Case reportBeneficial effect of tocilizumab in myasthenia gravis refractory to rituximab
Introduction
Myasthenia gravis (MG) is an autoimmune neuromuscular disease caused by antibodies that disrupt acetylcholine signalling at the neuromuscular junction, leading to fluctuating fatigability and weakness of the ocular, bulbar, respiratory and/or limb muscles [1,2]. In most cases autoantibodies are directed at the acetylcholine receptor (AChRab). AChRab positive MG principally occurs in three different forms: early onset MG (EOMG), late onset MG (LOMG) and thymoma-associated MG [1,2].
The medical treatment of MG consists of symptom relieving acetylcholine esterase inhibitors, but also entails targeting of underlying autoimmune inflammation. This can be achieved by surgically removing the thymus in cases of EOMG and thymoma-associated MG and/or the use of immune suppressants [3]. The latter group traditionally consists of corticosteroids and oral agents such as azathioprine, mycophenolate mofetil and cyclosporine; all having certain risks of adverse effects and some considered to have a long induction time, while repeated infusions with intravenous immunoglobulins (IvIg) can provide more rapid effects. Evidence of efficacy of newer biological drugs in MG has emerged more recently. Eculizumab, a C5a complement blocker, has shown promising results in a phase II trial [4]. A phase III trial with eculizumab was recently completed, but detailed outcomes have not yet been made available. In addition, rituximab, an anti-CD20 B cell depleting drug, has shown promising effects in several published case series, recently summarized in a meta-analysis [5]. However, not all patients respond to these treatments and there is a need to explore additional therapeutic options.
Tocilizumab is an anti-interleukin-6-receptor humanized monoclonal antibody introduced in Japan in 2005 as a treatment for Castleman's disease, but later receiving approval by EMA (2009) and FDA (2010) for rheumatoid arthritis and juvenile idiopathic arthritis [6]. Experimental studies have shown that interleukin-6 (IL-6) stimulates the production of autoantibodies from plasma cells [7], which makes it an interesting candidate drug for antibody-mediated diseases. In fact, tocilizumab has shown promising effects in neuromyelitis optica (NMO), an autoimmune condition caused by autoantibodies towards the aquaporin-4 water transportation channel [8,9]. A further development of tocilizumab, named SA237, is currently being tested in two phase III NMO trials. Collectively, this makes anti-IL-6 therapy an interesting option in MG, also supported by the clinical outcomes in the two patients treated with tocilizumab for refractory MG reported here.
Section snippets
Case report
Case 1 is a woman born in 1994 with severe MG since the onset in 2005. She also suffers from mild cognitive impairment and epilepsy. Her MG symptoms were generalized from onset. AChRab titres initially were negative, within a few months increasing to high levels (>200 nmol/L). Neurophysiology showed a disturbed neuromuscular transmission typical of MG on repetitive nerve stimulation (RNS) and single fibre-electromyography (SF-EMG). The first year she had only minor relief of repeated IvIg
Discussion
In these two patients with refractive MG and high titres of AChRab in serum treatment with tocilizumab resulted in distinct clinical improvement. Traditional immune suppressant therapies used in MG, such as azathioprine, mycophenolate mofetil, cyclosporine, have a broad action on the immune system. However, not all patients benefit and others may have treatment-associated side effects. There is therefore a need to develop alternative treatment strategies for these patients. In this sense both
Acknowledgements
The reporting of clinical data was approved by the patients and the ethical review board of Stockholm (2016/828-31). FP is funded by the Swedish Medical Research Council (grant 2014-3077).
References (20)
- et al.
Myasthenia gravis
Lancet
(2001) - et al.
Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity
Lancet Neurol
(2009) - et al.
Early rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-Act-Early): a multicentre, randomised, double-blind, double-dummy, strategy trial
Lancet
(2016) - et al.
International consensus guidance for management of myasthenia gravis: executive summary
Neurology
(2016) - et al.
A randomized, double-blind, placebo-controlled phase II study of eculizumab in patients with refractory generalized myasthenia gravis
Muscle Nerve
(2013) - et al.
Efficacy and safety of rituximab for myasthenia gravis: a systematic review and meta-analysis
J Neurol
(2015) - et al.
Tocilizumab as monotherapy or combination therapy for treating active rheumatoid arthritis: a meta-analysis of efficacy and safety reported in randomized controlled trials
Arthritis Res Ther
(2016) - et al.
Interleukin 6 signaling promotes anti-aquaporin 4 autoantibody production from plasmablasts in neuromyelitis optica
Proc Natl Acad Sci USA
(2011) - et al.
Efficacy of the anti-IL-6 receptor antibody tocilizumab in neuromyelitis optica: a pilot study
Neurology
(2014) - et al.
Interleukin 6 receptor blockade in patients with neuromyelitis optica nonresponsive to anti-CD20 therapy
JAMA Neurol
(2013)
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