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, 3 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. 4

Timing of Onset

Pembrolizumab-induced MG typically presents early in the treatment course. 5 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. 5, 6 The median time to onset for neurologic irAEs ranges from 4 to 13 weeks across different checkpoint inhibitors. 7

Clinical Presentation

Ocular Manifestations

• Ptosis (drooping eyelids) - often the initial presenting symptom 5, 6, 8
• Diplopia (double vision) - frequently reported 2, 8, 9
• Extraocular muscle weakness causing ophthalmoplegia 8
• Pupils characteristically remain normal - this is a critical distinguishing feature from third nerve palsy 10, 11

Bulbar and Generalized Symptoms

• Dysphagia (difficulty swallowing) 2
• Dysarthria (difficulty speaking) 2
• Dysphonia (voice changes) 2
• Facial muscle weakness 3
• Proximal limb weakness - more common in generalized MG 5
• Respiratory compromise - life-threatening manifestation requiring immediate intervention 2, 6

Associated Features

• Fatigable or fluctuating muscle weakness - hallmark characteristic 10
• Symptoms worsen with activity and improve with rest 10
• 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 3, 10, 11
• Anti-striated muscle antibodies 3, 10
• Muscle-specific kinase (MuSK) antibodies if AChR negative 3, 11
• Lipoprotein-related protein 4 (LRP4) antibodies if AChR negative 11
• Anti-titin antibodies - may be positive in checkpoint inhibitor-induced cases 8

Important caveat: Seronegative MG can occur with pembrolizumab, meaning negative antibody testing does not exclude the diagnosis. 5, 8 Clinical presentation and electrodiagnostic studies remain critical.

Electrodiagnostic Studies

• Repetitive nerve stimulation (RNS) - shows decremental response 3, 10, 11
• Single-fiber EMG with jitter studies - has >90% sensitivity for ocular MG 10
• Standard EMG and nerve conduction studies may be normal early in disease 10

Additional Testing

• Ice pack test - highly specific for ocular MG; apply ice over closed eyes for 2 minutes and observe for improvement in ptosis 10
• Edrophonium test - may be negative in some cases 8
• Creatine kinase (CK) levels - essential to evaluate for concurrent myositis 2, 12
• Cardiac troponin and electrocardiography - mandatory to screen for myocarditis 2, 4
• Cardiac MRI if troponin elevated or ECG abnormal 2
• Pulmonary function testing with negative inspiratory force (NIF) and vital capacity (VC) 3, 11, 13

Management Algorithm

Grade 1 (Mild Ocular Symptoms Only)

• Hold pembrolizumab until symptoms stabilize 3
• Initiate pyridostigmine 30 mg orally three times daily, titrate to maximum 120 mg four times daily based on response 10, 11, 13
• Monitor closely for progression to generalized symptoms 10
• Consider resuming pembrolizumab only if symptoms completely resolve and patient remains Grade 1-2 (MGFA Class I-II) 11

Grade 2 (Moderate Symptoms, Limiting Instrumental ADLs)

• Permanently discontinue pembrolizumab 3
• Neurology consultation - urgent 3
• 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) 3, 11
• Continue pyridostigmine with dose optimization 11, 13
• Rule out infection before initiating immunosuppression 3

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

This constitutes a medical emergency requiring immediate intensive care.

• Permanently discontinue pembrolizumab 3, 1
• ICU-level monitoring with continuous respiratory assessment 4, 3
• Urgent neurology and cardiology consultation 4, 3
• Methylprednisolone pulse dosing 1-2 g/day IV 2, 3, 11
• IVIG 2 g/kg total dose administered as 0.4 g/kg/day over 5 consecutive days 3, 11, 13
• OR plasmapheresis for 5 days (alternative to IVIG) 2, 3, 11
• Do NOT use sequential therapy (PLEX followed by IVIG) - no more effective than either alone 13
• Continue pyridostigmine unless intubation required 13
• Frequent pulmonary function monitoring with NIF and VC measurements 3, 11, 13
• Daily neurologic evaluations 13
• Consider rituximab if no improvement after 3 days of steroids and IVIG/PLEX 12

Critical Medications to Avoid

Patients with pembrolizumab-induced MG must strictly avoid medications that worsen neuromuscular transmission: 7, 10, 11, 13

• β-blockers 7, 10, 11
• Intravenous magnesium 7, 10, 11
• Fluoroquinolone antibiotics (ciprofloxacin, levofloxacin, moxifloxacin) 7, 10, 11, 13
• Aminoglycoside antibiotics (gentamicin, tobramycin) 7, 10, 11, 13
• Macrolide antibiotics (azithromycin, erythromycin) 7, 10, 11, 13
• Metoclopramide 13
• Barbiturate-containing medications 11, 13

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 9
• Respiratory involvement doubles mortality risk (60% vs 33%) and triples the risk of incomplete symptom resolution 9
• Overall mortality rate excluding cancer progression is approximately 30% in published case series 9
• Fatal outcomes have been documented even with aggressive treatment including steroids, pyridostigmine, IVIG, and plasmapheresis 6
• Approximately 50-80% of patients with initial ocular symptoms will develop generalized MG within a few years if checkpoint inhibitor therapy continues 10, 11

Special Considerations

Rechallenge with Pembrolizumab

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

• Prophylactic low-dose steroids 9
• Close monitoring for symptom recurrence 9
• 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. 5 Early conversations about acceptable blood fractions are essential to develop an appropriate treatment plan. 5

Pregnancy

IVIG may be preferred over plasmapheresis in pregnant women due to fewer monitoring requirements. 13

Key Clinical Pitfalls

• Do not dismiss early ocular symptoms - ptosis and diplopia after pembrolizumab initiation warrant immediate evaluation, not observation 5, 6
• Seronegative MG can occur - negative antibody testing does not exclude the diagnosis 5, 8
• Always screen for concurrent myositis and myocarditis - check CK, troponin, and ECG in all suspected cases 2, 3, 4
• 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 11, 13
• Avoid high-dose steroids initially in MG - can cause short-term symptom exacerbation 3, 11
• Respiratory function can deteriorate rapidly - frequent monitoring is mandatory 3, 11, 13