P047 The triple M threat of check-point inhibitors - an emerging overlap syndrome
Authors: Mootoo Amanda , Masood Ammara , Maghsoudlou Panayiotis , D'Cruz David 
Published: April 2022

Abstract

Background/Aims
The objective of this abstract is to raise awareness on an emerging overlap syndrome of life-threatening immune-related adverse events, manifesting as a triad of myositis, myocarditis and myasthenia gravis in immune check-point inhibitor (ICI) treated patients. It highlights the success of combination, aggressive and prompt immunosuppression with high dose intravenous steroid, cyclophosphamide, rituximab and intravenous immunoglobulin therapy, in two patients presenting at Guy’s and St Thomas’s Hospital, London with this overlap syndrome following pembrolizumab therapy.

Methods
Case presentation. Case 1: 75-year-old Caucasian gentleman receives one dose of pembrolizumab for metastatic melanoma. Two weeks later, he presents with myalgia, weakness, elevated CK 10,000. Troponin T is raised 459, ECG shows right bundle branch block (RBBB) and on day 3, he rapidly descends into complete heart block then cardiac arrest. Return of spontaneous circulation is obtained and a permanent pacemaker (PPM) inserted. On day 6, myocardial biopsy confirms acute myocarditis. He develops progressive muscle weakness, dysphagia and Type 2 respiratory failure. He receives 3 doses of IV methylprednisolone, in addition to intravenous immunoglobulins (IVIG) and intravenous cyclophosphamide. EMG shows mild myopathic features, positive AChR antibody, SSA/Ro60 and myositis-specific SRP antibodies and he becomes dependent on non-invasive ventilation. He commences pyridostigmine for myasthenia gravis. On day 19 two doses 1g Rituximab two weeks apart is administered. Monthly IVIG continues for three months and he completes 6 cycles of 500mg cyclophosphamide. A year following discharge, he is maintained on prednisolone 5mg OD with no additional immunosuppression and significantly improved muscle strength. Case 2: 77-year-old Caucasian gentleman receives one dose of pembrolizumab for metastatic melanoma. Four weeks later, he presents with myalgia, bilateral ptosis, muscle weakness and breathlessness. Bloods show CK 6467, troponin T 1058. He promptly receives 3 doses of IV methylprednisolone in addition to IVIG. A PPM is inserted electively as ECGs show RBBB and intermittent bradyarrhythmias. His anti-Ro/SSA-52 antibody is positive and AChR and myositis-specific antibodies are negative. He trials neostigmine due to persistent ptosis. On Day 6, muscle biopsy confirms immune-mediated necrotising myositis and he commences intravenous cyclophosphamide 500mg followed by 5 further cycles. On day 7, 1g intravenous rituximab is administered and repeated two weeks later, additional to monthly IVIG for five months. 6 months later, his CK has normalised and he has no residual muscle weakness.

Results
n/a

Conclusion
Although a rare complication of ICIs, this triad of myositis, myocarditis and myasthenia gravis can be potentially severe and fatal. With ICI reshaping the prognosis of several cancers and pembrolizumab gaining recent further approvals, we will increasingly encounter this therapeutic challenge. Therefore, raising awareness of this overlap syndrome amongst rheumatologists is even more critical to allow for prompt recognition and treatment with immunosuppression.

Disclosure
A. Mootoo: None. A. Masood: None. P. Maghsoudlou: None. D. D'Cruz: None.