Rituximab for the Treatment of Multiple Sclerosis: A Retrospective Observational Cohort in Morocco ()
1. Introduction
MS is a chronic inflammatory demyelination disease of the central nervous system. It was first described in 1868 by Jean-Martin Charcot, and since then several forms of the disease have been identified. MS is the commonest non-traumatic disabling disease to affect young adults, especially women. In 2020, an estimated 2.8 million people were affected by MS worldwide [1].
The etiology and pathogenesis of MS remain unclear, and the most likely theory is that genetic susceptibility at birth and exposure to environmental factors during one’s life trigger an immune reaction directed against CNS autoantigens [2] [3]. MS has historically been considered an autoimmune disease mediated by CD4+ T cells with an imbalance between helper-1 CNS-reactive effector T cells, Th17, and regulatory T cells [2] [3]. However, an important paradigmatic shift in the immunology of MS has occurred in the past decade. It is now clear the important role of B cells in the pathogenesis of MS [2] [4]. The presence and persistence of oligoclonal bands in the CSF in 90% of patients with MS is also an indirect marker of the involvement of B cells in this theory. The efficacy of anti-CD20 treatments through depletion of B cells has also drawn the attention of researchers to the involvement of B cells in the pathogenesis of MS.
Although its efficacy, safety profile, and treatment regimen in MS are not well codified, RTX is a frequently used off-label anti-CD20 for the treatment of MS in several countries [5] [6] [7]. This work aims to evaluate the efficacy and safety of the use of RTX on a Moroccan population with MS.
2. Methods
Objectives of the study:
• Evaluate the clinical and radiological efficacy of RTX in Moroccan patients with MS.
• Evaluate the tolerance of RTX at the time of infusion and the Adverse events (AEs) recorded since the initiation of RTX. The grades of AEs are according to the Common Terminology Criteria for Adverse Events.
Study protocol:
Monocentric retrospective cohort within the neurology department of hospital university HASSAN II FES, from January 01, 2017, to July 31, 2020, including 47 patients followed for MS and treated with RTX with at least a 6-month follow-up.
• Inclusion criteria:
Patients with a diagnosis of MS according to the McDonalds 2010 and 2017 criteria and treated with RTX with at least 6 months of follow-up.
• Exclusion criteria:
• RTX start date is recent: less than 6 months follow-up.
• Patient lost to follow-up.
• To assess clinical effectiveness, annualized relapse rates and Expanded Disability Status Scale (EDSS) scores before and after rituximab initiation were collected from medical records.
• The baseline MRI was defined as the most recent MRI before the RTX initiation. We recorded the presence and number of new lesions in follow-up MRI
• The Adverse events (AEs) recorded since the initiation of RTX was collected from medical records.
• The therapeutic regimen used in our center.
• Initial 2 doses: 1000 mg intravenous infusions once; repeat dose 2 weeks later.
• Subsequent doses: 500 mg IV every 6 to 12 months.
• Premedication: 1 g of paracetamol and L’hydroxyzine (at a dose of 50 mg) orally 30 to 60 minutes before each infusion then direct intravenous injection of methylprednisolone (120 mg) 30 min before starting the rituximab infusion.
Statistical analysis
Statistical analysis was performed using SPSS software. Descriptive results were presented in the form of numbers and percentages for qualitative variables. Quantitative variables were presented in the form of an average accompanied by their standard deviation in the case of normal distribution, otherwise by the median with its extremes. The statistical significance threshold was set at 0.05.
3. Results
75 patients followed in the Neurology department for the demyelinating disease of the CNS, were treated by RTX (n = 63 MS and n = 12 Neuromyelitis Optica).
Among the 63 MS, we excluded 12 MS patients who had just started RTX and 4 who had been lost to sight (Figure 1).
Of 47 patients with MS, the average age was 39 ± 12 years, with a female predominance of 61.7% (n = 29) with a sex ratio F/M of 1.6.
The average duration of disease progression of MS was 8 ± 5 years. The most common progressive form was RRMS in 83% (n = 39). The median EDSS before RTX initiation was 5.5 (0 to 7). The annualized relapse rate (ARR) in the 24 months before RTX initiation is 0.8. The socio-demographic and clinical characteristics of the patient are summarized in Table 1.
Reasons for rituximab initiation among MS patients are described in Table 2. The reasons mainly were lack of efficacy with previous treatment in 24 patients
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Table 1. Socio-demographic and clinical characteristics of the patient.
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Table 2. Reasons for rituximab initiation.
(51%), and active disease in 16 patients (34%). RTX was proposed in 5 patients (10.6%) for intolerance to previous treatment (3 had an intolerance to cyclophosphamide and 2 to azathioprine).
The mean duration of RTX treatment was 21.8 ± 14.3 months. The ARR decreased from 0.8 to 0.2 after RTX initiation. 83% (n = 37) were relapse-free, in 5 patients (10.6%) had a single relapse, and 6.4% (n = 3) had 2 relapses.
During the observation time, the median EDSS remained unchanged at 70.2% (n = 33), and there was an improvement at 21.4% (n = 11). Progression was noted in 6.4% (n = 3), of which 2 developed a secondarily progressive form and one refused to take her treatment during the COVID-19 pandemic.
The mean time for the baseline MRI was 4 ± 2 months. The average time for the control MRI was 16 ± 3 months. 78.7% (n = 37) had at least one control MRI, of which 83.7% (n = 30) had a stable MRI with no new lesions. 13.5% (n = 5) had a single new T2 lesion, and 5.4% (n = 2) had 2 new T2 lesions. Contrast enhancing lesions were absent in all patients who had an MRI with an injected T1 sequence (n = 25).
The side effects observed during the infusion were reported at 27.6% (n = 13). All these SEs were classified as grades 1 and 2 and no serious incident of hypersensitivity was recorded. For this side effect, the flow rate of the infusion was reduced and we did not stop completely the treatment.
Infections were observed in 19% (n = 9): All these infections were upper respiratory infections or lower urinary tract infections classified as grade 1 or grade 2.
Abortion was at 10 weeks of amenorrhea in one patient whose pregnancy occurred at 20 weeks from the last RTX infusion.
No cancerous or autoimmune complications have been reported so far.
4. Discussion
RTX is a chimeric anti-CD20 monoclonal antibody that was developed in the 1990s as a treatment for B-cell non-Hodgkin lymphomas [2]. Over time, this indication has been extended to other autoimmune diseases such as rheumatoid arthritis and Gougerot-Sjogren syndrome [2] [5]. Several recent studies have also suggested the effectiveness of RTX in some peripheral and central inflammatory neurological diseases, in particular MS [4] [5] [6] [7].
RTX binding to the CD20 causes depletion of CD20-expressing B-cells and T-cells. A depletion of autoreactive B cells will interfere with cell-mediated antigen presentation and impair T cell activation, antibody production, and cytokine secretion [2]. RTX works through three main mechanisms: induction of apoptosis, complement-dependent cytotoxicity, and antibody-dependent cellular cytotoxicity [2] [4] [5] [6].
CD20 is a very specific marker of B cells from the pre-B stage and on mature B cells, but it is not expressed on hematopoietic stem cells, or on the earliest precursors of the B line, or on plasma cells, thus making it possible to explain the transient nature of the depletion of B cells and the normal level of immunoglobulins in treated patients, which explains its acceptable safety profile [4].
It has been described that a subset of T cells also express CD20 and therefore their depletion may contribute to the therapeutic effect of RTX [2] [5].
A randomized, double-blind, phase II controlled study of RTX against placebo, over 48 weeks, including 104 patients with RRMS (HERMES study), proved its clinical and radiological efficacy with an acceptable safety profile [6]. The randomized phase III trial (OLYMPUS) of RTX, involving 439 patients with primary progressive MS was negative, but the analysis of the subgroups showed a significant slowing of the progression of the disability in young patients (age < 51 years) with gadolinium-enhancing lesions on MRI [7].
In a review of the literature of 38 studies concerning the off-label use of RTX in RRMS, RTX appears to be effective in comparison to the placebo, IFNs, and glatiramer acetate [8] [9] [10]. A prospective phase III study (RIFUND-MS: NCT02746744) compares RTX to dimethyl fumarate in RRMS in Sweden, and the results are not yet been published of RTX.
Real-world data Off-label use of RTX in the treatment of MS is widespread throughout the world for its efficacy, its safety profile, and its easy administration [1] [2] [9] - [15], but protocols remain heterogeneous and uncodified.
We report our experience regarding the use of off-label RTX in Moroccan patients with MS with a mean treatment duration of 21.8 months. RTX has been used mainly as second-line therapy in patients with RRMS or in the case of first-line active forms. We observed a significant reduction in the ARR and the number of new lesions in the follow-up MRI after rituximab initiation.
The demographic data of our series are similar to the literature data concerning the population with MS. The diagnostic delay and the particular severity of MS in Moroccan patients may explain the high baseline EDSS in our series [16].
AEs during infusion are of variable severity, sometimes requiring treatment in an intensive care unit (18). Their incidence varies from 25% to 85% of cases [17]. This risk is more frequent when RTX is used in hematological malignancies than in autoimmune diseases [18] [19] [20].
Premedication, in particular glucocorticoid infusion, increases tolerance to first courses and reduces the risk of occurrence of serious AEs [2] [19] [20].
In our series, with compliance with premedication, no serious AEs during infusion were reported.
Data on the safety of RTX are reassuring based on the long-standing use of RTX in many diseases other than with low risks of serious opportunistic infections or malignancy [18] [19] [20].
The risk of serious infectious complications under RTX is explained by several hypotheses such as B cell depletion, hypogammaglobulinemia, and neutropenia [18] [19] [20] [21] [22].
It is important to note that the risk of infectious complications is also related to the indication of RTX, comorbidities, age, and association with other immunosuppressants. To minimize this risk, screen for hepatitis B and pulmonary tuberculosis, offer pneumococcal vaccination, and monitor white blood cells count and immunoglobulin levels before RTX infusion [21] [22].
A few rare cases of PML under RTX have been reported in other indications other than MS and it seems that the risk of PML is not related to the number of cures or the length of exposure to RTX [22] [23] [24] [25].
In our practice, hepatitis B serology as well as screening for pulmonary tuberculosis and serum protein electrophoresis is routinely done before initiating RTX. Pneumococcal vaccination should be done routinely but not necessarily before initiation.
Data on the safety of RTX are reassuring based on the long-standing use of RTX in many diseases other than with low risks of serious opportunistic infections or malignancy [18] [19].
The risk of malignancy on RTX appears similar to that of the general population [18]. Our study has some limitations. First, the number of included patients is small. Second, our study was a retrospective longitudinal study.
5. Conclusions
Despite some methodological limitations, our work, like many series, confirms the efficacy and tolerance profile in MS and the easy administration of the treatment. From an economic point of view, it seems accessible compared to other long-term treatments.
So RTX represents an attractive therapeutic alternative, especially with resource-limited settings in developing countries like MOROCCO.
Ethical Approval
The local ethic committee approved this study.