Pembrolizumab-Induced Myasthenic Crisis with HyperCKemia in a Patient with Thymoma

Dear Editor,

Immune checkpoint inhibitors (ICIs) mark a new era for cancer treatment, since they act against immune checkpoint proteins and increase antitumor immunity.¹ Despite their efficacy against several cancers, immune-related adverse events (IRAEs) can occur as complications. Neurological complications of ICIs are rare, but they have diverse clinical manifestations.² Myasthenia gravis (MG) is a neurological complication of ICIs.³ Here we report a patient who developed severe MG with hyperCKemia after receiving pembrolizumab therapy for thymoma.

A 49-year-old woman was admitted with a 4-day history of general weakness, dyspnea, and dysphagia. Three days prior to the presentation she had received the second course of pembrolizumab (200 mg) for a thymoma with multiple metastases. She had no history of a neuromuscular disorder or similar complaints. Neurological examinations revealed right ptosis without ophthalmoplegia, severe dysarthria with hypophonia, and dysphagia. Weakness of the neck and proximal-dominant upper and lower extremity was noted. The Tensilon test was negative. Laboratory tests revealed marked elevation of serum creatine kinase (CK) (8,362 IU/l). One week later the patient tested positive for the anti-acetylcholine-receptor antibody (6.60 nmol/L).

The patient developed labored breathing on day 5 of hospitalization, which worsened and was associated with marked hypercapnia. She was transferred to the intensive care unit, and mechanical ventilation was initiated. She received a high dose of a corticosteroid (1,000 mg/day methylprednisolone for 5 days) and subsequently received intravenous immunoglobulin (0.4 g/kg/day for 5 days). Her CK level normalized and the weakness in the extremities improved; however, her other symptoms did not improve, and she still required mechanical ventilation. She underwent seven cycles of plasmapheresis on alternate days. She recovered gradually and was weaned off ventilation. She was discharged after 12 weeks of hospitalization without complications.

Pembrolizumab is a humanized monoclonal antibody targeting the programmed cell death 1 (PD-1) receptor and acts as a competitive inhibitor to PD-1 receptor binding ligands.² The pathomechanism of IRAEs caused by PD-1 inhibitors has not been fully elucidated. IRAEs could be related to increased T-cell activity and autoantibody and inflammatory cytokine levels. MG is an autoimmune disease involving multifaceted autoimmune processes including pathogenetic T-helper 17 cells, regulatory T cells, and proinflammatory cytokines,⁴ and so MG may develop as an IRAE. Neurological complications have been reported in approximately 3% of patients receiving PD-1 inhibitor therapy, with the most common being neuromuscular complications including MG, myopathy/myositis, and peripheral neuropathy.²

Since thymoma may be associated with MG, we were unable to clearly distinguish whether subclinical MG was exacerbated on pembrolizumab administration, caused by pembrolizumab, or was a manifestation of the underlying thymoma regardless of pembrolizumab administration. However, the clinical symptoms of our patient combined with the temporal relationship between pembrolizumab administration and symptom development suggest that MG with hyperCKemia was induced by pembrolizumab administration. Another study found that ICI-induced new-onset MG progressed more rapidly to severe MG and overlapped more frequently with myositis, compared to in pre-existing MG exacerbation.⁵

In the present case, MG crisis was accompanied by hyper-CKemia, which suggested myopathy, whereas the electromyographic findings showed no evidence of myopathy. It is unclear whether myopathy was present since electromyography could not be performed in the acute stage and a muscle biopsy could not be performed. There are several previous reports of pembrolizumab-associated MG with myopathy.⁶,⁷,⁸ Takamatsu et al.⁹ reported 17 cases of MG with hyperCKemia associated with ICIs. In most cases, respiratory failure or worsening of MG symptoms was noted immediately after MG onset, while death occurred in some cases.⁷,⁸

ICI-induced MG ranges from mild neurological deterioration to death, and hyperCKemia may induce more-severe symptoms. It is therefore important to consider new-onset MG or MG exacerbation in patients treated with ICIs. Early detection and active treatment may improve the outcome.