|CASE REPORT AND REVIEW OF THE LITERATURE
|Year : 2021 | Volume
| Issue : 1 | Page : 73-78
Pembrolizumab-induced myasthenia gravis in a patient with thymic carcinoma: A case report and review of the literature
Seyma Ciftci Aykac1, Büşra Erkılınç2, Burhanetti Uludağ1
1 Department of Neurology, Faculty of Medicine, Ege University, Izmir, Turkey
2 Department of Neurology, University Hospitals Cleveland Medical Center, Cleveland, OH, United States
|Date of Submission||02-Jul-2020|
|Date of Decision||21-Sep-2020|
|Date of Acceptance||24-Sep-2020|
|Date of Web Publication||26-Mar-2021|
Seyma Ciftci Aykac
Department of Neurology and Clinical Neurophysiology, Faculty of Medicine, Ege University, Izmir
Source of Support: None, Conflict of Interest: None
Pembrolizumab is an immune checkpoint inhibitor. Most cases of myasthenia gravis (MG) reported with the use of immune checkpoint inhibitors have been in melanomas, and small and non-small cell lung carcinoma, but there are no reported cases in thymic epithelial carcinoma. A 57-year-old male with thymic carcinoma presented with symptoms of diplopia, drooping eyelids, and difficulty in talking and swallowing after a second dose of pembrolizumab. Contrast-enhanced brain magnetic resonance imaging, laboratory tests, and electroneuromyography were normal. Single-fiber electromyography showed increased jitter (six muscle fibers were collected, range of jitter 29–140 μs, mean 75 μs; normal <35 μs) in bilateral orbicularis oculi muscles supporting MG. Serum screening showed no any positivity for acetylcholine receptor and muscle-specific tyrosine kinase autoantibodies. The patient died of bulbar dysfunction related to aspiration pneumonia despite receiving intravenous immunoglobulin and methylprednisolone therapy. Physicians should be alert to possible exacerbations of autoimmune diseases and associated risks, especially during treatment with checkpoint inhibitors in thymic malignancy.
Keywords: Myasthenia gravis, pembrolizumab, thymic carcinoma
|How to cite this article:|
Aykac SC, Erkılınç B, Uludağ B. Pembrolizumab-induced myasthenia gravis in a patient with thymic carcinoma: A case report and review of the literature. Neurol Sci Neurophysiol 2021;38:73-8
|How to cite this URL:|
Aykac SC, Erkılınç B, Uludağ B. Pembrolizumab-induced myasthenia gravis in a patient with thymic carcinoma: A case report and review of the literature. Neurol Sci Neurophysiol [serial online] 2021 [cited 2022 Sep 27];38:73-8. Available from: http://www.nsnjournal.org/text.asp?2021/38/1/73/311962
| Introduction|| |
Although thymomas from thymic epithelial tumors are associated with myasthenia gravis (MG) and other autoimmune paraneoplastic disorders, thymic carcinomas are not typically related to paraneoplastic autoimmune disorders, and MG is rarely seen. Pembrolizumab is an immune checkpoint inhibitor and a monoclonal antibody that blocks the programmed cell death 1 (PD-1) receptor. In recent years, immune checkpoint inhibitors such as pembrolizumab have been used frequently in epithelial tumors, including thymic epithelial tumors. Neurologic complications such as encephalitis, transverse myelitis, immune neuropathies, myositis, and MG due to these agents are reported in 5% of cases. Although the incidence of MG associated with anti-PD-1 antibody therapy is low, it can cause clinical exacerbations in patients with preexisting MG.,
In our report, we present a patient who developed MG after pembrolizumab treatment for thymic carcinoma. We think that our case is unique because thymic carcinoma and pembrolizumab alone are rare causes of MG and our patient had these two rare causes together.
| Case Report|| |
A 57-year-old male patient presented to the clinic with symptoms of diplopia, drooping eyelids, and difficulty in talking and swallowing for the last 2 months. In his medical history, he had a carrier state for hepatitis B with previous tenofovir use. In 2011, an asymptomatic mediastinal mass was detected during routine medical screening. After the mass which metastasized to the pleura in clinical follow-up, thymic carcinoma was diagnosed and he received radiotherapy and chemotherapy in 2015. In 2017, the first dose of pembrolizumab was given, and this time, he had no symptoms. Immediately after the second dose of pembrolizumab, he presented with ocular and bulbar symptoms such as double vision, drooping eyelids, and difficulty in talking and swallowing.
A neurologic examination revealed that the left eye deviated laterally in the primary position, and also, the medial deviation of both eyes and the upward movement of the left eye were restricted. Moreover, there was a weakness of the orbicularis oculi muscles bilaterally. He had nasal speech, but his pharyngeal reflex was normal, and there were also no abnormalities in the movement and position of the palatal arch and uvula. Contrast-enhanced brain magnetic resonance imaging was negative for any intracranial pathology. Liver and renal function tests, serum electrolytes, creatine kinase levels, and hemogram were normal. We did found no abnormal electrophysiologic findings in nerve conduction studies in the upper and lower extremities and needle electromyography (EMG) of the proximal-distal limb and cranial muscles (sternocleidomastoid and trapezius). Then, single-fiber EMG was performed which showed increased jitter (six muscle fibers were collected, range of jitter 29–140 μs, mean 75 μs; normal <35 μs) in bilateral orbicularis oculi muscles, supporting MG. Acetylcholine receptor and muscle-specific tyrosine kinase autoantibodies were screened in serum, but both were negative.
The patient was given 1 g/kg/day intravenous immunoglobulin for 3 days and methylprednisolone 1.5 mg/kg/day (total 96 mg/day) sequentially because of bulbar symptoms. Under methylprednisolone treatment (96 mg/day), the patient showed no improvement in bulbar function and died 2 months later of aspiration pneumonia.
| Discussion|| |
Pembrolizumab is an anti-PD-1 monoclonal antibody. It shows antitumor activity by binding to the PD-1 receptor and inhibiting its ability to interact with its ligands. In this way, it attenuates the antitumor immune response normally seen in tumor growth. The mechanism by which checkpoint inhibitors trigger autoimmunity is not fully understood. It may play a role in the dysregulation of a preexisting immune response to self-antigens and may also cause proliferation of effector T-cells with impairment of regulatory T-cells and dysfunctional interaction with antigen-presenting cells.
The first case of MG induced by pembrolizumab was described in a phase 1 trial evaluating increasing doses of pembrolizumab in 207 patients. Although the majority of the few MG cases reported with the use of immune checkpoint inhibitors were melanomas, there have also been cases of small cell and non-small cell lung carcinoma and carcinosarcoma. All reported cases of immune checkpoint inhibitor-associated MG occurred within the first four infusions and most occurred after the first dose. In our case, myasthenic symptoms started immediately after the second infusion. Cases of MG associated with immune checkpoint inhibitors in the literature are summarized in [Table 1].
Three-quarters of patients with MG have thymic abnormalities, but mostly, the defined abnormalities are thymic hyperplasia rather than thymoma. Moreover, data on patients with MG with thymic carcinoma are scant. The diagnosis of thymic carcinoma in our patient was confusing; did the malignancy or pembrolizumab play a role in the development of MG? However, the appearance of myasthenic symptoms with pembrolizumab, although it had been stable for 6 years, brought to mind the immune-related adverse effect of pembrolizumab. Maybe the malignancy originating from thymus facilitated the emergence of this side event. In a study evaluating the effects of pembrolizumab in 40 patients with thymic epithelial carcinoma, immune-related adverse effects were seen in six patients, but MG was not reported. In another phase 2 study in which pembrolizumab was used, regardless of thymic carcinoma or thymoma, the authors concluded that the immune checkpoint inhibitor was active in thymic epithelial tumors and showed a higher risk of autoimmune toxicity in thymic epithelial tumors than in other tumor types.
Immune adverse effects associated with immune checkpoint inhibitors are less likely to respond to immunosuppressant and immunomodulatory therapies. Zimmer et al. described a fatal case of pembrolizumab-induced MG; the patient died after her third infusion for lung, lymph node, and soft-tissue metastases of melanoma. Our patient was also treatment resistant. We could not control his symptoms completely, and he died of aspiration pneumonia.
Consequently, physicians should be mindful of possible exacerbations of autoimmune diseases and associated risks during treatment with immune checkpoint inhibitors. Therefore, when planning treatment with pembrolizumab in thymic epithelial tumors, both the pathologic malignancy type and pretreatment immune disorder should be considered.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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