Neuromyelitis optica (NMO) is a chronic inflammatory disease of the central nervous system that affects the optic nerves and spinal cord resulting in visual impairment and myelopathy. There is a growing body of evidence that immunotherapeutic agents targeting T and B cell functions, as well as active elimination of proinflammatory molecules from the peripheral blood circulation, can attenuate disease progression. In this review, we discuss the immunotherapeutic options and the treatment strategies in NMO. We also analyze the pathogenic mechanisms of the disease in order to provide recommendations regarding treatments. 1. Introduction Neuromyelitis optica (NMO), also known as Devic’s disease, is a chronic inflammatory disease of the central nervous system (CNS) that preferentially targets the optic nerves and spinal cord [1]. The overall disease incidence has been estimated at 1？:？100,000 and that it has a predilection for middle-aged, non-Caucasian females [2]. NMO spectrum disorders (NMOSD) encompass a variation of this classical picture in that patients may have brain involvement or a more limited presentation such as isolated transverse myelitis or an optic neuritis [3]. Historically, many thought of NMO as a rare variant of multiple sclerosis (MS). Given the identification of unique clinical and radiological differences and the discovery of the NMO-IgG, an autoantibody against aquaporin-4 (aqp4), it is now understood to be its own entity with distinct pathogenesis, diagnostic criteria, prognosis, and treatment [1–5]. Until recently, NMO was considered a disease of limited therapeutic options and poor prognosis. Research over the last decade brought new understanding of the disease pathogenesis that translated into immunotherapy directed against this disease. Moreover, there is a growing body of evidence that NMO can be controlled by immunotherapeutics targeting its cellular and humoral immune mechanisms. We review the immunotherapy of NMO, the various treatment options, and the clinical strategies that are typically encountered in practice. 2. Neuromyelitis Optica: An Overview NMO is a neurological disorder that classically presents as a case of severe bilateral optic neuritis associated with a transverse myelitis [1–5]. The typical disease onset is either acute or subacute, and the symptoms are likely to persist without treatment. Optic neuritis results in decreased or a complete loss of vision. Transverse myelitis is usually extensive and spans more than 3 consecutive vertebral segments. Deficits related to myelitis include paralysis and sensory
References
[1]
D. M. Wingerchuk, V. A. Lennon, S. J. Pittock, C. F. Lucchinetti, and B. G. Weinshenker, “Revised diagnostic criteria for neuromyelitis optica,” Neurology, vol. 66, no. 10, pp. 1485–1489, 2006.
[2]
D. M. Wingerchuk, W. F. Hogancamp, P. C. O'Brien, and B. G. Weinshenker, “The clinical course of neuromyelitis optica (Devic's syndrome),” Neurology, vol. 53, no. 5, pp. 1107–1114, 1999.
[3]
D. M. Wingerchuk, V. A. Lennon, C. F. Lucchinetti, S. J. Pittock, and B. G. Weinshenker, “The spectrum of neuromyelitis optica,” The Lancet Neurology, vol. 6, no. 9, pp. 805–815, 2007.
[4]
J. I. O'Riordan, H. L. Gallagher, A. J. Thompson et al., “Clinical, CSF, and MRI findings in Devic's neuromyelitis optica,” Journal of Neurology Neurosurgery and Psychiatry, vol. 60, no. 4, pp. 382–387, 1996.
[5]
P. V. A. Lennon, D. M. Wingerchuk, T. J. Kryzer et al., “A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis,” The Lancet, vol. 364, no. 9451, pp. 2106–2112, 2004.
[6]
T. Misu, K. Fujihara, I. Nakashima, S. Sato, and Y. Itoyama, “Intractable hiccup and nausea with periaqueductal lesions in neuromyelitis optica,” Neurology, vol. 65, no. 9, pp. 1479–1482, 2005.
[7]
K. Tashiro, K. Ito, and Y. Maruo, “MR imaging of spinal cord in Devic disease,” Journal of Computer Assisted Tomography, vol. 11, no. 3, pp. 516–517, 1987.
[8]
F. Masuhr, M. Busch, K. Wetzel, L. Harms, and E. Schielke, “Relapsing myelitis with pathological visual evoked potentials: a case of neuromyelitis optica?” European Journal of Neurology, vol. 9, no. 4, pp. 430–432, 2002.
[9]
D. B. Fernandes, A. S. Raza, R. G. Nogueira et al., “Evaluation of inner retinal layers in patients with multiple sclerosis or neuromyelitis optica using optical coherence tomography,” Ophthalmology, vol. 57, no. 3, pp. 387–394, 2012.
[10]
B. G. Weinshenker, D. M. Wingerchuk, S. Vukusic et al., “Neuromyelitis optica IgG predicts relapse after longitudinally extensive transverse myelitis,” Annals of Neurology, vol. 59, no. 3, pp. 566–569, 2006.
[11]
J. E. Cosnett, “Multiple sclerosis and neuromyelitis optica in tropical and subtropical countries,” Medical Hypotheses, vol. 7, no. 1, pp. 61–63, 1981.
[12]
S. Yoshimura, N. Isobe, T. Matsushita et al., “Distinct genetic and infectious profiles in Japanese neuromyelitis optica patients according to anti-aquaporin 4 antibody status,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 84, no. 1, pp. 29–34, 2013.
[13]
H. Zéphir, I. Fajardy, O. Outteryck et al., “Is neuromyelitis optica associated with human leukocyte antigen?” Multiple Sclerosis, vol. 15, no. 5, pp. 571–579, 2009.
[14]
V. A. Lennon, T. J. Kryzer, S. J. Pittock, A. S. Verkman, and S. R. Hinson, “IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel,” Journal of Experimental Medicine, vol. 202, no. 4, pp. 473–477, 2005.
[15]
P. Agre and D. Kozono, “Aquaporin water channels: molecular mechanisms for human diseases,” FEBS Letters, vol. 555, no. 1, pp. 72–78, 2003.
[16]
L. Sabater, A. Giralt, A. Boronat et al., “Cytotoxic effect of neuromyelitis optica antibody (NMO-IgG) to astrocytes: an in vitro study,” Journal of Neuroimmunology, vol. 215, no. 1-2, pp. 31–35, 2009.
[17]
T. Vincent, P. Saikali, R. Cayrol et al., “Functional consequences of neuromyelitis optica-IgG astrocyte interactions on blood-brain barrier permeability and granulocyte recruitment,” Journal of Immunology, vol. 181, no. 8, pp. 5730–5737, 2008.
[18]
Y. Li, H. Wang, Y. Long, Z. Lu, and X. Hu, “Increased memory Th17 cells in patients with neuromyelitis optica and multiple sclerosis,” Journal of Neuroimmunology, vol. 234, no. 1-2, pp. 155–160, 2011.
[19]
C. F. Lucchinetti, R. N. Mandler, D. McGavern et al., “A role for humoral mechanisms in the pathogenesis of Devic's neuromyelitis optica,” Brain, vol. 125, no. 7, pp. 1450–1461, 2002.
[20]
S. F. Roemer, J. E. Parisi, V. A. Lennon et al., “Pattern-specific loss of aquaporin-4 immunoreactivity distinguishes neuromyelitis optica from multiple sclerosis,” Brain, vol. 130, no. 5, pp. 1194–1205, 2007.
[21]
D. Lefkowitz and J. N. Angelo, “Neuromyelitis optica with unusual vascular changes,” Archives of Neurology, vol. 41, no. 10, pp. 1103–1105, 1984.
[22]
R. N. Mandler, L. E. Davis, D. R. Jeffery, and M. Kornfeld, “Devic's neuromyelitis optica: a clinicopathological study of 8 patients,” Annals of Neurology, vol. 34, no. 2, pp. 162–168, 1993.
[23]
R. N. Mandler, W. Ahmed, and J. E. Dencoff, “Devic's neuromyelitis optica: a prospective study of seven patients treated with prednisone and azathioprine,” Neurology, vol. 51, no. 4, pp. 1219–1220, 1998.
[24]
B. G. Weinshenker, P. C. O'Brien, T. M. Petterson et al., “A randomized trial of plasma exchange in acute central nervous system inflammatory demyelinating disease,” Annals of Neurology, vol. 46, no. 6, pp. 878–886, 1999.
[25]
M. Bonnan and P. Cabre, “Plasma exchange in severe attacks of neuromyelitis optica,” Multiple Sclerosis International, vol. 2012, Article ID 787603, 9 pages, 2012.
[26]
A. Polgár, C. Rózsa, V. Müller, J. Matolcsi, G. Poór, and E. V. Kiss, “Devic's syndrome and SLE. Challenges in diagnosis and therapeutic possibilities based on two overlapping cases,” Autoimmunity Reviews, vol. 10, no. 3, pp. 171–174, 2011.
[27]
D. M. Wingerchuk, S. J. Pittock, C. F. Lucchinetti, V. A. Lennon, and B. G. Weinshenker, “A secondary progressive clinical course is uncommon in neuromyelitis optica,” Neurology, vol. 68, no. 8, pp. 603–605, 2007.
[28]
C. Costanzi, M. Matiello, C. F. Lucchinetti et al., “Azathioprine: tolerability, efficacy, and predictors of benefit in neuromyelitis optica,” Neurology, vol. 77, no. 7, pp. 659–666, 2011.
[29]
A. Jacob, M. Matiello, B. G. Weinshenker et al., “Treatment of neuromyelitis optica with mycophenolate mofetil: retrospective analysis of 24 patients,” Archives of Neurology, vol. 66, no. 9, pp. 1128–1133, 2009.
[30]
S. Watanabe, T. Misu, I. Miyazawa et al., “Low-dose corticosteroids reduce relapses in neuromyelitis optica: a retrospective analysis,” Multiple Sclerosis, vol. 13, no. 8, pp. 968–974, 2007.
[31]
K. Miyamoto and S. Kusunoki, “Intermittent plasmapheresis prevents recurrence in neuromyelitis optica,” Therapeutic Apheresis and Dialysis, vol. 13, no. 6, pp. 505–508, 2009.
[32]
B. O. Khatri, J. Kramer, M. Dukic, M. Palencia, and W. Verre, “Maintenance plasma exchange therapy for steroid-refractory neuromyelitis optica,” Journal of Clinical Apheresis, vol. 27, no. 4, pp. 183–192, 2012.
[33]
B. A. C. Cree, S. Lamb, K. Morgan, A. Chen, E. Waubant, and C. Genain, “An open label study of the effects of rituximab in neuromyelitis optica,” Neurology, vol. 64, no. 7, pp. 1270–1272, 2005.
[34]
A. Jacob, B. G. Weinshenker, I. Violich et al., “Treatment of neuromyelitis optica with rituximab: retrospective analysis of 25 patients,” Archives of Neurology, vol. 65, no. 11, pp. 1443–1448, 2008.
[35]
G. S. Bedi, A. D. Brown, S. R. Delgado, N. Usmani, B. L. Lam, and W. A. Sheremata, “Impact of rituximab on relapse rate and disability in neuromyelitis optica,” Multiple Sclerosis, vol. 17, no. 10, pp. 1225–1230, 2011.
[36]
S.-H. Kim, W. Kim, X. F. Li, I.-J. Jung, and H. J. Kim, “Repeated treatment with rituximab based on the assessment of peripheral circulating memory B cells in patients with relapsing neuromyelitis optica over 2 years,” Archives of Neurology, vol. 68, no. 11, pp. 1412–1420, 2011.
[37]
H. L. Pellkofer, M. Krumbholz, A. Berthele et al., “Long-term follow-up of patients with neuromyelitis optica after repeated therapy with rituximab,” Neurology, vol. 76, no. 15, pp. 1310–1315, 2011.
[38]
S. J. Pittock, V. A. Lennon, A. McKeon et al., “Eculizumab in AQP4-IgG-positive relapsing neurolmyelitis optica spectrum disorders: an open-label study,” The Lancet Neurology, vol. 12, no. 6, pp. 554–562, 2013.
[39]
T. Kageyama, M. Komori, K. Miyamoto et al., “Combination of cyclosporine A with corticosteroids is effective for the treatment of neuromyelitis optica,” Journal of Neurology, vol. 260, no. 2, pp. 627–634, 2012.
[40]
B. Weinstock-Guttman, M. Ramanathan, N. Lincoff et al., “Study of mitoxantrone for the treatment of recurrent neuromyelitis optica (Devic disease),” Archives of Neurology, vol. 63, no. 7, pp. 957–963, 2006.
[41]
A. Minagar and W. Sheramata, “Treatment of Devic's with methotrexate and prednisone,” International Journal of Multiple Sclerosis Care, vol. 2, pp. 39–43, 2000.
[42]
J. Bakker and L. Metz, “Devic's neuromyelitis optica treated with intravenous gamma globulin (IVIG),” Canadian Journal of Neurological Sciences, vol. 31, no. 2, pp. 265–267, 2004.
[43]
B. C. Kieseier, O. Stüve, T. Dehmel et al., “Disease amelioration with tocilizumab in a treatment-resistant patient with neuromyelitis optica: implication for cellular immune responses,” Archives of Neurology, vol. 7, no. 3, pp. 390–393, 2012.
[44]
T. Takahashi, K. Fujihara, I. Nakashima et al., “Anti-aquaporin-4 antibody is involved in the pathogenesis of NMO: a study on antibody titre,” Brain, vol. 130, no. 5, pp. 1235–1243, 2007.
[45]
M. Bonnan, R. Valentino, M. Bonnan, H. Mehdaoui, D. Smadja, and P. Cabre, “Plasma exchange in severe spinal attacks associated with neuromyelitis optica spectrum disorder,” Multiple Sclerosis, vol. 15, no. 4, pp. 487–492, 2009.
[46]
Y. M. Lim, S. Y. Pyun, B. H. Kang, J. Kim, and K. K. Kim, “Factors associated with the effectiveness of plasma exchange for the recruitment of NMO-IgG positive neuromyelitis optica spectrum disorders,” Multiple Sclerosis Journal, vol. 19, no. 9, pp. 1216–1218, 2012.
[47]
M. Keegan, A. A. Pineda, R. L. McClelland, C. H. Darby, M. Rodriguez, and B. G. Weinshenker, “Plasma exchange for severe attacks of CNS demyelination: predictors of response,” Neurology, vol. 58, no. 1, pp. 143–148, 2002.
[48]
C. Cuffari, “A physician's guide to azathioprine metabolite testing,” Gastroenterology and Hepatology, vol. 2, no. 1, pp. 58–63, 2006.
[49]
H. Jeong and B. Kaplan, “Therapeutic monitoring of mycophenolate mofetil,” Clinical Journal of the American Society of Nephrology, vol. 2, no. 1, pp. 184–191, 2007.
[50]
B. M. Greenberg, D. Graves, G. Remington et al., “Rituximab dosing and monitoring strategies in neuromyelitis optica patients: creating strategies for therapeutic success,” Multiple Sclerosis Journal, vol. 18, no. 7, pp. 1022–1026, 2012.
[51]
J. W. Lindsey, K. M. Meulmester, S. A. Brod, F. Nelson, and J. S. Wolinsky, “Variable results after rituximab in neuromyelitis optica,” Journal of the Neurological Sciences, vol. 317, no. 1-2, pp. 103–105, 2012.
[52]
I. Nakashima, T. Takahashi, B. A. C. Cree et al., “Transient increases in anti-aquaporin-4 antibody titers following rituximab treatment in neuromyelitis optica, in association with elevated serum BAFF levels,” Journal of Clinical Neuroscience, vol. 18, no. 7, pp. 997–998, 2011.
[53]
H. L. McLeod and C. Siva, “The thiopurine S-methyltansferase gene locus—implications for clinical pharmacogenomics,” Pharmacogenomics, vol. 3, no. 1, pp. 89–98, 2002.
[54]
R. J. Flanagan and L. Dunk, “Haematological toxicity of drugs used in psychiatry,” Human Psychopharmacology, vol. 23, no. 1, pp. 27–41, 2008.
[55]
J. Palace, M. I. Leite, A. Nairne, and A. Vincent, “Interferon beta treatment in neuromyelitis optica: increase in relapses and aquaporin 4 antibody titers,” Archives of Neurology, vol. 67, no. 8, pp. 1016–1017, 2010.
[56]
R. C. Axtell, C. Raman, and L. Steinman, “Interferon-β exacerbates Th17-mediated inflammatory disease,” Trends in Immunology, vol. 32, no. 6, pp. 272–277, 2011.
[57]
J.-H. Min, B. J. Kim, and K. H. Lee, “Development of extensive brain lesions following fingolimod (FTY720) treatment in a patient with neuromyelitis optica spectrum disorder,” Multiple Sclerosis, vol. 18, no. 1, pp. 113–115, 2012.
[58]
A. Jacob, M. Hutchinson, L. Elsone et al., “Does natalizumab therapy worsen neuromyelitis optica?” Neurology, vol. 79, no. 10, pp. 1065–1066, 2012.
[59]
S. J. Pittock, V. A. Lennon, J. De Seze et al., “Neuromyelitis optica and non-organ-specific autoimmunity,” Archives of Neurology, vol. 65, no. 1, pp. 78–83, 2008.
[60]
J. Sellner, B. Hemmer, and M. Mühlau, “The clinical spectrum and immunobiology of parainfectious neuromyelitis optica (Devic) syndromes,” Journal of Autoimmunity, vol. 34, no. 4, pp. 371–379, 2010.
[61]
W. Li, M. Minohara, H. Piao et al., “Association of anti-Helicobacter pylori neutrophil-activating protein antibody response with anti-aquaporin-4 autoimmunity in Japanese patients with multiple sclerosis and neuromyelitis optica,” Multiple Sclerosis, vol. 15, no. 12, pp. 1411–1421, 2009.
[62]
M. Koga, T. Takahashi, M. Kawai, K. Fujihara, and T. Kanda, “A serological analysis of viral and bacterial infections associated with neuromyelitis optica,” Journal of the Neurological Sciences, vol. 300, no. 1-2, pp. 19–22, 2011.
[63]
Z. Ren, Y. Wang, T. Duan et al., “Cross-immunoreactivity between bacterial aquaporin-Z and human aquaporin-4: potential relevance to neuromyelitis optica,” Journal of Immunology, vol. 189, no. 9, pp. 4602–4611, 2012.
[64]
P. O. Barros, U. C. Linhares, B. Teixeira et al., “High in vitro immune reactivity to Escherichia coli in neuromyelitis optica patients is correlated with both neurological disabilities and elevated plasma lipopolysaccharide levels,” Human Immunology, vol. 74, no. 9, pp. 1080–1087, 2013.
[65]
M. Varrin-Doyer, C. M. Spencer, U. Schulze-Topphoff et al., “Aquaporin 4-specific T cells in neuromyelitis optica exhibit a Th17 bias and recognize Clostridium ABC transporter,” Annals of Neurology, vol. 72, no. 1, pp. 53–64, 2012.
[66]
Y.-Q. Feng, N. Guo, F. Huang, X. Chen, Q.-S. Sun, and J.-X. Liu, “Anti-tuberculosis treatment for Devic's neuromyelitis optica,” Journal of Clinical Neuroscience, vol. 17, no. 11, pp. 1372–1377, 2010.
[67]
M. C. Papadopoulos and A. S. Verkman, “Aquaporin 4 and neuromyelitis optica,” The Lancet Neurology, vol. 11, no. 6, pp. 535–544, 2012.
[68]
L. Tradtrantip, H. Zhang, S. Saadoun et al., “Anti-aquaporin-4 monoclonal antibody blocker therapy for neuromyelitis optica,” Annals of Neurology, vol. 71, no. 3, pp. 314–322, 2012.
[69]
L. Tradtrantip, J. Ratelade, H. Zhang, and A. S. Verkman, “Enzymatic deglycosylation converts pathogenic neuromyelitis optica anti-aquaporin-4 immunoglobulin G into therapeutic antibody,” Annals of Neurology, vol. 73, no. 1, pp. 77–85, 2013.
