77-year old male with metastatic melanoma presented to hospital with leg weakness, hoarseness, dyspnea, and ptosis 1 week after first cycle of ipilimumab and nivolumab and 3 days after COVID-19 vaccine. He had bradycardia with heart block, and hepatorenal failure. Exam was remarkable for dysarthria, right eye ptosis, hip flexion weakness 4+/5, without fatigability.  Labs showed CK 21,325, Troponin-T 4,888, Aldolase 307, AChR antibody positive, and Anti-Striated Muscle Antibody 1:3840. Vital Capacity (VC) was 1.9L and Negative Inspiratory Force (NIF) -20cmH2O. Patient received BiPAP, plasmapheresis, and methylprednisolone 1000mg. After this, he developed fatigability of ocular muscles, voice, and proximal arms; VC dropped to 1.3L. He was diagnosed with triple overlap syndrome, but MG manifested after receiving first dose of high-dose steroids. Heart biopsy showed lymphohystiocytic inflammation. Muscle biopsy showed focal and dispersed lymphomononuclear cell endomysial infiltration. Electromyography demonstrated patchy myositis in lower extremities. Patient completed 3 days of high-dose steroids, 5 days of plasmapheresis, abatacept, and rituximab, followed by slow steroid taper. He did not require intubation despite tenuous respiratory status.

nIRAE of the PNS are rare potential complications of immunotherapy, usually presenting by 6 weeks, although overlap syndrome can present hyper-acutely after 1 dose. Our patient presented 1 week after first treatment, perhaps influenced by COVID vaccine. Management of nIRAE is consensus-based, as no standard evidence-based treatment exists.  Our patient was successfully treated with plasmapheresis prior to high-dose steroids (obviating steroid-induced myasthenic crisis), abatacept and rituximab. The myasthenic crisis was successfully managed with BiPAP, avoiding intubation, and he ultimately improved.