To determine early risk of relapse after switch from natalizumab to fingolimod; to compare the switch experience to that in patients switching from interferon-β/glatiramer acetate (IFN-β/GA) and ...those previously treatment naive; and to determine predictors of time to first relapse on fingolimod.
Data were obtained from the MSBase Registry. Relapse rates (RRs) for each patient group were compared using adjusted negative binomial regression. Survival analyses coupled with adjusted Cox regression were used to model predictors of time to first relapse on fingolimod.
A total of 536 patients (natalizumab-fingolimod n = 89; IFN-β/GA-fingolimod n = 350; naive-fingolimod n = 97) were followed up for a median 10 months. In the natalizumab-fingolimod group, there was a small increase in RR on fingolimod (annualized RR ARR 0.38) relative to natalizumab (ARR 0.26; p = 0.002). RRs were generally low across all patient groups in the first 9 months on fingolimod (RR 0.001-0.13). However, 30% of patients with disease activity on natalizumab relapsed within the first 6 months on fingolimod. Independent predictors of time to first relapse on fingolimod were the number of relapses in the prior 6 months (hazard ratio HR 1.59 per relapse; p = 0.002) and a gap in treatment of 2-4 months compared to no gap (HR 2.10; p = 0.041).
RRs after switch to fingolimod were low in all patient groups. The strongest predictor of relapse on fingolimod was prior relapse activity. Based on our data, we recommend a maximum 2-month treatment gap for switches to fingolimod to decrease the hazard of relapse.
This study provides Class IV evidence that RRs are not higher in patients with multiple sclerosis switching to fingolimod from natalizumab compared to those patients switching to fingolimod from other therapies.
Background:
Effectiveness of cladribine tablets, an oral disease-modifying treatment (DMT) for multiple sclerosis (MS), was established in clinical trials and confirmed with real-world experience.
...Objectives:
Use real-world data to compare treatment patterns and clinical outcomes in people with MS (pwMS) treated with cladribine tablets versus other oral DMTs.
Methods:
Retrospective treatment comparisons were based on data from the international MSBase registry. Eligible pwMS started treatment with cladribine, fingolimod, dimethyl fumarate, or teriflunomide tablets from 2018 to mid-2021 and were censored at treatment discontinuation/switch, death, loss to follow-up, pregnancy, or study period end. Treatment persistence was evaluated as time to discontinuation/switch; relapse outcomes included time to first relapse and annualized relapse rate (ARR).
Results:
Cohorts included 633 pwMS receiving cladribine tablets, 1195 receiving fingolimod, 912 receiving dimethyl fumarate, and 735 receiving teriflunomide. Individuals treated with fingolimod, dimethyl fumarate, or teriflunomide switched treatment significantly more quickly than matched cladribine tablet cohorts (adjusted hazard ratio (95% confidence interval): 4.00 (2.54–6.32), 7.04 (4.16–11.93), and 6.52 (3.79–11.22), respectively). Cladribine tablet cohorts had significantly longer time-to-treatment discontinuation, time to first relapse, and lower ARR, compared with other oral DMT cohorts.
Conclusion:
Cladribine tablets were associated with a significantly greater real-world treatment persistence and more favorable relapse outcomes than all oral DMT comparators.
Background:
Behavioral symptoms, such as apathy and depression, are common in multiple sclerosis (MS) but their relationship with cognitive and clinical characteristics often remains ...underinvestigated and not monitored over time.
Objective:
The aim of this study was to assess the evolution of cognitive profile of patients affected by MS in relation to apathy and depression using a 2-year follow-up study.
Methods:
Two years after the first assessment, 100 of 125 MS patients were re-evaluated on a comprehensive neuropsychological battery, and on specific scales for assessment of apathy (Apathy Evaluation Scale—Self-reported) and depression (Hamilton Depression Rating Scale).
Results:
After 2 years (T1), we found a relatively consistent prevalence of apathy (about 40%) and a reduction in prevalence of depression (from 44% to 30%). Higher level of apathy at baseline predicted the progressive cognitive changes at follow-up; and patients with apathy without depression (“pure” apathy) than patients without apathy had poorer performance on the interference task of the Stroop test assessing inhibitory control.
Conclusion:
The present results suggested that apathy in MS was associated with more severe executive dysfunctions (in particular cognitive control). Apathy rather than depression predicted cognitive impairment in MS over time.
To evaluate the rate of return of disease activity after cessation of multiple sclerosis (MS) disease-modifying therapy.
This was a retrospective cohort study from 2 large observational MS ...registries: MSBase and OFSEP. Patients with relapsing-remitting MS who had ceased a disease-modifying therapy and were followed up for the subsequent 12 months were included in the analysis. The primary study outcome was annualized relapse rate in the 12 months after disease-modifying therapy discontinuation stratified by patients who did, and did not, commence a subsequent therapy. The secondary endpoint was the predictors of first relapse and disability accumulation after treatment discontinuation.
A total of 14,213 patients, with 18,029 eligible treatment discontinuation epochs, were identified for 7 therapies. Annualized rates of relapse (ARRs) started to increase 2 months after natalizumab cessation (month 2-4 ARR 0.47, 95% CI 0.43-0.51). Commencement of a subsequent therapy within 2-4 months reduced the magnitude of disease reactivation (mean ARR difference: 0.15, 0.08-0.22). After discontinuation of fingolimod, rates of relapse increased overall (month 1-2 ARR: 0.80, 0.70-0.89) and stabilized faster in patients who started a new therapy within 1-2 months (mean ARR difference: 0.14, -0.01 to 0.29). The magnitude of disease reactivation for other therapies was low but reduced further by commencement of another treatment 1-10 months after treatment discontinuation. Predictors of relapse were a higher relapse rate in the year before cessation, female sex, younger age, and higher EDSS score. Commencement of a subsequent therapy reduced both the risk of relapse (HR 0.76, 95% CI 0.72-0.81) and disability accumulation (0.73, 0.65-0.80).
The rate of disease reactivation after treatment cessation differs among MS treatments, with the peaks of relapse activity ranging from 1 to 10 months in untreated cohorts that discontinued different therapies. These results suggest that untreated intervals should be minimized after stopping antitrafficking therapies (natalizumab and fingolimod).
This study provides Class III that disease reactivation occurs within months of discontinuation of MS disease-modifying therapies. The risk of disease activity is reduced by commencement of a subsequent therapy.
Age at onset (AAO) in multiple sclerosis (MS) is an important marker of disease severity and may have prognostic significance. Understanding what factors can influence AAO may shed light on the ...aetiology of this complex disease, and have applications in the diagnostic process.
The study cohort of 22 162 eligible patients from 21 countries was extracted from the MSBase registry. Only patients with MS aged ≥16 years were included. To reduce heterogeneity, only centres of largely European descent were included for analysis. AAO was defined as the year of the first symptom suggestive of inflammatory central nervous system demyelination. Predictors of AAO were evaluated by linear regression.
Compared with those living in lower latitudes (19.0-39.9°), onset of symptoms was 1.9 years earlier for those at higher latitudes (50.0-56.0°) (p=3.83×10
). A reciprocal relationship was seen for ambient ultraviolet radiation (UVR), with a significantly increasing AAO for patients with MS per each quartile increment of ambient UVR (p=1.56×10
). We found that the AAO of female patients was ∼5 months earlier than male patients (p=0.002). AAO of progressive-onset patients with MS were ∼9 years later than relapsing-onset patients (p=1.40×10
).
An earlier AAO in higher latitude regions was found in this worldwide European-descent cohort and correlated inversely with variation in latitudinal UVR. These results suggest that environmental factors which act at the population level may significantly influence disease severity characteristics in genetically susceptible populations.
Abstract Objective We investigated the effect of glatiramer acetate (GA) on the modulation of immune cell subpopulations and serum levels of multiple immune/metabolic markers in patients with ...relapsing–remitting multiple sclerosis (RRMS) to understand whether the treatment with GA could induce a specific change in the immunometabolic asset of patients with RRMS. Material and methods We performed an extensive peripheral blood immunophenotyping and measured serum levels of several parameters involved in the pathogenesis of RRMS and also relevant in the pathogenesis of metabolic syndrome and obesity such as leptin, soluble leptin-receptor (sLep-R), myeloperoxidase (MPO), soluble CD40 ligand (sCD40-L), soluble tumor necrosis factor-receptor (sTNF-R), monocyte chemoattractant protein 1 (MCP-1), soluble Inter-Cellular Adhesion Molecule-1 (sICAM-1) and osteoprotegerin (OPG), in 20 naïve-to-treatment RRMS patients and 20 healthy controls. We repeated these analyses over time at 6 and 12 months after starting GA treatment. Results Our analysis showed that naïve-to-treatment RRMS patients had a lower number of CD16+ CD56+ NK cells, CD19+ B cells, CD4+ T cells co-expressing the MHC class II activation marker HLA-DR (CD4+ DR+ ) and naïve CD4+ CD45RA+ T cells in basal conditions. GA treatment induced a specific and significant decrease of circulating CD19+ B cells. Naïve-to-treatment RRMS patients also showed a significantly higher number of CD4+ T cells with a memory phenotype (CD4+ CD45RO+ ) whose peripheral frequency was not affected by GA treatment. These changes over time associated with a higher serum concentration of leptin and lower levels of MPO. GA treatment also reduced significantly the circulating levels of sCD40-L and sTNF-R overtime. Conclusions Our data suggest that the clinical outcome of GA treatment is associated with changes in immune cell subpopulations and modulation of specific immunometabolic markers. These data add substantial evidence of the immune modulating effect of GA during RRMS and could be of relevance in understanding the pathogenesis of disease and its follow-up.
Background:
The current best practice suggests yearly magnetic resonance imaging (MRI) to monitor treatment response in multiple sclerosis (MS) patients.
Objective:
To evaluate the current practice ...of clinicians changing MS treatment based on subclinical new MRI lesions alone.
Methods:
Using MSBase, an international MS patient registry with MRI data, we analysed the probability of treatment change among patients with clinically silent new MRI lesions.
Results:
A total of 8311 MRI brain scans of 4232 patients were identified. Around 26.9% (336/1247) MRIs with one new T2 lesion were followed by disease-modifying therapy (DMT) change, increasing to 50.2% (129/257) with six new T2 lesions. DMT change was twice as likely with new T1 contrast enhancing compared to new T2 lesions odds ratio (OR): 2.43, 95% confidence interval (CI): 2.00–2.96 vs OR: 1.26 (95% CI: 1.22–1.29). DMT change with new MRI lesions occurred most frequently with ‘injectable’ DMTs. The probability of switching therapy was greater only after high-efficacy therapies became available in 2007 (after, OR: 1.43, 95% CI: 1.28–1.59 vs before, OR: 0.98, 95% CI: 0.520–1.88).
Conclusion:
MS clinicians rely increasingly on MRI alone in their treatment decisions, utilizing low thresholds (1 new T2 lesion) for optimizing MS therapy. This signals a shift towards no evidence of disease activity (NEDA)-3 since high-efficacy therapies became available.
Background
The clinical benefit of galcanezumab, demonstrated in randomized clinical trials (RCTs), remains to be quantified in real life. This study aimed at evaluating the effectiveness, safety and ...tolerability of galcanezumab in the prevention of high-frequency episodic migraine (HFEM) and chronic migraine (CM) in a real-life setting.
Methods
This multicenter prospective observational cohort study was conducted between November 2019 and January 2021 at 13 Italian headache centers. Consecutive adult HFEM and CM patients clinically eligible were enrolled and treated with galcanezumab subcutaneous injection 120 mg monthly with the first loading dose of 240 mg. The primary endpoint was the change in monthly migraine days (MMDs) in HFEM and monthly headache days (MHDs) in CM patients after 6 months of therapy (V6). Secondary endpoints were the Numerical Rating Scale (NRS), monthly painkiller intake (MPI), HIT-6 and MIDAS scores changes, ≥50% responder rates (RR), the conversion rate from CM to episodic migraine (EM) and Medication Overuse (MO) discontinuation.
Results
One hundred sixty-three patients (80.5% female, 47.1 ± 11.7 years, 79.8% CM) were included. At V6, MMDs reduced by 8 days in HFEM and MHDs by 13 days in CM patients (both
p
< .001). NRS, MPI, HIT-6 and MIDAS scores significantly decreased (
p
< .001). Ten patients (6.1%) dropped out for inefficacy and classified as non-responders. Patients with ≥50%RRs, i.e. responders, were 76.5% in the HFEM and 63.5% in the CM group at V6. Among CM patients, the V6 responders presented a lower body mass index (
p
= .018) and had failed a lower number of preventive treatments (
p
= .013) than non-responders. At V6, 77.2% of CM patients converted to EM, and 82.0% ceased MO. Adverse events, none serious, were reported in up to 10.3% of patients during evaluation times.
Conclusions
Galcanezumab in real life was safe, well tolerated and seemed more effective than in RCTs. Normal weight and a low number of failed preventives were positively associated with galcanezumab effectiveness in CM patients.
Trial registration
ClinicalTrials.gov
NCT04803513
.
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