Immune checkpoint inhibitors (ICI) such as cytotoxic T-cell lymphocyte associated antigen-4 (CTLA-4) and programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) blocking agents are indicated as a standard of care in several cancers [1–3]. Their use is expected to expand, including in the adjuvant setting, leading to an increase in the population of cancer patients exposed to these therapies [4–8]. However, the clinical benefit of ICIs can be limited by toxicities caused by off-target inflammatory and autoimmune responses, which can be life-threatening, and may require treatment discontinuation and initiation of immunosuppressants. A challenging population is patients who have a dual diagnosis of autoimmune diseases and cancer, requiring the use of ICIs [9–11]. A recent systematic review of the literature summarized the evidence on adverse events associated with ICI use in patients with preexisting autoimmune diseases and found that most of these patients (75%) are susceptible to develop flare of the underlying autoimmunity (50%), and/or new onset immune-related adverse events (irAEs) (34%) [9]. Although adverse events improved in most patients (90%), some (17%) required permanent ICI discontinuation or remained at risk of serious complications including fatality (4%).

ICI-related neurologic adverse events are relatively infrequent but pooled analyses have shown severe morbidity and fatalities [12, 13]. Myasthenia gravis (MG) is a neuromuscular disease that was reported to have a critical clinical outcome including death post-ICI use in cancer patients. The limited number of cases described in the literature with either new onset MG [14–19], or with a flare of preexisting MG [9], after ICI, limits our ability to characterize the clinical features and outcome of this disease and to optimize its diagnosis and management. Here we describe the clinical and diagnostic features of 65 patients with MG in the setting of ICI, discuss their management strategies, and summarize their clinical outcomes.

A total of 5898 patients received ICI at MD Anderson. Among these, 14 (0.24%) were diagnosed with MG. Of 10,442 unique articles from the literature, 46 publications describing 53 patients met inclusion criteria (Additional file 2: Figure S1), including two patients who had been identified from MD Anderson [21]. Therefore, a total of 65 patients were included in our final analysis; 58 fulfilled the criteria for a definite diagnosis of MG and the remaining patients had probable MG.

Our data support that MG is a life-threatening irAE with an acute onset and rapid deterioration shortly after ICI initiation. Approximately two-thirds of our patients developed severe muscle weakness (MGFA class V) with respiratory dysfunction requiring mechanical support in 45%.

Our findings support that ICI-related MG has several unique features compared to iMG, which typically manifests as a milder disease where most patients fall under MGFA classes I and II [26], and which has a slower clinical deterioration course that may take 2–3 years to progress to class V [29, 30]. Age at diagnosis of ICI-related MG in our cohort was also significantly older than in patients with iMG [26]. This raises the question of whether elderly patients with cancer are more susceptible to this particular adverse event. We also observed that more than one-third of our patients developed MG overlapping with myositis/myocarditis; those patients seemed to have more severe symptoms and worse clinical outcomes than patients with MG alone. Of note, we believe that myositis may have been underdiagnosed in our cohort, as many patients reported in the literature had myalgias and elevated CPK but the concurrent diagnosis of myositis was not discussed. The overlap of these two entities, in addition to myocarditis, has been described in only 0.9% of patients with iMG, and is frequently associated with thymoma [31, 33, 34], progression to myasthenic crisis [31, 35], and positive striational antibodies, the latter are believed to be markers of poor prognosis [36].

The underlying immunobiology is not well studied in ICI-related MG. Gene expression analysis of peripheral blood mononuclear cells was performed before and after nivolumab in one patient who developed MG/myositis/myocarditis, and revealed an increased expression of CD8 and cytolytic activity markers, whereas CD4+ T-cell and T regulatory cell activity seemed suppressed [22]. In another patient with nivolumab-related MG/myositis, peripheral blood lymphocyte analysis showed an elevated CD8:CD4 ratio of 1.4 [37], these findings can possibly be related to the activity of nivolumab regardless of induction of MG.

For almost all patients in our cohort (96%), hospitalization and corticosteroids were recommended, and severity of symptoms at initial presentation failed to predict the course of disease. For instance, few patients initially presented with mild ocular symptoms but suddenly progressed to respiratory failure despite initiation of steroids. Our data suggest that patients who received IVIG or PLEX as a first-line treatment experienced better MG outcomes than those who received steroids alone (95% vs 63% improvement of MG symptoms, p = 0.011). Our results also suggest that IVIG or PLEX may be most effective when used as the first-line regimen, as several patients who deteriorated after initial use of steroids failed to improve despite a second-line use of IVIG or PLEX. In contrast to our findings, the clinical practice guidelines for management of ICI-related MG recommend adding IVIG or PLEX if patients had no improvement/worsening on steroid alone, or presented with severe symptoms (MGFA class III to V) [38, 39]. Given the acute onset and rapid deterioration of ICI-related MG, we recommend the early use of IVIG or PLEX in the first-line regimen regardless of the severity of initial symptoms. In fact, the use of steroids as a sole first-line therapy might not be ideal for management considering that these drugs might take several weeks to show clinical response [40]. Additionally, it is well known that steroid use can cause an acute exacerbation of iMG symptoms [41]. Although this worsening has been described as transient, it occurs in 50% of patients, and includes a serious risk of progression to respiratory failure [42]. On the other hand, the use of IVIG and PLEX have led to favorable outcomes in most patients with severe iMG [43–45], and their early use is recommended preceding or simultaneously with steroids to overcome the risk of a transient worsening, especially in patients with severe disease [40, 46, 47]. One should keep in mind that the use of steroids alone in ICI-related MG might be associated with an even worse prognosis as these patients might not be able to survive a transient worsening of symptoms following steroids because of their old age and advanced malignancy. Of note, these patients typically require steroids at higher doses compared to iMG because of the concurrent myositis/myocarditis as well as other organ toxicities. Moreover, the role of steroids in controlling immune dysregulation in these patients might be limited by the constant presence of the original trigger; the circulating ICIs, as their half-life ranges from 14.7 to 27.3 days depending on the agent [48, 49]. Therefore, elimination of the pathogenic antibodies and ICI mAbs from the sera of patients using IVIG or PLEX could mediate a faster improvement of symptoms. Given the small number of patients and the retrospective nature of our study, we were unable to estimate the frequency of a steroid induced exacerbation in our cohort. However, our data might suggest the need to reassess the current recommendations for management of ICI-related MG.

Death primarily due to MG complications was reported in 23% of our cohort. In regards to tumor response, our data show that the clinical benefit rate in melanoma patients reaches up to 75% suggesting a possibly enhanced antitumor immune response. Our findings could also suggest that short-term immune modulation using IVIG or PLEX along with steroids might not alter the durability of tumor response to ICI.

The decision to rechallenge patients with ICI-related MG using an ICI is a dilemma that we do not currently have an answer for. Although our data partially suggest a safe re-administration of ICI after resolution of MG symptoms and while on maintenance therapy, the number of patients was too small to infer with confidence any definitive conclusions. It is well-known that iMG is mostly characterized to have a “monophasic” clinical course. However, whether ICI-related MG have similar clinical pattern remains unclear, since our data have shown that all patients who were rechallenged or continued on ICI were kept on immunosuppressive therapy.

We did not observe differences in the clinical course and outcomes of ICI-related MG between patients who experienced flare of a preexisting MG and those with a new onset disease. Given the lack of prospective cohort studies, the true incidence rate of MG flare after ICI in patients with a prior diagnosis of MG cannot be currently estimated. Moreover, whether patients who develop new onset MG, in fact, have had a subclinical autoimmunity that manifested only after exposure to ICI remains questionable. Therefore, further longitudinal studies are needed to validate these findings and judiciously evaluate if screening for MG should be considered before initiation of ICI.

To our knowledge, our study represents the largest cohort of patients with ICI-related MG, and the most comprehensive systematic review of the literature. Although it is limited by its retrospective nature, our findings help clinicians gain familiarity with the severity and the rapidly progressive course of ICI-related MG, and suggest a possibly enhanced management recommendation with early use of IVIG/PLEX. Additionally, our data provide a safety signal that would help clinicians consider the risks and benefits for each individual patient predominantly elderly and those receiving ICI as an adjuvant therapy.

In summary, MG in the setting of ICI use is an acute and life-threatening adverse event with varied clinical presentations and rapid deterioration. Therefore, it is critical that patients, primarily those receiving adjuvant ICI, be aware of this possible complication. The healthcare providers should also be mindful of the need for a multidisciplinary approach and a multimodal aggressive therapy. Preclinical studies are warranted to enhance our understanding of the immunobiology of this irAE, so we can carefully evaluate the risk benefit ratio of ICI use in susceptible patients. Multi-institutional clinical trials are needed to establish the ideal therapeutic approach for this life-threatening complication.