The Use of Mycophenolate Mofetil for Treatment of Neuromyelitis Optica

This summary was prepared by Hanni Siegel from the originally published article, “Treatment of Neuromyelitis Optica with Mycophenolate Mofetil: Retrospective Analysis of 24 Patients,” Anu Jacob, MD, MRCP, DM; Marcelo Matiello, MD; Brian G. Weinshenker, MD; Dean M. Wingerchuk, MD; Claudia Lucchinetti, MD; Elizabeth Shuster, MD; Jonathan Carter, MD; B. Mark Keegan, MD; Orhun H. Kantarci, MD; Sean J. Pittock, MD.  Archives of Neurology, 2009; Vol. 66 (No. 9), pp. 1128-11331.    

Neuromyelitis Optica (NMO) is a rare, usually relapsing, inflammatory demyelinating disorder in which the optic nerve and the spinal cord are the targets of the immune system2.  With each relapse, there is an accumulation 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.  Neuromyelitis Optica-IgG (NMO-IgG) is an autoantibody specific for astrocyte water channel aquaporin 43,4, and its presence in patient serum serves as a biomarker that reliably identifies relapsing NMO or NMO spectrum disorders (NMO-IgG seropositive patients with optic neuritis, and NMO-IgG seropositive patients with longitudinally extensive transverse myelitis) 5and is predictive of relapse6,7.  Given that accumulation of disability is associated with relapse, one of the goals of treatment should be prevention of continued attacks.  Current strategies employ the use of immunosuppressive drugs8 such as azathioprine9, corticosteroids10, mitoxantrone11, and rituximab12,13.  Small case series of the use of these immunosuppressive treatments have provided evidence of their efficacy, but no randomized controlled trials have been conducted in patients with NMO, given the rarity of this disease. 

The study summarized here examined the experiences of 24 patients with NMO (n=15) or an NMO spectrum disorder (NMO-IgG seropositive optic neuritis, n=1; NMO-IgG seropositive longitudinally extensive transverse myelitis, n=8) who received mycophenolate mofetil for the treatment of NMO.  The median dose was 2000mg/day (range, 750-3000mg/day).  Mycophenolate mofetil (Cellcept, F. Hoffman-La Roche, Basel, Switzerland) inhibits the proliferation of T and B Cells as well as the production of antibody14.  Currently, it is widely used in cardiac and renal transplantation, and its use in the treatment of various autoimmune conditions is growing.  Mycophenolate mofetil is a promising treatment option, as there appears to be fewer adverse effects, and it can be administered orally.  These 24 patients were being treated at one of three of the following Mayo Clinic sites: Rochester, MN; Scottsdale, AZ; and Jacksonville, FL.

Patient gender was female in 79% of the cases, and the median age was 56 years, ranging from 34 to 77 years.  The median time from initial diagnosis to initial treatment with mycophenolate mofetil was 4.2 years (range, 0.1 – 39 years).  Mycophenolate mofetil was the first therapy tried for 7 of the patients.  Among the other 17 patients, adverse effects of medication (n=7), continued relapses (n=8), and contraindication of azathioprine (n=2) were the reasons for switching to mycophenolate mofetil.  The drugs used prior to treatment with mycophenolate mofetil were azathioprine (n= 12), interferons (n= 9), prednisone (n= 7), mitoxantrone (n= 2), IV-immunoglobulins (n= 2), glatiramer acetate (n= 4), cyclophosphamide (n= 3), methotrexate (n= 2), and IV-methylprednisone (n= 1).  Additionally, 9 of the patients were undergoing additional therapies while being treated with mycophenolate mofetil.  These treatments were prednisone (n=5), methylprednisone (pulsed IV, n=2; IV, n=1; orally, n=1) and IV-Immunoglobulin (n=1).   The median duration of treatment with mycophenolate mofetil was 27.4 months (range 1-89 months).  The post treatment period for which follow-up information was available through telephone contact ranged from 18 to 89 months (median= 27 months). During the follow-up time, 5 of the patients stopped treatment for various reasons, including death (n=1), relapses (n=2), adverse effects (n=1), and one patient chose to switch to rituximab.  For the individual clinical profiles of the patients included in the study, please refer to the original study, specifically the Clinical Characteristics of Patients Treated with Mycophenolate Mofetil Table, p. 1130.

The relapse rate was significantly decreased from a median of 1.28 relapses per year (range 0.23 – 11.78) to a median of 0.9 relapses per year (range 0 – 1.56) following treatment with mycophenolate mofetil.  79% of the patients saw a decrease in their annualized relapse rate.  The decrease in relapse rate remained significant even after excluding the patients undergoing treatment with mycophenolate mofetil for less than 6 months, the patients undergoing concomitant immunotherapies, and the one patient who died. The median Expanded Disability Status Scale (EDSS) score also decreased (demonstrating physical improvement) from the time of commencement of treatment with mycophenolate mofetil (6, range, 0-8) to the time of last follow up (5.5, range, 0-10), however this decrease did not reach statistical significance.  When looking on a more individualized level, the EDSS score improved for 7 patients (median reduction = 1 point, range 0.5-2.5), stabilized for 15 patients, and worsened for 2 of the patients.

There were several adverse events that occurred during the treatment and follow-up periods that must be acknowledged.  One patient, who continued to relapse approximately every 6 months during treatment with mycophenolate mofetil, died 54 months following initiation of treatment of complications most likely associated with the continued attacks and consequent disability. The following adverse effects were reported by one patient each: headache, constipation, easy bruising, anxiety, hair loss, diarrhea and abdominal pain.  One patient discontinued therapy due to low white blood cell counts.

This case series demonstrated an association between reduction in rate of relapse and either reduction or stabilization of disability scores and treatment with mycophenolate mofetil.  There are several factors that limit the conclusions that can be drawn from the data.  Potentially confounding factors include the presence of concomitant therapies in 38% of the patients, as well as possible residual effects of medications used prior to treatment with mycophenolate mofetil.  It is possible that the reduction in relapse rate observed could be attributed to regression toward the mean (i.e., if relapses were frequent for an individual in the last few years by the law of averages it can only get  better now!).  Also, while the case series illustrates promise for the efficacy of mycophenolate mofetil in the treatment of NMO and NMO spectrum disorders, there are some safety concerns regarding the use of this drug.  There are toxicity concerns, and while no cases of progressive multifocal leukoencephalopathy have been reported in patients undergoing mycophenolate mofetil monotherapy, cases have been reported in transplant (kidney, heart, and lung) recipients and in systemic lupus erythematosus when mycophenolate mofetil was used in conjunction with or following other immunosuppressive treatments.  To give an idea of frequency, in a study examining 32,757 kidney transplant recipients, 9 cases were identified.  This is a very small percentage, but worth noting. 

The most common treatment of NMO is either prednisone alone or prednisone combined with azathioprine.  This is based on a case series of 7 patients who showed significant improvement in EDSS scores and absence of relapse9.  Mitoxantrone is another treatment option.  Improvement was seen in a case series of 5 patients, however there was not a complete absence of relapse and cardiotoxicity is a concern with this medication, limiting the amount of time a patient can take this medication.  Rituximab is another immunosuppressive medication used to treat NMO, and in a case series of 25 patients treated with rituximab, a decrease in rates of relapse, as well as improvement or stabilization in disability scores in 80% of patients was observed.  However, use of rituximab may be associated with infection risk (20% of patients experienced infection that may have been due to the immunosuppressive effects of the drug) and 28% of the patients experienced adverse effects related to intravenous infusion. 

While the conclusions that can be drawn from this small retrospective study are limited, they still offer insight for clinicians trying to make informed treatment decisions. This study provides evidence that it is possible that the use of mycophenolate mofetil reduces the frequency of inflammatory attacks and could result in stabilization of disability.  The treatment options discussed above have also been found to be associated with a reduction in relapse rates and disability scores.  Because controlled clinical trials have not been performed, definitive conclusions regarding the superiority of one treatment over another cannot be drawn.  Therefore, clinicians must consider potential for adverse effects, treatment cost, and need for immediate immunosupression when choosing the most appropriate treatment for individuals with NMO or NMO spectrum disorders.

References

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