EDITORIAL
Devic disease Translational medicine at work
Stefan Rose-John, PhD Ralf Gold, MD
Correspondence to Dr. Rose-John:
[email protected] Neurology® 2014;82:1294–1295
More than a century after histopathologic achievements in understanding multiple sclerosis, substantial molecular progress has permitted greater understanding of disease heterogeneity. For acute demyelinating lesions, Lassmann et al.1 proposed a classification based on molecular findings from diagnostic biopsies and autopsies. The understanding of neuromyelitis optica (NMO; Devic disease) has been further advanced by the discovery of the aquaporin-4 water channel as a target of autoantibodies in more than 80% of patients with NMO.2 Koch-Witebsky criteria have been partially fulfilled in NMO, because passive transfer of purified aquaporin antibodies to rodents creates similar clinical signs and histopathology of NMO, although these do not recapitulate human disease in all aspects.3 In one study, anti-KIR 4.1 antibodies occurred in approximately 50% of patients4; this finding is of interest because the KIR 4.1 channel is expressed close to the aquaporin channel on astrocytic endfeet. NMO has other differentiating features of import for individualized medicine. First-line and escalating therapies for multiple sclerosis may be detrimental: interferon b, natalizumab (targets a4-integrin), and fingolimod (acts a sphingosine-1-phosphate analog) can lead to deterioration of NMO. Other work has identified interleukin (IL)-6– responsive and even IL-6–dependent plasmablasts as involved in disease activity.5 IL-6 is a cytokine that is substantially elevated in most if not all inflammatory states.6 IL-6 binds to a membrane-bound receptor (IL-6R) and subsequently associates with the ubiquitously expressed receptor subunit gp130, thereby initiating intracellular signaling. It is of interest that cells, which lack IL-6R expression, can be stimulated by the complex of IL-6 and soluble IL-6R, which is released by proteolytic cleavage of the membranebound receptor.6 Given the expression pattern of IL-6, targeting the bioactivity of this cytokine is a rational therapeutic approach for the treatment of autoimmune diseases. Indeed, treatment with the neutralizing monoclonal antibody tocilizumab,
directed against the human IL-6R, has proven successful in patients with rheumatoid arthritis, Castleman disease, and systemic juvenile idiopathic arthritis. Tocilizumab has meanwhile been approved in more than 100 countries for the treatment of rheumatoid arthritis.7 Because IL-6 was increased in serum and CSF during relapse periods in patients with NMO,8 IL-6–targeted therapy seemed to be warranted. In this issue of Neurology®, Araki et al.9 describe the treatment of 7 patients with anti–aquaporin-4 positive NMO with the antibody tocilizumab for 1 year. All patients had previously been treated with oral prednisolone and immunosuppressants such as azathioprine. The authors report that the annualized relapse rate decreased in these patients from 2.9 to 0.4. Similar outcomes occurred in 3 patients with anti–aquaporin-4 positive NMO who were treated for 18 months.10 Of interest, in these patients, despite B-cell depletion during rituximab therapy, the annualized relapse rate decreased from 3.0 to 0.6 upon treatment with tocilizumab, thereby underlining the effectiveness of IL-6–targeted therapy of NMO.10 Araki et al. also noted that chronic pain in the trunk and extremities, which seems to be more typical for the Asian variant of NMO, gradually subsided upon treatment with tocilizumab. In a recent study with gene-modified mice in which the signaling receptor subunit gp130 was deleted from nociceptive neurons, where it is usually expressed, there were reduced levels of inflammatory pain.11 The results of the study by Araki et al. therefore clearly demonstrate that targeting the human IL-6R might be a therapeutic option for the treatment of chronic pain and thus may open new therapeutic avenues. AUTHOR CONTRIBUTIONS Stefan Rose-John: drafting/revising the manuscript. Ralf Gold: drafting/ revising the manuscript, study supervision.
STUDY FUNDING No targeted funding reported.
See page 1302 From the Institute of Biochemistry (S.R.-J.), Christian-Albrechts-Universität zu Kiel; and Department of Neurology (R.G.), St. Josef-Hospital, Ruhr-University Bochum, Germany. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial. 1294
© 2014 American Academy of Neurology
DISCLOSURE S. Rose-John reports no disclosures. R. Gold serves on scientific advisory boards for TEVA, Biogen Idec, Bayer Schering, and Novartis; has received speaker honoraria from Biogen Idec, TEVA, Bayer-Schering, and Novartis; serves on the editorial boards of Therapeutic Advances in Neurological Diseases, Journal of Neuroimmunology, and Experimental Neurology; serves as a consultant for Biogen Idec, ELAN, TEVA, and Chugai Inc.; and receives research support from TEVA, Biogen Idec, Bayer Schering, Merck Serono, and Novartis. Go to Neurology.org for full disclosures.
REFERENCES 1. Lassmann H, Brück W, Lucchinetti C. Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy. Trends Mol Med 2001;7:115–121. 2. Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 2004;364:2106–2112. 3. Bradl M, Misu T, Takahashi T, et al. Neuromyelitis optica: pathogenicity of patient immunoglobulin in vivo. Ann Neurol 2009;66:630–643. 4. Srivastava R, Aslam M, Kalluri SR, et al. Potassium channel KIR4.1 as an immune target in multiple sclerosis. N Engl J Med 2012;367:115–123.
5.
6.
7.
8.
9.
10.
11.
Chihara N, Aranami T, Sato W, et al. Interleukin 6 signaling promotes anti-aquaporin 4 autoantibody production from plasmablasts in neuromyelitis optica. Proc Natl Acad Sci U S A 2011;108:3701–3706. Jones SA, Scheller J, Rose-John S. Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J Clin Invest 2011;121:3375–3383. Tanaka T, Narazaki M, Kishimoto T. Therapeutic targeting of the interleukin-6 receptor. Annu Rev Pharmacol Toxicol 2012;52:199–219. Jarius S, Wildemann B. AQP4 antibodies in neuromyelitis optica: diagnostic and pathogenetic relevance. Nat Rev Neurol 2010;6:383–392. Araki M, Matsuoka T, Miyamoto K, et al. Efficacy of the anti–IL-6 receptor antibody tocilizumab in neuromyelitis optica: a pilot study. Neurology 2014;82:1302–1306. Ayzenberg I, Kleiter I, Schröder A, et al. Interleukin 6 receptor blockade in patients with neuromyelitis optica nonresponsive to anti-CD20 therapy. JAMA Neurol 2013;70:394–397. Andratsch M, Mair N, Constantin CE, et al. Reversal of cancer pain through anti-interleukin-6 treatment. J Neurosci 2009;29:13473–13483.
Neurology 82
April 15, 2014
1295
