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<jats:p> Neuromyelitis optica spectrum disorder (NMOSD) is a rare inflammatory demyelinating disorder of the central nervous system (CNS). Aquaporin-4 (AQP4) antibodies in the serum are highly specific for the diagnosis of NMOSD, but the sensitivity remains under 90% allowing for diagnosis of AQP4 IgG seronegative disease. It remains of crucial importance to identify seronegative NMOSD myelitis as early as the first attack to initiate long-term treatment that will reduce future relapses and disability and to avoid potentially harmful treatments such as those of multiple sclerosis (MS). Over the years, many spinal imaging features have been reported to favour the diagnosis of NMOSD, but only longitudinally extensive transverse myelitis (LETM) was specific enough to make the diagnostic criteria in the AQP4 IgG seronegative cases. Bright spotty lesions (BSLs), which are defined as hyperintense lesions on axial T2-weighted images and sometimes associated with T1 low signal, are now reported to have a higher specificity and sensitivity compared to LETM in predicting a diagnosis of NMOSD against other causes of myelitis. In the review, we aim to highlight the position of BSLs in diagnosing NMOSD as well as its possible role as a prognostic factor for the clinical outcome. </jats:p>

<jats:p> Addressing a person in the context of their disease must be done respectfully. As a person with multiple sclerosis (MS), my preference is to be referred to as such. Some people with MS refer to themselves as MSers, MS warriors, MS sufferers, and that’s fine. A person with MS can refer to themselves in the context of their disease in the manner they choose. People without MS should use terminology most respectful and acceptable to the broadest of the minority. Academics sometimes use persons with MS to refer to an infinite number of people. Not only is this incorrect but use of persons has broadly fallen out of favour in recent decades. In this personal viewpoint I discuss these issues from a lived experience perspective. </jats:p>

<jats:sec><jats:title>Background:</jats:title><jats:p> As patents for multiple sclerosis (MS) therapies expire, follow-on disease-modifying treatments (FO-DMTs) become available at reduced cost. Concerns exist that cheaper FO-DMTs are used simply to reduce healthcare costs. However, the well-being of people with MS should take priority. </jats:p></jats:sec><jats:sec><jats:title>Objectives:</jats:title><jats:p> To identify best practices for FO-DMT development and use by agreeing on principles and consensus statements through appraisal of published evidence. </jats:p></jats:sec><jats:sec><jats:title>Methods:</jats:title><jats:p> Following a systematic review, we formulated five overarching principles and 13 consensus statements. Principles and statements were voted on by a multidisciplinary panel from 17 European countries, Argentina, Canada and the United States. </jats:p></jats:sec><jats:sec><jats:title>Results:</jats:title><jats:p> All principles and statements were endorsed by &gt;80% of panellists. In brief, FO-DMTs approved within highly regulated areas can be considered effective and safe as their reference products; FO-DMTs can be evaluated case by case and do not always require Phase III trials; long-term pharmacovigilance and transparency are needed; there is lack of evidence for multiple- and cross-switching among FO-DMTs; and education is needed to address remaining concerns. </jats:p></jats:sec><jats:sec><jats:title>Conclusion:</jats:title><jats:p> Published data support the use of FO-DMTs in MS. The consensus may aid shared decision-making. While our consensus focused on Europe, the results may contribute to enhanced quality standards for FO-DMTs use elsewhere. </jats:p></jats:sec>

<jats:sec><jats:title>Background:</jats:title><jats:p> Patients with relapsing–remitting multiple sclerosis commonly switch between disease-modifying therapies (DMTs). Identifying predictors of relapse when switching could improve outcomes. </jats:p></jats:sec><jats:sec><jats:title>Objective:</jats:title><jats:p> To determine predictors of relapse hazard when switching to cladribine. </jats:p></jats:sec><jats:sec><jats:title>Methods:</jats:title><jats:p> Data of patients who switched to cladribine, grouped by prior disease-modifying therapy (pDMT; interferon-β/glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod or natalizumab (NTZ)), were extracted from the MSBase Registry. Predictors of relapse hazard during the treatment gap and the first year of cladribine therapy were determined. </jats:p></jats:sec><jats:sec><jats:title>Results:</jats:title><jats:p> Of 513 patients, 22 relapsed during the treatment gap, and 38 within 1 year of starting cladribine. Relapse in the year before pDMT cessation predicted treatment gap relapse hazard (hazard ratio (HR) = 2.43, 95% confidence interval (CI)  = 1.03–5.71). After multivariable adjustment, relapse hazard on cladribine was predicted by relapse before pDMT cessation (HR = 2.00, 95% CI = 1.01–4.02), treatment gap relapse (HR = 6.18, 95% confidence interval (CI) = 2.65–14.41), switch from NTZ (HR compared to injectable therapies 4.08, 95% CI = 1.35–12.33) and age at cladribine start (HR = 0.96, 95% CI = 0.91–0.99). </jats:p></jats:sec><jats:sec><jats:title>Conclusion:</jats:title><jats:p> Relapse during or prior to the treatment gap, and younger age, are of prognostic relevance in the year after switching to cladribine. Switching from NTZ is also independently associated with greater relapse hazard. </jats:p></jats:sec>

<jats:sec><jats:title>Background:</jats:title><jats:p> In the absence of evidence from randomised controlled trials, observational data can be used to emulate clinical trials and guide clinical decisions. Observational studies are, however, susceptible to confounding and bias. Among the used techniques to reduce indication bias are propensity score matching and marginal structural models. </jats:p></jats:sec><jats:sec><jats:title>Objective:</jats:title><jats:p> To use the comparative effectiveness of fingolimod vs natalizumab to compare the results obtained with propensity score matching and marginal structural models. </jats:p></jats:sec><jats:sec><jats:title>Methods:</jats:title><jats:p> Patients with clinically isolated syndrome or relapsing remitting MS who were treated with either fingolimod or natalizumab were identified in the MSBase registry. Patients were propensity score matched, and inverse probability of treatment weighted at six monthly intervals, using the following variables: age, sex, disability, MS duration, MS course, prior relapses, and prior therapies. Studied outcomes were cumulative hazard of relapse, disability accumulation, and disability improvement. </jats:p></jats:sec><jats:sec><jats:title>Results:</jats:title><jats:p> 4608 patients (1659 natalizumab, 2949 fingolimod) fulfilled inclusion criteria, and were propensity score matched or repeatedly reweighed with marginal structural models. Natalizumab treatment was associated with a lower probability of relapse (PS matching: HR 0.67 [95% CI 0.62-0.80]; marginal structural model: 0.71 [0.62-0.80]), and higher probability of disability improvement (PS matching: 1.21 [1.02 -1.43]; marginal structural model 1.43 1.19 -1.72]). There was no evidence of a difference in the magnitude of effect between the two methods. </jats:p></jats:sec><jats:sec><jats:title>Conclusions:</jats:title><jats:p> The relative effectiveness of two therapies can be efficiently compared by either marginal structural models or propensity score matching when applied in clearly defined clinical contexts and in sufficiently powered cohorts. </jats:p></jats:sec>

<jats:sec><jats:title>Background:</jats:title><jats:p> Information on performance of multiple sclerosis (MS) diagnostic criteria is scarce for populations from Latin America, Asia, or the Caribbean. </jats:p></jats:sec><jats:sec><jats:title>Objective:</jats:title><jats:p> To assess performance of revised 2017 McDonald criteria as well as evaluate genetic ancestry in a group of MS patients from Argentina experiencing a debut demyelinating event. </jats:p></jats:sec><jats:sec><jats:title>Methods:</jats:title><jats:p> Demographic and clinical characteristics, cerebrospinal fluid (CSF), and magnetic resonance imaging (MRI) findings and new T2 lesions were recorded at baseline and during relapses. Diagnostic accuracy in predicting conversion to clinically defined MS (CDMS) based on initial imaging applying revised 2017 criteria was evaluated and genetic ancestry-informative markers analyzed. </jats:p></jats:sec><jats:sec><jats:title>Results:</jats:title><jats:p> Of 201 patients experiencing their first demyelinating event (median follow-up 60 months), CDMS was confirmed in 67. We found 2017 diagnostic criteria were more sensitive (84% vs 67%) and less specific (14% vs 33%) than 2010 criteria, especially in a group of patients revised separately, presenting positive oligoclonal bands (88% vs 8%). Genetic testing performed in 128 cases showed 72% of patients were of European ancestry and 27% presented genetic admixture. </jats:p></jats:sec><jats:sec><jats:title>Conclusion:</jats:title><jats:p> 2017 McDonald criteria showed higher sensitivity and lower specificity compared with 2010 criteria, shortening both time-to-diagnosis and time-to-treatment implementation. </jats:p></jats:sec>

<jats:sec><jats:title>Background:</jats:title><jats:p> CLASSIC-MS evaluated the long-term efficacy of cladribine tablets in patients with relapsing multiple sclerosis. </jats:p></jats:sec><jats:sec><jats:title>Objective:</jats:title><jats:p> Report long-term mobility and disability beyond treatment courses received in CLARITY/CLARITY Extension. </jats:p></jats:sec><jats:sec><jats:title>Methods:</jats:title><jats:p> This analysis represents CLASSIC-MS patients who participated in CLARITY with/without participation in CLARITY Extension, and received ⩾1 course of cladribine tablets or placebo ( N = 435). Primary objective includes evaluation of long-term mobility (no wheelchair use in the 3 months prior to first visit in CLASSIC-MS and not bedridden at any time since last parent study dose (LPSD), i.e. Expanded Disability Status Scale (EDSS) score &lt;7). Secondary objective includes long-term disability status (no use of an ambulatory device (EDSS &lt; 6) at any time since LPSD). </jats:p></jats:sec><jats:sec><jats:title>Results:</jats:title><jats:p> At CLASSIC-MS baseline, mean ± standard deviation EDSS score was 3.9 ± 2.1 and the median time since LPSD was 10.9 (range = 9.3–14.9) years. Cladribine tablets–exposed population: 90.6% ( N = 394), including 160 patients who received a cumulative dose of 3.5 mg/kg over 2 years. Patients not using a wheelchair and not bedridden: exposed, 90.0%; unexposed, 77.8%. Patients with no use of an ambulatory device: exposed, 81.2%; unexposed, 75.6%. </jats:p></jats:sec><jats:sec><jats:title>Conclusion:</jats:title><jats:p> With a median 10.9 years’ follow-up after CLARITY/CLARITY Extension, findings suggest the sustained long-term mobility and disability benefits of cladribine tablets. </jats:p></jats:sec>

<jats:sec><jats:title>Background:</jats:title><jats:p> Multiple sclerosis patients experience 3–6 times more seizures than the general population, but observations vary among studies. Seizure risk in disease-modifying therapy recipients remains unknown. </jats:p></jats:sec><jats:sec><jats:title>Objective:</jats:title><jats:p> The objective of this study was to compare seizure risk in multiple sclerosis patients receiving disease-modifying therapy versus placebo. </jats:p></jats:sec><jats:sec><jats:title>Methods:</jats:title><jats:p> MEDLINE(OVID), Embase, CINAHL, and ClinicalTrials.gov were searched from database inception until August 2021. Phase 2–3 randomized, placebo-controlled trials reporting efficacy and safety data for disease-modifying therapies were included. Network meta-analysis followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, using Bayesian random effects model for individual and pooled (by drug target) therapies. Main outcome was log<jats:sub>e</jats:sub> seizure risk ratios [95% credible intervals]. Sensitivity analysis included meta-analysis of non-zero-event studies. </jats:p></jats:sec><jats:sec><jats:title>Results:</jats:title><jats:p> A total of 1993 citations and 331 full-texts were screened. Fifty-six included studies (29,388 patients—disease-modifying therapy = 18,909; placebo = 10,479) reported 60 seizures (therapy = 41; placebo = 19). No individual therapy was associated with altered seizure risk ratio. Exceptions were daclizumab (−17.90 [−65.31; −0.65]) and rituximab (−24.86 [−82.71; −1.37]) trending toward lower risk ratio; cladribine (25.78 [0.94; 4.65]) and pegylated interferon-beta-1a (25.40 [0.78; 85.47]) trended toward higher risk ratio. Observations had wide credible intervals. Sensitivity analysis of 16 non-zero-event studies revealed no difference in risk ratio for pooled therapies (l0.32 [−0.94; 0.29]) </jats:p></jats:sec><jats:sec><jats:title>Conclusion:</jats:title><jats:p> No evidence of association was found between disease-modifying therapy and seizure risk—this informs seizure management in multiple sclerosis patients. </jats:p></jats:sec>

<jats:sec><jats:title>Background:</jats:title><jats:p> Data on corpus callosum involvement in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are limited. </jats:p></jats:sec><jats:sec><jats:title>Objective:</jats:title><jats:p> The objective of the study was to compare callosal lesions in MOGAD, multiple sclerosis (MS), and aquaporin-4-IgG positive neuromyelitis optica spectrum disorder (AQP4+NMOSD). </jats:p></jats:sec><jats:sec><jats:title>Results:</jats:title><jats:p> Callosal lesion frequency was similar in MOGAD (38/171 (22%)), MS (24/72 (33%)), and AQP4+NMOSD (18/63 (29%)). Clinical phenotypes included encephalopathy (47%) and focal supratentorial (21%) or infratentorial (45%) deficits. None had callosal-disconnection syndromes. Maximal callosal-T2-lesion diameter (median (range)) in millimeter was similar in MOGAD (21 (4–77)) and AQP4+NMOSD (22 (5–49); p = 0.93) but greater than in MS (10.5 (2–64)). Extracallosal extension (21/38 (55%)) and T2-lesion resolution (19/34 (56%)) favored MOGAD. </jats:p></jats:sec><jats:sec><jats:title>Conclusions:</jats:title><jats:p> Despite similar frequency and imaging overlap, larger lesions, sagittal midline involvement, and lesion resolution favored MOGAD. </jats:p></jats:sec>

<jats:sec><jats:title>Background:</jats:title><jats:p> Data on the humoral vaccine response in patients on anti-interleukin-6 (IL-6) receptor therapy remain scarce. </jats:p></jats:sec><jats:sec><jats:title>Objective:</jats:title><jats:p> The main objective of our study was to investigate the humoral response after vaccination against SARS-CoV-2 in neuromyelitis optica spectrum disorder (NMOSD)/myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) patients treated with anti-IL-6 receptor therapy. Secondarily, we analyzed relapse activity timely associated with vaccination. </jats:p></jats:sec><jats:sec><jats:title>Methods:</jats:title><jats:p> In this retrospective cross-sectional multicenter study, we included 15 healthy controls and 48 adult NMOSD/MOGAD patients without previous COVID-19 infection. SARS-CoV-2 spike protein antibody titers during anti-IL-6 receptor therapy were compared to anti-CD20 antibody therapy, oral immunosuppressants, and to nonimmunosuppressed individuals. </jats:p></jats:sec><jats:sec><jats:title>Results:</jats:title><jats:p> We observed 100% seroconversion in the anti-IL-6 receptor treatment group. Titers of SARS-CoV-2 spike protein antibodies were lower compared to healthy controls (720 vs 2500 binding antibody units (BAU)/mL, p = 0.004), but higher than in the anti-CD20 (720 vs 0.4 BAU/mL, p &lt; 0.001) and comparable to the oral immunosuppressant group (720 vs 795 BAU/mL, p = 1.0). We found no association between mRNA-based vaccines and relapse activity in patients with or without immunotherapy. </jats:p></jats:sec><jats:sec><jats:title>Conclusions:</jats:title><jats:p> Despite being lower than in healthy controls, the humoral vaccine response during anti-IL-6 receptor therapy was evident in all patients and substantially stronger compared to anti-CD20 treatment. No relevant disease activity occurred after mRNA vaccination against SARS-CoV-2. </jats:p></jats:sec>