must be included in trials for greater generalizability of research and therefore, more inclusive treatment plans. In this study, we aimed to evaluate how representation of non-White groups in phase III trials of approved disease-modifying therapies (DMTs) has evolved over time and how race and ethnicity are reported in medical journals and on manufacturer websites.Methods:We conducted a systematic review of the PubMed database from 1995 to June 2020 to identify manufacturer-sponsored phase III trials for FDA-approved MS DMTs. We explored how race and ethnicity were reported in trial publications. Using studies where information was available, we analyzed the representation of non-White pMS over time and compared to multinational census data. Additionally, we reviewed patient- and healthcare provider (HCP)-facing websites of available DMTs to assess the dissemination of information on racial and ethnic representation in trials.Results:44 phase III trial publications were reviewed, representing 45 trials, among which 17 (37.8%) did not report race or ethnicity, 14 (31.1%) reported race and ethnicity as proportion of White participants only, and 14 (31.1%) reported two or more races/ethnicities. When compared to multinational census data, non-White pMS were significantly underrepresented in MS trials. Due to lack of data, trends in representation of other races and ethnicities could not be assessed. No patient- nor HCP-facing DMT websites reported data on race and ethnicity in pivotal trials. Study results are available on our study dashboard.Conclusion:Race and ethnicity are underreported in MS DMT trial publications, and race and ethnic representation are omitted from manufacturer websites. When available, data show that non-White pMS are significantly underrepresented in MS trials. The availability of this information is crucial for patients, together with their HCPs, to make informed decisions about their care.
IMPORTANCE A neurophysiologic signature of the melanopsin-mediated persistent constriction phase of the pupillary light reflex may represent a surrogate biomarker for the integrity of the retinohypothalamic tract, with potential utility for investigating alterations in homeostatic mechanisms associated with brain disorders and implications for identifying new treatments.OBJECTIVE To characterize abnormalities of retinal architecture in patients with multiple sclerosis (MS) and corresponding alterations in the melanopsin-mediated sustained pupillary constriction response. DESIGN, SETTING, AND PARTICIPANTSThe case-control study was an experimental assessment of various stimulus-induced pupillary response characteristics and was conducted at a university clinical center for MS from September 6, 2012, to February 2015. Twenty-four patients with MS (48 eyes) and 15 individuals serving as controls (30 eyes) participated. The melanopsin-mediated, sustained pupillary constriction phase response following cessation of a blue light stimulus was compared with the photoreceptor-mediated pupillary constriction phase response following cessation of a red light stimulus. Optical coherence tomography was used to characterize the association between pupillary response characteristics and alterations in retinal architecture, specifically, the thickness of the retinal ganglion cell layer and inner plexiform layer (GCL + IPL). MAIN OUTCOMES AND MEASURESAssociation of pupillary response characteristics with alterations in retinal architecture. RESULTSOf 24 patients with MS included in the analysis, 17 were women (71%); mean (SD) age was 47 (11) years. Compared with eyes from individuals with MS who had normal optical coherence tomography-derived measures of retinal GCL + IPL thickness, eyes of patients who had GCL + IPL thickness reductions to less than the first percentile exhibited a correspondingly significant attenuation of the melanopsin-mediated sustained pupillary response (mean [SD] pupillary diameter ratios at a point in time, 0.18 [0.1] vs 0.33 [0.09]; P < .001, generalized estimating equation models accounting for age and within-patient intereye correlations). CONCLUSIONS AND RELEVANCEIn this case-control study, attenuation of the melanopsin-mediated sustained pupillary constriction response was significantly associated with thinning of the GCL + IPL sector of the retina in the eyes of patients with MS, particularly those with a history of acute optic neuritis. Melanopsin-containing ganglion cells in the retina represent, at least in part, the composition of the retinohypothalamic tract. As such, our findings may signify the ability to elucidate a putative surrogate neurophysiologic signature that correlates with a constellation of homeostatic mechanisms in both health and illness.
ObjectiveTo determine whether the punctuated administration of low-dose rituximab, temporally linked to B-cell hyperrepopulation (defined when the return of CD19+ B cells approximates 40%–50% of baseline levels as measured before alemtuzumab treatment inception), can mitigate alemtuzumab-associated secondary autoimmunity.MethodsIn this hypothesis-driven pilot study, 10 patients received low-dose rituximab (50–150 mg/m2), a chimeric anti-CD20 monoclonal antibody, after either their first or second cycles of alemtuzumab. These patients were then routinely assessed for the development of autoimmune disorders and safety signals related to the use of dual monoclonal antibody therapy.ResultsFive patients received at least 1 IV infusion of low-dose rituximab, following alemtuzumab therapy, with a mean follow-up of 41 months. None of the 5 patients developed secondary autoimmune disorders. An additional 5 patients with follow-up over less than 24 months received at least 1 infusion of low-dose rituximab treatment following alemtuzumab treatment. No secondary autoimmune diseases were observed.ConclusionsAn anti-CD20 “whack-a-mole” B-cell depletion strategy may serve to mitigate alemtuzumab-associated secondary autoimmunity in MS by reducing the imbalance in B- and T-cell regulatory networks during immune reconstitution. We believe that these observations warrant further investigation.Classification of evidenceThis study provides Class IV evidence that for people with MS, low-dose rituximab following alemtuzumab treatment decreases the risk of alemtuzumab-associated secondary autoimmune diseases.
Hypercalcemia from tumors has been associated with Posterior Reversible Encephalopathy Syndrome (PRES) but the mechanism remains unclear. In this article, we describe a case of PRES caused by hypercalcemia from lymphoma. We summarize the available scientific evidence linking hypercalcemia to failure of cerebral autoregulation and potentially PRES. A major link is the hypomagnesemia induced by hypercalcemia. While this concept requires further clinical testing and validation, it is clinically significant for the management of PRES, even when not directly caused by hypercalcemia.
We ascertained the magnitude of the visual illusion associated with the PF, and the corresponding magnitude of neutral density filtering necessary to abolish it.
This review highlights our current knowledge of the underlying disease mechanisms in MS, explores the inflammatory and neurodegenerative consequences of tissue damage, and examines physiologic factors that contribute to bioenergetic homeostasis within the CNS of affected patients.
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