In recent years, several disease-modifying therapies have been developed for the treatment of multiple sclerosis (MS). Cladribine transiently depletes B and T lymphocytes, with subsequent gradual ...cell recovery. No cases are reported in literature describing Cladribine drug-induced liver injury (DILI). We describe the case of a 19-year-old woman who developed acute idiosyncratic liver injury 12 days after treatment with Cladribine. Post-marketing adverse event reporting is of paramount importance to allow an early recognition and treatment. Moreover, evaluation of the physiopathological mechanism underlying drug-induced hepatic toxicity can provide clinicians with valuable instruments for prevention and treatment.
Purpose To study the accommodation process in normal eyes using a commercially available clinical system based on swept-source anterior segment optical coherence tomography (AS-OCT). Setting ...Ophthalmology Department, University of Parma, Italy. Design Evaluation of diagnostic technology. Methods Right eyes were analyzed using swept-source AS-OCT (Casia SS-1000). The optical vergence of the internal coaxial fixation target was adjusted during imaging to obtain monocular accommodation stimuli with different amplitudes (0, 3.0, 6.0, and 9.0 diopters D). Overlapping of real and conjugate OCT images enabled imaging of all the anterior segment optical surfaces in a single frame. Central corneal thickness (CCT), anterior chamber depth (ACD), and lens thickness were extracted from the OCT scans acquired at different static accommodation stimulus amplitudes. The crystalline lens was analyzed dynamically during accommodation and disaccommodation by acquiring sequential OCT images of the anterior segment at a rate of 8 frames per second. The lens thickness was extracted from the temporal sequence of OCT images and plotted as a function of time. Results The study analyzed 14 eyes of 14 subjects aged 18 to 46 years. During accommodation, the decrease in the ACD was statistically significant ( P < .05), as were the increase in the lens thickness ( P < .001) and the slight movement forward of the lens central point ( P < .01). The CCT and anterior chamber width measurements did not change statistically significantly during accommodation. The lens thickness at 0 D was positively correlated with age ( P < .01). Conclusion High-resolution real-time imaging and biometry of the accommodating anterior segment can be effectively performed using a commercially available swept-source AS-OCT clinical device. Financial Disclosure No author has a financial or proprietary interest in any material or method mentioned.
Literature data reporting SARS-CoV-2 infection in multiple sclerosis (MS) patients recently treated with immunodepleting agents as cladribine and alemtuzumab are very limited. The relationship ...between iatrogenic immunodeficiency and risk related to SARS-CoV-2 infection and its severe complications is still not clear. Cautiously, the start of immunosuppressant drugs as alemtuzumab and cladribine during the current COVID-19 pandemic is not recommended unless treatment benefits significantly outweigh potential risks. We report the case of a 30-year-old female MS patient infected by SARS-CoV-2 virus 4 months after alemtuzumab II cycle, while she was still leukopenic and lymphopenic. She had no complications and also presented milder COVID-related signs and symptoms as compared to her coinfected relatives (father, mother and her partner). Anti-S1 and S2 SARS-CoV-2 antibodies, tested 1 month and a half after the infection, resulted positive. We review all cases reported in literature of SARS-CoV-2 infection in MS patients treated with alemtuzumab. None of them had complications or severe disease.
A demographic shift in multiple sclerosis (MS) is leading to an increased number of elderly people with MS (pwMS) and a rise in late-onset MS (LOMS) cases. This shift adds complexity to the treatment ...management of these patients, due to enhanced treatment-associated risks and the possible interplay between immunosenescence and disease-modifying therapies (DMTs).
In the present paper, we performed a systematic review of the current evidence concerning the relationship between aging and treatment management in elderly pwMS. Our literature search identified 35 original studies relevant to this topic.
The gathered evidence consistently indicates a diminished efficacy of DMTs in older pwMS, particularly in preventing disability accrual. Against this background, high-efficacy therapies (HETs) appear to show less benefit over moderate-low-efficacy DMTs in older patients. These data mainly derive from observational retrospective studies or meta-analyses conducted on randomized clinical trials (RCTs). RCTs, however, exclude pwMS older than 55 years, limiting our ability to acquire robust evidence regarding this patient group.
Regarding treatment discontinuation in elderly pwMS with stable disease, the available data, which mainly focuses on older injectable DMTs, suggests that their suspension appears to be relatively safe in terms of disease activity. Nevertheless, the first RCT specifically targeting treatment discontinuation recently failed to demonstrate the non-inferiority of treatment discontinuation over continuation, in terms of MRI activity. On the other hand, the evidence on the impact of discontinuation on disease progression is more conflicting and less robust. Furthermore, there is an important lack of studies concerning sequestering DMTs and virtually no data on the discontinuation of anti-CD20 monoclonal antibodies.
De-escalation strategy is gaining attention as a de-risking approach alternative to complete treatment discontinuation. It may be defined as the decision to shift from HETs to less potent DMTs in elderly pwMS who have a stable disease. This strategy could reduce treatment-related risks, while minimizing the risk of disease activity and progression potentially associated with treatment discontinuation. This approach, however, remains unexplored due to a lack of studies.
Given these findings, the present scenario underlines the urgent need for more comprehensive and robust studies to develop optimized, data-driven treatment strategies for elderly pwMS and LOMS, addressing the unique challenges of MS treatment and aging.
•Prevalence of elderly people with MS (pwMS) and late-onset MS cases is increasing.•Elderly pwMS treatment present challenges with risk-benefit balance concerns.•Reduced DMT efficacy in elderly pwMS: especially HETs show lesser benefits.•DMTs discontinuation: safe regarding disease activity, data on progression lacking.•De-escalation strategy may balance risks and control disease effectively.
Objective
This study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID‐19) in people with multiple sclerosis ...(PwMS).
Methods
We retrospectively collected data of PwMS with suspected or confirmed COVID‐19. All the patients had complete follow‐up to death or recovery. Severe COVID‐19 was defined by a 3‐level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death. We evaluated baseline characteristics and MS therapies associated with severe COVID‐19 by multivariate and propensity score (PS)‐weighted ordinal logistic models. Sensitivity analyses were run to confirm the results.
Results
Of 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID‐19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty‐eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized.
After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti‐CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio OR = 2.37, 95% confidence interval CI = 1.18–4.74, p = 0.015) with increased risk of severe COVID‐19. Recent use (<1 month) of methylprednisolone was also associated with a worse outcome (OR = 5.24, 95% CI = 2.20–12.53, p = 0.001). Results were confirmed by the PS‐weighted analysis and by all the sensitivity analyses.
Interpretation
This study showed an acceptable level of safety of therapies with a broad array of mechanisms of action. However, some specific elements of risk emerged. These will need to be considered while the COVID‐19 pandemic persists. ANN NEUROL 2021;89:780–789
Disability accrual in multiple sclerosis may occur as relapse-associated worsening or progression independent of relapse activity. The role of progression independent of relapse activity in early MS ...is yet to be established. The objective of this multicentre, observational, retrospective cohort study was to investigate the contribution of relapse-associated worsening and progression independent of relapse activity to confirmed disability accumulation in patients with clinically isolated syndrome and early relapsing-remitting multiple sclerosis, assessed within one year from onset and with follow-up >/= 5 years (n = 5169). Data were extracted from the Italian Multiple Sclerosis Register. Confirmed disability accumulation was defined by an increase in Expanded Disability Status Scale score confirmed at 6 months, and classified per temporal association with relapses. Factors associated with progression independent of relapse activity and relapse-associated worsening were assessed using multivariable Cox regression models. Over a follow-up period of 11.5 ± 5.5 years, progression independent of relapse activity occurred in 1427 (27.6%) and relapse-associated worsening in 922 (17.8%) patients. Progression independent of relapse activity was associated with older age at baseline (HR = 1.19; 95CI 1.13-1.25, p < 0.001), having a relapsing-remitting course at baseline (HR = 1.44; 95CI 1.28-1.61, p < 0.001), longer disease duration at baseline (HR = 1.56; 95%CI 1.28-1.90, p < 0.001), lower Expanded Disability Status Scale at baseline (HR = 0.92; 95CI 0.88-0.96, p < 0.001), lower number of relapses before the event (HR = 0.76; 95CI 0.73-0.80, p < 0.001). Relapse-associated worsening was associated with younger age at baseline (HR = 0.87; 95CI 0.81-0.93, p < 0.001), having a relapsing-remitting course at baseline (HR = 1.55; 95CI 1.35-1.79, p < 0.001), lower Expanded Disability Status Scale at baseline (HR = 0.94; 95CI 0.89-0.99, p = 0.017), higher number of relapses before the event (HR = 1.04; 95CI 1.01-1.07, p < 0.001). Longer exposure to disease modifying drugs was associated with a lower risk of both progression independent of relapse activity and relapse-associated worsening (p < 0.001). This study provides evidence that in early relapsing-onset multiple sclerosis cohort, progression independent of relapse activity was an important contributor to confirmed disability accumulation. Our findings indicate that insidious progression appears even in the earliest phases of the disease, suggesting that inflammation and neurodegeneration can represent a single disease continuum, in which age is one of the main determinants of disease phenomenology.
B-cell-depleting treatments, such as ocrelizumab and rituximab (anti-CD20), reduce humoral response to SARS-CoV-2 in people with Multiple Sclerosis (pwMS) and Neuromyelitis Optica Spectrum Disorder ...(NMOSD) and are associated with an increased risk of a more severe course of COVID-19 disease. The combination of tixagevimab and cilgavimab was authorized for COVID-19 prevention in immunocompromised subjects at high risk of severe COVID-19 disease, including patients treated with anti-CD20. Few real-world studies are available regarding the use of tixagevimab/cilgavimab in pwMS/NMOSD. In the present study, we describe the use of tixagevimab/cilgavimab for SARS-CoV-2 pre-exposure prophylaxis in a cohort of pwMS and NMOSD, treated with ocrelizumab and rituximab respectively.
26 subjects were treated with tixagevimab/cilgavimab, while we used 18 patients as the control group. We collected clinical data at baseline in all patients and during scheduled follow up evaluations. SARS-CoV-2 serological status pre- and post-tixagevimab/cilgavimab treatment was available for 10 patients.
We observed no adverse events following tixagevimab/cilgavimab treatment. Post-tixagevimab/cilgavimab anti-Spike-1-RBD IgG were significantly higher when compared to baseline values. No difference was found when comparing the percentage of COVID-19 infections between groups. All patients infected with SARS-CoV-2 had mild disease which did not require hospitalization. In patients treated with tixagevimab/cilgavimab, the rate of infection among patients exposed to SARS-CoV-2 was lower, without reaching statistical significance. We observed a significantly longer negativization time in the treated group.
Our results are not consistent with what was observed in the registration trial and some more recent studies. We did not observe a difference in COVID-19 incidence nor in disease severity in MS and NMOSD between treated and untreated patients. Our different results may be partially explained by the change in SARS-CoV-2 variants epidemiology (i.e. reduced efficacy of tixagevimab and cilgavimab against the currently dominant variants) as well as different patient selection included in the trial and different dose of tixagevimab/cilgavimab used in other studies. The present report provides a real-life experience with tixagevimab/cilgavimab in pwMS and NMOSD treated with anti-CD20, with findings that are in line with the current SARS-CoV-2 epidemiology and the recent evidence regarding SARS-CoV-2 variants. Our results warrant further research to best treat patients in the present and future pandemic scenario.
The comparative effectiveness of fingolimod versus interferon beta/glatiramer acetate was assessed in a multicentre, observational, prospectively acquired cohort study including 613 patients with ...relapsing multiple sclerosis discontinuing natalizumab in the Italian iMedWeb registry. First, after natalizumab suspension, the relapse risk during the untreated wash-out period and during the course of switch therapies was estimated through Poisson regression analyses in separated models. During the wash-out period an increased risk of relapses was found in patients with a higher number of relapses before natalizumab treatment (incidence rate ratio = 1.31, P = 0.0014) and in patients discontinuing natalizumab due to lack of efficacy (incidence rate ratio = 2.33, P = 0.0288), patient's choice (incidence rate ratio = 2.18, P = 0.0064) and adverse events (incidence rate ratio = 2.09, P = 0.0084). The strongest independent factors influencing the relapse risk after the start of switch therapies were a wash-out duration longer than 3 months (incidence rate ratio = 1.78, P < 0.0001), the number of relapses experienced during and before natalizumab treatment (incidence rate ratio = 1.61, P < 0.0001; incidence rate ratio = 1.13, P = 0.0118, respectively) and the presence of comorbidities (incidence rate ratio = 1.4, P = 0.0097). Switching to fingolimod was associated with a 64% reduction of the adjusted-risk for relapse in comparison with switching to interferon beta/glatiramer acetate (incidence rate ratio = 0.36, P < 0.0001). Secondly, patients who switched to fingolimod or to interferon beta/glatiramer acetate were propensity score-matched on a 1-to-1 basis at the switching date. In the propensity score-matched sample a Poisson model showed a significant lower incidence of relapses in patients treated with fingolimod in comparison with those treated with interferon beta/glatiramer acetate (incidence rate ratio = 0.52, P = 0.0003) during a 12-month follow-up. The cumulative probability of a first relapse after the treatment switch was significantly lower in patients receiving fingolimod than in those receiving interferon beta/glatiramer acetate (P = 0.028). The robustness of this result was also confirmed by sensitivity analyses in subgroups with different wash-out durations (less or more than 3 months). Time to 3-month confirmed disability progression was not significantly different between the two groups (Hazard ratio = 0.58; P = 0.1931). Our results indicate a superiority of fingolimod in comparison to interferon beta/glatiramer acetate in controlling disease reactivation after natalizumab discontinuation in the real life setting.
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