ReviewMyasthenia gravis: An emerging toxicity of immune checkpoint inhibitors
Introduction
Over the past 5 years, targeted immunotherapy has created a major paradigm shift within the therapeutic landscape of numerous solid tumours. Manipulation of pathways which mediate blunting of anti-tumour immunity has predominantly focussed on the development of inhibitors directed against the immune checkpoint modulators such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) and its ligand, PD-L1. The introduction of these novel agents has not only witnessed unprecedented extensions in survival outcomes for patients with malignant melanoma, lung, renal and head/neck cancers but reveals a plethora of immune-related toxicities for which early recognition and appropriate clinical management are paramount. Autoimmune events including hepatitis, colitis, pneumonitis, dermatitis, nephritis, endocrinopathies and hypophysitis are well-recognised phenomena which represent a manifestation of dysregulated inflammation induced by immune checkpoint inhibition. As the use of these targeted agents expand, further toxicity issues have emerged. Recently, this has been exemplified by both de novo presentations and exacerbations of pre-existing myasthenia gravis (MG) which, to date, has been reported in 22 cases in the literature. Herein, we present a new presentation of ocular MG (oMG) followed by a succinct review of cases highlighting this phenomenon.
Section snippets
Case report
An 85-year-old woman with metastatic melanoma with left axillary lymphadenopathy commenced single-agent pembrolizumab (2 mg/kg; every 3 weeks) and tolerated the first cycle without any significant toxicity. Shortly after the second cycle, she presented with diplopia that was subsequently followed by asymmetrical bilateral ptosis (L > R). The remaining neurological examination was unremarkable, and there was no evidence of oesophageal dysmotility or respiratory compromise. Brain magnetic
Anti-PD-1 inhibitor-induced myasthenia gravis
In addition to this aforementioned report, since the introduction of PD-1 and PD-L1 immune checkpoint inhibitors, there have been several publications highlighting a causal relationship with the manifestation of de novo MG (Table 1).
Indeed, March et al. [1] recently documented a fatal case in a 63-year-old male with malignant melanoma of the right scalp, which had metastasised to the liver and brain, who was also treated with pembrolizumab. Two weeks after the first cycle, he presented with
Anti-CTLA-4 inhibitor-induced myasthenia gravis
To date, there have been four cases of MG with the anti-CTLA-4 antibody, ipilimumab; all of which have been de novo presentations [12], [13], [14]. Intriguingly, all cases occurred within 6 weeks of initiation of ipilimumab and were not associated with any mortality. Liao et al. [12] reported a case of a 70-year-old female with uveal melanoma and liver metastases who was commenced on ipilimumab. After the second infusion, she developed generalised myalgia, dysphagia, odynophagia, bilateral
Combination immune checkpoint inhibitor therapy-induced myasthenia gravis
Currently, there are two reports of combination immune checkpoint inhibitor therapy inducing MG. The first case by Antonia et al. [15] notes a patient who received durvalumab (anti-PD-L1 inhibitor; 10 mg/kg) and tremelimumab (anti-CTLA-4 inhibitor; 1 mg/kg) delivered on a 4-week schedule [15]. The patient was diagnosed with advanced NSCLC and developed MG within 10 d of initiating treatment. Unfortunately, there is a paucity of further information on the patient profile and treatment history
PD-1 inhibitor exacerbation of myasthenia gravis
In addition to de novo MG, there have been four such reports [18], [19], [20], [21] of patients with exacerbations of pre-existing MG as a direct consequence of immune checkpoint inhibition.
One such case reported by Lau et al. [18] documents a 75-year-old man, with a known history of non-thymomatous AChR-Ab positive generalised MG maintained on azathioprine, who was diagnosed with metastatic melanoma. Two weeks after the second cycle of pembrolizumab, he presented with ataxia, neck weakness and
Discussion
Historically, the excitement generated by the introduction of novel therapies within the treatment armament for oncology patients is also moderated by the emergence of an often unique constellation of toxicities which require prompt recognition and robust clinical management. This is particularly emphasised by the immune-related adverse events (irAEs) associated with immune checkpoint inhibitors. Zimmer et al. [6] published a study of 496 patients being treated with anti-PD-1 therapy in which
Conclusion
With the advent of immune checkpoint inhibitors, there have been significant advances in the treatment of a number of malignancies. However, the recognition of timing and treatment of irAEs with these therapies is integral to the clinical management of patients undertaking immunotherapy. Although neurological sequelae of immune checkpoint inhibitors are relatively rare, MG, in particular, is becoming an increasingly recognised phenomenon, with potentially fatal outcomes witnessed in just under
Conflict of interest statement
None declared.
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