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Neuromyelitis Optica
Optimized Azathioprine Can Be Effective for Neuromyelitis Optica
Weight-based dosing, laboratory monitoring for biologic effect, and concurrent use of prednisone are important for treatment success.
Azathioprine is often used to prevent relapses in patients with neuromyelitis optica (NMO), but data on its efficacy are limited. These researchers retrospectively examined open-label azathioprine use in 99 patients with NMO. Treating clinicians optimized azathioprine dose by testing for thiopurine methyltransferase (TPMT) genetic variation (which affects drug metabolism), by prescribing concurrent high-dose corticosteroids for the initial 6 months and low-dose corticosteroids for breakthrough disease activity, and by considering body weight and hematologic parameters. Median follow-up was 22 months (range, 12–180).
Annualized relapse rates (ARRs) were assessed in 70 patients with at least 12 months of follow-up. ARR decreased significantly from 2.18 before treatment, to 0.52 in those treated with 
2.0 mg/kg/day and 0.82 in those treated with <2.0 mg/kg/day; the difference between these treatment groups was significant. About one third of patients were free of relapses on treatment. In 52 patients, concomitant prednisone was prescribed (median starting dose, 60 mg, tapered over a median of 12 months). Among all patients, ARR declined from 0.51 in the first year to 0.27 subsequently. An increase of >5 points in mean corpuscular volume (MCV) was associated with a decline in ARR during treatment. The median Expanded Disability Status Scale score was 3.5 both before and after treatment. Azathioprine was discontinued in 38 patients: 22 because of adverse effects, 13 because of inadequate efficacy, and 3 after developing lymphoma.
Comment: Although this trial of azathioprine use in NMO was not randomized or controlled, the authors raise several issues that are critical to optimizing this therapy. Azathioprine remains a reasonable treatment option for NMO because of its low cost and because several retrospective studies suggest efficacy. Disadvantages include a delay in effect necessitating at least several months of prednisone, the need for detailed monitoring, gastrointestinal intolerability for some, and an uncommon association with lymphoma (3% in this series).
Titration to biologic effect is important. The authors advocate a weight-based dose of 2.5 to 3.0 mg/kg/day after determining TPMT status, and then monitoring MCV. Other clinicians titrate to white cell count 3000 per mm3, or lymphocyte count 1000 per mm3.
Oral immunosuppressive agents (azathioprine and mycophenolate mofetil) can be used particularly in patients without frequent relapses and with 6 months of concomitant prednisone. For those with rapid and severe relapses, rituximab provides a more rapid therapeutic effect. For aggressive NMO, rituximab might be useful initially to gain disease control before instituting azathioprine or another purine inhibitor.
source: Journal Watch Neurology
Muscle Involvement in Neuromyelitis Optica
Are organs outside of the central nervous system affected in NMO?
Neuromyelitis optica (NMO) is an inflammatory central nervous system (CNS) disease associated with autoantibodies that target aquaporin-4, an astrocyte water channel. These researchers report on three patients who developed initial NMO symptoms following transient, self-limited episodes of fatigue and creatine kinase (CK) elevation (range, 12,520–59,660 IU/L) of unknown cause. The cases were identified through retrospective review of 733 serum samples from a diagnostic laboratory that provides testing for aquaporin-4 antibodies. In one pediatric case, CK elevation recurred without an associated NMO relapse (NMO relapses occurred independently). The authors could find no cause for the CK elevations; muscle biopsies were not performed.
Because aquaporin-4 is also the main water channel expressed in fast-twitch skeletal muscle fibers, the authors developed three hypotheses regarding NMO pathogenesis. In the first, exposure of muscle aquaporin-4 resulting from muscle destruction of any cause induces development of autoantibodies and T cells reactive against aquaporin-4. In the second, preexisting autoantibodies target aquaporin-4 in both muscle and the CNS. In the third, muscle injury activates preexisting autoantibodies and T cells reactive to aquaporin-4, resulting in blood–brain barrier disruption and facilitating an immune attack on CNS tissue.
Comment: Accumulating evidence, including from novel animal models of NMO, supports the pathogenic potential of aquaporin-4 autoantibodies in NMO. Spinal cord and optic nerve, and, to a lesser degree, the brain, are targets of inflammatory attacks. However, aquaporin-4 is also present on certain cells of the muscle, gut, kidney, and retinal systems, raising questions about why no dysfunction of these organs is clinically evident in NMO. The current report provides a systematic, albeit retrospective and nonspecific, assessment of muscle injury in NMO and suggests that such involvement may be underrecognized. Just as in the CNS, where some lesions are destructive and others are rapidly reversible, various physical and immunological factors may make systemic aquaporin-4 a less clinically important antigenic target. However, more-systematic pathological study of all tissues that express aquaporin-4 will enhance our understanding of NMO pathobiology.
— Dean M. Wingerchuk, MD, MSc, FRCP(C)
Dr. Wingerchuk is Professor of Neurology, Mayo Clinic College of Medicine, Mayo Clinic Arizona, Scottsdale.
Published in Journal Watch Neurology August 10, 2010
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