Myasthenia gravis induced or exacerbated by immune checkpoint inhibitors: a rising concern

Abstract

Immune checkpoint inhibitors can cause immune side effects, with myasthenia gravis (MG) being relatively rare. With this review, we present 66-year-old man with melanoma treated with pembrolizumab who developed MG. With immuno-oncology (IO) single agent usage, 42 cases reported new-onset MG and 9 cases reported exacerbation of pre-existing MG. Among the patients who had new-onset MG after administration of programmed cell death protein 1 (PD-1) inhibitors, 14 patients (38.8%) developed severe respiratory failure and required intubation and 10 patients (27.02%) died. Among the patients with exacerbation of pre-existing MG after receiving PD-1 inhibitors, 1 patient (11.1%) required intubation, and no death was reported. Combination IO therapy-induced MG was reported in seven cases, with at least two cases complicated by respiratory failure and one death. Our observations suggest a possible difference in the severity of the disease and outcome among different IO therapy options.

Background

For the last decade, advancements in immuno-oncology revolutionised cancer patient’s management.¹ Currently, inhibiting cytotoxic lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis is implicated for treatment of many malignancies.² This leads to disinhibition of cytotoxic T cells, resulting in antitumour activity.² As a result, unique immune-related side effects affecting any organ or tissue may arise.³ Interestingly, these complications may manifest as known autoimmune syndrome. Little is known about how immune check point inhibitors induced side effects are different from sporadic alloimmunisation.⁴ Neurological immune side effects, though are rare, may lead to rapid and severe deterioration of the patient condition.⁵ Rarely, some patient may experience myasthenia gravis (MG) type syndrome, which can lead to significant morbidity and mortality if not recognised promptly.⁶ In such cases, to provide best diagnostic and therapeutic interventions, multidisciplinary approach, involving neurologist, medical oncologist and other medical specialties, is required.⁷ Here, we report a case of a 66-year-old man with metastatic melanoma who developed MG after receiving the second dose of pembrolizumab. We also performed an extensive review of already existing reports in relation to this topic.

Case presentation

A 66-year-old man was diagnosed with stage IB cutaneous malignant melanoma in 2017. Primary tumour was 1.5-millimetre thick without ulceration, located over left periaricular site. His oncological history is also significant for locally advanced left tonsillar squamous cell carcinoma, which was treated with radiation therapy and cetuximab. Unfortunately, patient was diagnosed with metastatic recurrent melanoma in July 2018. He was found to have bilateral axillary lymphadenopathy and treatment with pembrolizumab was initiated. The patient presented to the clinic on day 10 of cycle 2 of pembrolizumab therapy complaining of diplopia, hoarseness, dysphagia and dysphonia. Laboratory analysis revealed an elevation in both aspartate transaminase and alanine transaminase, consistent with grade two hepatic toxicity. The patient was found to have progressive ptosis during the day, bilateral vocal paralysis and nasal regurgitation. Constellation of these symptoms raised concern for MG-type syndrome. Anti-titin, anti-acetylcholine receptor and Purkinje cell/neuronal nuclear antibodies were not present in the serum. MRI of the brain showed no evidence of metastatic disease.

Differential diagnosis

Although the clinical picture is similar to MG, underlying disease pathology may not be the same and likely not completely understood for immune toxicity. The case we reported could be a case of seronegative MG. Around 10%–20% of patients with MG do not have acetylcholine receptor (AChR) antibodies (seronegative). Among this group of patients, some might have antibodies to a membrane-linked muscle-specific kinase (MuSK).

Treatment

Pembrolizumab was discontinued and the patient was started on pulse steroid therapy with intravenous methylprednisolone 60 mg three times per day for both grade two hepatic toxicity and MG. The patient’s severe dysphagia and muscular weakness necessitated percutaneous endoscopic gastrostomy tube insertion and tracheostomy placement due to the high risk of aspiration and vocal cord paralysis.

Outcome and follow-up

Later, hoarseness and double vision did resolve with these interventions. Unfortunately, vocal cord paralysis was persistent. A positron emission tomography scan in 3 months showed a decrease in the size and the intensity of activity in both axillae. The patient had no progression of metastatic melanoma thereafter. Unique findings in our case is with just two doses of pembrolizumab and since then even without any further line of therapy, the relative stability of metastatic adenopathy and survival reaching >30 months.

Discussion

We performed a detailed and extensive search of medical databases, including Google Scholar and PubMed, looking for all published cases of MG (new cases or exacerbation of pre-existing disease) initiation of immune checkpoint inhibitors (ICI) treatment. We used the following medical subject heading terms: MG, ICI, anti-PD-1 antibody, anti-PD-L1 antibody and anti-CTLA-4 antibody. We searched the reference lists found in relevant articles, including previously published literature reviews and textbooks, manually. As a result of this extensive search and screening of articles, besides our own reported case, we were able to identify 58 reported cases of MG (new cases or exacerbation of pre-existing disease) during or after ICI treatment. Of these, 36 cases reported new-onset MG (table 1) and 9 cases reported exacerbation of pre-existing MG after initiation (table 2) of PD-1 inhibitors. Administration of CTLA-4 inhibitors and PD-L1 inhibitors caused the new onset of MG in four cases (table 3) and two cases (table 4), respectively. In addition, seven cases reported that they developed MG after administration of a combination of ICI medications (table 5).

Table 1.

New onset MG after utilisation of PD-1 inhibitors

Study	Publish year	Age	Gender	PD-1 inhibitor	Cancer type and stage	Anti-AChR Ab	Anti-MuSK/anti-striational Abs	Previous history of MG	Time between initiation of treatment and onset of symptoms (days)	Initial symptoms	Severe respiratory failure requiring intubation	Initial treatment	MG-related outcome
Our case	2020	66	M	Pembrolizumab	Metastatic melanoma	Negative	Negative	No	24	Diplopia, hoarseness and dysphagia	No	Pulse steroid therapy, percutaneous endoscopic gastrostomy (PEG) and tracheostomy placement	Improved
Zimmer et al8	2016	69	F	Pembrolizumab	Metastatic melanoma	Negative	Negative	No	28	Eye movement disorder, bilateral diplopia and shortness of breath	No	Pyridostigmine, prednisone, methylprednisolone, intravenous immune globulin (IVIG) and plasmapheresis	Died
Alnahhas and Wong9	2017	84	M	Pembrolizumab	Metastatic melanoma	Positive	Negative	No	30	Progressive weakness and dysphagia	Yes (refused)	Pyridostigmine, prednosine and IVIG	Died (unclear if it was related to MG)
Makarious et al (ocular MG)10	2017	85	F	Pembrolizumab	Metastatic melanoma	Negative	Negative	No	31	Diplopia and asymmetrical bilateral ptosis (L>R)	No	IVIG, prednisone and pyridostigmine	Improved (died later from unrelated cardiac issues)
Nguyen et al11	2017	81	M	Pembrolizumab	Metastatic melanoma	Negative	Negative	No	58	Bilateral ptosis	No	Prednisone	Improved
Nguyen et al11	2017	86	F	Pembrolizumab	Metastatic melanoma	Negative	Negative	No	41	Bilateral ptosis and dysphagia	No	Methylprednisolone and oral prednisolone	Improved
Gonzalez et al12	2017	71	F	Pembrolizumab	Metastatic uterine carcinoma (CA)	Negative	Negative	No	63	Dysphagia, diplopia and dysartheria	No	Pyridostigmine and prednisone	Improved
March et al13	2018	63	M	Pembrolizumab	Metastatic melanoma	Positive	Negative	No	14	Right ptosis, puffiness, blurred vision and shortness of breath	Yes	Pyridostigmine, prednosine, IVIG and plasma exchange	Died
Algaeed et al14	2018	73	M	Pembrolizumab	Recurrent melanoma	Positive	Not reported	No	21	Left eyelid droop and shortness of breath	Yes	Pyridostigmine	Improved
Hibino et al15	2018	83	M	Pembrolizumab	Lung squamous cell carcinoma (SCC) stage IVb	Negative	Negative	No	38	Narrowing visual field and easy fatigability eye leads	No	Pyridostigmine and prednisone	Improved
Huh et al16	2018	34	F	Pembrolizumab	Thymic SCC	Positive	Unknown	No	unknown	Diplopia, dysphagia and dyspnoea	No	IVIG, methylprednisolone, prednisone and plasmapheresis	Improved
Erkilinc et al17	2018	57	M	Pembrolizumab	Thymoma	Negative	Negative	No	30	Double vision, drooping eyelids and difficulty with talking and swallowing		IVIG, methylprednisolone and pyridostigmine	Improved
Onda et al (ocular MG)18	2019	73	M	Pembrolizumab	Lung adenocarcinoma	Negative	Positive (anti-titin Ab positive)	No	23	Diplopia, ptosis and external ophthalmoplegia without general muscle weakness	No	Ascending-dose regimen of prednisolone and steroid pulse therapy	Improved
Noda et al19	2019	77	F	Pembrolizumab	Lung adenocarcinoma	Positive	Positive (anti-titin Ab positive)	No	49	Limb and neck weakness, dyspnoea and dysphasia	Yes (non-invasive positive-pressure ventilation and tracheotomy positive pressure ventilation)	IVIG, immune absorption therapy and plasma exchange therapy	Improved
Todo et al20	2020	63	M	Pembrolizumab	Bladder carcinoma	Negative	Negative	No	12–34	Left ptosis and diplopia	No	Prednisolone	Improved
Szuchan et al21	2020	70	F	Pembrolizumab	Metastatic thymic cancer	Yes	Unknown	No	21	Shortness of breath	Yes	High-dose intravenous methylprednisolone	Improved
Lopez et al22	2015	65	M	Nivolumab	Renal cell carcinoma (RCC)	Positive	Negative	No	15	Dyspnoea, diplopia and bilateral ptosis	Yes	High dose glucocorticoids (GC)+IVIG	Died
Polat and Donofrio23	2016	65	M	Nivolomab	Non-small cell lung cancer (NSCLC)	Negative	Negative	No	31	Blurred vision and bilateral ptosis	No	Pyridostigmine	Improved
Sciacca et al24	2016	81	M	Nivolumab	NSCLC stage IV	Negative	Unknown	No	28	Bilateral ptosis, nasal speech and proximal limb weakness	No	Prednisone	Improved
Shirai et al25	2016	81	F	Nivolumab	Melanoma	Positive	Negative	No	21	Dyspnoea	Yes (refused)	Treatment refused by the patient	Died
Kimura et al26	2016	80	M	Nivolumab	Melanoma	Positive	Negative	No	14	Fatigue, anorexia, stable dyspnoea	Yes	High dose GC, IVIG and plasma exchange	Stable disease
Chang et al27	2017	75	M	Nivolumab	Bladder SCC	Positive	Negative	No	39	Double vision, fatigue and severe shortness of breath (SOB)	No Bilevel positive airway pressure (BiPAP)	Pyridostigmine and IVIG	Died(Hospice)
Chen et al28	2017	65	M	Nivolumab	Lung SCC	Negative	Unknown	No	33	Weakness of four extremities	Yes (family refused)	Pyridostigmine+high dose GC	Died
Mehta et al29	2017	73	M	Nivolumab	Metastatic RCC	Positive	Unknown	No	14	Fatigue, haematuria and progressive weakness	Yes	Pyridostigmine+high dose GC	Long-term ventilator support
Tanaka et al30	2017	70 s	F	Nivolumab	Malignant melanoma	Positive	Unknown	No	31	Ptosis	No	Prednisone and pyridostigmine	Improved
Fukasawa et al31	2017	69	F	Nivolumab	Advanced lung adenocarcinoma	Positive	Unknown	No	1 week after the third cycle	Generalised weakness and double vision	No	Methylprednisolone and prednisone	Improved
Konoeda et al32	2017	74	F	Nivolumab	Advanced colon cancer	Positive	Unknown	No	5 days after the second course	Bilateral ptosis	No (required BiPAP)	Oral prednisolone, IVIG and plasma exchange	Improved
Tan et al33	2017	45	M	Nivolumab	NSCLC	Positive	Unknown	No	14	Dyspnoea, ptosis and ophthalmoplegia	Yes	Methylprednisolone, pyridostigmine and IVIG	Improved
Hasegawa et al34	2017	76	F	Nivolumab	NSCLC	Positive	Unknown	No	After the second cycle of nivolumab	Left eyelid ptosis, dyspnoea and muscle weakness	No	Plasma exchange, IVIG and low-dose prednisolone	Improved
Kang et al35	2018	75	N	Nivolumab	H&N SCC	Positive	Positive	No	21	Severe fatigue, generalised weakness and bilateral ptosis	Yes	Methylprednisolone, oral prednisolone and plasma exchange	Died
Yousef et al36		67	M	Nivolumab	SCC left parotid gland stage IV	Negative	Positive	No	35	Difficulty rising from chair and climbing stairs	No (BiPAP)	IVIG+prednisone	Improved
Sawai et al37	2019	84	F	Nivolumab	RCC	Negative	Unknown	No	15	Blepharoptosis, diplopia, weakness of extremities and dysphagia	Yes (refused by patient and family)	IVIG and steroid pulse therapy	Died
Isami et al38	2019	53	M	Nivolumab	NSCLC	Negative	Positive	No	30	Bilateral ptosis and bulbar palsy	No	Prednisolone	Improved
Sun et al39	2019	83	M	Nivolumab	Recurrent urothelial CA	Positive	Positive	No	21	Hoarseness, difficulty speaking and swallowing, and generalised weakness	Yes	Methylprednisolone+plasma exchange	Home hospice with tracheostomy
Kim et al40	2019	76	M	Nivolumab	NSCLC	Positive	Unknown	No	45	Gait disturbance	No	Methylprednisolone, prednisone and pyridostigmine	Improved
Nakanishi et al41	2020	78	M	Nivolumab	RCC	Positive	Unknown	No	After the second course of nivolumab	Neck pain and altered mental status	Yes (refused by family)	Prednisolone	Died
Pouchelon et al42	2020	78	M	Nivolumab	Bronchial squamous cell carcinoma	Negative	Negative	No	Unknown	Difficulty holding his head and ptosis of the right eye	Yes (intubation was not done)	Prednisone, IVIG and plasma exchange	Died

Ab, antibody; AChR, acetylcholine receptor; MG, myasthenia gravis; MuSK, muscle-specific kinase; PD-1, programmed cell death protein 1; PEG, percutaneous endoscopic gastrostomy.

Table 2.

Exacerbation of pre-existing MG after initiation of PD-1 inhibitors

Study	Publish year	Age	Gender	PD-1 inhibitor	Cancer type and stage	Anti-AChR Ab	Anti-MuSK/anti-striated muscle Ab	Previous history of MG	Time between initiation of treatment and onset of symptoms (days)	Initial symptoms	Severe respiratory failure requiring intubation	Initial treatment	MG-related outcome
Zhu and Li43	2016	59	F	Pembrolizumab	Metastatic melanoma	Negative	Negative	Yes (generalised MG)	42	Rapidly progressive hoarseness and dysphagia	No	IVIG, plasmapheresis and prednisone	Improved
Phadke et al44	2016	75	M	Pembrolizumab	Metastatic melanoma	Positive	Unknown	Yes	21	Diplopia, bilateral ptosis and respiratory distress	No (BiPAP)	Pyridostigmine, plasma exchange, IVIG and rituximab	Improved
Lau et al45	2016	75	M	Pembrolizumab	Metastatic melanoma	Positive	Unknown	Yes	25	Difficulty walking and neck weakness	No bilevel positive airway pressure (BiPAP)	Methylprednisolone, prednisone, IVIG and azathioprine	Improved
Earl et al46	2018	74	M	Pembrolizumab	Metastatic melanoma	Positive	Negative	Yes	12 days after his second infusion	Ptosis, diplopia, dysphagia and proximal limb weakness	No	Pyridostigmine, prednisone and plasma exchange mycophenolate	Discharged to inpatient hospice and ultimately died
Maeda et al47	2016	79	M	Nivolumab	Metastatic melanoma	Positive	Unknown	Yes	106	Diplopia and facial weakness	No	Pyridostigmine+prednisone	Improved
Cooper et al48	2017	68	F	Nivolumab	Non-small cell lung cancer (NSCLC) stage IV	Positive	Negative	Yes	84 days	Difficulty walking, dysartheria and diplopia	No (refused by patient)	Pyridostigmine, prednisone and plasma exchange	Admitted to hospice
Mitsune et al49	2018	62	F	Nivolumab	Primary neuroendocrine carcinoma (CA) of trachea	Positive	Positive	Yes (ocular MG)	25 days	Generalised fatigue and muscle weakness	No	Methylprednisolone	Improved
Agrawal Yash et al50	2019	51	M	Nivolumab	Melanoma stage IIIB	Negative	Negative	Yes and history of Interferon alfa (IFNa) induced MG	6 days	Constipation, worsening right arm and hand numbness and paraesthesia	No	Pyridostigmine+high-dose glucocorticoid	Improved
Kamien et al51	2019	76	M	Nivolumab	Oesophageal CA	Positive (orignal GM positive but significantly uptrended during exacerbation	Unknown	Yes (generalised MG)	7 days after the second dose. 79 days after the first dose (72 days gap between the first and the second doses	Diplopia, weakness of upper extremities and drolling	No	Pyridostigmine+high-dose GC	Improved

Ab, antibody; AChR, acetylcholine receptor; MG, myasthenia gravis; MuSK, muscle-specific kinase; PD-1, programmed cell death protein 1.

Table 3.

Cases of CTLA-4-induced MG

Study	Publish year	Age	Gender	Cancer type and stage	Anti-AChR Ab	Anti-MuSK/anti-striated muscle Ab	Previous history of MG	Time between initiation of treatment (Rx) and onset of symptoms	Initial symptoms	Severe respiratory failure requiring intubation	Initial treatment	MG-related outcome
Liao et al63	2014	70	F	Metastatic melanoma	Positive	Positive	No	70 days	Generalised myalgia and dysphagia	No	Solu-medrol, plasmapheresis and intravenous immune globulin (IVIG)	Improved
Johnson et al56	2015	69	F	Melanoma stage IIIA	Positive	Negative	No	42 days	Diplopia, dysphagia and ptosis	No	Pyridostigmine	Improved
Johnson et al56	2015	73	M	Melanoma stage IIIB	Positive	Unknown	No	After 2 doses (probably 21 days)	Shortness of breath (SOB) and proximal limb weakness	No	Pyridostigmine and high-dose glucocorticoid	Improved
Montes et al64	2018	74	M	Metastatic melanoma	Negative	Unknown	No	43 days	SOB and proximal limb weakness	No	Pyridostigmine and high-dose glucocorticoid	Improved

Ab, antibody; AChR, acetylcholine receptor; CTLA-4, cytotoxic lymphocyte-associated protein 4; MG, myasthenia gravis; MuSK, muscle-specific kinase.

Table 4.

Cases of PD-L1-induced MG

Study	Publish year	Age	Gender	PD-L1 inhibitor	Cancer type and stage	Anti-AChR Ab	Anti-MuSK/anti-striated muscle Ab	Previous history of MG	Time between initiation of treatment (Rx) and onset of symptoms	Initial symptoms	Severe respiratory failure requiring intubation	Initial treatment	MG-related outcome
Brahmer et al53	2012	Unknown	Unknown	Anti-PD-L1 antibody (not specified)	Unknown	Unknown	Unknown	Unknown	Unknown	Unknown	Unknown	Unknown	Unknown
Thakolwiboon et al65	2019	87	M	Atezolizumab	Urothelial carcinoma	Positive	Positive	No	21 days	Double vision and ptosis	No	Intravenous immune globulin (IVIG) and low-dose oral pyridostigmine	Died due to cardiac arrest
Shah et al66	2019	81	F	Atezolizumab	Urachal cancer	Negative	Negative	No	60 days	Head droop, left facial droop and voice change	Yes	Plasma exchange and rituximab	Comfort care

Ab, antibody; AChR, acetylcholine recpetor; MG, myasthenia gravis; MuSK, muscle-specific kinase; PD-L1, programmed death-ligand 1.

Table 5.

Cases of MG induced by combination of ICI therapy

Study	Publish year	Age	Gender	Immune checkpoint inhibitors (ICI)	Cancer type and stage	Anti-AChR Ab	Anti-MuSK/anti-striated muscle Ab	Previous history of MG	Time between initiation of treatment (Rx) and onset of symptoms	Initial symptoms	Severe respiratory failure requiring intubation	Initial treatment	MG-related outcome
Loochtan et al67	2015	70	M	Nivolumab+ipilimumab	Small cell lung cancer (SCLC) stage	Positive	Positive	No	16 days	Ptosis and diplopia	Yes	Prednisone and plasmapheresis	Comfort care
Chen et al52	2017	57	M	Nivolumab+ipilimumab	Non-small cell lung cancer (NSCLC)	Positive	Unknown	No	14 days	Drooping of eyelids, dropped head, limb weakness, unsteadiness in walking and mild dyspnoea	No	Prednisolone and pyridostigmine	Improved from MG but died from sepsis in the same hospitalisation
Werner et al68	2019	62	M	Nivolumab+ipilimumab	Melanoma (clark-level III)	Negative	Negative	No	28 days	Fatigue and ptosis of right eye	No	Pyridostigmine+high-dose glucocorticoids	Improved
Fazel et al54	2019	78	F	Nivolumab+ipilimumab	Metastatic melanoma	Unknown	Positive	No	5 days	Diplopia, proximal muscle weakness and myalgia	Yes (refused by the patient)	Methylprednisolone+ Intravenous immune globulin (IVIG)	Inpatient hospice
Leaver et al69	2020	55	M	Nivolumab+ipilimumab	Metastatic melanoma	Negative	Negative	No	28 days	Blurred vision, mild bilateral ptosis and fatigable left arm abduction	No	Prednisolone	Improved
Antonia et al55	2016			Durvaluma+tremelimumab	Advanced NSCLC	Unknown	Unknown	Unknown	14 days	Unknown	Unknown	Unknown	Died
Yousef et al36		65	F	Durvalumab+tremelimumab	Liomyosarcoma stage IV with lung metastasis	Positive	Positive	No	After the first dose	Back pain and stooped posture with difficulty lifting her head	No	Plasma exchange+ Intravenous immune globulin (IVIG) + prednisone	Improved

Ab, antibody; AChR, acetylcholine receptor; MG, myasthenia gravis; MuSK, muscle-specific kinase.

Among 36 reported cases of new onset of the MG after administration of PD-1 inhibitors, 15 cases were related to pembrolizumab^8–21 and 21 cases happened after using nivolumab.^22–42 In the patients with exacerbation of the pre-existing MG, four were related to pembrolizumab^43–46 and five were related to nivolumab.^47–51 AChR antibody was positive in 20 patients (51.2%) with new onset of MG and 7 patients (77.7%) with exacerbation of the pre-existing MG. We considered developing severe respiratory failure requiring bilevel positive airway pressure (BiPAP) or endotracheal intubation and death as unfavourable outcomes of disease. Among the patients who had new-onset MG after administration of PD-1 inhibitors, 14 patients (38.8%) developed severe respiratory failure due to MG and required intubation from which 11 patients received nivolumab,22 25 26 28 29 33 35 37 39 41 42 and 3 received pembrolizumab.^{9 13 14} Three patients (8%) who all received nivolumab required BiPAP.^{27 32 36} Ten patients (27.02%) passed away as a result of MG, among which 8 patients received nivolumab22 25 27 28 35 37 41 42 and 2 patients were on pembrolizumab.^{8 13} One patient required long-term ventilation support²⁹ and one patient was placed on hospice care.³⁹

Among the patients with exacerbation of pre-existing MG after receiving PD-1 inhibitors, patient (11.1%) who was receiving nivolumab required intubation,⁴⁸ and 2 patients (22.1%) required BiPAP.^{44 45} Both these patients that required BiPAP were receiving pembrolizumab. No death was reported in patients with exacerbation of pre-existing MG, but two of them were placed on hospice care.^{46 48} Among reported cases of PD-1 inhibitor-associated new-onset MG, the mean duration for the onset of symptoms was 29.06 days post initiation of the PD-1 inhibitor. Among those with exacerbation of the pre-existing MG after receiving PD-1 inhibitor, the mean duration for the onset of symptoms was 43.2 days post initiation of the medication. Among four reported cases of ipilimumab-associated MG, all were new-onset cases. The mean duration for the onset of symptoms was 44 days post initiation of ipilimumab. No death was reported (table 4).

We found seven reported cases of immune checkpoint inhibitor combination therapy-associated MG (table 5). Five patients received nivolumab+ipilimumab and the other two received durvalumab+tremelimumab. Among these patients, the mean duration for the onset of symptoms was 17.5 days post initiation of combination therapy. Among this group of patients, at least 2 patients (28.5%) developed severe respiratory failure requiring endotracheal intubation (28.5%) and 1 (14.2%) died as a result of MG. In one case, the symptoms of MG were improving, but he died from sepsis in the same hospitalisation.⁵² Two patients were placed on comfort/hospice care.^{53 54} Antonia et al developed a multicentre study to evaluate for safety and antitumor activity of durvalumab plus tremelimumab in non-small cell lung cancer. In this study, they reported a patient with NSCLC who received durvalumab 20 mg/kg every 4 weeks plus tremelimumab 1 mg/kg. This patient developed MG within 10 days of initiating treatment and eventually passed away as a result of MG. Although considering the outcome of death, we can guess this patient developed severe respiratory failure requiring endotracheal intubation but unfortunately despite detailed evaluation of the manuscript, we could not find more information about this patient, including the course of treatment or the need for intubation.⁵⁵

Over the last couple of years, immune checkpoint inhibitors utilisation has emerged as an effective treatment for different types of advanced cancers.^{56 57} Despite impressive benefits were observed from using ICI agents in patients with different types of cancer, utilisation of these medications was associated with the occurrence of serious adverse events related to excessive immune system activation, known as immune-related adverse events (irAEs).⁵⁸ MG is an autoimmune disorder that targets neuromuscular junction where acetylcholine is the main neurotransmitter.⁵⁹ It is believed that autoantibodies against the AChR or muscle-specific tyrosine kinase are responsible for the clinical features.^{60 61} The main characteristic of the disease is fatigable weakness variably involving ocular, bulbar, respiratory and limb muscles.⁶² MG is estimated to occur in 0.1%–0.2% of patients receiving immunotherapy.^{56 63}

In June 2012, Brahmer et al reported the first case of new onset of MG in a patient treated with an ICI medication. They conducted the study of ‘Safety and activity of anti-PD-L1 antibody in patients with advanced cancer’. In which they have enrolled patients with different types of advanced cancer in a dose-escalation phase of the trial of anti-PD-L1 antibody administration. Based on the reported results, among 125 patients who received 10 mg/kg of anti-PD-L1 antibody (the highest dose), 1 patient developed MG.⁵³ Since then, multiple cases reported indicating the development of MG after using ICI agents. The number of reported cases who developed new-onset MG or exacerbation of pre-existing disease after initiation of ICI treatment over the last couple of years has been continuously increasing. We found 7 cases reported in 2018. This number increased to 13 cases in 2019. Regarding the reported cases in 2020, as of 31 May, we found 6 reported cases, including our case. This increasing pattern indicates the importance of gathering more information about this side effect of ICI therapy for different cancers. Our observations show that the prevalence of developing severe respiratory failure due to MG, which required intubation of patients, was higher in cases with new onset of MG after using PD-1 inhibitors compared to those with pre-existing MG who had exacerbation of the disease after using PD-1 inhibitors (38.8% vs 11.1%). We had a similar observation for the reported death outcome (27.02% vs no death). In addition, the mean duration for the onset of symptoms after initiation of PD-1 inhibitor was much shorter in patients with new-onset MG compared to exacerbation of the pre-existing disease (29.06 days vs 43.2 days). These data could probably suggest a more severe presentation of the disease and a worse outcome in the new onset of MG after using PD-1 inhibitors. Although more studies are needed to confirm this observation, we can suggest more careful monitoring of the patients without previous history of MG for the symptoms of this disease while being treated with PD-1 inhibitors.

None of the four patients who received ipilimumab developed the severe disease and they all improved without any unfavourable outcome. Also, the mean duration for the onset of symptoms after initiation of ipilimumab was 44 days, which is the longest duration among all ICI agents. This might be suggestive of milder presentation of ipilimumab-induced MG.

In contrast, 42.8% of patients who received the combination of ICI medications developed severe respiratory failure requiring endotracheal intubation, which is the highest rate among the patients who developed MG after administration of ICI agents. In addition, the mean duration for the onset of symptoms of MG was 17.5 days post initiation of combination therapy, which is the shortest duration among all ICI agents. We can suggest that the patient who develops MG after combination therapy with ICI medications probably is at a higher risk to develop a more severe presentation of the disease.

All of these suggestions need to be evaluated more by performing further studies. This will lead to a better understanding of these irAEs of ICI therapy and can help in better management and eventually better outcome of this disease.

Although MG is considered asone of the rare irAEs of ICI therapy, considering an increasing number of reported cases with MG related to ICI therapy, the clinicians need to enhance their understanding of this phenomenon. Our observations suggest possible differences in the severity of the disease and outcome among different ICI therapy options. More studies are needed to evaluate these suggestions.

Learning points.

• Considering an increasing number of reported cases with myasthenia gravis (MG) related to immune checkpoint inhibitors (ICI) therapy, clinicians need to enhance their understanding of this phenomenon.

• Our observations suggest a possible difference in the severity of MG related to ICI therapy among different ICI therapy regimens.

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