Immune checkpoint inhibitor-associated myasthenia gravis, myositis, and myocarditis overlap syndrome.

Case reports of immune checkpoint inhibitor (ICI) overlap syndrome of myasthenia gravis, myositis and myocarditis, are increasing in the published literature. This is a potentially fatal adverse event of ICIs and emergency physicians need to be familiar with this triad when patients present to the emergency department (ED). We performed a retrospective chart review of the electronic medical record between September 1, 2016 to March 9, 2020. We identified patients with the overlap syndrome who presented to our ED. Seven patients were identified. Most were female and treated with a programmed cell death-1 inhibitor. Most patients presented with abnormal vital signs and the most common symptoms were ptosis, diplopia, dyspnea and fatigue. Most required supplemental oxygen and had a prolonged length of stay. All received steroids in addition to other immunomodulators. Two patients died. Presence of one of the diagnosis should lead to evaluation for the others. Suspicion should be raised by patients presenting with ptosis, muscular weakness, fatigue and dyspnea. Early recognition of this triad can allow for early administration of high-dose glucocorticoids (1-2 mg/kg of prednisone or equivalent), which is the mainstay of treatment. However, it is likely that patients will need further immunomodulators and therefore, will need hospitalization. Emergency physicians should be aware of this potentially lethal triad in cancer patients receiving ICIs. The life-saving interventions in the ED include recognizing the triad, airway support, administration of high-dose glucocorticoids, and early involvement of a multidisciplinary team.

Lipe DN ，Galvis-Carvajal E ，Rajha E ，Wechsler AH ，Gaeta S ... -  《-》

Inflammatory Myositis in Cancer Patients Receiving Immune Checkpoint Inhibitors.

To estimate the incidence of immune checkpoint inhibitor-related myositis (ICI-myositis) in cancer patients receiving ICIs, and to report associated clinical manifestations, patterns of care, and outcomes. We identified a retrospective cohort of patients receiving ICIs between 2016 and 2019 seen at the University of Texas MD Anderson Cancer Center. Cases of ICI-myositis were identified using International Classification of Disease codes and confirmed by reviewing medical records and pathology, as available. A total of 9,088 patients received an ICI. Thirty-six patients (0.40%) were identified as having ICI-myositis: 17 patients (47%) with ICI-myositis alone and 19 (53%) with overlap manifestations (5 patients with myocarditis, 5 with myasthenia gravis, and 9 with both). The incidence of ICI-myositis was 0.31% in those receiving ICI monotherapy and 0.94% in those receiving combination ICI therapy (relative risk 3.1 [95% confidence interval 1.5-6.1]). Twenty-five patients (69%) received ≥1 treatment in addition to glucocorticoids: plasmapheresis in 17 patients (47%), intravenous immunoglobulin in 12 (33%), and biologics in 11 (31%). Patients with overlap conditions had worse outcomes than those with myositis alone, and 79% of them developed respiratory failure. Eight patients died as a result of ICI-myositis, and all had overlap syndrome with myasthenia gravis or myocarditis (P < 0.05); 75% of these patients had a concomitant infection. ICI-myositis is a rare but severe adverse event. More than half of the patients presented with overlap manifestations and had deleterious outcomes, including respiratory failure and death. None of the patients with ICI-myositis alone died as a result of adverse events. Optimal treatment strategies have yet to be determined.

Aldrich J ，Pundole X ，Tummala S ，Palaskas N ，Andersen CR ，Shoukier M ，Abdel-Wahab N ，Deswal A ，Suarez-Almazor ME ... -  《-》

Immune Checkpoint Inhibitor-Induced Myocarditis with Myositis/Myasthenia Gravis Overlap Syndrome: A Systematic Review of Cases.

The development of immune checkpoint inhibitors (ICIs) represents a paradigm shift in the treatment of cancers. Despite showing remarkable efficacy, these agents can be associated with life-threatening immune-related adverse events. In recent years, several cases of myocarditis with myositis and/or myasthenia gravis overlap syndrome (IM3OS) have been reported. However, given the rarity, the clinical features and outcomes of these cases remain poorly understood. We, therefore, attempted to systematically review and summarize all cases of IM3OS reported in the literature. Studies reporting IM3OS were identified in Embase and MEDLINE. Only case reports and case series published in journals or presented at conferences were included. We conducted a systematic review according to the PRISMA Harms guidelines. A total of 60 cases were eligible. The patients' median age was 71 years, and the majority (67%) were males; melanoma was the most common indication for ICIs (38%). The most-reported symptoms were fatigue (80%) and muscle weakness (78%). The median number of doses to the development of IM3OS was one. The average creatine kinase level was 9,645 IU/L. Cardiac arrhythmias occurred in 67% of patients, and 18% had depressed ejection fraction. Initial treatment consisted of immunosuppression with high-dose steroids and supportive therapies. Sixty percent of the patients died in hospital because of acute complications. IM3OS can be associated with significant mortality and morbidity. Prospective studies are needed to understand the optimal approach to diagnose and manage these patients and to develop biomarkers to predict the occurrence and severity of this rare but serious condition. Clinicians should suspect coexisting myositis and/or myasthenia gravis in all patients with immune checkpoint inhibitor-induced myocarditis, given their propensity to occur together. Early recognition and prompt treatment with the help of a multidisciplinary team might help improve the outcomes of this life-threatening condition.

Pathak R ，Katel A ，Massarelli E ，Villaflor VM ，Sun V ，Salgia R ... -  《-》

Nivolumab and Ipilimumab-induced myositis and myocarditis mimicking a myasthenia gravis presentation.

The rapidly growing field of cancer immunotherapy has led to the development of new treatments such as immune checkpoint inhibitors. These agents are monoclonal antibodies that enable tumor-reactive T cells to overcome regulatory mechanisms and produce effective antitumor responses. The use of immune checkpoint inhibitors is expected to progressively increase because they have shown promising therapeutic outcomes in multiple types of cancer and clinicians should be aware of their possible side-effects. We report a case of a man diagnosed with a non-microcytic lung carcinoma who started treatment with a combination of immune checkpoint inhibitors (Nivolumab and Ipilimumab). He subsequently developed binocular diplopia, fatigue, mild dyspnea and upper back pain resembling a myasthenia gravis presentation. Finally, a diagnosis of immune checkpoint inhibitor-related myositis and myocarditis was made. The detection of GFAP antibodies in CSF has unclear clinical and pathogenic significance and they may rather represent an epiphenomenon of the immune inflammation process.

Valenti-Azcarate R ，Esparragosa Vazquez I ，Toledano Illan C ，Idoate Gastearena MA ，Gállego Pérez-Larraya J ... -  《-》

Characterization of Immune Checkpoint Inhibitor-Induced Myasthenia Gravis Using the US Food and Drug Administration Adverse Event Reporting System.

Myasthenia gravis (MG) is a rare but fatal adverse event of immune checkpoint inhibitors (ICIs). We assessed whether patient characteristics differed between those with ICI-related myasthenia gravis and those with idiopathic myasthenia gravis. Reports from the US Food and Drug Administration Adverse Event Reporting System were analyzed. Multivariate analyses were conducted to evaluate the associations between age, sex, and ICI treatment and the reporting rate of myasthenia gravis. Among 5 464 099 cases between 2011 and 2019, 53 447 were treated with ICIs. Myasthenia gravis was reported more often in ICI users. Multiple logistic regression analyses showed that the reporting rate of ICI-related myasthenia gravis did not differ significantly between men and women; however, it was higher in older people than in younger people (adjusted odds ratio, 2.4 [95%CI, 1.84-3.13]). We also investigated useful signs for the early detection of myositis and myocarditis, which are fatal when overlapping with ICI-related myasthenia gravis. Patients with elevated serum creatine kinase or troponin levels were more likely to have concurrent myositis and myocarditis. Unlike idiopathic myasthenia gravis, there was no sex difference in the development of ICI-related myasthenia gravis, which may be more common in older people. Considering the physiological muscle weakness that occurs in the elderly, it may be necessary to monitor ICI-related myasthenia gravis more closely in older people.

Niimura T ，Zamami Y ，Miyata K ，Mikami T ，Asada M ，Fukushima K ，Yoshino M ，Mitsuboshi S ，Okada N ，Hamano H ，Sakurada T ，Matsuoka-Ando R ，Aizawa F ，Yagi K ，Goda M ，Chuma M ，Koyama T ，Izawa-Ishizawa Y ，Yanagawa H ，Fujino H ，Yamanishi Y ，Ishizawa K ... -  《-》