With the availability of nearly 20 medications approved for relapsing forms of multiple sclerosis (MS), there is growing pressure to better define how to select the most appropriate treatment for a given individual, particularly at the time of diagnosis. MS disease-modifying therapies differ in efficacy in reducing risks of relapse and lesions on brain magnetic resonance imaging (MRI) at the group level. However, these data can be hard to apply to an individual person with MS, who may have no further discernable MS activity after starting a specific therapy or may have dramatic breakthrough disease. Further, it is not entirely clear how different treatment approaches relate to longer-term disability risk. Randomized clinical trials have demonstrated short-term benefits of some specific higher-efficacy therapies with respect to disability outcomes compared to another, specific moderate-efficacy therapy, but these trials have not tested treatment strategies; in particular, escalation after ongoing MS activity is not typically allowed in such protocols. In the real world, people with MS who have breakthrough disease on a moderate-efficacy therapy often change medication, switching to a different moderate-efficacy medication or escalating to a higher-efficacy therapy. Some observational data suggest early use of higher-efficacy therapies may reduce longer-term risk of disability, but these studies were not able to account for confounding by indication or other biases.
To provide an overview of the state of knowledge surrounding the effects of various treatment strategies on longer-term MS outcomes.
In this session, we will review the literature that addresses treatment strategies in early MS, particularly assessing the impacts of using a more aggressive therapy as the first treatment versus adopting an escalation approach. We will also discuss two ongoing randomized trials, TRaditional versus Early Aggressive Therapy for MS (TREAT-MS) and Determining the Effectiveness of earLy Intensive Versus Escalation Approaches for RRMS (DELIVER-MS), which seek to systematically determine if a given treatment strategy best prevents longer-term disability and brain atrophy.
There remains a large gap in knowledge regarding how specific treatment strategies during early MS in the real world optimally prevent, delay, or reduce intermediate- to longer-term disability accrual. The infectious risks and other complications associated particularly with higher-efficacy treatments are a major concern for people with MS and their clinicians, perhaps made even more clear during the COVID-19 pandemic.
It is critical to define if applying a specific treatment strategy across the board confers long-term benefits for functioning. Ongoing pragmatic randomized clinical trials will provide key information about the relative benefits and risks of various treatment strategies.
Even prior to the introduction of RIS criteria, longitudinal clinical data from individuals with incidentally identified T2 lesions suggestive of multiple sclerosis (MS) were described. Healthy individuals who do not exhibit signs of neurological dysfunction commonly have brain MRI studies performed for a reason other than an evaluation for MS that reveal unexpected anomalies highly suggestive of demyelinating plaques given their size, location, and morphology. These healthy subjects lack symptomatology suggestive of MS and fulfill formal criteria for the radiologically isolated syndrome (RIS), a recently described MS subtype that expands upon the phenotype of at-risk individuals for future demyelinating events. A formal description of RIS was first introduced in 2009 by Okuda et al., to define this relevant cohort of individuals who are at risk for future demyelinating events.
In European or North American observational studies, the authors have found that up to 30-45% of patients presenting with a RIS will present clinical progression. The presence of asymptomatic lesions in the cervical cord provides an increased risk of progression, either to a relapsing or to progressive MS.
The consortium studying epidemiology of RIS worldwide (RISC) presented their first retrospective cohort. The 5-year observed conversion rate to the first clinical event was 34%. Of converters within this time period, 9.6% fulfilled criteria for primary progressive MS. In the multivariate model, age, sex (male), and lesions within the cervical or thoracic spinal cord were identified as significant predictors for the development of a first clinical event. In the 10-year update, more than half of the RIS have converted with 4 risk factors at baseline which are young age, CSF positivity, Spinal cord, and infratentorial lesions.
Despite advancements in the characterization of RIS subjects and in our understanding of risk factors for initial symptom development, the natural course of such cases and risk-profiles for a seminal neurological event, from prospectively acquired data, remain unclear. Prospective studies are mandatory to increase our knowledge about these asymptomatic patients. Many experts groups in the USA, Europe, and South America have proposed guidelines to follow the RIS subjects. The recommendation is not to treat off label these subjects as 2 phases 3 studies are ongoing in the USA and Europe with dimethylfumarate and teriflunomide.
Rituximab (RTX) is an anti-CD20 monoclonal antibody, widely used as an off-label treatment for multiple sclerosis (MS). Despite well-known efficacy and safety, RTX regimen has not yet been standardized.
We aimed to compare efficacy and safety data of two different rituximab doses at two large Catalan multiple sclerosis centres.
A two-centre ambispective study considering all MS patients that have received at least one RTX cycle until February 2020 was conducted. In Barcelona centre (BC), RTX regimen used was 2g intravenously (IV), at least during 3 cycles, followed by 1g every 6 months, while in Girona centre (GC), was 2g IV, at least the first cycle, followed by 500mg every 6 months. Patients were clinically followed every 6 months with lab tests, and brain MRI scans were performed at baseline and yearly thereafter. Baseline clinical, radiological and demographic characteristics were collected. Annual relapse rate (ARR), contrast-enhancing lesions (CELs) and new T2 lesions at one and third year on treatment, as well as EDSS changes at last follow-up visit, were evaluated. Also, the dynamics of CD19% lymphocytes and IG immunoglobulin (IgG) values in serum, as well as the incidence of adverse events (AE) were described.
A total of 303 patients (249 at BC and 54 at GC) were included. Main reason to start RTX was clinical progression plus inflammatory activity (clinical, radiological or both) (45.8% BC vs 79.6% GC). No differences on age at RTX onset, gender and disease duration were found between both centres. At baseline, mean ARR was 0.37±0.6 (BC) vs. 0.33±0.5 (GC); median EDSS was 5.5 (1-9.0) (BC) vs. 6.0 (1-8.0) (GC); and proportion of MRI with CELs was 32.4% (BC) vs. 42.6% (GC). ARR decrease to 0.05 (87.5%, p<0.001) for BC vs. 0.03 (90.3%, p=0.018) for GC at first year, and to 0.08 (88.3%, p=0.016) vs. 0 (100%, p=0.172) at third year. Considering only progressive MS phenotypes, 79.4% vs. 71.4% of patients remained stable or improved the EDSS. Regarding MRI findings, percentages of patients with CELs and new T2 lesions (BC vs GC) were 2.7% vs. 8% and 19% vs. 16% at one year; and 0% vs. 0% and 12% vs. 0% at third year. AE incidence was higher at BC during the first year (14.8% vs 4.1%). No difference in the dynamics of CD19% lymphocytes was found, while IgG values decreased significantly in the BC cohort throughout the first 3 years.
In the treatment of multiple sclerosis, low doses of rituximab seem to offer similar effectiveness with better safety profile than high doses.
to date, no consensus exists on how aggressively and timely treat relapsing-remitting multiple sclerosis (RRMS) patients.
To evaluate disability trajectories in a cohort of RRMS patients stratified according to two different disease modifying therapy (DMT) strategies, early intensive treatment (EIT) or moderate-efficacy treatment followed by escalation to higher-efficacy DMT (ESC).
RRMS patients with ≥5-year follow-up and ≥3 visits after start DMT, and a first visit within 3 years from disease onset were selected from the Italian MS Registry. EIT group included patients who received, as first DMT, fingolimod, natalizumab, mitoxantrone, alemtuzumab, ocrelizumab, cladribine. ESC group included those who received the high efficacy DMT after ≥1 year of glatiramer acetate, interferons, azathioprine, teriflunomide or dimethylfumarate treatment. Patients were 1:1 propensity score(PS)-matched for characteristics at the first DMT. The follow-up time from the first DMT start has been segmented into 12-month periods. The disability trajectories were evaluated by applying a longitudinal model for repeated measures with an autoregressive variance-covariance structure. The effect of early versus late start of high-efficacy DMT was assessed by the mean annual EDSS changes compared to baseline values (delta-EDSS) in EIT and ESC groups.
The study cohort included 2,652 RRMS patients from 62 Italian MS centers. The PS matching procedure produced 365 pairs. The median (IQR) follow-up after the first DMT start was 8.5 (6.5–11.7) years. All of the ESC patients escalated to a higher-efficacy DMT after a median time of 5.1 (3.1–8.4) years. The estimated baseline EDSS with relative confidence interval (95% CI) value was 2.52 (2.33-2.71) in the ESC group and 2.45 (2.26-2.64) in the EIT group. Mean delta-EDSS at each 12 month period were all significantly (p<0.02) higher in the ESC group compared to the EIT group. In particular, the mean delta-EDSS differences between the two groups tend to increase from 0.1 (0.01-0.19, p=0.03) at 1 year to 0.30 (0.07-0.53, p=0.009) at 5 years and to 0.67 (0.31-1.03, p=0.0003) at 10 years.
Our results indicate that EIT strategy is more effective than ESC strategy in controlling disability progression and the effect tends to increase over time despite patients in the ESC group escalated to a higher-efficacy DMT.