What is the diagnosis for a patient with chronic pancreatitis, pancreatic ductal dilatation, and severe pain and vomiting, who is IgG4 negative, has no cancer, and has not responded to prednisone (40mg tapering to 10mg) therapy?

Diagnosis: IgG4-Negative Autoimmune Pancreatitis (Type 2 AIP) or Chronic Pancreatitis with Steroid-Refractory Disease

This patient most likely has either Type 2 autoimmune pancreatitis (which is IgG4-negative) or has progressed to a fibrotic, non-inflammatory phase of disease that will not respond to further steroids alone. The lack of response to adequate steroid therapy (40mg prednisone tapered to 10mg) combined with IgG4-negativity and recurrent severe symptoms indicates the need for immediate diagnostic re-evaluation and alternative therapeutic strategies. 1

Critical Diagnostic Considerations

The complete lack of steroid response after 2-4 weeks strongly suggests either an incorrect diagnosis or progression to irreversible fibrotic disease. 1, 2

Type 2 Autoimmune Pancreatitis Features

• Type 2 AIP is characteristically IgG4-negative with normal serum IgG4 levels and negative autoimmune antibodies 3
• Presents with pancreatic ductal dilatation and chronic inflammation with lymphocytic infiltrate on biopsy 3
• Can still respond to prednisone despite IgG4-negativity, though this patient has not responded 3

Alternative Diagnoses to Exclude

Lack of objective radiological improvement at weeks 4-8 on steroids mandates reconsideration of the diagnosis. 1, 4

• Primary sclerosing cholangitis (PSC): Routine steroid use provides no therapeutic benefit in PSC, unlike IgG4-related disease 1
• Chronic pancreatitis (non-autoimmune): Drug-induced (though thiopurines typically cause acute pancreatitis within 3-4 weeks), gallstone-related, or alcohol-related disease 1
• Occult malignancy: Despite negative initial workup, pancreatic adenocarcinoma can mimic autoimmune pancreatitis 5, 6
• Fibrotic phase of disease: Irreversible fibrosis will not respond to immunosuppression 1, 4

Immediate Diagnostic Steps Required

Obtain Tissue Diagnosis

Endoscopic ultrasound-guided core biopsy of the pancreas is essential to establish a definitive diagnosis and exclude malignancy. 1

• Look for lymphoplasmacytic infiltration with >10 IgG4-positive plasma cells per high-power field (supports Type 1 AIP despite negative serum IgG4) 1
• Granulocytic epithelial lesions suggest Type 2 AIP 3
• Dense fibrosis without active inflammation indicates non-reversible disease 1
• Exclude adenocarcinoma, which can be misdiagnosed as AIP 5, 6

Repeat Cross-Sectional Imaging

MRCP or CT should be performed now to assess for radiological response to steroids and evaluate for complications. 1, 7

• Lack of improvement in pancreatic swelling or ductal changes after 4-8 weeks of steroids suggests wrong diagnosis or fibrotic disease 1, 4
• Evaluate for pancreatic duct strictures, pseudocysts, or other complications requiring intervention 1
• Assess for features distinguishing PSC from IgG4-SC: long strictures with prestenotic dilatations favor IgG4-SC, while peripheral duct pruning and pseudodiverticulae favor PSC 1

Assess for Inflammatory Bowel Disease

Screen for IBD, as approximately 70% of PSC patients have IBD, compared to only 5.6% of IgG4-related disease patients. 1

• Colonoscopy with biopsies if not already performed 1
• Presence of IBD strongly favors PSC over autoimmune pancreatitis 1

Management Algorithm Based on Findings

If Type 2 AIP Confirmed on Biopsy

Add azathioprine 2 mg/kg/day immediately as steroid-sparing maintenance therapy while continuing current prednisone dose. 7, 8

• Do not taper steroids further until clinical and biochemical response achieved 7, 2
• Consider TPMT genotyping before starting azathioprine to predict toxicity risk 7
• Monitor CBC every 3-6 months for cytopenias 7
• Target 83% remission rate achievable with azathioprine monotherapy at this dose 7

If Fibrotic Disease Without Active Inflammation

Steroids should be discontinued and focus shifted to symptomatic management and evaluation for endoscopic or surgical intervention. 1

• Pancreatic enzyme replacement for exocrine insufficiency 1
• Endoscopic therapy for ductal strictures causing obstruction 7
• Pain management strategies for chronic pancreatitis 1
• Surgical consultation if refractory symptoms or complications 1

If PSC Diagnosed

Discontinue steroids immediately, as they provide no benefit and cause harm in PSC. 1

• Start ursodeoxycholic acid 10-15 mg/kg/day 7
• Manage complications of cholestasis 1
• Screen for cholangiocarcinoma and colorectal cancer if IBD present 1

If Malignancy Cannot Be Excluded

Refer urgently to specialist multidisciplinary team with pancreaticobiliary expertise. 2

• Some patients with presumed pancreatic cancer have undergone unnecessary pancreaticoduodenectomy when they actually had AIP 5
• Conversely, delaying cancer diagnosis is catastrophic for mortality 5, 6

Critical Pitfalls in This Case

The most dangerous error is assuming this is steroid-responsive autoimmune pancreatitis without tissue confirmation, leading to delayed diagnosis of malignancy or PSC. 1, 2, 5

• Serum IgG4 is elevated in only 90% of Type 1 AIP patients—negativity does not exclude the diagnosis but should prompt tissue sampling 9, 5, 6
• Lack of steroid response is highly atypical for autoimmune pancreatitis and demands diagnostic reconsideration 1, 2
• Continuing steroids without response causes harm through steroid complications without therapeutic benefit 1
• Relying on imaging alone is insufficient—even specialists have high interobserver variation in distinguishing IgG4-SC from PSC and malignancy on cholangiography 1

Monitoring During Diagnostic Workup

While awaiting definitive diagnosis:

• Monitor liver enzymes, bilirubin, and lipase weekly to detect worsening obstruction or pancreatitis 1
• Assess for signs of cholangitis (fever, rigors) requiring urgent intervention 1
• Evaluate nutritional status and provide pancreatic enzyme supplementation if steatorrhea present 1
• Do not use serum IgG4 levels to monitor disease activity as they do not correlate with treatment response 2

The current 10mg prednisone dose should not be tapered further until a definitive diagnosis is established and appropriate therapy initiated. 7, 2