Myositis and myasteniform syndrome related to pembrolizumab

Abstract

This case report concerns a 63-year-old man affected by metastatic undifferentiated liposarcoma. After receiving pembrolizumab as a second-line treatment in a clinical trial, the patient experienced an immune-mediated myocarditis, myositis and myasteniform syndrome. The last two adverse events showed significant clinical relevance in terms of severity, duration and the required specific treatment.

Initial treatment approach consisted in pulses of 1 g of methylprednisolone, followed by 2 mg/kg/day, with clinical improvement. After 12 days, the immune-mediated myasteniform syndrome worsened, with dysphagia, dysphonia, bilateral palpebral ptosis and respiratory difficulty. Due to the refractoriness to glucocorticoid treatment, it was decided to initiate intravenous immunoglobulin at 2 g/kg, followed by 2 mg/kg every 4 weeks once discharged and mycophenolate 500 mg/12 hours, in order to reduce the dose of glucocorticoids.

After 2 months, the patient presented an optimal clinical evolution, without muscular weakness and referred to an improvement in dysphagia and speech.

Background

The emergence of immune checkpoint inhibitors (ICI) has represented an improvement in the survival of certain malignancies associated with a poor prognosis, such as melanoma, lung cancer, kidney cancer and head and neck cancer, among others. In addition, many trials are studying the application of these drugs to other tumour localizations.

The immune checkpoints, such as CTLA-4, PD-1 and PDL-1, on which immunotherapy acts, are responsible for the maintenance of immune homeostasis.¹ Under physiological conditions, immune checkpoints are crucial to prevent the development of autoimmunity and maintain autotolerance.² In this sense, tumour cells express numerous genetic and epigenetic alterations, resulting in neoantigens that the immune system should target. However, they often escape the immune system following secretion of suppressor factors, surface expression of immunosuppressive molecules, or recruitment of other immunosuppressive cells.³ Thus, inhibition of CTLA-4 or PD-1 may increase the tumour-specific immune response of T lymphocytes.

The blockade of immune control points has resulted in a particular set of side effects called immunorelated adverse events (irAEs), different from those produced by traditional cytotoxic chemotherapy, and which require specific therapeutics and management.⁴ Many of these are driven by the same immunological mechanisms responsible for the drugs’ therapeutic effects, namely, blockade of inhibitory mechanisms that suppress the immune system and protect body tissues from an unconstrained acute or chronic immune response.⁵

Recognition of symptoms and early intervention are key objectives in the management of immunotherapy-related toxicity. The main inflammatory or autoimmune adverse events include diarrhoea, colitis, hepatitis, encephalitis, skin toxicities and endocrine diseases. The incidence and prevalence of immunotherapy-related toxicity are not yet fully known; many of the existing figures are based on the trials of ipilimumab, pembrolizumab and nivolumab. The reported incidence of irAEs associated with immunotherapy treatment varies widely between drugs and trials from 15% to 90%. Severe irAEs requiring immunosuppression, temporary or definitive treatment discontinuation are estimated at 0.5%–13% in monotherapy.⁶

Among the irAEs, the neurological type has a low incidence, with myasthenia gravis (MG) and encephalitis being the ones associated with a worse prognosis. On many occasions, due to rapid progression of irAEs or refractoriness to glucocorticoid treatment, additional immunosuppressive therapies are required, such as intravenous immunoglobulin (IVIG), plasmapheresis, mycophenolate mofetil, rituximab or cyclosporine.⁷

The case developed below is a sample of the therapeutic approach and clinical evolution of a patient presenting different irAEs associated with pembrolizumab treatment, among which myositis associated with a myasteniform syndrome stands out. Clinical pharmacists have an important role both in the description and management of drug adverse effects, especially if innovative drugs, with limited evidence on their risk benefit profile, are involved.

Case presentation

The case involved a 63-year-old man affected by metastatic undifferentiated liposarcoma (mediastinum, peritoneal and muscular). Brain CT was performed ruling out brain metastases. As far as interesting relevant medical history, the patient had Barret’s oesophagus operated in 2008.

Between January and June 2019, the patient received six cycles of doxorubicin at a dose of 75 kg/m² every 21 days, showing a partial response to the treatment. As myocardial damage, including acute left ventricular failure, can occur with doxorubicin, it is recommended to assess left ventricular ejection fraction (LVEF) before and regularly during and after treatment with doxorubicin. After chemotherapy treatment, the echocardiography performed showed LVEF values maintained at 67%—the same as the previous one in January—as well as the absence of valvulopathies.

As a second line, it was decided to initiate pembrolizumab treatment in the context of a clinical trial. Six days after the administration of the first cycle, the patient consulted his primary care centre for an acute event of diplopia, palpebral ptosis, intense myalgia predominating in the lower extremities, proximal muscle weakness, dysphagia, dysphonia and asthenia. He did not present oedema and denied chest pain, palpitations, dyspnoea, orthopnea or paroxysmal nocturnal dyspnoea. The use of statins or other concomitant medication that could be responsible for the current event was ruled out. It was decided to perform an echocardiogram, where a 40% LVEF was observed (normal value ranges (NVR) >55%). After this finding and according to the suspected diagnosis of myositis and/or immune-mediated myocarditis, it was decided to transfer the patient to our centre.

Once admitted, a cytolysis pattern was observed with: aspartate aminotransferase (AST) 1057 U/L (NVR 8–40), alanine aminotransferase (ALT) 770 U/L (NVR 5–54), creatine kinase (CK) 14 448 U/L (NVR 60–330) and lactate dehydrogenase 2448 U/L (NVR 100–330).

In addition, the following analytical parameters were altered: troponin 18 353 ng/L (NVR undetectable), brain natriuretic peptide 2789 pg/mL (NVR<100) and lactate 4 mmol/L (NVR 0.8–2.2).

No deterioration of renal function or electrolytes was observed.

During the first 24 hours of admission, an atrioventricular block (AVB) was observed, so it was decided to transfer the patient to the intensive care unit (ICU) for closer monitoring.

Differential diagnosis

In this context and taking into account the recent start of pembrolizumab as well as the clinical situation it presented at the time of admission, the services of oncology, neurology, cardiology, pharmacy, rheumatology and systemic diseases unit, acting as a multidisciplinary team, jointly addressed the complications possibly related to immunotherapy and described below.

• Myositis: the patient presented a CK of 14 448 U/L and clinical muscle weakness of proximal predominance. A muscle biopsy was compatible with immune-mediated myositis. An electromyography was also performed which showed mild myogenic signs of the facial musculature and proximal musculature of the upper and lower extremities, with few signs of muscle fibre destruction (myositis) identified. There was no evidence of neuromuscular transmission defect or peripheral polyneuropathy.

• Transaminase elevation: the patient presented an AST of 1057 U/L and an ALT of 770 U/L, but no signs of liver failure. It is justified as a probable elevation within the context of myositis.

• Myocarditis: the patient presented a troponin peak of 18 353 ng/L, a slight biventricular dysfunction and a marked damage of the cardiac conduction system with progression to full AVB, which forced the implantation of a ventricular pacemaker.

• Myasteniform syndrome: suspected by palpebral ptosis, diplopia and dysphagia presented. In a complementary way, the presence of antiAChR (+) and anti-MuSK (−) antibodies was determined, which confirmed the initial suspicion of myasteniform syndrome associated with ICI.

When dealing with a suspected adverse drug effect, there are algorithms in the literature used to analyse the causal relationship between the administration of the drug and the generation of adverse effects. Naranjo’s algorithm⁸ is a 10-question questionnaire that classifies the suspicion into four categories according to the score obtained—definite (≥9), probable (5–8), possible (1–4) and doubtful (≤0). In this case, as shown in table 1, when applying the Naranjo algorithm, a value of 7 was obtained, which corresponds to an adverse reaction probably related to the administration of pembrolizumab.

Table 1.

Naranjo algorithm (adapted from Naranjo et al⁸) for estimating the probability of adverse drug reactions associated with pembrolizumab

Question	Answer	Score
1. Are there previous conclusive reports on this reaction?	Yes	1
2. Did the adverse event appear after the suspected drug was given?	Yes	2
3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was given?	Yes	1
4. Did the adverse reaction appear when the drug was readministered?	Do not know or not done	0
5. Are there alternative causes that could have caused the reaction?	No	2
6. Did the reaction reappear when a placebo was given?	Do not know or not done	0
7. Was the drug detected in any body fluid in toxic concentrations?	Do not know or not done	0
8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased?	Do not know or not done	0
9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure?	No	0
10. Was the adverse event confirmed by any objective evidence?	Yes	1
Naranjo score		7

Treatment

A priori, the pharmacological approach to try to stop and reverse immune-mediated myocarditis and myasteniform syndrome was treatment with glucocorticoids. The patient received three pulses of 1 g of methylprednisolone. Next, the administration of 2 mg/kg/day was continued. After 10 days of admission, methylprednisolone was continued at 1 mg/kg/day.

The first 48 hours, although basal oxygen saturation remained above 98%, due to an increased sensation of dyspnoea, the patient needed high flow nasal oxygen therapy, which was withdrawn 48 hours after his admission to ICU.

Analytically, there was a trend towards normalisation of the analytical parameters that were altered at the time of admission (figure 1), (AST, ALT, CK, lactate dehydrogenase and troponins), according to the improvement of the initial complications associated with immunotherapy.

Figure 1.

Evolution of the analytical parameters altered at the time of admission. ALT, alanine aminotransferase; AST, aspartate aminotransferase; CK, creatine kinase; LDH, lactate dehydrogenase.

Once clinically stable, the patient was discharged from the ICU and admitted to the hospitalisation plant, where after 2 days he presented bulbar dysfunction associated with a worsening of his previous dysphagia, which required the placement of a nasogastric tube, dysphonia and bilateral palpebral ptosis with respiratory difficulty without apparent trigger, as well as fluctuating dysarthria without time predominance. These findings are related to a worsening of the associated immune-mediated myasteniform syndrome. Following the recommendations of the National Comprehensive Cancer Network (NCCN) guidelines (table 2), IVIG was added at 2 g/kg distributed over 5 days, maintaining the 2 mg/kg/day base treatment with glucocorticoids.

Table 2.

Recommendations for the management of toxicities secondary to immunotherapy according to the NCCN (version 1.2020)

Adverse event	Grade	Recommendation
Nervous system (myasteniform syndrome)	2	Oral pyridostigmine starting at 30 mg three times a day and gradually increased to a maximum of 120 mg four times a day as tolerated and based on symptoms Administer corticosteroids (prednisone 1–1.5 mg/kg orally per day) if symptoms grade 2; wean based on symptom improvement
	3–4	Methylprednisolone 1–2 mg/kg/day (steroid taper based on symptom improvement); initiate plasmapheresis or IVIG if no improvement/worsening on steroids or severe symptoms
	Avoid medications that can worsen myasthenia (localisation, beta blockers, ciprofloxacin, intravenous magnesium and macrolides)

IVIG, intravenous immunoglobulin.

Treatment with IVIG improved the patient’s myositis with a decrease in CK values compared with previous days (day 10: 2317, day 20: 643). The patient showed a progressive improvement in mobility and ambulation. However, neurological symptoms associated with myasteniform syndrome, such as dysphagia and dysphonia, continued. On the other hand, some authors suggest that the administration of methylprednisolone at a dose of 1 mg/kg/day is associated with a transient deterioration of muscle strength in one-third to one-half of the patients. In this regard, with the intention of maintaining the immunosuppression necessary to address the clinical situation of the patient and according to the evidence, it was decided to add mycophenolate 500 mg/12 hours to the treatment.⁹ This made it possible to reduce the dose of methylprednisolone, which until then had continued at 2 mg/kg/day.

According to cardiology terms, normalisation of LVEF values was observed as the patient’s clinical condition improved, from 40% at the time of ICU admission to 53% and 65% at 10 and 20 days after ICU admission, respectively, two points below the last recorded LVEF value a year earlier.

Outcome and follow-up

After 35 days of hospitalisation and given the improvement of the patient, it was decided to discharge him. As domiciliary treatment, immunosuppression was maintained with mycophenolate 500 mg/12 hours, prednisone 40 mg/24 hours in descending doses and IVIG 2 mg/kg every 4 weeks. Due to myasteniform dysphagia and clinical symptoms, feeding by nasogastric tube was maintained.

It has now been 2 months since the patient was discharged from hospital. He continues to come to the daytime hospital every 4 weeks for the administration of the IVIG treatment. Gradually, the dose of prednisone has been reduced. He presents an optimal clinical evolution, without muscular weakness and refers an improvement in dysphagia and speech. He has managed to increase the viscosity and volume of the doses so that a month after his discharge, the nasogastric tube was removed.

Discussion

The aim of presenting this case, in addition to describing a rare and serious adverse event related with pembrolizumab, is to provide evidence of its treatment.

Neuromuscular-type adverse events have a low incidence, but can have serious and rapid consequences, with mortality of up to 30% of cases.⁵

Currently, there are four predominant modalities of treatment for MG: symptomatic treatment (anticholinesterase inhibitors: pyridostigmine), chronic immuno-modulating treatment (glucocorticoids and immunosuppressants: azathioprine, cyclosporine and mycophenolate mofetil), rapid immunomodulating treatments (IVIG and plasmaphaeresis) and surgical treatment (thymectomy). Pyridostigmine is useful for maintenance therapy, yet most patients with MG will require some degree of immunomodulation.

According to the guidelines for the management of irAEs, in the case of myasteniform syndrome grade 3–4, intravenous glucocorticoids are indicated. But when there is glucocorticoid refractoriness and/or clinical worsening, there are no definitive results on the immunomodulatory treatments to be used. Decisions are based on the pharmacological approach to other autoimmune disorders, clinical cases reported and individual patient characteristics.¹⁰ The decision algorithms proposed in cases of worsening and/or refractoriness to glucocorticoid treatment are considered:

• ‘Management of Immunotherapy-Related Toxicities, version 1.2020’ of the NCCN: initiate plasmapheresis or IVIGs 2 g/kg.¹⁰

• ‘Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations’ of the toxicity management group within the Society for Immunotherapy of Cancer: consider plasmapheresis if there is no improvement after 3 days of treatment.⁵

In the medical literature, we find clinical cases reported in which the management of myasteniform syndrome as irAEs is addressed. Makarious et al made a review that gathers 23 reported cases where 72.7% were de novo presentations, 18.2% were exacerbations of pre-existing MG and 9.1% were exacerbations of subclinical MG.⁴ This is a limitation in our case, as it could be an exarcerbation of a subclinical MG not known by the patient. Makarious et al conclude that, among the different therapies used, pyridostigmine alone was found to provide minimal benefit unless symptoms were non-progressive and minimal. Both IVIG and plasmaphaeresis have been reported to provide a significant clinical reduction in symptoms.⁴

Taking into account the few therapeutic options to limit the progression of the neurological picture and according to the published evidence, it was decided, together with the multidisciplinary team, to start the exceptional treatment with IVIG at 2 g/kg every 4 weeks. It is agreed to follow the patient closely in order to evaluate the suitability of maintaining the treatment and its duration.

Learning points.

• Immune checkpoint inhibitors improve substantially patient outcome but can cause several immunorelated adverse events (irAEs), whose early diagnosis and initiation of management can alleviate terrible complications.

• Myositis and myasteniform syndrome are both relatively rare but potentially fatal irAEs following pembrolizumab treatment.

• Decision-making on the therapeutic approach to these adverse effects described in the literature is scarce.

• Steroids are first-line therapy for severe nervous system toxicities caused by PD-1 therapy, but some cases are refractory to steroids and require additional approaches such as plasmapheresis or intravenous immunoglobulin.

• Working with multidisciplinary teams is integral to the success of managing these complex and potentially fatal cases.

Ethics statements

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