Safety and Efficacy of Rituximab in Multiple Sclerosis: A Retrospective Observational Study

Objective. To evaluate the efficacy and safety of rituximab in multiple sclerosis in a clinical practice setting. Methods. Clinical data for all adult patients with multiple sclerosis (MS) treated with off-label rituximab at a single MS center in Lebanon between March 2008 and April 2017 were retrospectively collected from medical charts. The main efficacy outcomes assessed were annualized relapse rate (ARR) and proportion of patients free from relapses, disability progression, or magnetic resonance imaging (MRI) activity. Results. A total of 89 rituximab-treated patients were included: 59 relapsing-remitting MS (RRMS) and 30 progressive MS (PMS). Patients were treated with 1000 or 2000 mg rituximab IV every 6–12 months for a mean duration of 22.2 ± 24.8 months. The subjects were 65.2% females with a mean age of 40.5 ± 12.3 years and a mean disease duration of 7.9 ± 6.2 years. During treatment, the ARR decreased from 1.07 at baseline to 0.11 in RRMS (p<0.0001) and from 0.25 to 0.16 in PMS patients (p=0.593). The mean Expanded Disability Status Scale (EDSS) remained unchanged in both RRMS and PMS patients. Between baseline and the last follow-up, the percent of patients free from any new MRI lesions increased from 18.6% to 92.6% in the RRMS group and from 43.3% to 82% in the PMS group. No evidence of disease activity (NEDA) was achieved in 74% of patients at 1 year of treatment. A total of 64 adverse events (AEs) (71.9%) were recorded with the most common being infusion-related reactions in 25.8% of patients, all mild in nature. Two of our rituximab-treated patients experienced serious AEs requiring surgical interventions: pyoderma gangrenosum vaginalis with perianal abscess and fistula and an increase in the size of a meningioma. No case of progressive multifocal leukoencephalopathy (PML) was detected. Conclusion. In our real-world cohort, rituximab was well-tolerated and effective in reducing relapse rate and disability progression in relapsing-remitting and progressive MS patients.

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Impact of natural menopause on multiple sclerosis: a multicentre study

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2019-320587 ◽

2019 ◽

Vol 90 (11) ◽

pp. 1201-1206 ◽

Cited By ~ 8

Author(s):

Damiano Baroncini ◽

Pietro Osvaldo Annovazzi ◽

Nicola De Rossi ◽

Giulia Mallucci ◽

Valentina Torri Clerici ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cigarette Smoking ◽

Relapse Rate ◽

Disability Progression ◽

Natural Menopause ◽

Multicentre Cohort Study ◽

Disability Status ◽

Speed Up ◽

Multicentre Cohort

ObjectiveTo study the effect of natural menopause on multiple sclerosis clinical course.MethodsThis was an observational, retrospective, multicentre, cohort study. Menopause onset was defined by the final menstrual period (FMP) beyond which no menses occurred for 12 months. We included multiple sclerosis (MS) patients with FMP occurred after 2005 and a recorded follow-up of at least 2 years pre-FMP and post-FMP. We excluded patients with primary progressive course, iatrogenic menopause and with other confounders that could mask menopause onset. We compared relapse-rate and expanded disability status scale (EDSS) scores pre-FMP and post-FMP, searching for possible interactions with age, disease duration, cigarette smoking and nulliparity status.Results148 patients were included (mean observation: 3.5 years pre-FMP and post-FMP). Most patients (92%) received disease-modifying therapies, mainly first-lines. After menopause the annualised relapse rate (ARR) significantly decreased (from 0.21±0.31 to 0.13± 0.24; p=0.005), while disability worsened (increase of mean 0.4 vs 0.2 points after menopause; p<0.001). Older age and long-lasting disease were associated with ARR reduction (p=0.013), but not with disability worsening. Cigarette smokers showed a trend to a higher disability accumulation after menopause (p=0.059).ConclusionNatural menopause seems to be a turning point to a more progressive phase of MS. Relapse rate is also reduced after menopause, but this effect could be driven most by ageing and shifting to progressive phase in patients with long-lasting disease. Cigarette smoking could speed up disability progression after menopause.

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Treatment of multiple sclerosis with rituximab: A multicentric Italian–Swiss experience

Multiple Sclerosis Journal ◽

10.1177/1352458519872889 ◽

2019 ◽

Vol 26 (12) ◽

pp. 1519-1531 ◽

Cited By ~ 5

Author(s):

Chiara Zecca ◽

Francesca Bovis ◽

Giovanni Novi ◽

Marco Capobianco ◽

Roberta Lanzillo ◽

...

Keyword(s):

Multiple Sclerosis ◽

Relapse Rate ◽

B Lymphocyte ◽

Outcome Analysis ◽

Off Label ◽

Disability Status ◽

Relapsing Remitting ◽

First Relapse ◽

Anti Cd20

Background: Rituximab, an anti-CD20 monoclonal antibody leading to B lymphocyte depletion, is increasingly used as an off-label treatment option for multiple sclerosis (MS). Objective: To investigate the effectiveness and safety of rituximab in relapsing–remitting (RR) and progressive MS. Methods: This is a multicenter, retrospective study on consecutive MS patients treated off-label with rituximab in 22 Italian and 1 Swiss MS centers. Relapse rate, time to first relapse, Expanded Disability Status Scale (EDSS) progression, incidence of adverse events, and radiological outcomes from 2009 to 2019 were analyzed. Results: A total of 355/451 enrolled subjects had at least one follow-up visit and were included in the outcome analysis. Annualized relapse rate significantly decreases after rituximab initiation versus the pre-rituximab start year in RRMS (from 0.86 to 0.09, p < .0001) and in secondary-progressive (SP) MS (from 0.34 to 0.06, p < .0001) and had a slight decrease in primary-progressive (PP) MS patients (from 0.12 to 0.07, p = 0.45). After 3 years from rituximab start, the proportion of patients with a confirmed EDSS progression was 14.6% in the RRMS group, 24.7% in the SPMS group, and 41.5% in the PPMS group. No major safety concerns arose. Conclusion: Consistently with other observational studies, our data show effectiveness of rituximab in reducing disease activity in patients with MS.

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De-escalating rituximab dose results in stability of clinical, radiological, and serum neurofilament levels in multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458520952036 ◽

2020 ◽

pp. 135245852095203

Author(s):

Giulio Disanto ◽

Paolo Ripellino ◽

Gianna C Riccitelli ◽

Rosaria Sacco ◽

Barbara Scotti ◽

...

Keyword(s):

Multiple Sclerosis ◽

Comparable Efficacy ◽

High Dose ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

T2 Lesions ◽

Disability Status ◽

Relapsing Remitting ◽

Magnetic Resonance Imaging Mri

Background: Phase II and observational studies support the use of rituximab in multiple sclerosis. Standard protocols are lacking, but studies suggest comparable efficacy between low- and high-dose regimens. Objective: To evaluate effectiveness and safety of de-escalating rituximab dose from 1000 to 500 mg/6 months in multiple sclerosis. Methods: Patients were switched from rituximab 1000 to 500 mg/6 months and prospectively followed for 12 months. Relapses, disability, occurrence of brain/spinal magnetic resonance imaging (MRI) lesions, serum neurofilament light chain (NfL), CD19+ B cell, and IgG concentrations were analyzed. Results: Fifty-nine patients were included (37 relapsing-remitting, 22 secondary progressive). No relapses occurred, with no difference in expanded disability status scale (EDSS) between baseline (4 (2.5–4.5) and 12 months (3.5 (2.5–5.5) p = 0.284). Overall, three new T2 lesions appeared during follow-up. NfL concentration was stable between baseline (7.9 (5.9–45.2) pg/mL) and 12 months (9.1 (5.9–21.3) pg/mL, p = 0.120). IgG concentrations decreased with greater rituximab load (coefficient = −0.439, p = 0.041). IgG deficient patients had greater risk of infections (OR = 6.27, 95% CI = 1.71–22.9, p = 0.005). Conclusion: De-escalating rituximab dose from 1000 to 500 mg/6 months is safe, results in clinical and radiological stability, and does not affect serum NfL over 12 months. Rituximab load negatively influences IgG concentrations, and IgG deficient patients are at higher risk of infections.

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Determinants of therapeutic lag in multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458520981300 ◽

2021 ◽

pp. 135245852098130

Author(s):

Izanne Roos ◽

Emmanuelle Leray ◽

Federico Frascoli ◽

Romain Casey ◽

J William L Brown ◽

...

Keyword(s):

Multiple Sclerosis ◽

Expanded Disability Status Scale ◽

Disability Progression ◽

Delayed Onset ◽

Disease Characteristics ◽

Disability Status ◽

Male Sex ◽

Pre Treatment ◽

Patient Subgroups

Background: A delayed onset of treatment effect, termed therapeutic lag, may influence the assessment of treatment response in some patient subgroups. Objectives: The objective of this study is to explore the associations of patient and disease characteristics with therapeutic lag on relapses and disability accumulation. Methods: Data from MSBase, a multinational multiple sclerosis (MS) registry, and OFSEP, the French MS registry, were used. Patients diagnosed with MS, minimum 1 year of exposure to MS treatment and 3 years of pre-treatment follow-up, were included in the analysis. Studied outcomes were incidence of relapses and disability accumulation. Therapeutic lag was calculated using an objective, validated method in subgroups stratified by patient and disease characteristics. Therapeutic lag under specific circumstances was then estimated in subgroups defined by combinations of clinical and demographic determinants. Results: High baseline disability scores, annualised relapse rate (ARR) ⩾ 1 and male sex were associated with longer therapeutic lag on disability progression in sufficiently populated groups: females with expanded disability status scale (EDSS) < 6 and ARR < 1 had mean lag of 26.6 weeks (95% CI = 18.2–34.9), males with EDSS < 6 and ARR < 1 31.0 weeks (95% CI = 25.3–36.8), females with EDSS < 6 and ARR ⩾ 1 44.8 weeks (95% CI = 24.5–65.1), and females with EDSS ⩾ 6 and ARR < 1 54.3 weeks (95% CI = 47.2–61.5). Conclusions: Pre-treatment EDSS and ARR are the most important determinants of therapeutic lag.

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A Pilot Study of 24-h Motor Activity Patterns in Multiple Sclerosis: Pre-Planned Follow-Up at 2 Years

Clocks & Sleep ◽

10.3390/clockssleep3030023 ◽

2021 ◽

Vol 3 (3) ◽

pp. 366-376

Author(s):

Lorenzo Tonetti ◽

Federico Camilli ◽

Sara Giovagnoli ◽

Vincenzo Natale ◽

Alessandra Lugaresi

Keyword(s):

Multiple Sclerosis ◽

Motor Activity ◽

Activity Pattern ◽

Activity Patterns ◽

Expanded Disability Status Scale ◽

Disability Status ◽

Relapsing Remitting ◽

Edss Score ◽

Activity Prognosis

Early multiple sclerosis (MS) predictive markers of disease activity/prognosis have been proposed but are not universally accepted. Aim of this pilot prospective study is to verify whether a peculiar hyperactivity, observed at baseline (T0) in early relapsing-remitting (RR) MS patients, could represent a further prognostic marker. Here we report results collected at T0 and at a 24-month follow-up (T1). Eighteen RRMS patients (11 females, median Expanded Disability Status Scale-EDSS score 1.25, range EDSS score 0–2) were monitored at T0 (mean age 32.33 ± 7.51) and T1 (median EDSS score 1.5, range EDSS score 0–2.5). Patients were grouped into two groups: responders (R, 14 patients) and non-responders (NR, 4 patients) to treatment at T1. Each patient wore an actigraph for one week to record the 24-h motor activity pattern. At T0, NR presented significantly lower motor activity than R between around 9:00 and 13:00. At T1, NR were characterized by significantly lower motor activity than R between around 12:00 and 17:00. Overall, these data suggest that through the 24-h motor activity pattern, we can fairly segregate at T0 patients who will show a therapeutic failure, possibly related to a more active disease, at T1. These patients are characterized by a reduced morning level of motor activation. Further studies on larger populations are needed to confirm these preliminary findings.

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Prospective study of multiple sclerosis with early onset

Multiple Sclerosis Journal ◽

10.1191/1352458502ms786oa ◽

2002 ◽

Vol 8 (2) ◽

pp. 115-118 ◽

Cited By ~ 93

Author(s):

A Ghezzi ◽

C Pozzilli ◽

M Liguori ◽

M G Marrosu ◽

N Milani ◽

...

Keyword(s):

Multiple Sclerosis ◽

First Year ◽

Hormonal Changes ◽

Disability Status ◽

Definite Multiple Sclerosis ◽

Relapsing Remitting ◽

Clinically Definite Multiple Sclerosis ◽

The Mean ◽

And Gender

Fifty-four subjects (36 females and 18 males) affected by clinically definite multiple sclerosis (MS) and with onset of the disease at 15 years of age or before were prospectively studied in five Italian MS centres. Female/male ratio was 4.7 in subjects with age ≥12 years, suggesting a role of hormonal changes in triggering MS onset. The mean follow-up duration was 10.9-5.6 years. The functional systems more frequently involved at onset were the pyramidal and brainstem (both in 28% of cases). The onset was monosymptomatic in 31 subjects (57%). The course was relapsing-remitting in 39 subjects (72%) and relapsing-progressive in 15 (28%). Disability was assessed by the Expanded Disability Status Scale (EDSS): the mean score after 8 years of follow up was 3.5 (-2.5). The score was <4 in 68% of cases, between 4 and 6 in 8% of cases, > 6 in 24% of cases. Disability after 8 years was highly predicted by disability in the first year (p=0.008). There was a tendency to a worse prognosis in relation to the number of relapses in the first 2 years (p=0.08). The outcome was not influenced by the characteristics of symptoms at onset, age and gender.

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Should We Use Clinical Tools to Identify Disease Progression?

Frontiers in Neurology ◽

10.3389/fneur.2020.628542 ◽

2021 ◽

Vol 11 ◽

Author(s):

Hernan Inojosa ◽

Undine Proschmann ◽

Katja Akgün ◽

Tjalf Ziemssen

Keyword(s):

Multiple Sclerosis ◽

Clinical Markers ◽

Disability Progression ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Secondary Progressive ◽

Disability Status ◽

Relapsing Remitting ◽

Clinical Tools

The presence of disability progression in multiple sclerosis (MS) is an important hallmark for MS patients in the course of their disease. The transition from relapsing remitting (RRMS) to secondary progressive forms of the disease (SPMS) represents a significant change in their quality of life and perception of the disease. It could also be a therapeutic key for opportunities, where approaches different from those in the initial phases of the disease can be adopted. The characterization of structural biomarkers (e.g., magnetic resonance imaging or neurofilament light chain) has been proposed to differentiate between both phenotypes. However, there is no definite threshold between them. Whether the risk of clinical progression can be predicted by structural markers at early disease phases is still a focus of clinical research. However, several theories and pathological evidence suggest that both disease phenotypes are part of a continuum with common pathophysiological mechanisms. In this case, the clinical evaluation of the patients would play a preponderant role above destruction biomarkers for the early identification of disability progression and SPMS. For this purpose, the use of clinical tools beyond the Expanded Disability Status Scale (EDSS) should be considered. Besides established functional tests such as the Multiple Sclerosis Functional Composite (MSFC), patient's neurological history or digital resources may help neurologists in the decision-taking. In this article, we discuss arguments for the use of clinical markers in the detection of secondary progressive MS and the characterization of progressive disease activity.

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Response to interferon-beta therapy in relapsing-remitting multiple sclerosis: a comparison of different clinical criteria

Multiple Sclerosis Journal ◽

10.1191/135248506ms1278oa ◽

2006 ◽

Vol 12 (3) ◽

pp. 281-286 ◽

Cited By ~ 26

Author(s):

E Portaccio ◽

V Zipoli ◽

G Siracusa ◽

S Sorbi ◽

M P Amato

Keyword(s):

Multiple Sclerosis ◽

Relapse Rate ◽

Interferon Beta ◽

Clinical Criteria ◽

Predictors Of Response ◽

Lower Baseline ◽

Disability Status ◽

Relapsing Remitting ◽

One Year ◽

Relapsing Remitting Multiple Sclerosis

We assessed the proportion and potential predictors of response to interferon-beta (IFNβ) therapy in relapsing-remitting (RR) multiple sclerosis (MS) patients, comparing different definitions of response: a) lower relapse rate during therapy compared to the year and the two years before therapy, b) reduction of relapse rate during therapy of at least 30% compared to the two years before therapy, c) no relapse during treatment, d) no progression on the Expanded Disability Status Scale (EDSS). Among 147 RR patients treated for at least one year, 33 received IFNβ-1b subcutaneously (SC) (Betaferon), 59 IFNβ-1a intramuscularly (Avonex) and 55 IFNβ-1a SC (Rebif). Using definitions a), b) and d), 72%, 73% and 73% patients, respectively, were considered responders. Forty-four per cent of our patients were completely relapse free. In the logistic regression model, using definitions a) and b), a higher relapse rate in the two years preceding the therapy turned out to be a significant predictor of response. Considering definition c), lower baseline relapse rate was associated with a more favourable response.

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Comparison of rituximab originator (MabThera®) to biosimilar (Truxima®) in patients with multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458520912170 ◽

2020 ◽

pp. 135245852091217 ◽

Cited By ~ 2

Author(s):

Thomas Perez ◽

Audrey Rico ◽

Clémence Boutière ◽

Adil Maarouf ◽

Marjorie Roudot ◽

...

Keyword(s):

Multiple Sclerosis ◽

Adverse Events ◽

Efficacy And Safety ◽

Middle Income ◽

Middle Income Countries ◽

Disability Status ◽

Baseline Characteristics ◽

Magnetic Resonance Imaging Mri ◽

Improve Access

Background: Rituximab’s originator MabThera® or Rituxan® has demonstrated high efficacy in multiple sclerosis (MS). Because of the patent expiration, rituximab biosimilars have been developed. However, because a biosimilar is not the exact copy of the originator, the efficacy and safety of a biosimilar may significantly differ. Objectives: To compare the efficacy and safety of the biosimilar Truxima® and the originator MabThera® in MS. Methods: Consecutive MS patients receiving MabThera® or Truxima® were prospectively followed during 1 year after treatment introduction. Allocation to each treatment depended on the period of introduction and not the physician’s choice. Lymphocyte count, clinical and magnetic resonance imaging (MRI) activity, Expanded Disability Status Scale (EDSS), and adverse events were compared. Results: In total, 105 and 40 patients received MabThera® and Truxima®, respectively. The two groups did not differ in baseline characteristics. Effect on CD19+ lymphocytes and disease activity were similar during follow-up. EDSS remained stable, with no difference between groups. Adverse events were similar between groups. Conclusion: The efficacy and safety of the rituximab biosimilar Truxima® seem equivalent to the originator MabThera® in MS patients. Truxima® could represent a relatively cheap and safe therapeutic alternative to MabThera® and could improve access to highly efficient therapy for MS in low- or middle-income countries.

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BEST-MS: A prospective head-to-head comparative study of natalizumab and fingolimod in active relapsing MS

Multiple Sclerosis Journal ◽

10.1177/1352458520969145 ◽

2020 ◽

pp. 135245852096914

Author(s):

Mikael Cohen ◽

Lydiane Mondot ◽

Florence Bucciarelli ◽

Béatrice Pignolet ◽

David-Axel Laplaud ◽

...

Keyword(s):

Multiple Sclerosis ◽

Prospective Study ◽

Relapse Rate ◽

Group Versus ◽

Lower Probability ◽

Highly Active ◽

Relapsing Remitting ◽

Annualized Relapse Rate ◽

Magnetic Resonance Imaging Mri ◽

A Prospective Study

Background: There are few head-to-head studies to compare highly active treatments in multiple sclerosis (MS) Objective: The aim of this study was to compare the effectiveness between natalizumab (NTZ) and fingolimod (FTY) in active relapsing–remitting MS Method: Best Escalation STrategy in Multiple Sclerosis (BEST-MS) is a multicentric, prospective study with a 12-month follow-up including patients with active MS. Treatment choice was at the discretion of physician. Clinical and magnetic resonance imaging (MRI) data were collected at baseline and at 12 months. The primary outcome was the proportion of patients reaching no evidence of disease activity (NEDA) at 12 months. Secondary outcomes included annualized relapse rate and MRI activity. Results: A total of 223 patients were included (NTZ: 109 and FTY: 114). Treatment groups were well balanced at baseline. Proportion of NEDA patients was 47.8% in NTZ group versus 30.4% in FTY group ( p = 0.015). This superiority was driven by annualized relapse rate and MRI activity. In the multivariate analysis, treatment group was the only factor associated with NEDA at 12 months with a lower probability in FTY group (odds ratio (OR) = 0.49, p = 0.029). Conclusion: BEST-MS is a prospective study that compared head-to-head the effectiveness of NTZ and FTY in active relapsing–remitting MS. Our results suggest a superiority of NTZ over FTY.

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