Immune Checkpoint Inhibitor Adverse Event Management — Part 4: Cardiac, Neurologic, Renal, and Musculoskeletal irAEs

Cardiac Immune-Related Adverse Events

Myocarditis

Immune-mediated myocarditis is the most feared cardiac irAE because of its high mortality rate, reported at 25% to 50% in published case series. Although uncommon (overall incidence approximately 0.04%–1.1%), it is the leading cause of irAE-related death. It is more common with combination anti-CTLA-4 plus anti-PD-1 therapy and tends to present early in the treatment course, often within the first 1–3 cycles (median onset approximately 30 days). Myocarditis may co-occur with myositis and/or myasthenia gravis in an overlap syndrome that carries an even higher mortality.^{1 2 3 4}

Clinical presentation:

• Chest pain, dyspnea, palpitations
• New heart failure symptoms (orthopnea, lower extremity edema)
• Syncope, presyncope
• Fatigue, malaise (may be subtle early presentation)
• Arrhythmias (atrial fibrillation, ventricular tachycardia, heart block)
• Cardiogenic shock in severe cases
• Concurrent myositis symptoms (proximal weakness, elevated CK) in 25%–30%

Workup:

Grading and Management:

Critical management principles for myocarditis:

• Permanently discontinue ICI for any grade of myocarditis – this is one of the few irAEs where grade 1 mandates permanent discontinuation.^{1 3}
• Do not wait for cardiac MRI to initiate treatment – if clinical suspicion is high and troponin is elevated, start high-dose corticosteroids immediately.
• Avoid NSAIDs (may worsen myocardial inflammation).
• Screen for concurrent myositis (CK, aldolase) and myasthenia gravis (AChR antibodies, bedside respiratory function) – the overlap syndrome is common and affects management.
• Taper corticosteroids very slowly (minimum 8–12 weeks) with serial troponin monitoring; do not taper until troponin is normal and cardiac function has stabilized or improved.
• Infliximab is generally avoided in myocarditis due to its association with worsening heart failure in cardiac patients.⁴

Pericarditis and Pericardial Effusion

Immune-mediated pericarditis is less common than myocarditis but may present as isolated pericarditis or as a component of myopericarditis. Pericardial effusions can also occur without overt inflammation.

Presentation: Chest pain (pleuritic, positional), friction rub, dyspnea, signs of tamponade (hypotension, JVD, muffled heart sounds) in severe cases.

Workup: ECG (diffuse ST elevation, PR depression), echocardiogram (effusion size, tamponade physiology), troponin (rule out concurrent myocarditis), cardiac MRI (pericardial enhancement), CRP/ESR.

Arrhythmias and Conduction Abnormalities

New arrhythmias (atrial fibrillation, ventricular tachycardia, supraventricular tachycardia) and conduction abnormalities (AV block, bundle branch block) may occur as isolated events or as manifestations of myocarditis. Any new arrhythmia in an ICI-treated patient warrants:

• Troponin measurement (rule out myocarditis)
• ECG, continuous telemetry
• Echocardiogram
• Cardiac MRI if myocarditis suspected
• Cardiology consultation
• Management per standard electrophysiology guidelines, with concurrent irAE workup

Neurologic Immune-Related Adverse Events

Neurologic irAEs are uncommon (1%–5% overall) but include some of the most serious and potentially fatal complications of ICI therapy. They encompass both central and peripheral nervous system manifestations. A high index of suspicion is required because neurologic irAEs can be rapidly progressive and life-threatening.^{1 2 3 5}

Overview of Neurologic irAEs

Peripheral Neuropathy

Myasthenia Gravis

ICI-associated myasthenia gravis can be de novo or a flare of preexisting subclinical disease. It is often more severe than idiopathic MG, with higher rates of myasthenic crisis and respiratory failure. It frequently co-occurs with myocarditis and/or myositis (overlap syndrome), which carries a mortality rate of approximately 30%–50%.^{1 5}

Clinical presentation: Ptosis, diplopia, dysphagia, dysarthria, proximal limb weakness, respiratory failure (myasthenic crisis), fatigable weakness.

Workup:

Management:

Critical principles:

• Always check troponin and CK in ICI-associated MG – the myocarditis-myositis-MG overlap has extremely high mortality and changes management urgency
• Avoid medications that worsen MG: aminoglycosides, fluoroquinolones, magnesium, beta-blockers, calcium channel blockers (use with caution), neuromuscular blocking agents
• Permanently discontinue ICI for any grade of MG

Encephalitis

Immune-mediated encephalitis can present as limbic encephalitis, diffuse encephalitis, or meningitis-encephalitis. It is rare but carries high morbidity.^{1 5}

Clinical presentation: Altered mental status, confusion, memory impairment, personality changes, seizures, focal neurologic deficits, fever (may or may not be present).

Workup:

Management:

Guillain-Barre Syndrome

Renal Immune-Related Adverse Events

Immune-mediated nephritis occurs in approximately 1% to 3% of ICI-treated patients, with a higher incidence in combination regimens. The most common pattern is acute interstitial nephritis (AIN), although immune-complex glomerulonephritis, minimal change disease, and other glomerulopathies have been reported.^{1 2 3}

Clinical Presentation

• Rising serum creatinine (often the only finding initially)
• Proteinuria (usually subnephrotic in AIN; may be nephrotic in glomerulonephritis)
• Pyuria and white blood cell casts (suggestive of AIN)
• Hematuria
• Eosinophiluria (in some cases of AIN)
• Systemic symptoms (fever, rash) occur in a minority of cases

Grading

Differential Diagnosis

• Pre-renal azotemia (dehydration, hypotension, heart failure)
• Nephrotoxic drugs (NSAIDs, contrast dye, antibiotics, cisplatin, other chemotherapy)
• Urinary tract obstruction (tumor, stones)
• Tumor infiltration of kidneys
• Thrombotic microangiopathy
• Other glomerulonephritis or vasculitis

Workup

Grade-Based Management of Immune-Mediated Nephritis

Musculoskeletal Immune-Related Adverse Events

Musculoskeletal irAEs are relatively common, with arthralgias reported in up to 15% to 20% of ICI-treated patients. However, clinically significant inflammatory arthritis, myositis, and polymyalgia-like syndromes also occur and can be functionally debilitating.^{1 2 6}

Inflammatory Arthritis

ICI-associated inflammatory arthritis can mimic rheumatoid arthritis, reactive arthritis, psoriatic arthritis, or large-joint oligoarthritis. Unlike many other irAEs, inflammatory arthritis often persists beyond ICI discontinuation and may require prolonged immunosuppressive therapy.

Clinical patterns:

• Large-joint oligoarthritis (most common)
• Symmetric polyarthritis (RA-like)
• Enthesitis, dactylitis, axial involvement (spondyloarthritis-like)
• Tenosynovitis

Workup: CRP, ESR, RF, anti-CCP antibodies, ANA, HLA-B27, uric acid, joint aspiration (if effusion to rule out crystal disease and septic arthritis), plain radiographs or MRI of affected joints.

Key points:

• Inflammatory arthritis frequently persists even after ICI discontinuation and may require months to years of anti-rheumatic therapy
• Low-dose prednisone (10–20 mg/day) is often effective and avoids the higher doses needed for other irAEs
• DMARDs can be initiated concurrently with ongoing ICI if the clinical situation warrants continued cancer treatment⁶

Myositis

ICI-associated myositis is uncommon (1%–2%) but can be severe, particularly when it co-occurs with myocarditis and myasthenia gravis (overlap syndrome). It presents with proximal muscle weakness and markedly elevated CK.^{1 5}

Clinical presentation: Proximal limb weakness (difficulty rising from chair, climbing stairs), myalgias, elevated CK (often markedly, > 10x ULN), dysphagia, respiratory muscle involvement (diaphragmatic weakness).

Workup:

Management:

Polymyalgia Rheumatica-Like Syndrome

A polymyalgia rheumatica (PMR)-like syndrome with bilateral shoulder and hip girdle pain and stiffness, elevated ESR/CRP, and dramatic response to low-dose corticosteroids has been reported with ICI therapy.

Management:

• Prednisone 15–20 mg/day (usually sufficient; dramatically effective)
• May continue ICI once symptoms controlled
• Taper slowly over 2–3 months; relapse is common with rapid taper
• Rheumatology consultation if atypical features or poor response
• Screen for concurrent giant cell arteritis (temporal headache, jaw claudication, visual symptoms) – if present, escalate to prednisone 1 mg/kg/day and urgent ophthalmology and rheumatology consultation

References