Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory demyelinating disorder of the central nervous system with preferential involvement of the optic nerve and spinal cord[
Recent evidence points to B cell-mediated humoral immunity in the pathogenesis of NMOSD. Rituximab (RTX), a monoclonal antibody targeting the CD20 antigen on B cells, has been found to be effective in several modest quality studies in terms of reducing relapse rates and improving patients’ outcomes[
In each patient, a diagnosis of NMOSD was made based on criteria described by the International Panel for Neuromyelitis optica (NMO) Diagnosis of 2015[
This study was registered under the National Medical Research Register, Ministry of Health Malaysia (NMRR-19-291-46157 S1).
This clinical outcome study is a retrospective analysis of patients with aggressive NMOSD treated with RTX in the Neurology Department at Kuala Lumpur Hospital from 2005 to 2018. The study included eight NMOSD patients who had received one course of RTX induction therapy. Clinical, laboratory and neuroimaging data from both in-patient admission and outpatient records of all patients were collected and analyzed. The primary outcomes included were the number of relapses, EDSS, annualized relapse rates (ARR), and modified Rankin Scale (mRS) before and after treatment. The EDSS was used to quantify the disability of our patients. It was assessed during six-monthly follow-up. ARR was defined as the number of clinical attacks per year. The secondary objective was to analyse the side effects of a single course rituximab treatment.
During the acute attack, high dose intravenous methylprednisolone at 1000 mg daily was given for 5 days. Patients who continued to deteriorate or did not show significant improvement in clinical signs and symptoms after 2 weeks treatment were given plasma exchange (consisting of five cycles each). RTX was used thereafter for aggressive NMOSD patients who continued to have frequent relapses in a year while on oral immunosuppressant therapy.
All patients received RTX infusion as per our Department’s protocol
Protocol of single dose rituximab as induction therapy for aggressive NMOSD patients in Kuala Lumpur Hospital, Malaysia. NMOSD: neuromyelitis optica spectrum disorder; IPND: international panel for neuromyelitis optica diagnosis
While on RTX therapy, all patients had their pre-existing conventional steroid-sparing agents withdrawn and they were only re-initiated as per protocol 2 to 4 weeks after RTX induction therapy to prevent cumulative effects of infection or hematological and liver dysfunction amongst the patients.
Data collected was analyzed using SPSS version 24 software, to look at descriptive data; means, medians, percentages and Wilcoxon signed rank test for differences between pre and post treatment in patients with NMOSD.
From January 2008 to May 2018, 8 out of 194 patients (4.1%) with NMOSD in our hospital database received a single course of RTX infusion. The mean age of disease onset was 44.5 years (SD = 11). Six (75%) of them were female, with a female to male ratio of 3:1. The patient’s demographic and clinical characteristics are listed in
Characteristics of 8 neuromyelitis optica spectrum disorder patients treated with rituximab
Pt | Age | Sex | Dis dur (yrs) | AQP4 ab | Number of relapses before RTX | Prior ISS received before RTX | Dis dur before RTX (yrs) | Dur of ISS prior to RTX (yrs) | EDSS | EDSS | ARR (yrs) | mRS | Post RTX f/up (yrs) | TBNK B cell % | Maintenance post RTX | |||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
ON | TM | AZA | MMF | MTX | alii | Pre RTX | Post RTX (6 mo) | Post RTX (1 yr) | Pre RTX | Post RTX | Pre RTX | Post RTX | ||||||||||
1 | 56 | F | 3 | + | 3 | 1 | + | - | + | - | 0.5 | 0.3 | 5.0 | 2.0 | 1.0 | 4.0 | 0 | 4 | 2 | 2 | NA | MTX 5 mg weekly |
2 | 31 | F | 10 | + | 7 | 1 | + | + | - | IVIg Cyclo | 3 | 0.6 | 4.0 | 2.5 | 2.5 | 1.7 | 0.1 | 3 | 2 | 6 | NA | MMF 1 g bd |
3 | 53 | F | 11 | + | 3 | 4 | + | - | - | INF beta-1a | 4 | 2.2 | 6.5 | 2.0 | 1.0 | 1.4 | 0 | 4 | 2 | 6 | 1% | AZA 50 mg od |
4 | 61 | M | 8 | + | - | 2 | + | - | - | - | 3 | 0.7 | 9.0 | 9.0 | 9.0 | 0.6 | 0 | 5 | 5 | 4 | NA | Pred 10 mg od |
5 | 30 | F | 17 | + | 9 | 2 | + | - | - | - | 10 | 3 | 3.5 | 2.0 | 1.0 | 1.0 | 0 | 3 | 2 | 7 | NA | AZA 50 mg od |
6 | 41 | M | 6 | + | 3 | 1 | + | - | + | - | 3 | 3.7 | 2.0 | 1.0 | 1.0 | 1.3 | 0 | 2 | 1 | 2 | NA | AZA 125 mg od |
7 | 43 | F | 10 | + | 1 | 3 | + | - | - | - | 3 | 1 | 7.0 | 6.5 | 6.5 | 1.3 | 0.1 | 4 | 4 | 6 | 3% | Pred 5 mg od |
8 | 41 | M | 13 | + | 10 | 7 | + | + | - | IVIg | 7 | 5 | 6.5 | 4.5 | 4.0 | 3.0 | 0 | 4 | 3 | 5 | NA | AZA 100 mg od |
Pt: patient; Dis: disease; dur: duration; yrs: years; mo: month; alii: others; AQP4 ab: aquaporin 4 antibody; RTX: rituximab; ON: optic neuritis; TM: transverse myelitis; ISS: immunosuppressants; AZA: azathioprine; MMF: mycophenolate mofetil; MTX: methotrexate; IVIg: intravenous immunoglobulin; ARR: annualized relapsed rate; mRS: modified rankin scale; EDSS: expanded disability status scale; TBNK: T-cell, B-cell and NK cell; bd: twice a day; od: once daily; pred: prednisolone; -: negative; NIL: nothing; +: positive
All patients had previously received immunosuppressants for a mean duration of 2 years (SD = 1.7) prior to RTX; they were either on AZA (eight patients), MMF (two patients) or methotrexate (two patients)
The mean EDSS value prior to RTX treatment was 5.4 and after treatment, it improved to 3.6 (
Relapses in patients with neuromyelitis optica spectrum disorder before and after treatment with rituximab. The mean follow-up duration after RTX therapy was 4.7 years. The use of rituximab was associated with significant reduction in the mean annualized relapse rate from 4.7 to 0.5 attacks per year after treatment (
Rituximab was well tolerated and none of our patients who received the therapy developed any short-term adverse effects such as infusion related allergic reaction, fever, abdominal symptoms or hematological disorders. There was no reported case of progressive multifocal encephalopathy, malignancies, hypogammaglobulinemia or septicemia during the mean follow up period of 4.7 years (2 to 7 years) following RTX treatment.
In patients with NMOSD, recurrent clinical relapses can lead to rapid accumulation of disability and clustering of attacks. Aggressive immunosuppressive therapy remains the mainstay of NMOSD treatment to reduce the number of destructive demyelinating events. NMOSD is thought to be an aquaporinopathy that is predominantly humorally mediated, with complex interplay between B cells, T cells, complement and cytokines. Since the first open-label study evaluating RTX in NMO patients by Cree
However, in our resource limited setting, RTX is expensive and obtaining the medication for our patients remains a huge challenge. Thus, we had to use a dosing schedule of lower frequency and a single course of RTX was applied followed by oral immunosuppression to treat these patients. Data collected retrospectively, showed a significant reduction in the frequency of relapses, ARR in NMOSD patients with aggressive disease especially in those failing conventional immunomodulators. Remission was also maintained in 75% of patients for 4 years. Similar to the study conducted by Bedi
To date, there has been no standard guideline or consensus on RTX treatment for patients with NMOSD. Existing protocols used to induce and maintain remission are characterized by heterogeneity in terms of infusion and monitoring schedules and methods. Previous studies practiced either prescheduled RTX induction regimen every 6 months, or retreatment based on B cell depletion monitoring[
In resource-limited hospitals, a single induction course of RTX treatment may be a therapeutic and economic option to suppress disease activity. We recognized that oral prednisolone during RTX treatment may potentially confound the analysis, however the overlapping benefit of steroids with RTX may be crucial to avoid sudden withdrawal of immunosuppressants that can potentially cause an early relapse. The doses of steroids were kept stable during this period and other immunosuppressants were withdrawn to prevent possible adverse events.
Several studies have shown the benefits of low dose RTX in terms of improvement in ARR, disability scores and time to next relapse[
Unlike the meta-analysis published by Damato
Nevertheless, there are several limitations to our study. Firstly, being a retrospective study, the analysis of data from medical records was subjected to recording bias. In addition, the patient group at baseline was heterogenous with regard to their pre-RTX status and have variable disease duration, number of relapses and EDSS severity. Oral immunosuppressant maintenance therapies and steroid doses following RTX treatment were also variable. Although our results were derived from a tertiary care institution, our sample size was small, which further highlights the challenges of access to RTX at tertiary establishments in a resource-limited setting.
In conclusion, pulse induction therapy with a single course of RTX followed by subsequent de-escalation to oral immunosuppressants may be a convenient and economical approach in managing NMOSD patients. In resource-limited hospitals with restricted access to RTX, such an approach can potentially be effective to reduce relapses and improve EDSS scores with minimal side effects. This treatment plan allowed adequate time for optimization of other oral medications to achieve their therapeutic benefits. Moreover, the ability to achieve and maintain remission suggests that RTX has long-term effects extending beyond treatment discontinuation. Nevertheless, we concede that a further, larger prospective cohort study is required to demonstrate the efficacy of such a treatment approach.
The authors would like to thank the Director General of Health Malaysia for the permission to publish this paper.
Performed data acquisition, analysis and interpretation, prepared the manuscript, Tables and Figures: Ong TL
Made substantial contributions to the conception and design of the study and performed data analysis and interpretation: Viswanathan S
Performed data acquisition, analysis and interpretation. Contributed in manuscript preparation: Ong S, Hiew FL
All data used for this study were collected as part of ongoing work under the auspices of the Demyelinating Disease Database, established at the Neurology Department of Kuala Lumpur Hospital.
None.
All authors declared that there are no conflicts of interest.
Informed consent, either verbal or written, was obtained from patients for the use of retrospective data with longitudinal follow-up for this study.
Not applicable.
© The Author(s) 2020.