Patient-reported outcomes (PROs) are essential for understanding the effects of MS and its treatments on patients’ lives; they play an important role in multiple sclerosis (MS) research and practice. ...We present the protocol for an observational study to prospectively assess the effect of cladribine tablets on PROs and their correlation to disability and physical activity in adults with highly active relapsing MS switching from a first disease modifying drug (DMD) to cladribine tablets in routine clinical practice at study sites in Italy. The primary objective will be to evaluate changes from baseline in the impact of highly active MS on self-assessed physical functioning 52 weeks after the switch to cladribine tablets using the Multiple Sclerosis Impact Scale-29 (MSIS-29). Secondary objectives will include self-assessed psychological impact of highly active MS in daily life and general health after the switch to cladribine tablets as well as changes in cognitive function, anxiety, and depression symptoms. Additional PRO measures will include the Hospital Anxiety and Depression Scale (HADS), the EuroQoL 5-Dimension 5-Level (EQ-5D-5L), the Work Productivity and Activity Impairment Questionnaire: Multiple Sclerosis (WPAI:MS), and the Patient-Reported Outcomes Measurement Information System (PROMIS). Wearable devices will acquire activity data (step counts, walking speed, time asleep, and energy expenditure). Additional clinical, radiological, and laboratory data will be collected when available during routine management. The findings will complement data from controlled trials by providing insight from daily clinical practice into the effect of cladribine tablets on the patient’s experience and self-assessed impact of treatment on daily life.
Cladribine tablets are a highly effective option for the treatment of relapsingremitting multiple sclerosis (RRMS).
The study aims to evaluate the effectiveness of cladribine in a real-world setting.
...This prospective real-world study consecutively screened all RRMS patients from seven different MS centers in Sicily (Italy) who completed the 2-year treatment course of cladribine tablets in the period between 11
March 2019 and 31
October 2021. Data about Expanded Disability Status Scale (EDSS), relapses, previous treatments, adverse events (AEs) and magnetic resonance imaging (MRI) were collected. Patients who were previously treated with other DMTs were further stratified into moderately active treatment (MAT) and highly active treatment (HAT) patients.
A total of 217 patients (70% women, with a mean age of 38.4 ± 11.3 years) were enrolled. Fifty patients (23.0%) were naïve to treatment and 167 (77%) switched from other disease modifying therapies. After the second year of treatment, about 80% were EDSS progression free, 88% remained relapse-free at T24, and 48% of patients were MRI activity-free. Kaplan Meier analyses showed significant differences between MT and HAT in terms of time to first clinical relapse (HR: 2.43, IC 1.02- 5.76;
= 0.04), time to the first new T1-gadolinium enhancing lesion (HR: 3.43, IC 1.35-8.70;
= 0.009) and time to MRI worsening (HR: 2.42, IC 1.15-5.09;
= 0.02).
This study confirmed that cladribine is an effective treatment for MS, particularly in naïve patients and those who have switched from MATs.
Background:
The MSBase prediction model of treatment response leverages multiple demographic and clinical characteristics to estimate hazards of relapses, confirmed disability accumulation (CDA), and ...confirmed disability improvement (CDI). The model did not include Multiple Sclerosis Severity Score (MSSS), a disease duration-adjusted ranked score of disability.
Objective:
To incorporate MSSS into the MSBase prediction model and compare model accuracy with and without MSSS.
Methods:
The associations between MSSS and relapse, CDA, and CDI were evaluated with marginal proportional hazards models adjusted for three principal components representative of patients’ demographic and clinical characteristics. The model fit with and without MSSS was assessed with penalized r2 and Harrell C.
Results:
A total of 5866 MS patients were started on disease-modifying therapy during prospective follow-up (age 38.4 ± 10.6 years; 72% female; disease duration 8.5 ± 7.7 years). Including MSSS into the model improved the accuracy of individual prediction of relapses by 31%, of CDA by 23%, and of CDI by 24% (Harrell C) and increased the amount of variance explained for relapses by 49%, for CDI by 11%, and for CDA by 10% as compared with the original model.
Conclusion:
Addition of a single, readily available metric, MSSS, to the comprehensive MSBase prediction model considerably improved the individual accuracy of prognostics in MS.
The complexity of understanding cancer risk in MS is increased by inconsistencies in study design, and the lack of age-, sex-, and ethnicity-specific risk estimates. Aims of our study were to ...estimate the incidence of cancers in the MS population of Catania (Italy) and to evaluate the impact of disease-modifying treatments (DMTs) in cancer risk.
We screened 2,730 PwMS according to the MS criteria of Mc Donald 2010 referring to MS center of Catania in the period between 2003 and 2013. We matched database of MS patients with the Integrated Cancer of Catania-Messina-Siracusae-Enna. We calculated age and sex specific standardized incidence ratios (SIR) and the relative risk (RR) of developing cancer in MS patients treated with at least two different DMTs compared to who received one or no treatment.
Out of 2,730, 1,180 MS patients (67.1% females; mean age 41.2 ± 12.9) were enrolled. We found 36 cancers. Global SIR was 1.18 (CI95% 0.78-1.58), with a significantly higher risk in men with a range age of 20 to 50 years 2.84; (CI95% 1.59-4.09) and in women over 50 years 1.82 (CI95% 1.08-2.55). RR of developing cancer was 1.99 (CI95% 1.14-3.45) in MS patients switching one DMT and 3.38 (CI95% 1.83-6.22) in who switched at least twice.
Our results demonstrated that cancer risk was not increased in our MS population; but age and sex different distribution may partly drive cancer risk. Higher cancer risk in MS patients switching more than two DMTs should take into account in treatment decision making.
As of today, 20 disease-modifying drugs (DMDs) have been approved for the treatment of relapsing multiple sclerosis (MS) and, based on their efficacy, they can be grouped into moderate-efficacy DMDs ...and high-efficacy DMDs. The choice of the drug mostly relies on the judgment and experience of neurologists and the evaluation of the therapeutic response can only be obtained by monitoring the clinical and magnetic resonance imaging (MRI) status during follow up. In an era where therapies are focused on personalization, this study aims to develop a modeling infrastructure to predict the evolution of relapsing MS and the response to treatments. We built a computational modeling infrastructure named Universal Immune System Simulator (UISS), which can simulate the main features and dynamics of the immune system activities. We extended UISS to simulate all the underlying MS pathogenesis and its interaction with the host immune system. This simulator is a multi-scale, multi-organ, agent-based simulator with an attached module capable of simulating the dynamics of specific biological pathways at the molecular level. We simulated six MS patients with different relapsing-remitting courses. These patients were characterized based on their age, sex, presence of oligoclonal bands, therapy, and MRI lesion load at the onset. The simulator framework is made freely available and can be used following the links provided in the availability section. Even though the model can be further personalized employing immunological parameters and genetic information, we generated a few simulation scenarios for each patient based on the available data. Among these simulations, it was possible to find the scenarios that realistically matched the real clinical and MRI history. Moreover, for two patients, the simulator anticipated the timing of subsequent relapses, which occurred, suggesting that UISS may have the potential to assist MS specialists in predicting the course of the disease and the response to treatment.
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Background
Fingolimod (FNG) is associated with the development of symptomatic macular edema (ME) in a small subset of multiple sclerosis (MS) patients. By using spectral domain optical ...coherence tomography (SD-OCT), an increase in the total macular volume (TMV) was rarely detected during the first months of treatment.
Objectives
The objective of this study is to assess whether FNG treatment leads to long-term macular changes in a real-life setting.
Methods
Sixty RRMS patients starting FNG, according to therapeutic indication, were enrolled at three Italian MS centers and followed for 2 years.
Results
The mean TMV did not change between baseline and the follow-up. No patients experienced visual acuity drop during the follow-up.
Conclusions
Initiation of FNG in MS is associated with a modest, not significant, increase in macular volume followed by no further significant changes over 2 years, highlighting the good safety profile of such treatment in MS.
Multiple sclerosis is an autoimmune inflammatory disease that affects the central nervous system through chronic demyelination and loss of oligodendrocytes. Since the relapsing-remitting form is the ...most prevalent, relapse-reducing therapies are a primary choice for specialists. Universal Immune System Simulator is an agent-based model that simulates the human immune system dynamics under physiological conditions and during several diseases, including multiple sclerosis. In this work, we extended the UISS-MS disease layer by adding two new treatments, i.e., cladribine and ocrelizumab, to show that UISS-MS can be potentially used to predict the effects of any existing or newly designed treatment against multiple sclerosis. To retrospectively validate UISS-MS with ocrelizumab and cladribine, we extracted the clinical and MRI data from patients included in two clinical trials, thus creating specific cohorts of digital patients for predicting and validating the effects of the considered drugs. The obtained results mirror those of the clinical trials, demonstrating that UISS-MS can correctly simulate the mechanisms of action and outcomes of the treatments. The successful retrospective validation concurred to confirm that UISS-MS can be considered a digital twin solution to be used as a support system to inform clinical decisions and predict disease course and therapeutic response at a single patient level.
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Trace elements have been hypothesised to be involved in the pathogenesis of Multiple Sclerosis and volcanic degassing is the major natural sources of trace elements. Both incidence of Multiple ...Sclerosis in Catania and volcanic activity of Mount Etna have been significantly increased during the last 30 years. Due to prevailing trade winds direction, volcanic gases from Etna summit craters are mostly blown towards the eastern and southern sectors of the volcano.
To evaluate the possible association between Multiple Sclerosis and exposure to volcanogenic trace elements.
We evaluated prevalence and incidence of Multiple Sclerosis in four communities (47,234 inhabitants) located in the eastern flank and in two communities (52,210 inhabitants) located in the western flank of Mount Etna, respectively the most and least exposed area to crater gas emissions.
A higher prevalence was found in the population of the eastern flank compared to the population of the western one (137.6/100,000 versus 94.3/100,000; p-value 0.04). We found a borderline significantly higher incidence risk during the incidence study period (1980-2009) in the population of the eastern flank 4.6/100,000 (95% CI 3.1-5.9), compared with the western population 3.2/100,000 (95% CI 2.4-4.2) with a RR of 1.41 (95% CI 0.97-2.05; p-value 0.06). Incidence risks have increased over the time in both populations reaching a peak of 6.4/100,000 in the eastern flank and of 4.4/100.000 in the western flank during 2000-2009.
We found a higher prevalence and incidence of Multiple Sclerosis among populations living in the eastern flank of Mount Etna. According to our data a possible role of TE cannot be ruled out as possible co-factor in the MS pathogenesis. However larger epidemiological study are needed to confirm this hypothesis.
One of the most common adverse event of interferon beta (IFNβ) therapy for multiple sclerosis is flu-like syndrome (FLS), which has been reportedly related to increased levels of cytokines such as ...interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α). Average cytokine levels can be affected by single nucleotide polymorphism in the gene promoter regions. To investigate whether IL-6 -174 G>C and TNF-α -376 G>A polymorphisms could be correlated to the incidence of FLS, and whether an anti-inflammatory/antipyretic therapy may influence FLS development, a prospective observational study was performed in 190 treatment naïve, multiple sclerosis patients who started IM IFNβ-1a 30mcg once weekly. The identification of IL-6 -174 G>C and TNF-α -376 G>A polymorphisms was achieved by performing an amplification-refractory mutation system. Serum IL-6 levels were measured using enzyme-linked immunosorbent assay in blood samples taken before therapy and then after the first and last IFNβ-1a injection of the follow-up. FLS-related symptoms were recorded by patients once per week during the first 12 weeks of therapy into a self-reported diary. We found that patients carrying at least one copy of the C allele at position -174 in the promoter of IL-6 gene produced lower levels of IL-6 and were less prone to develop FLS, which was also less severe. On the contrary, the polymorphism of TNF-α had no effect on FLS. Patients taking the first dose of anti-inflammatory/antipyretic therapy in the peri-injection period (within 1 hour) experienced a reduced FLS severity. In conclusion, the study of IL-6 -174 G>C polymorphism would allow the identification of patients lacking the C nucleotide on both alleles who are at risk of a more severe FLS, and may be addressed to a timely and stronger anti-inflammatory/antipyretic therapy for a more effective FLS prevention.
ObjectiveTo investigate pregnancy-related disease activity in a contemporary multiple sclerosis (MS) cohort.MethodsData were obtained from the MSBase Registry. Term/preterm pregnancies conceived from ...2011-2019 were included (modern cohort). Annualised relapse rates (ARR) were calculated before, during and after pregnancy. Predictors of intrapartum and early postpartum (1st3 months) relapse were determined by clustered logistic and Cox regression analyses, respectively.ResultsWe included 1640 pregnancies from 1452 women. Disease-modifying therapy (DMT) used in the one-year preconception included natalizumab (n=219), fingolimod (n=147), dimethyl fumarate (DMF; n=57) and low-efficacy therapies (n=845). Preconception ARR by DMT class used before conception were: natalizumab, 0.29 (95% CI 0.22-0.37); fingolimod, 0.37 (0.28-0.49); DMF, 0.24 (0.13-0.41); low-efficacy, 0.29 (0.25-0.33); and none, 0.24 (0.19-0.31). Among women who used fingolimod or natalizumab, ARR increased during pregnancy. Intrapartum ARR decreased in preconception DMF, low-efficacy or no DMT groups. ARR spiked after delivery across all DMT groups. Natalizumab continuation into pregnancy reduced the odds of relapse during pregnancy (OR 0.76 per month 0.60-0.95, p=0.017). DMT re-initiation with natalizumab protected against postpartum relapse (HR 0.11 0.04-0.32, p<0.0001). Breastfeeding women were less likely to relapse (HR 0.61 0.41-0.91, p=0.016).ConclusionWomen with MS prescribed natalizumab or fingolimod preconception had higher rates of intrapartum and postpartum relapse. In women considered to be at high relapse risk, use of natalizumab before pregnancy and continued up to 32-34 weeks gestation, with early re-initiation after delivery is an effective option to minimise relapse risks. Strategies of DMT use have to be balanced against potential foetal/neonatal complications.
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