The Use of Rituximab for Treatment of Neuromyelitis Optica

This summary was prepared by Hanni Siegel from the originally published article, “Treatment of Neuromyelitis Optica with Rituximab: Retrospective Analysis of 25 Patients, ” Anu Jacob, MD, MRCP, DM; Brian G. Weinshenker, MD; Ivo Violich, BS; Nancy McLinskey, MD; Lauren Krupp, MD; Robert J. Fox, MD; Dean M. Wingerchuk, MD; Mike Boggild, MD, MRCP; Cris S. Constantinescu, PhD; Aaron Miller, MD; Tracy De Angelis, MD; Marcelo Matiello, MD; Bruce A. C. Cree, MD, PhD, MCR; Archives of Neurology, 2008; Vol. 65 (No. 11), pp. 1143-14481.  Hanni works in the Lerner Research Institute at the Cleveland Clinic doing research in transplantation immunology.   

Neuromyelitis Optica (NMO) is a rare, usually relapsing, inflammatory demyelinating disorder with a high early mortality rate2.   In NMO, the optic nerve and the spinal cord are the targets of the immune system.  With each relapse, there is an accumulation of the extent of disability, and within five years of the initial attack, half of the individuals diagnosed with NMO require the use of a wheelchair and just over half have become functionally blind2.  The current options to treat NMO are based on studies of small numbers of patients, and include a variety of immunomodulatory (drugs used in the treatment of MS) or immunosuppressive medications.  These drugs can work in a variety of ways.  They can bind to immune cells and block their ability to function, prevent them from proliferating, deplete them, or stimulate them to function in a modified way.  The goal is to prevent the ramped up immune response that is responsible for damaging the body, and different immunosuppressive medications work in different ways.  Although some successes has been reported using glatiramer acetate (two patients were reported to have gone into remission on this MS drug) 3,4, it has been found that immunomodulatory medications such as this do not appear to effectively treat NMO in a majority of patients 5,6.  Additionally, with the immunosuppressive medications that have been tried, patients frequently continue to experience relapses2.  Azathioprine is the most commonly used of these, but cyclophosphamide, mitoxantrone, cyclosporine, methotrexate and mycophenolate mofetil have also been used7-10.  

The study summarized here examined the experiences of 25 patients who received rituximab for the treatment of NMO, primarily because other treatments were not working effectively to reduce attacks.  Rituximab is an antibody that binds to a molecule on the surface of B cells, the cells in the body responsible for producing antibody.  These 25 patients were being treated at one of the following centers: University of California – San Francisco, San Francisco, CA; Stony Brook Hospital, Stony Brook, NY; Mayo Clinic, Rochester, MN; Mayo Clinic, Scottsdale, AZ; The Walton Center, Liverpool, England; Mellen Center, Cleveland Clinic, Cleveland, OH; and Mt. Sinai Hospital, New York, NY.  Patients were included in the study if they had relapsing NMO (n=23) or NMO-IgG seropositive longitudinally extensive Transverse Myelitis (n= 2), received at least one dose of rituximab, and were followed for at least 6 months after being treated with rituximab.

Patient gender was overwhelmingly female (88%), and the median age was 38 years, ranging from 7 to 65 years.  Two of the patients were children.  The median time from initial diagnosis to initial treatment with rituximab was four and a half years (range, 0.8 – 17 years).  The median time between last relapse prior to treatment with rituximab and initiation of treatment with rituximab was 1 month (range, 0-7 months).  Of the 20 patients tested, 70% were found to be NMO-IgG seropositive.  For 23 of the patients, rituximab was used due to inefficacy of prior treatment options.  The drugs used prior to treatment with rituximab were Azathioprine (n= 14), Interferon-beta (n= 12), Prednisone (n= 10), Mitoxantrone (n= 7), IV-Immunoglobulins (n= 7), Glatiramer acetate (n= 4), Cyclophosphamide (n= 3), Hydroxychloroquine (n= 1), Methotrexate (n= 1), and Mycophenolate mofetil (n= 1).  The median number of immunotherapy treatments tried prior to treatment with rituximab was 2 (range, 0-6).  Rituximab was the first therapy used for 2 of the patients.  Additionally, 5 of the patients were undergoing additional therapies while being treated with rituximab. These treatments were Prednisone (n=2), Azathioprine (n= 1), Azathioprine and Prednisone (n= 1), and Interferon-beta (n= 1).  Seventeen patients were retreated with rituximab, either at planned intervals following a relapse, or because of the identified presence of B cells.   The median treatment interval was 8 months (range 4-26 months). The post treatment period for which follow-up information was available ranged from 6 to 40 months following initial treatment with rituximab.  During the follow-up time, 7 of the patients stopped treatment for various reasons, including death (n=2), relapses (n=2), and pregnancy (n=1).  For the individual clinical profiles of the patients included in the study, please refer to the original study, specifically the Clinical Profile Table, p. 1145.

For all 25 patients, the relapse rate was significantly decreased from a median of 1.7 relapses per year (range 0.5 – 5) to a median of 0 relapses per year (range 0 – 3.2) following treatment with rituximab.  The decrease in annual relapse rate remained significant even after excluding the patients followed for less than 1 year after treatment with rituximab, the patients undergoing concomitant immunotherapies, and the two patients who died. The median Expanded Disability Status Scale (EDSS) score also significantly decreased (demonstrating physical improvement) from the time of commencement of treatment with rituximab (7, range, 3-9.5) to the time of last follow up (5, range, 3-10).  When looking on a more individualized level, the EDSS score improved for 11 patients, stabilized for 9 patients, and worsened for 5 of the patients.

There were several adverse events that occurred during the treatment and follow-up periods that must be acknowledged.  One patient died following a severe relapse.  This individual had also developed recurrent Clostridium difficile colitis and a urinary tract infection prior to relapsing.  One patient developed fatal septicemia related to a urinary tract infection.  Short-term ill effects related to the infusion of rituximab were observed in 28% of the patients.  Additionally, 3 patients developed new or reactivated infections; one individual developed herpes simplex and positive tuberculin skin test, one individual developed herpes zoster, and one patient developed a cutaneous fungal infection.  Finally, one patient with preexistent seborrheic dermatitis experienced worsening of the condition.   

Rituximab is a drug that suppresses the immune system.  Although it is an inflammatory immune response that is ultimately responsible for the damage caused to the body in NMO, the immune system is a mechanism that is meant to protect and defend the human body.  If some part of the immune system is suppressed, the body can become more vulnerable to other threats.  The infections observed in these patients were not definitively linked to the immunosuppressive effects of rituximab, but the safety concerns remain.  It has not been determined how the risk of infections with rituximab treatment compares to the risk associated with other immunosuppressive treatments.
 
There are several factors that limit the conclusions that can be drawn from the data.  The treatment regimen was not the same for all patients examined; eighteen patients received 375mg/m² once a week for 4 weeks, four of the patients received 1000mg twice, with two weeks between infusions, and the treatment regimen for the remaining 3 patients was unknown.   The presence of B cells was not monitored in all patients; therefore it is unknown how well the treatment worked to actually deplete B cells and if the timing of retreatment was optimal.  Potentially confounding factors include the presence of concomitant therapies in 20% of the patients, as well as possible residual effects of medications used prior to treatment with rituximab.  Finally, it is possible that, because of the timing of pre- and post-treatment EDSS scores, the improvements seen could have been attributed to recovery after a relapse rather than to treatment with rituximab.

Randomized, controlled clinical trials are the gold standard for determining how well a treatment works.  Due to the rarity of this disease, studies analyzing the efficacy of treatment options involve small numbers of patients and the possible confounding variables cannot be eliminated.  While the conclusions that can be drawn from a retrospective study such as this are limited, they are still quite valuable and can help clinicians make more informed treatment decisions.  Especially given the possibility of severe disability from recurring attacks and the risk of mortality for patients with NMO, any information that can assist with treatment decisions is critically important.  It is still not clear whether rituximab should be a first line treatment for NMO; there are other immunosuppressive drugs that are more widely available and less expensive.  This study provides evidence that it is possible that the use of rituximab reduces the frequency of inflammatory attacks and could result in actual physical improvements as measured by EDSS scores for people with NMO.

References
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