Successful use of an immune checkpoint inhibitor in a patient with myasthenia gravis in remission

Immune checkpoint inhibitors (ICIs) are increasingly being used to treat solid tumors such as melanoma. ICIs facilitate T cell-mediated action on tumor cells and may promote both the onset and worsening of autoimmune diseases. ICI-related neurotoxicity is rare, and myasthenia gravis (MG) develops in fewer than 1% of patients. In these cases, it usually arises de novo. Mild ocular symptoms can develop up to 15 weeks after initiating ICI but they usually respond to steroids. However, ICI-related MG seems to be more severe than idiopathic MG. In particular, facialbulbar weakness rapidly worsened within 1 week in 8 of 12 patients with nivolumab-related MG. Prompt shortacting immunosuppressive therapy including plasmapheresis appeared to be efficacious; however, mortality was 25% in that study. Data on safety of ICI treatment in patients with other pre-existing autoimmune diseases are limited. Here, we describe a 49-year-old woman treated with nivolumab for recurrent central nervous system (CNS) lymphoma. At 21 years of age, she developed severe oculobulbar weakness and quadriparesis due to generalized acetylcholine receptor (AChR) antibody (ab)-positive MG. Prompt thymectomy revealed lymphofollicular hyperplasia. Pyridostigmine and azathioprine were administered for 24 months, prednisone for the first 8 months. One year later. the patient reached complete stable remission (CSR) with AChR-ab titers of 5 nmol/L (reference< 0.4 nmol/L). Fourteen years later, a primary CNS lymphoma was diagnosed. Complete remission (CR) of lymphoma was achieved after high-dose chemotherapy and autologous stem cell transplantation (ASCT). The lymphoma recurred twice within the following 11 years. After achieving CR for the 3rd time, maintenance therapy including 24 cycles of nivolumab (3 mg/kg twice a month) was initiated. At this point, CSR of MG had been maintained for 25 years. No clinical or electrophysiological findings of myasthenia were present; AChR-ab titer was 0. At 36 months after completing nivolumab treatment no clinical evidence of MG or lymphoma was observed. No AChR-ab were detected, and no neurophysiological signs of MG were present. The patient did not develop any other immune-related adverse event. Here, nivolumab treatment was successful in a patient with pre-existing MG, in contrast to case reports of ICIrelated myasthenic crises and death in MG patients even when in remission. ICI-related autoimmunity may also include concurrent myositis and myocarditis mimicking or aggravating myasthenic weakness, possibly requiring ventilatory support. Our patient was unusual as she presented with longstanding CSR after thymectomy and ASCT, both representing significant immune treatments for MG. Furthermore, she was younger than average among ICIrelated MG patients. Her underlying disease was CNS lymphoma: indeed, nivolumab does not represent standard treatment for this tumor. In conclusion, MG patients receiving ICI treatment are at higher risk of sudden and rapid symptom deterioration, possibly leading to refractory weakness. It is not possible to identify those patients in whom MG will not be exacerbated after ICI treatment. However, our case underscores the fact that treatment may be feasible in selected MG patients with longstanding CSR. Careful clinical monitoring is essential to recognize myasthenic symptoms immediately in these patients. Ethical Publication Statement: We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.