Neuromyelitis optica (NMO) or Devic's disease is a relatively rare and frequently severe autoimmune inflammatory disorder of the central nervous system (CNS) that, in the majority of cases (~90%), has a relapsing rather than a monophasic course.1 It is difficult to determine the exact incidence or prevalence of NMO because of evolving diagnostic criteria, as well as a lack of separation in the published literature between NMO and optic spinal presentations of multiple sclerosis (MS).1–3 Based on estimates obtained from clinic-based case series conducted in the United States and Europe, the frequency of NMO relative to MS has been estimated at 1 to 2:100.1 Reports regarding the prevalence of NMO vary, ranging from 0.51 to 4.4 per 100,000 people per year.4,5 By contrast, MS is far more common, affecting 69.1 per 100,000 person-years throughout the world.6 A meta-analysis published in 2015, however, concluded that the number of NMO patients is likely to increase as awareness of the disease increases and diagnostic criteria are more widely adopted.5
The pathology of NMO is complex.7 The disease is characterized by severe, frequently bilateral optic neuritis and/or longitudinally extensive transverse myelitis.8,9 The pathophysiology of NMO is likely of autoimmune character, with immunoglobulin G (IgG) autoantibodies targeted against the aquaporin-4 (AQP4) water channel (widely expressed in the optic nerves and spinal cord) found in the serum of approximately 75% of NMO patients.8,10 Aquaporin-4-reactive T cells, which produce interleukin (IL)-17, occur more frequently in NMO patients than healthy controls, suggesting a role for Th17 cells in NMO pathogenesis.11 Demonstration of a pathogenic role for the (AQP4) antibody and the suggested involvement of the IL-17 axis have marked significant advances in the understanding of NMO.4,8,9,11
There is substantial evidence, including clinical, neuroimaging, immunologic, and immunopathologic data, that distinguishes NMO from MS.1 Classically, patients with bilateral optic neuritis and nonspecific brain magnetic resonance imaging (MRI) findings failing to meet the criteria for MS and who also have longitudinally extensive spinal cord lesions and meet the NMO-IgG criteria would likely be diagnosed with NMO.1 Revised diagnostic methods were published in 2006 with the objective of providing optimal criteria to distinguish NMO from MS and have now become widely accepted.1–3
In contrast to the improvements in the diagnosis of NMO, until recently, the advances in treatment have been slow.1 Some immunomodulating agents that are effective in MS (ie, β-interferons) were found to exacerbate NMO.8,12,13 Glatiramer acetate has not been found to be effective (it has been used in only 2 case studies),8 and natalizumab did not demonstrate any positive impact on NMO.14,15 Because NMO is far less prevalent than MS, there has historically been a deficiency of randomized clinical trials for this condition, resulting in a lack of validated treatment strategies and Food and Drug Administration (FDA)–approved medications, making real-life clinical observations important.8,16 Sequential therapeutic plasma exchange (PLEX; plasmapheresis) and systemic corticosteroids are used off-label for treatment of exacerbations, with intravenous methylprednisolone (IVMP) considered as first-line therapy.1 Off-label treatments directed toward preventing exacerbations include azathioprine, methotrexate, mycophenolate mofetil, intravenous immunoglobulin, regular systemic steroids, and rituximab, the latter considered the most accepted option.8,17 Recently, however, eculizumab, the first treatment specifically studied and indicated for NMO spectrum disorder (NMOSD), was approved by the FDA in June 2019, for AQP4-IgG-positive NMOSD.18 The anti-IL-6R antibody tocilizumab has also shown promise in case studies and clinical trials in patients with NMO and NMOSD, with additional studies ongoing, and the anti-CD19 antibody inebelizumab is under investigation.8,19–23
There is no published literature on the safety and efficacy of adrenocorticotropic hormone (ACTH; H.P. Acthar Gel [repository corticotropin injection]; Mallinckrodt ARD Inc, Hazelwood, MO) for the treatment of acute NMO. It has, however, been demonstrated as safe and effective in the treatment of exacerbations in patients with relapsing MS.24,25 The clinical application of ACTH is very similar to that of systemic steroids despite a different mechanism of action, including the targeting of melanocortin receptors not targeted by steroids.26,27 Therefore, it is hypothesized that ACTH may provide an alternative treatment option for patients who are not responding adequately to systemic steroids or who cannot be treated with them or other immunosuppressive agents because of severe adverse events (AEs). This report summarizes single-provider observations on the efficacy, safety, and tolerability of ACTH in a series of NMO patients who did not respond adequately to previous treatments with steroids and who declined other treatments options offered to them. This study was conducted with institutional review board approval from the University of Southern California. Patient consent was not required.
Retropsective chart review of patients treated between 2008 and 2017 was conducted, and 6 patients were identified. Their mean age was 48.6 years, and mean duration of NMO was 8.0 years. All patients' cerebrospinal fluid tested negative for oligoclonal bands at the time of diagnosis. Five of 6 patients were seropositive for AQP4 antibody, and 1 patient was seronegative for AQP4 antibodies and was anti–myelin oligodendrocyte glycoprotein (MOG) negative. Patients had previously received IVMP for their initial NMO exacerbations followed by monthly use of IVMP for a mean of 7.0 months (as they had declined other off-label steroid-sparing and potentially relapse-preventing treatments). Adrenocorticotropic hormone was initiated for a subsequent exacerbation, which developed while on recent/monthly IVMP treatment. Demographic data, clinical characteristics, and disease history for each patient are presented in Table 1.
Each patient had previously received 1 g of IVMP sodium succinate (Solu-Medrol; Pfizer, New York, NY) for initial relapse, followed by continuous use of IVMP every 4 weeks for at least 6 months (with the exception of patient 6, who was treated with IVMP for 5 days with no adequate response) before altering the treatment approach because of clinical relapses while on monthly IVMP (n = 5) and/or inadequate response to initial IVMP (n = 1). All patients were given the option to switch to treatment with rituximab, but declined. Adrenocorticotropic hormone was then proposed as an alternative option to replace systemic steroids. Adrenocorticotropic hormone gel was administered intramuscularly (IM) 80 U (1 mL) per day for 7 days (to address the ongoing relapse), followed by 80 U given once every 2 weeks (for long taper down/maintenance). Regular clinical evaluations every 1 to 3 months with potential relapse assessments, Expanded Disability Status Scale (EDSS) scores, laboratory tests, and AE assessments were performed. Patient-reported outcomes were recorded and characterized as having the following grades: no change, minimally improved/worsened, moderately improved/worsened, or significantly improved/worsened as compared with baseline.
The course of treatment and clinical observations for each patient are presented in Table 2. Generally, patients had an increase in EDSS from the time of diagnosis (mean, 6.50) to their first change in treatment (mean, 6.67), and the majority of changes in treatment were preceded by clinical relapses (Table 2). For some patients, decrease of EDSS (mean, 6.33) was observed after initiation of ACTH treatment. None of the patients had relapses after initiation of ACTH for the time of this observation. The duration of ACTH treatment ranged from 4 to 10 months. Blood glucose measurements were within normal limits, and laboratory tests demonstrated no safety concerns while patients were on ACTH. Annual follow-up brain, cervical, and thoracic MRIs have been stable with no new or active lesions or other signs of disease progression.
Patient-reported AEs are included in Table 3 and compared with IVMP across categories common with IVMP treatment: insomnia, changes in mood, irritability, and others. Patients characterized AEs experienced during ACTH treatment as improved or unchanged compared with those experienced during treatment with systemic corticosteroids, although 1 patient reported edema of both lower extremities that was only present during treatment with ACTH. It also was noted that 2 patients with pressure ulcers reported a better status while on ACTH as compared with their experience with IVMP. Patient-reported AEs that were potentially treatment related included edema and acne, as well as urinary tract infection and insomnia, with the last 2 being generally reported by affected patients as less severe with ACTH than IVMP.
This is the first published case series that provides clinical and paraclinical observations on ACTH treatment experience among individuals with NMO who previously had inadequate response (largely by experiencing clinical relapses) or could not tolerate systemic steroids. The results obtained from these 6 patients demonstrate that treatment with ACTH could be a promising option for acute NMO patients who do not respond to or cannot tolerate systemic steroids such as IVMP. In these cases, fewer AEs were reported for patients receiving ACTH compared with IVMP, and reported AEs were less severe than those experienced with IVMP. The small number of clinical cases observed here does not allow for firm conclusions or clinical recommendations; however, these assessments are consistent with our observations in more than 100 MS patients over 15 years, who received ACTH for MS relapses and also reported milder adverse effects of ACTH as compared with their experience with systemic steroids. Clearly, the significant price difference between systemic steroids and ACTH makes the use of ACTH only feasible when systemic steroids use is not possible or rational, as it was in our cases.
Currently, there is only 1 FDA-approved therapeutic disease modifying treatment option for NMO, and many of the therapies used for treatment of MS are either not effective in NMO or have the potential to exacerbate the condition. For acute NMO treatment, systemic steroids and PLEX are the current standard. For those cases not responding to systemic steroids, an alternative pharmacological option is needed. A recent study showed distinctly different immunology profiles of ACTH and systemic steroids, providing further knowledge of the distinctions between the 2 treatment approaches.28 Observed results suggest that the treatment experience of acute NMO patients with ACTH could be positive in those who previously failed systemic steroids such as IVMP. The decrease in relapses after ACTH initiation in this study may be associated with the previously reported reduction in inflammatory cytokines observed after ACTH treatment (but not IVMP),28 and perhaps other mechanisms of ACTH, including possible targeting of broadly distributed melanocortin receptors including those within the CNS.
Our observations suggest that ACTH should be further evaluated as an alternative option for acute NMO patients who either fail or cannot tolerate systemic steroids such as IVMP. Larger, prospective, controlled clinical studies are still needed to make clinical recommendations concerning ACTH for treatment of NMO.
The author thanks Aric Fader, PhD, and Michelle Jones, PhD, of MedVal Scientific Information Services, LLC (Princeton, NJ) for medical writing and editorial assistance, which followed Good Publication Practice for Communicating Company-Sponsored Medical Research: The GPP3 Guidelines.
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