A Cascade of Pembrolizumab-Induced Autoimmune Toxicities with Mixed Responses to Corticosteroids
Authors: Rosemary Habib, Jamie Gordon, Robert Zielinski
Journal: Journal of Thoracic Oncology (2017)

In their article “Pembrolizumab-Induced Encephalopathy: A Review of Neurological Toxicities with Immune Checkpoint Inhibitors,” Byrne et al.1Feng S, Coward J, McCaffrey E, Coucher J, Kalokerinos P, O’Byrne K. Pembrolizumab-induced encephalopathy: a review of neurological toxicities with immune checkpoint inhibitors. J Thorac Oncol. https://doi.org/10.1016/j.jtho.2017.08.007, accessed September 5, 2017.Google Scholar provide important insights into the management of immunotherapy-related neurological adverse effects. Specifically, they make reference to a case report published by Liao et al.,2Liao B. Shroff S. Kamiya-Matsuoka C. Tummala S. Atypical neurological complications of ipilimumab therapy in patients with metastatic melanoma.Neuro Oncol. 2014; 16: 589-593Crossref PubMed Scopus (220) Google Scholar who discuss the management of ipilimumab-induced myasthenia gravis (MG). There are a number of published case reports describing the development and management of MG in patients treated with programmed cell death 1 inhibitors with variable outcomes. We would like to add insight from our own experience with managing pembrolizumab-induced MG in a 75-year-old patient who received two cycles of pembrolizumab for metastatic mesothelioma. The following adverse events developed: autoimmune hypothyroidism; grade 3 hepatitis; and MG characterized by new unilateral left eyelid ptosis, mild neck and proximal upper and lower limb weakness, and dysphagia to solid and liquid food without signs of respiratory compromise. The patient began receiving prednisone, 1 mg/kg daily, for management of these adverse events; however, she later required admission to the hospital with severe dysphagia and respiratory compromise. Pulsed intravenous methylprednisolone, 1 g, and intravenous immunoglobulin were administered daily for 5 days for management of acutely worsening neurological symptoms, followed by prednisone, 1 mg/kg daily, which was administered orally. The patient was admitted to the intensive care unit for noninvasive ventilation. She required nasogastric feeding for her severe dysphagia. Serologic testing was strongly positive for acetylcholine receptor antibody, and myopathy was evident on nerve conduction studies and electromyography. The results of repetitive stimulation testing were negative for a decrement of compound muscle action potential. A diagnosis of MG was made on the basis of laboratory test results and clinical features. Eight days later, hypoxic and hypercapnic respiratory failure secondary to pneumonia developed. The decision was made to cease all active treatments, and sadly the patient died. Multiple synchronous immune-related adverse events (irAEs) occur relatively rarely (at a rate of 2%–3%). We highlight a potential serious therapeutic conflict with the early management of irAEs by using corticosteroids and the possible precipitation of myasthenic crisis in a patient with new-onset acetylcholine receptor antibody–positive MG. Given the severity of the patient’s bulbar symptoms, we wonder whether earlier treatment with concurrent anticholinesterase inhibitors and intravenously administered immunoglobulin would have altered her disease course and potentially the ultimate outcome. Corticosteroids are the mainstay of therapy for all subgroups of patients with MG. However, their beneficial effects lag by a period of 2 to 6 weeks, during which time an initial deterioration in neurological symptoms requiring management in the intensive care setting can occur, even with concurrent use of anticholinesterase therapy.3Gilhus N.E. Verschuuren J.J. Myasthenia gravis: subgroup classification and therapeutic strategies.Lancet Neurol. 2015; 14: 1023-1036Abstract Full Text Full Text PDF PubMed Scopus (561) Google Scholar, 4Gilhus N.E. Myasthenia gravis.N Engl J Med. 2016; 375: 2570-2581Crossref PubMed Scopus (422) Google Scholar, 5Warmolts J.R. Engel W.K. Benefit from alternate-day prednisone in myasthenia gravis.N Engl J Med. 1972; 286: 17-20Crossref PubMed Scopus (93) Google Scholar Patients with compromised respiratory or bulbar function should be admitted to the hospital and closely monitored during early treatment.3Gilhus N.E. Verschuuren J.J. Myasthenia gravis: subgroup classification and therapeutic strategies.Lancet Neurol. 2015; 14: 1023-1036Abstract Full Text Full Text PDF PubMed Scopus (561) Google Scholar If concurrent irAEs exist with MG, necessitating daily prednisone use and/or if myasthenic symptoms are moderate to severe, strong consideration should be given to providing inpatient treatment with close neurological monitoring. An awareness of precipitation of a myasthenic crisis with corticosteroid therapy is a salient teaching point. Pembrolizumab-Induced Encephalopathy: A Review of Neurological Toxicities with Immune Checkpoint InhibitorsJournal of Thoracic OncologyVol. 12Issue 11PreviewThe use of immune checkpoint inhibitor (ICI) therapy in the treatment of solid organ malignancies is becoming increasingly common. This has prompted the recognition of a new class of immune-related adverse effects (irAEs) stemming from the upregulation of T-cell activity causing autoimmunity. Neurological irAEs are a rare complication of ICIs that can lead to long-term morbidity. We report a rare case of encephalopathy after treatment with pembrolizumab, to which the patient achieved durable disease response despite discontinuation of therapy. Full-Text PDF Open Access