Rituximab in Neuromyelitis Optica Spectrum Disorders: Our Experience.

BACKGROUND: Neuromyelitis optica (NMO) is an inflammatory demyelinating central nervous system disease, with recurrent attacks of severe bilateral optic neuritis and longitudinally extensive transverse myelitis. Aggressive immunosuppression is essential to prevent clinical relapses and permanent disability. Rituximab, a monoclonal antibody to CD20, has been found effective in several reports and small uncontrolled studies. There is a paucity of data regarding its use in Indian patients.
OBJECTIVES: The aim of this study was to report the results of rituximab treatment in NMO spectrum disorders (NMOSDs) in the Indian scenario.
METHODS: This study is a retrospective, observational study including 13 NMOSD patients treated with rituximab. After initial therapy in the acute episode with IV methylprednisolone and if needed plasma exchange, therapy was initiated as a cycle of intravenous rituximab, two doses 2 weeks apart of 1 g each. Subsequent cycles were advised at intervals of every 6 months. The primary outcome measure was annualized relapse rate (ARR), defined as a number of clinical attacks per year. Clinical adverse events were recorded throughout the study.
RESULTS: In the study, mean ARR reduced from 2.61 to 0.09 after therapy (P = 0.000685). Of 13 patients, 8 (61.54%) were completely relapse free after starting treatment with rituximab. Treatment was well tolerated and no serious adverse events were noted.
CONCLUSIONS: The treatment of NMOSDs with rituximab in Indian patients reduces the frequency of relapses and is well tolerated.

INTRODUCTION

Neuromyelitis optica (NMO) is a well-recognized inflammatory demyelinating central nervous system disease, typically characterized by severe bilateral optic neuritis and longitudinally extensive transverse myelitis.[1] Most patients have pathogenic autoantibodies in their serum against the astrocytic water channel – aquaporin 4 (AQP4).[2] AQP4 antibody positivity has now been found in a wider range of clinical and magnetic resonance imaging manifestations, leading to the broader concept of NMO spectrum disorders (NMOSDs).[3]

The treatment of NMOSD is primarily immunosuppressive. In the acute phase, high-dose methylprednisolone, plasma exchange, or intravenous immunoglobulin (if no better with steroids) are used to control inflammation for rapid recovery.[4] However, the course is punctuated by severe clinical relapses with rapid and permanent disability. Aggressive long-term treatment is essential. Immunosuppressive agents such as azathioprine (AZA) and mycophenolate mofetil (MYC) have been reported to reduce relapse risk and preserve neurological function.[45678] Recently, rituximab, a monoclonal antibody to CD20, has been found to be effective in several reports and small uncontrolled studies.[9] We present our experience with the use of rituximab in Indian patients.

METHODS

This study is a retrospective, observational study in a tertiary hospital in urban India. It included 13 NMOSD patients. All patients of NMOSD seen in a single neurology outpatient department (OPD) from January 1, 2010, to August 1, 2016, who had taken rituximab for at least 2 years, were included in the study. The patients were required to have a diagnosis of NMOSD as per the 2015 international consensus on NMOSD.[3]

Data of all patients were collected from OPD records, OPD database, and admission records. Wherever needed, this was supplemented by telephonic conversation with the patients. The data collected included demographic details; clinical details of number, type, and timing of attacks; and details of rituximab treatment including duration, timings, side effects, and monitoring details.

At the initiation of treatment, rituximab was given as a slow IV infusion of two doses 2 weeks apart of 1 g each. Patients were carefully monitored for infusion reactions and premedicated with IV hydrocortisone 100 mg, IV pheniramine 45 mg, and oral acetaminophen 500 mg. Subsequent cycles were advised at the same dose at time intervals of every 6 months. At all follow-ups, the records of interim admissions elsewhere were also noted. No patient was given concomitant immunosuppressants while receiving rituximab.

Relapses were defined as objective worsening or new neurological symptoms lasting at least 24 h. The acute relapses were treated with high-dose intravenous methylprednisolone. If a severe disability persisted after corticosteroid therapy, plasma exchange was performed. Clinical adverse events were recorded throughout the study.

The primary outcome measure used was annualized relapse rate (ARR), defined as a number of clinical attacks per year. The collected data [Table 1] were analyzed using descriptive statistics and paired t-test.

Table 1

Clinical profile and outcome measures of study patients

RESULTS

Patients’ characteristics

A total of 55 patients of NMOSD were evaluated during the study. Of 55 patients, 16 were started on rituximab as these patients had severe myelopathy with or without optic neuropathy. Three of these patients were excluded from the study as the duration of treatment with rituximab was <2 years. Thus, this study included 13 patients, of which 3 (23%) were male and 10 (77%) were female. The ages of the patients ranged from 12 to 69 years with a mean of 44.1 years. Nine patients (69.23%) had attacks of both optic neuritis and myelitis, whereas four patients (30.77%) had only spinal cord symptoms. Twelve patients (92.31%) were AQP4 antibody positive. The remaining one patient (7.69%) was negative (tested while on steroids) but had characteristic radiological features of NMOSD and satisfied the criteria for diagnosis.

The median interval from onset of NMO to treatment with rituximab was 1 year, 9 months (range: 5 months to 19 years). Before starting rituximab, the patients had a median of three attacks (range: 2–20). Five patients received other long-term immunosuppressant therapy before starting rituximab. Two patients received AZA, two received mitoxantrone, and one received MYC. These patients were switched to rituximab in view of continuing relapse despite these treatments. Eight patients with severe myelopathy (47.06%) were directly started on rituximab before trying other maintenance immunosuppressive treatment. The mean ARR before starting rituximab was 2.60 attacks per year.

Treatment efficacy

The mean duration of treatment with rituximab was 5 years, 1 month (range: 3 years to 9 years and 3 months). The patients received between 2 and 11 cycles of rituximab (mean 5). In the study, 8 (61.54%) of 13 patients were completely relapse free after starting treatment with rituximab. Five patients (38.46%) suffered relapses. Mean ARR reduced from 2.61 to 0.09 after therapy (P = 0.000685). Even in each patient who had relapses, the ARR dropped after starting rituximab and the mean ARR in these patients dropped from 2.42 to 0.24 relapses per year, a decrease of 90.08%.

Relapses during treatment

There were a total of seven relapses in five patients (38.46%). The mean interval between a relapse and last dose of rituximab was 7 months. Four relapses (57%) were associated with delayed retreatment and 3 (43%) occurred within 6 months of the last rituximab dose. The patients who had relapses due to delayed retreatment were noted to be residing in towns faraway from our center, and all had logistic difficulties in returning for a dose on time.

Safety of rituximab treatment

None of the patients suffered any serious adverse effects of the drug including progressive multifocal encephalopathy, malignancies, or major infections. Minor upper respiratory tract infections and one case of cutaneous herpes occurred. Infusion-related reactions were noted in four patients likely due to inadvertent rapid infusion rate. None of these adverse effects led to discontinuation of rituximab.

DISCUSSION

In patients with NMOSD, repeated and severe clinical relapses lead to rapid accumulation of disability. This can be in the form of permanent blindness, loss of ambulatory function, and sphincter involvement.[1] Up to half of NMO diagnosed patients become wheelchair bound or functionally blind in 5 years of disease onset.[10] Disability is directly related to the number of relapses, which add to the burden of destructive multifocal inflammatory lesions. Thus, aggressive immunosuppressive therapy to reduce the relapses is the mainstay of NMOSD treatment. As yet, there are no large-scale randomized control trials to suggest effective treatment guidelines. AZA and MYC had been tried with some success.[5678] These studies demonstrated a reduced relapse rate and disability over the treatment period.

Recently, there have been several uncontrolled studies from different countries for treating NMO using rituximab.[9] In 2005, Cree et al. reported the first open-label study evaluating rituximab in eight NMO patients.[11] They showed a significant reduction in relapses as well as improvement in disability (as measured by expanded disability status scale score) in their patients. A retrospective multicenter analysis of 25 NMO patients in 2008 and two in 2011 (10 and 23 patients) showed similar reduction in relapses as well as disability.[121314] Overall, they suggest that rituximab is associated with reduced relapse rate, even in patients with particularly active disease despite other therapies. The current study in Indian patients also demonstrates a marked beneficial effect of rituximab treatment on patients with NMOSD.

There was a significant reduction of annualized relapse (P < 0.05). These findings agree with other studies reported previously.[9]

The evaluation of sustained efficacy and long-term tolerability of rituximab is important. This was supported by a 5-year follow-up retrospective case series of 30 NMOSD patients published in 2013.[15] This study included patients on long-term rituximab treatment and the mean duration of treatment was 4 years, 4 months, also suggesting long-term efficacy. In 2015, another retrospective analysis of 32 patients explored the response to rituximab in treatment-naïve NMO, with favorable results.[16]

Rituximab has been predominantly used in NMO patients as immunosuppressive therapy to prevent relapses, especially in those who do not respond well to other drugs such as AZA and mycophenolate. It is also being increasingly used as a first-line drug in patients with severe form of NMO. In this study also, the majority of the patients had severe form of NMO with both myelitis and optic neuritis, and all patients had myelitis. Five patients received rituximab as the second-line therapy and eight as the first-line drug in severely affected patients.

Rituximab is a monoclonal antibody to CD20 epitope present on all cells of the B cell lineage except plasma cells. Rituximab depletes CD20+ B cells, which are precursors of short-lived antibody-producing plasma cells, thereby suppressing antibody-mediated immunity and reducing AQP4 antibody levels as well.[131718] The dosing of rituximab in the above studies was of two types: 375 mg/m2/week for 4 weeks or two doses of 1 g each infused 2 weeks apart. In this study, we followed the second protocol, which minimized the number of admissions for the patients. The possibility of using lower doses has been explored, i.e., 100 mg/week, in a recent study in 2013, but requires more evidence to support efficacy.[18] This will likely require extensive B cell monitoring to confirm immune suppression. Advantages such as reduced side effects and cost are obvious.

A major gap in the current knowledge of rituximab treatment of NMOSD is the question of how and when patients with NMO should receive further treatment. Considering the cost of the drug and limited data of safety in NMOSD context, a strategy that minimizes unnecessary exposure is preferred. However, we know that each relapse leads to permanent neurological damage and increasing disability. Thus, waiting for reemergence of clinical symptoms is not possible. There are two methods by which retreatment can be planned.[19] The first is to follow a prespecified schedule. The common current practice is to retreat with an induction regimen every 6 months. This method may reduce follow-up visits and is easier to follow. Another method is to monitor the resulting level of B cell depletion. This strategy may be more effective and safer for chronic treatment. Some patients have poor B cell suppression with rituximab immunotherapy.[20] These are the patients who are likely to relapse before prescheduled dose after 6 months. The treatment monitoring strategy is especially useful in such cases. The objective and reliable therapeutic biomarkers for NMO are under evaluation. Initially, disease-specific biomarker-quantitative AQP4 antibody levels were suggested, but this is not sensitive enough.[13] Treatment-related biomarkers have been tried such as CD19 and CD27. This involves periodically measuring the frequency of memory B cells in peripheral blood. A recent prospective, observational study by Kim et al. used CD27 to monitor memory B cells, and a threshold of 0.05% of peripheral blood mononuclear cells was defined as the limit to start retreatment. This study also showed that targeting CD27+ memory B cells provides a better measure of rituximab efficacy than CD19+ B cells.[21] In the current study, rituximab cycles were given every 6 months.

As with previous studies, most relapses were observed shortly after rituximab induction, likely due to insufficient B cell depletion (as in patient 5) and after delayed retreatment (in patients 2 and 9). Three patients relapsed within 6 months of the last rituximab dose (patients 1, 8, and 9). These patients are likely to have early repopulation of memory B cells, making them prone to frequent relapses. In other studies, up to 17% of rituximab-treated patients had this problem.[20] In these patients, it would be especially useful to monitor CD19 or 27 levels to guide the timing of retreatment. Patient 9 had 3 relapses while on rituximab. The first one occurred at 3 months after the first cycle of rituximab. Despite this, the patients delayed retreatment several times, and relapses may occur in such a situation.

The long-term use of rituximab has shown a reasonable safety profile. It carries a very minor risk of progressive multifocal leukoencephalopathy, malignancies, and severe infections.[22] This study did not have any major adverse reactions, even in patients with longer follow-up. Overall, in other NMO studies mentioned before, rituximab showed an acceptable safety profile. This is also consistent with the data available on long-term use of rituximab rheumatoid arthritis patients.[22] Despite these studies, more data about rituximab long-term safety still need to be collected over time.

This study in Indian patients supports the effectiveness and safety of rituximab as reported in many studies. However, the limitation is that it is a retrospective study in a small number of patients. It will be desirable to have a study in a larger number of patients.

CONCLUSIONS

The treatment of NMOSDs with rituximab in Indian patients reduces the frequency of relapses and is well tolerated.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.