What is immune‑checkpoint inhibitor (ICI) pancreatitis?

What is ICI Pancreatitis?

ICI pancreatitis is a rare immune-related adverse event (irAE) characterized by pancreatic inflammation triggered by immune checkpoint inhibitor therapy, presenting either as asymptomatic lipase elevation or symptomatic acute pancreatitis with abdominal pain. 1

Definition and Classification

ICI pancreatitis, recently termed Type 3 autoimmune pancreatitis, is a distinct form of pancreatic injury caused by immune checkpoint inhibitors that target CTLA-4, PD-1, or PD-L1 pathways. 2 This represents part of the broader spectrum of gastrointestinal immune-related adverse events that occur when ICIs disrupt normal immune regulatory mechanisms. 1

Epidemiology and Risk Factors

• Acute pancreatitis from ICIs is rare, though asymptomatic elevations of lipase and amylase are more common. 1
• ICI-related pancreatic injury occurs in approximately 1.6% of patients receiving checkpoint inhibitor therapy overall. 3
• Combination ICI therapy (anti-CTLA-4 plus anti-PD-1) significantly increases risk compared to monotherapy. 2
• The presence of ≥2 other immune-related adverse events is strongly associated with ICI-induced acute pancreatitis (odds ratio 5.43), suggesting a systemic immune dysregulation pattern. 3
• Median time to onset is 57 days after ICI initiation, though events can occur throughout the first year of treatment. 4

Clinical Presentation

ICI pancreatitis exists on a spectrum:

• Asymptomatic hyperlipasemia: Elevated pancreatic enzymes without symptoms or imaging findings 2, 3
• Asymptomatic acute pancreatitis: Approximately 15% of patients with ICI-induced acute pancreatitis present without symptoms but have pancreatic inflammation on imaging. 3
• Symptomatic acute pancreatitis: Upper abdominal pain, nausea, vomiting, and elevated lipase (typically >2-3 times upper limit of normal). 1

Diagnostic Approach

Diagnosis requires temporal relationship to ICI exposure and exclusion of alternative etiologies, as only 29% of hyperlipasemia cases in ICI-treated patients are actually attributable to the therapy. 3

Essential workup includes:

• Serum lipase measurement (preferred over amylase for higher sensitivity). 5
• Cross-sectional imaging (CT or MRI) is diagnostically valuable in patients with significant hyperlipasemia, as a notable proportion of ICI-induced acute pancreatitis patients are asymptomatic but warrant treatment. 3
• Abdominal ultrasound to evaluate for gallstones and biliary obstruction. 1
• Exclusion of other causes: Check serum triglycerides (>1000 mg/dL indicates hypertriglyceridemia as etiology), calcium levels, and assess for alcohol use, gallstones, and medications. 5

Management Strategy

For Asymptomatic Lipase Elevation:

• Continue immunotherapy with monitoring per NCCN guidelines. 5
• Many patients (40%) can continue therapy uninterrupted if they do not meet criteria for acute pancreatitis. 3

For Moderate Acute Pancreatitis:

• Hold immunotherapy immediately. 5
• Initiate high-dose corticosteroids (1-2 mg/kg methylprednisolone or equivalent) with planned 6-week taper. 1, 5
• Provide supportive care including intravenous fluids. 3

For Severe Pancreatitis:

• Permanently discontinue immunotherapy. 5
• Start 2 mg/kg/day methylprednisolone or equivalent. 1
• Hospitalization is required, preferably at a referral center. 1

For Steroid-Refractory Disease:

This is a critical management challenge, as steroid-dependent or refractory ICI pancreatitis may develop chronic features including exocrine insufficiency and pancreatic atrophy. 6

• Consider azathioprine (2 mg/kg/day) as steroid-sparing maintenance therapy, based on similarities to autoimmune pancreatitis and successful case reports. 6
• Tacrolimus is another option supported by guidelines for other T-cell mediated ICI toxicities. 6
• Infliximab has been successfully used in at least one case of steroid-refractory ICI pancreatitis after multiple failed steroid tapers. 7

Long-Term Complications and Monitoring

• Exocrine pancreatic insufficiency develops in approximately 3% of all ICI pancreatic injury cases but is concentrated among those with acute pancreatitis. 3
• Endocrine insufficiency (diabetes) occurs in 9% of ICI pancreatic injury cases. 3
• Pancreatic atrophy may develop on imaging, resembling chronic autoimmune pancreatitis. 6
• Monitor patients with ICI-induced acute pancreatitis for exocrine pancreatic insufficiency with fecal elastase testing if steatorrhea develops. 3

Critical Pitfalls to Avoid

• Do not assume all pancreatitis in ICI-treated patients is drug-related: Only 29% of hyperlipasemia cases are attributable to ICIs; always exclude gallstones, alcohol, hypertriglyceridemia, and other causes. 3
• Do not rely on symptoms alone: 15% of ICI-induced acute pancreatitis presents asymptomatically, making imaging essential in patients with significant lipase elevation. 3
• Do not perform early CT scans: Imaging within 72 hours may underestimate pancreatic necrosis; wait until after 72 hours if assessing severity. 5
• Do not continue empiric steroids without proper diagnosis: The role and benefit of corticosteroids in ICI pancreatitis remain unclear, and holding immunotherapy risks cancer progression. 2
• Mortality from ICI-induced acute pancreatitis is 13.6%, making this a potentially life-threatening complication requiring aggressive management. 4