ArticlesSafety and efficacy of tocilizumab versus azathioprine in highly relapsing neuromyelitis optica spectrum disorder (TANGO): an open-label, multicentre, randomised, phase 2 trial
Introduction
Neuromyelitis optica spectrum disorder (NMOSD) is a severe disabling inflammatory autoimmune disease of the CNS frequently associated with a pathological humoral immune response against the aquaporin-4 (AQP-4) water channel. The disorder is most commonly characterised by recurrent relapses of optic neuritis and longitudinally extensive transverse myelitis.1, 2 Frequent relapses result in stepwise accumulation of neurological disability. Therefore, prevention of relapse is of paramount importance to reduce the risk of systemic disability over time.3, 4
Azathioprine, mycophenolate mofetil, and rituximab are the most commonly used therapies for patients with NMOSD. On the basis of retrospective, open-label studies, azathioprine (a purine analogue that blocks DNA synthesis) has been recommended as a first-line treatment to reduce relapse rate and ameliorate neurological disability in patients with NMOSD.5, 6 However, a substantial number of patients relapse and have side-effects with prolonged use of azathioprine.7 Additionally, because azathioprine is often used in conjunction with corticosteroids, its efficacy as a monotherapy remains unclear.8
Tocilizumab, the first humanised anti-interleukin (IL)-6 receptor monoclonal antibody, has been extensively used in patients with rheumatoid arthritis and juvenile idiopathic arthritis and is now approved for the treatment of several autoimmune diseases including giant cell arteritis.9 In previous case series, tocilizumab has been found to reduce the frequency of relapses and disability in patients with NMOSD10, 11, 12 including patients who have not responded to treatment with several immunosuppressants or the B-cell-depleting antibody rituximab. The IL-6 receptor monoclonal antibody satralizumab has been shown to significantly reduce the risk of NMOSD relapse compared with placebo.13 Disruption of IL-6 signalling might affect NMOSD disease activity via multiple pathways: reduction in AQP-4 autoantibody (AQP4-IgG) production, inhibition of pro-inflammatory T-cell differentiation, and lowering of blood–brain barrier permeability.14
Head-to-head comparison of therapeutics that act on distinct pathways presumed to be involved in NMOSD pathogenesis is imperative. Furthermore, evidence is needed to assess the benefit-to-risk ratio of newer medications (eg, IL-6 receptor, CD19, and C5 monoclonal antibodies) compared with more commonly used drugs such as azathioprine. We hypothesised that tocilizumab is superior to azathioprine in reducing the risk of relapse in patients with NMOSD. Therefore, we aimed to compare the safety and efficacy of tocilizumab with azathioprine in reducing the risk of relapse and disability in patients with highly relapsing NMOSD.
Section snippets
Study design and participants
TANGO was an open-label, multicentre, randomised phase 2 trial that recruited patients from six hospitals in China (Tianjin Medical University General Hospital [Tianjin], First Hospital of Shanxi Medical University [Taiyuan], The Third Hospital of Sun Yat-sen University [Guangzhou], Beijing Tiantan Hospital [Beijing], The Third People's Hospital of Datong [Datong], and Tianjin Huanhu Hospital [Tianjin]). Eligible patients were adults (≥18 years) with highly relapsing NMOSD diagnosed according
Results
Between Nov 1, 2017, and Aug 3, 2018, 118 patients were enrolled and randomly assigned to tocilizumab (n=59) or azathioprine (n=59), all of whom received at least one dose of the study drug and were included in the full analysis set for the primary outcome. Three participants (one [2%] of 59 patients in the tocilizumab group and two [3%] of 59 patients in the azathioprine group) discontinued the trial due to severe adverse events (appendix p 22) and two patients died (one [2%] in the
Discussion
To our knowledge, the TANGO study is the first trial to compare tocilizumab with azathioprine for the treatment of NMOSD. This study showed that patients given tocilizumab had a lower risk of NMOSD relapse, 12-week confirmed disability progression, and lower serum AQP4-IgG titres than did patients given azathioprine.
NMOSD is a rare, and severe disabling CNS autoimmune disorder, which at present is treated with a variety of immunosuppressive and biologic drugs.18 Most clinical investigations
Data sharing
Data collected for this study including individual participant data and study protocol will be available to others upon publication of the TANGO trial. All of the individual participant data collected during the trial, after de-identification, will be shared. Data will be available after approval of a proposal with a signed data access agreement to achieve aims in the approved prospectus. Proposals should be directed to [email protected].
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