Myasthenia gravis, myositis and myocarditis: a fatal triad of immune-related adverse effect of immune checkpoint inhibitor treatment

Abstract

Pembrolizumab, a humanised monoclonal antibody and immune checkpoint inhibitor (ICI) that blocks programmed death receptor 1 and its ligands, is an effective immunotherapy for malignancies such as melanoma, lung, head and neck, cancers, and Hodgkin’s lymphoma. It has an overall response rate between 73% and 83%, with complete response rate of 27%–30%. It is well tolerated with minor side effects in 70% of cases characterised by fatigue, rash, pruritus and diarrhoea. In rare cases, more serious and life-threatening complications can occur at a rate of 0.3%–1.3%. We report a case of a woman in her 70s with non-small-cell lung cancer treated with ICI. She presented to the emergency department with left-sided ptosis and muscle weakness 3 weeks of her first dose of pembrolizumab infusion as a treatment plan of her cancer. She was diagnosed with myasthenia gravis, myocarditis and myositis as ICI-induced immune-related adverse effects resistant to medical intervention. We wish to raise awareness of the triad of life-threatening complication of ICI therapy that accounts for 30%–50% of fatal complications.

Background

Pembrolizumab, an immune checkpoint inhibitor (ICI), is a first-line treatment in advanced non-small-cell lung cancer patients as a monotherapy. Life-threatening complications can occur in 0.3%–1.3% of ICI-treated patients.

Case presentation

A woman in her 70s presented with a history of shortness of breath on exertion, ongoing wheeze and a cough. She had a background of type 2 diabetes, hypertension, peripheral vascular disease and was a 40-pack-year smoker. Her initial chest X-ray showed a right hilar mass (figure 1A). CT chest confirmed the presence of a large right lung speculated mass (56 mm) with scattered pulmonary nodules. PET-CT showed markedly avid right upper lobe lung mass along with avid pulmonary nodules (figure 1B). Histology from CT-guided biopsy confirmed adenocarcinoma of the lung, stage T4N0M1a, and 90%–100% programmed death ligand (PD-L1) expression (figure 1C). Pembrolizumab monotherapy was started.

Figure 1.

Symptoms, treatment and outcome—triad of fatal adverse effect of ICI for non-small-cell lung cancer treatment. (A) Chest X-ray showed raised right hemidiaphragm in keeping with right phrenic nerve palsy. (B) PET-CT showed large, avid right upper lobe mass and pulmonary nodules, stage T4N0M1a. (C) Histology confirmed pulmonary adenocarcinoma with 90%–100% programmed death ligand expression. (D) ECG showed complete heart block with broad complex escape rhythm. AChR-AB, acetylcholine receptor antibody; AT-AB, plasma anti-titin antibody; CK, creatine kinase; ECHO, echocardiogram; hs-TNI, high sensitivity cardiac troponin I; ICI. immune checkpoint inhibitor; PD-L1, programmed death ligand 1; PET-CT, photon emission tomography-CT.

Three weeks after the first dose of 200 mg of pembrolizumab, the patient presented with left-sided partial ptosis and facial droop. She was haemodynamically stable and without fever. Her blood pressure was 130/80 mm Hg, heart rate 94 beats per minute and O₂ saturation 90% on room air. She had a widespread polyphonic wheeze, but no cardiac nor abdominal abnormality. Serum inflammatory markers, coagulation screen, kidney and liver function and haemoglobin levels were normal. Cardiac pathology was not suspected; hence, no serum biomarkers were requested.

Admission chest X-ray showed normal cardiac size, no major collapse or consolidation in the lungs, and no significant progression of the previously known mass overlying the right hilum. CT head excluded intracranial, bleed, infarct or extra-axial collection and metatstatic disease. MRI head scan was not possible due to the patient’s extreme claustrophobia. Diagnosis was still uncertain at this point. On the third day of admission, the patient developed left-sided visual blurriness and progressive ptosis, now also involving her right eye, although a left-sided ptosis remained more prominent. She was increasingly fatigued and short of breath and now required 2 L of oxygen via a nasal cannula to maintain her O₂ saturations above 90%. A CT pulmonary angiogram excluded pulmonary embolus, and the previously described lung lesion extended posteriorly and now invaded the oblique fissure of the right lung. Her progressive dyspnoea was not explained by the extent of tumour progression.

By day 4 of admission, she continued to deteriorate with abdominal breathing, a raised respiratory rate, and continued to require at 2 L of oxygen via a nasal cannula. Her ECG showed intermittent non-compromising atrial tachycardia. She developed pronounced bilateral ptosis and ophthalmoplegia with fatigable diplopia (that usually occurs after the eye muscle groups are used and lessens if they have some rest), and new evidence of Cogan’s lid twitch (consists of a brief overshoot twitch of the eyelid following sudden return of the eyes to primary position after a period of downgaze as an important characteristic for the diagnosis of myasthenia gravis). At the neurologist’s recommendation lumbar puncture and blood tests were performed to investigate a possible autoimmune reaction. Lumbar puncture showed normal opening pressure, and biochemical and microscopic analysis of the cerebrospinal fluid was unremarkable with no growth in the culture, and no oligoclonal bands to suggest inflammation.

Serum acetylcholine receptor antibody levels were raised at 59 mol/L, and a paraneoplastic western blot was positive for anti-titin antibody. At the same time serum creatine kinase levels were raised at 3663 IU/L. Subsequent cardiac serum biomarkers were requested to assess myocadial involvement. The high sensitivity cardiac troponin I levels were raised at 4141.5 ng/L. Echocardiogram showed left ventricular hypertrophy with normal biventricular systolic function. The cardiac chambers were normal in size, and there was no valvular pathology. Based on all clinical symptoms and investigation findings, ICI-induced immune-related adverse effects (irAE) was diagnosed with a triad of myasthenia gravis symptoms, myositis and myocarditis.

Over the next day her condition rapidly deteriorated and she developed complete heart block with a broad complex escape rhythm on 12 lead ECG (figure 1D). Although the patient was not compromised, it was clear that her further deterioration was imminent. Pacemaker insertion was attempted that morning, but she was unable to tolerate the procedure as she became very hypoxic on supine positioning and after multiple attempts the procedure was deemed unsafe and abandoned. Intravenous isoprenaline was started for chronotrop support, as an alternative to pacemaker implantation with good effect. The multidisciplinary team, involving an oncologist, neurologists, cardiologist and intensive care specialist, recommended high dose intravenous steroid, immunoglobulin infusion and physostigmine. This was discussed with the patient and her relative, and a shared plan was agreed for ward-based management. Over the next few days, she further desaturated, requiring advanced non-invasive ventilatory support. Chest X-ray showed a raised right hemidiaphragm due to phrenic nerve palsy (figure 1A). Despite the efforts to reverse pembrolizumab-related irAE with intravenous drug combinations, the patient died on the seventh day of admission.

Discussion

Immunotherapy with ICI is a novel and promising treatment for previously untreatable neoplasms.¹ This treatment is of value in frail patients as it circumvents the use of cytotoxic treatments and their well-documented adverse side effects.² Pembrolizumab is a programmed death protein 1 (PD-1) antibody. PD-1s are expressed on activated T cells and are an important immune response checkpoint as their activation generates a negative response signal to T cells, thereby halting any immune reaction that would follow.² Some tumour cells (as well as some phagocytic cells) are strong PD-L1 and PD-L2 expressors, thus activating PD-1 and helping tumour cells to evade the immune system and promote tumour growth. By inhibiting the binding of PD1 and PD-L1, ICIs like pembrolizumab have become an important anticancer tool as it permits an effective host immune response against tumorous cells.^{1 2}

Because of their mechanism of action, ICIs may evoke irAEs. Most reported adverse effects can be managed (though there is yet to be a consensus on the management of these), but some prove to be fatal. IrAEs usually happen in 70% of patients treated with PD-1 inhibitors and tend to mimic autoimmune disease manifestations. The most common adverse effects are mainly non-specific or include mild symptoms like fatigue, rash, pruritus and diarrhoea.³ In rare cases, more serious and life-threatening complications may occur at a rate of 0.3%–1.3% with different ICIs.² Some studies have suggested that myocarditis, myositis and neurological symptoms, in combination or in isolation, can be responsible for up to one-third of fatal outcomes. Other retrospective studies suggest that neurological and cardiac effects alone could be responsible for up to half of all deaths.^{3 4} The ‘overlap syndrome’ of myocarditis, myositis and myasthenia gravis has seen an increase in reporting and shown to have high rates of mortality (approximately 62.5%) when compared with these presentations in isolation.^5–10 This tends to be true predominantly with PD-1 or PD-L1 ICIs, when compared with anti-(cytotoxic T-lymphocyte–associated antigen 4) CTLA-4 ICIs.⁵

For patients with myasthenic symptoms, the mean age group reported is 72.9 $\pm$ 10 years.¹¹ The main symptoms associated with this are ocular symptoms like ptosis and diplopia (78%), limb weakness and gait disturbance (57.4%), dysarthria and facial palsy (38%) and dyspnoea (40.4%).¹¹ As for myocarditis component in this triad, the presentation is quite variable. Symptoms may vary from fatigue, chest pain or dyspnoea, or can present as acute arrhythmias, conduction disorders or heart failure, and can be challenging to diagnose.^{12 13} Myocarditis usually occurs early after initiation of treatment with ICI.⁷ In these patients, troponin elevation (although not always present) is usually associated with worse outcomes.⁸ Echocardiography can be normal even in patients with fulminant myocarditis.^13–16

Some studies report a median time to presentation with overlap syndrome of 30 days from the date of initiation of ICI treatment, with dyspnoea, ptosis, diplopia and fatigue the most common symptoms. As with our patient, these cases had high concentrations of serum creatine kinase and troponin.¹⁰ There is not sufficient evidence, and there are no clear guidelines for the management of ICI-induced complications; however, given the rapid deterioration and the possibly fatal outcome reported, it would be prudent to intervene at the early stage of diagnosis once clinical suspicion is raised.¹⁴ High dose corticosteroids are the recommended treatment for ICI-induced myocarditis with supportive treatment for heart failure and antiarrhythmics, as appropriate.¹⁴ Additional treatment with immunomodulators, plasma exchange and, rarely, advanced heart failure treatment with circulatory support may be considered in patients who do not respond as expected to corticosteroids.^{3 15}

The case we present here adds to the evidence that although rare, the triad of myocarditis, myositis and myasthenia gravis is a severe and life-threatening complication of ICI therapy (figure 2). The occurrence of any one of the components of this triad should trigger investigation for the other two given the rapid deterioration and poor outcome in these patients.

Figure 2.

Simplified diagram of the mechanism of action—triad of fatal adverse effect of ICI treatment. Pembrolizumab blocks the protective mechanism of cancer cells binding to PD-L1. The T cell surface antibody, hence, can bind to specific cell surface antigen and destroy the cancer cells. The same mechanism is true for the skeletal muscle cell, cardiac myocyte and the neuromuscular junction resulting in T cell-mediated autoimmune response and related symptoms such as myositis, myocarditis and myasthenia gravis. AChR-AB, acetylcholine receptor antibody; AT-AB, plasma anti-titin antibody; CK, creatine kinase; hs-TNI, high sensitivity cardiac troponin I; ICI, immune checkpoint inhibitor; PD-L1, programmed death ligand 1; PET-CT, photon emission tomography-CT.

Learning points.

• Immune checkpoint inhibitor (ICI) is an effective novel immunotherapy for various malignancies.

• Life-threatening complications manifest in 0.3%–1.3% of ICI-treated patients.

• Myasthenia gravis, myocarditis and myositis comprise a potentially fatal triad of immune-related adverse effects following ICI therapy and require prompt diagnosis and treatment.

• The occurrence of any one of the factors of this triad should prompt the investigation for the other two given the rapid deterioration and poor outcome.

• High dose intravenous corticosteroids are the recommended treatment for ICI-induced myocarditis with supportive therapy for heart failure and antiarrhythmics. Additional treatment with immunomodulators, plasma exchange and advanced heart failure management with circulatory support may be considered in patients who do not respond as expected to corticosteroids.

Ethics statements

Patient consent for publication

Consent obtained from next of kin.