Case report
Beneficial effect of tocilizumab in myasthenia gravis refractory to rituximab

https://doi.org/10.1016/j.nmd.2017.03.007Get rights and content

Highlights

Abstract

Muscle fatigue associated with myasthenia gravis is caused by autoantibodies interfering with neuromuscular transmission. Immunomodulating treatment is widely used in moderate to severe myasthenia, although the use of newer biological drugs except rituximab is rare. We describe the effect of tocilizumab, a blocker of interleukin-6 signalling, in two female myasthenia patients with high titres of serum acetylcholine receptor antibodies and insufficient response to rituximab. The first patient had been treated with high dose immunoglobulins regularly for several years and the second patient had been treated both with different oral immune suppressants and immunoglobulins before testing a low dose of rituximab without significant clinical effect. Subsequent treatment with tocilizumab resulted in clinical improvement within a few months. The first patient was switched back to rituximab, which resulted in worsening until tocilizumab was restarted. Tocilizumab can be a therapeutic option in cases not responding 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)

  • A. Vincent et al.

    Myasthenia gravis

    Lancet

    (2001)
  • M.N. Meriggioli et al.

    Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity

    Lancet Neurol

    (2009)
  • J.W. Bijlsma 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)
  • D.B. Sanders et al.

    International consensus guidance for management of myasthenia gravis: executive summary

    Neurology

    (2016)
  • J.F. Howard et al.

    A randomized, double-blind, placebo-controlled phase II study of eculizumab in patients with refractory generalized myasthenia gravis

    Muscle Nerve

    (2013)
  • R. Iorio et al.

    Efficacy and safety of rituximab for myasthenia gravis: a systematic review and meta-analysis

    J Neurol

    (2015)
  • X.M. Teitsma 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)
  • N. Chihara et al.

    Interleukin 6 signaling promotes anti-aquaporin 4 autoantibody production from plasmablasts in neuromyelitis optica

    Proc Natl Acad Sci USA

    (2011)
  • M. Araki et al.

    Efficacy of the anti-IL-6 receptor antibody tocilizumab in neuromyelitis optica: a pilot study

    Neurology

    (2014)
  • I. Ayzenberg et al.

    Interleukin 6 receptor blockade in patients with neuromyelitis optica nonresponsive to anti-CD20 therapy

    JAMA Neurol

    (2013)
There are more references available in the full text version of this article.

Cited by (56)

  • Cytokines network in primary membranous nephropathy

    2022, International Immunopharmacology
    Citation Excerpt :

    Tocilizumab, a monoclonal antibody of IL-6, is widely adopted for treating rheumatoid arthritis [37], and performs favorable therapeutic effect in some cases of membranous nephropathy secondary to Castleman's disease [38,39]. Many autoimmune myasthenia gravis patients with poor response to rituximab [40] are demonstrated to benefit from Tocilizumab. IL-6 is the center of inflammatory response, as well as the link between T and B cells.

  • Novel treatment strategies for acetylcholine receptor antibody-positive myasthenia gravis and related disorders

    2022, Autoimmunity Reviews
    Citation Excerpt :

    Blocking IL-6 with a monoclonal antibody against the interleukin showed a protection effect in EAMG clinical manifestations and a decrease of the autoantibody titers and a reduced number of B cells [277]. Treatment with tocilizumab (also known as atlizumab), a humanized monoclonal antibody targeting the IL-6 receptor, resulted in clinical improvement in two MG patients with high autoantibody levels and resistance to rituximab [278]. Recently, a few clinical trials targeting the IL-6 receptor for generalized MG have started, including a phase II clinical to evaluate the safety and efficacy of tocilizumab (NCT05067348) and a phase III clinical trial to study the safety and efficacy of satralizumab (NCT04963270).

  • Advances and ongoing research in the treatment of autoimmune neuromuscular junction disorders

    2022, The Lancet Neurology
    Citation Excerpt :

    Tocilizumab has been approved for the treatment of rheumatoid arthritis, and satralizumab for the treatment of neuromyelitis optica.81 Case reports of two female patients with acetylcholine receptor antibody-positive myasthenia gravis that responded favourably to treatment in terms of the QMG score with tocilizumab suggest possible efficacy in myasthenia gravis,17 but no clinical trial in myasthenia gravis or Lambert-Eaton myasthenic syndrome has been completed yet. Complement plays a pivotal part in the pathogenesis of acetylcholine receptor antibody-positive myasthenia gravis.82

  • Application of IL-6 antagonists in autoimmune disorders

    2022, Translational Autoimmunity: Treatment of Autoimmune Diseases
View all citing articles on Scopus
View full text