Can Keytruda (pembrolizumab) cause myasthenia gravis (mg)?

Can Keytruda Cause Myasthenia Gravis?

Yes, Keytruda (pembrolizumab) can cause myasthenia gravis (MG), which is a rare but potentially life-threatening immune-related adverse event that requires immediate recognition and aggressive treatment. 1

Incidence and Clinical Significance

Myasthenia gravis is a recognized immune-related adverse event (irAE) associated with pembrolizumab therapy, though it remains uncommon. 2 The FDA drug label for Keytruda specifically lists myasthenia gravis as a serious adverse reaction, with fatal cases documented. 1 In the KEYNOTE-869 trial evaluating pembrolizumab combined with enfortumab vedotin in cisplatin-ineligible urothelial cancer patients, myasthenia gravis occurred in 2.5% of patients and was fatal in 0.8% of cases. 1

The mortality risk is particularly elevated when MG occurs alongside other immune-related complications. Myositis frequently co-occurs with myasthenia gravis in checkpoint inhibitor-induced cases, and this combination carries an ominous prognosis with high mortality rates. 2 Approximately 12.5% of patients with checkpoint inhibitor-induced myositis also develop concurrent myasthenia gravis. 2 When myocarditis is also present alongside MG and myositis, the mortality rate increases substantially. 2

Timing of Onset

Pembrolizumab-induced MG typically presents early in the treatment course. 3 While neurologic adverse events generally occur around 6 weeks after checkpoint inhibitor initiation, MG has been documented as early as 2-4 weeks after the first pembrolizumab infusion. 3, 4 The median time to onset for neurologic irAEs ranges from 4 to 13 weeks across different checkpoint inhibitors. 2

Clinical Presentation

Ocular Manifestations

• Ptosis (drooping eyelids) - often the initial presenting symptom 3, 4, 5
• Diplopia (double vision) - frequently reported 2, 5, 6
• Extraocular muscle weakness causing ophthalmoplegia 5
• Pupils characteristically remain normal - this is a critical distinguishing feature from third nerve palsy 7, 8

Bulbar and Generalized Symptoms

• Dysphagia (difficulty swallowing) 2
• Dysarthria (difficulty speaking) 2
• Dysphonia (voice changes) 2
• Facial muscle weakness 2
• Proximal limb weakness - more common in generalized MG 3
• Respiratory compromise - life-threatening manifestation requiring immediate intervention 2, 4

Associated Features

• Fatigable or fluctuating muscle weakness - hallmark characteristic 7
• Symptoms worsen with activity and improve with rest 7
• Dropped head syndrome may occur in severe cases 2

Diagnostic Workup

When pembrolizumab-induced MG is suspected, immediate evaluation should include:

Serologic Testing

• Acetylcholine receptor (AChR) antibodies - first-line test 2, 7, 8
• Anti-striated muscle antibodies 2, 7
• Muscle-specific kinase (MuSK) antibodies if AChR negative 2, 8
• Lipoprotein-related protein 4 (LRP4) antibodies if AChR negative 8
• Anti-titin antibodies - may be positive in checkpoint inhibitor-induced cases 5

Important caveat: Seronegative MG can occur with pembrolizumab, meaning negative antibody testing does not exclude the diagnosis. 3, 5 Clinical presentation and electrodiagnostic studies remain critical.

Electrodiagnostic Studies

• Repetitive nerve stimulation (RNS) - shows decremental response 2, 7, 8
• Single-fiber EMG with jitter studies - has >90% sensitivity for ocular MG 7
• Standard EMG and nerve conduction studies may be normal early in disease 7

Additional Testing

• Ice pack test - highly specific for ocular MG; apply ice over closed eyes for 2 minutes and observe for improvement in ptosis 7
• Edrophonium test - may be negative in some cases 5
• Creatine kinase (CK) levels - essential to evaluate for concurrent myositis 2, 9
• Cardiac troponin and electrocardiography - mandatory to screen for myocarditis 2
• Cardiac MRI if troponin elevated or ECG abnormal 2
• Pulmonary function testing with negative inspiratory force (NIF) and vital capacity (VC) 2, 8, 10

Management Algorithm

Grade 1 (Mild Ocular Symptoms Only)

• Hold pembrolizumab until symptoms stabilize 2
• Initiate pyridostigmine 30 mg orally three times daily, titrate to maximum 120 mg four times daily based on response 7, 8, 10
• Monitor closely for progression to generalized symptoms 7
• Consider resuming pembrolizumab only if symptoms completely resolve and patient remains Grade 1-2 (MGFA Class I-II) 8

Grade 2 (Moderate Symptoms, Limiting Instrumental ADLs)

• Permanently discontinue pembrolizumab 2
• Neurology consultation - urgent 2
• Start prednisone 1-1.5 mg/kg orally daily (note: lower initial dose than typical to avoid short-term MG exacerbation with high-dose steroids) 2, 8
• Continue pyridostigmine with dose optimization 8, 10
• Rule out infection before initiating immunosuppression 2

Grade 3-4 (Severe/Life-Threatening Symptoms)

This constitutes a medical emergency requiring immediate intensive care.

• Permanently discontinue pembrolizumab 2, 1
• ICU-level monitoring with continuous respiratory assessment 2
• Urgent neurology and cardiology consultation 2
• Methylprednisolone pulse dosing 1-2 g/day IV 2, 8
• IVIG 2 g/kg total dose administered as 0.4 g/kg/day over 5 consecutive days 2, 8, 10
• OR plasmapheresis for 5 days (alternative to IVIG) 2, 8
• Do NOT use sequential therapy (PLEX followed by IVIG) - no more effective than either alone 10
• Continue pyridostigmine unless intubation required 10
• Frequent pulmonary function monitoring with NIF and VC measurements 2, 8, 10
• Daily neurologic evaluations 10
• Consider rituximab if no improvement after 3 days of steroids and IVIG/PLEX 9

Critical Medications to Avoid

Patients with pembrolizumab-induced MG must strictly avoid medications that worsen neuromuscular transmission: 2, 7, 8, 10

• β-blockers 2, 7, 8
• Intravenous magnesium 2, 7, 8
• Fluoroquinolone antibiotics (ciprofloxacin, levofloxacin, moxifloxacin) 2, 7, 8, 10
• Aminoglycoside antibiotics (gentamicin, tobramycin) 2, 7, 8, 10
• Macrolide antibiotics (azithromycin, erythromycin) 2, 7, 8, 10
• Metoclopramide 10
• Barbiturate-containing medications 8, 10

Prognosis and Outcomes

The prognosis for pembrolizumab-induced MG varies significantly based on severity and associated complications:

• Isolated ocular MG has better outcomes, with 75% achieving complete symptom resolution compared to 39% with generalized MG 6
• Respiratory involvement doubles mortality risk (60% vs 33%) and triples the risk of incomplete symptom resolution 6
• Overall mortality rate excluding cancer progression is approximately 30% in published case series 6
• Fatal outcomes have been documented even with aggressive treatment including steroids, pyridostigmine, IVIG, and plasmapheresis 4
• Approximately 50-80% of patients with initial ocular symptoms will develop generalized MG within a few years if checkpoint inhibitor therapy continues 7, 8

Special Considerations

Rechallenge with Pembrolizumab

Rechallenge is generally contraindicated after Grade 3-4 MG. 2 However, in select cases of Grade 1-2 MG with complete symptom resolution, rechallenge may be considered with:

• Prophylactic low-dose steroids 6
• Close monitoring for symptom recurrence 6
• Multidisciplinary discussion weighing cancer prognosis against MG risk 2

Jehovah's Witness Patients

For patients who refuse blood products, plasmapheresis is an acceptable alternative to IVIG that does not involve blood transfusion. 3 Early conversations about acceptable blood fractions are essential to develop an appropriate treatment plan. 3

Pregnancy

IVIG may be preferred over plasmapheresis in pregnant women due to fewer monitoring requirements. 10

Key Clinical Pitfalls

• Do not dismiss early ocular symptoms - ptosis and diplopia after pembrolizumab initiation warrant immediate evaluation, not observation 3, 4
• Seronegative MG can occur - negative antibody testing does not exclude the diagnosis 3, 5
• Always screen for concurrent myositis and myocarditis - check CK, troponin, and ECG in all suspected cases 2
• Normal cardiac enzymes do not completely rule out myocarditis - maintain high clinical suspicion 2
• IVIG is for acute treatment only - never use for chronic maintenance therapy in MG 8, 10
• Avoid high-dose steroids initially in MG - can cause short-term symptom exacerbation 2, 8
• Respiratory function can deteriorate rapidly - frequent monitoring is mandatory 2, 8, 10