Comparison of Relapse and Treatment Failure Rates Among Patients With Neuromyelitis Optica

Abstract

euromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system (CNS) distinct from multiple sclerosis (MS). It is characterized by optic neuritis (ON), longitudinally extensive transverse myelitis (TM), and, in approximately 70% of cases, the presence in serum of IgG antibodies that target aquaporin 4 (AQP4-IgG; also known as NMO-IgG). Patients with neuromyelitis optica spectrum disorder (NMOSD) are seropositive for AQP4-IgG and have evidence of an inflammatory event consistent with NMO, including TM, ON, or brainstem inflammation. Disease-modifying treatment for relapse prevention in patients with NMO and NMOSD requires immunosuppression because some immunomodulatory therapies used for MS appear to aggravate NMO. 1-3 Although no placebo-controlled or comparative randomized controlled trials of immunosuppressive therapies have been conducted for NMO and there is no consensus on how to select initial therapy, there is evidence that azathioprine, mycophenolate mofetil, and rituximab are effective in reducing relapse rates. 4-10 We conducted this retrospective study to compare relapse and treatment failure rates among NMO and NMOSD patients who received azathioprine, mycophenolate, or rituximab as their initial long-term immunosuppressive therapy at the Johns Hopkins Hospital and Mayo Clinic. Methods Institutional review board approval was obtained from the Johns Hopkins University and Mayo Clinic. Deidentified data were used; therefore, patient consent was not required. Patients were included if they were diagnosed as having NMO IMPORTANCE Neuromyelitis optica (NMO) is an inflammatory disease of the optic nerves and spinal cord that leads to blindness and paralysis. Effective immunosuppression is the standard of care for relapse prevention. OBJECTIVE To compare the relapse and treatment failure rates among patients receiving the 3 most common forms of immunosuppression for NMO: azathioprine, mycophenolate mofetil, and rituximab. DESIGN, SETTING, AND PARTICIPANTS We performed a retrospective, multicenter analysis of relapses in 90 patients with NMO and NMO spectrum disorder treated with azathioprine, mycophenolate, and/or rituximab at the Mayo Clinic and the Johns Hopkins Hospital during the past 10 years. MAIN OUTCOME AND MEASURE Annualized relapse rates. RESULTS Rituximab reduced the relapse rate up to 88.2%, with 2 in 3 patients achieving complete remission. Mycophenolate reduced the relapse rate by up to 87.4%, with a 36% failure rate. Azathioprine reduced the relapse rate by 72.1% but had a 53% failure rate despite concurrent use of prednisone. CONCLUSIONS AND RELEVANCE Initial treatment with rituximab, mycophenolate, and, to a lesser degree, azathioprine significantly reduces relapse rates in NMO and NMO spectrum disorder patients. Patients for whom initial treatment fails often achieve remission when treatment is switched from one to another of these drugs.

Present and Future Therapies in Neuromyelitis Optica Spectrum Disorders

“…Another retrospective study of 103 patients with AQP4-IgG-positive NMOSD confirmed these findings, revealed a reduction of the median ARR in 89 % of patients (median of 1.5 pretreatment to 0 on AZA), and an improvement or stabilization of the EDSS in 78 % of patients, but again had a high discontinuation rate of AZA (46 %) [78]. A third retrospective study of 31 patients with AQP4-IgG-positive or AQP4-IgG-negative NMOSD described a reduction in the mean ARR from 2.26 to 0.63 with a failure rate in 53 % of patients, despite concomitant prednisone therapy [79]. Another retrospective study of AZA plus long-term low-dose corticosteroid therapy in 77 Chinese patients found a relapse-free status at median follow-up of 19 months in 44 patients (57.1 %) and significant improvements of the ARR, EDSS, and modified Rankin Scale [80].…”

“…MMF treatment for a median of 20-27 months resulted in a reduction of the ARR by 80-93 % and improvement of the median EDSS in 3/ 4 studies (not reported in 1). More than 90 % of patients had stable or improved disability [83,84], and 46-65 % were relapse-free [79,81,83,84]. Discontinuation rates due to disease activity or side effects were 15-25 %.…”

“…Several studies including a total of almost 400 patients have shown that AZA reduces the ARR, sometimes associated with improvement of neurological disability [17,[74][75][76][77][78][79][80]. A retrospective study evaluating classical NMO and patients with AQP4-IgG-positive NMOSD reported a decrease in the mean ARR from 2.18 to 0.64 in 70 patients treated with AZA for >1 year, with or without concomitant corticosteroid therapy [77].…”

“…While the discussed studies have shown that AZA can reduce the ARR in patients with NMOSD, 2 recent retrospective studies suggested that the risk for further NMOSD attacks was significantly higher with AZA treatment than with B-celldepleting rituximab therapy [hazard ratio (HR) 2.12 and 1.82, respectively] [79,81], and that severe attacks occurred more often in patients treated with AZA (HR 11.66) [81]. AZA is given at a dose of 2-3 mg/kg/day, should be slowly tapered in with monitoring of hematological parameters and transaminases, and reaches clinical activity after 3-6 months.…”

“…It inhibits lymphocyte proliferation by suppression of guanosine nucleotide biosynthesis and is used for psoriasis, proliferative lupus nephritis, and renal transplant rejection. Four retrospective cohorts evaluating 24-58 patients with mostly AQP4-IgG-positive NMOSD have reported beneficial outcomes of MMF therapy with or without concomitant corticosteroids [79,81,83,84]. MMF treatment for a median of 20-27 months resulted in a reduction of the ARR by 80-93 % and improvement of the median EDSS in 3/ 4 studies (not reported in 1).…”