What is the next best step in managing a patient with chronic pancreatitis, negative IgG4, and no response to prednisone, with a history of pancreatitis and elevated lipase levels?

Management of Steroid-Refractory Chronic Pancreatitis with Negative IgG4

Given the negative IgG4, lack of response to prednisone, and absence of pancreatic atrophy or significant ductal changes, you should discontinue steroids and pursue tissue diagnosis to exclude malignancy, followed by symptomatic management for chronic pancreatitis rather than continued immunosuppression.

Reassess the Diagnosis

Your patient's presentation is atypical for autoimmune pancreatitis (AIP) for several critical reasons:

• Negative IgG4 argues strongly against IgG4-related disease, though serum IgG4 is elevated in only 50-80% of AIP cases 1
• Lack of steroid response is a red flag: A characteristic feature of IgG4-related disease is prompt clinical and radiographic response to steroid treatment, which occurs in 62-100% of cases 1, 2
• Absence of radiographic improvement after 4-8 weeks of steroids suggests either incorrect diagnosis or fibrotic, non-inflammatory phase of disease 1

The British Society of Gastroenterology explicitly states that lack of objective improvement in radiological abnormalities on repeat imaging at weeks 4-8 suggests either an incorrect diagnosis or a fibrotic, non-inflammatory phase 1.

Immediate Next Steps

1. Obtain Tissue Diagnosis

You must pursue histological confirmation before continuing any immunosuppressive therapy 1:

• Endoscopic ampullary biopsy with IgG4 immunostaining: This is positive in 52-72% of IgG4-related disease cases and can facilitate discrimination between IgG4-related disease and other conditions 1
• Look for >10 IgG4-positive plasma cells per high-power field with IgG4+/IgG+ ratio >40% 1
• EUS-guided fine-needle aspiration or core biopsy if a focal lesion is present, as this is effective in excluding malignancy 1
• ERCP with brush cytology and fluoroscopically guided endobiliary biopsy to exclude cholangiocarcinoma 1

2. Exclude Malignancy

Given the steroid non-response and elevated lipase with recurrent pancreatitis:

• Contrast-enhanced cross-sectional imaging (CT or MRI/MRCP) is essential to exclude pancreatic cancer or cholangiocarcinoma 1, 3
• MRI with contrast and MRCP is preferred for superior morphological information and detection of subtle lesions 3
• Pancreatic cancer can present with elevated lipase and recurrent pancreatitis-like symptoms 4

3. Discontinue Prednisone

Stop steroids if there is no objective response after a reasonable trial 5:

• The FDA label states: "If after a reasonable period of time there is a lack of satisfactory clinical response, prednisone should be discontinued and the patient transferred to other appropriate therapy" 5
• Continuing steroids without benefit exposes the patient to unnecessary side effects including immunosuppression, osteoporosis, and metabolic complications 5

Alternative Diagnoses to Consider

Primary Sclerosing Cholangitis (PSC)

• PSC shows similar cholangiographic changes to IgG4-related sclerosing cholangitis but does not respond to steroids 1
• Elevated serum IgG4 is found in 9-15% of PSC patients, but your patient is IgG4-negative 1
• Check for inflammatory bowel disease: 70% of PSC patients have IBD, compared to only 5.6% of IgG4-related disease patients 1

Chronic Pancreatitis (Non-Autoimmune)

Given the lack of steroid response and negative IgG4, this may be standard chronic pancreatitis from other causes:

• Evaluate for alcohol use, smoking, genetic mutations (PRSS1, SPINK1, CFTR)
• Assess for pancreatic exocrine insufficiency with fecal elastase
• Consider pancreatic enzyme replacement therapy for symptom management

Occult Malignancy

• Pancreatic adenocarcinoma can present with elevated IgG4 in some cases and mimic AIP 4
• Four of 10 patients with pancreatic mass lesions and normal IgG4 were ultimately diagnosed with pancreatic cancer after follow-up 4

If Tissue Confirms IgG4-Related Disease Despite Negative Serology

If histology shows >10 IgG4-positive plasma cells per high-power field with appropriate ratio:

• Add azathioprine 2 mg/kg/day as steroid-sparing agent while continuing a prednisone taper 2, 6, 7
• Consider rituximab for steroid-refractory disease 2
• The combination of prednisone with azathioprine showed good clinical, biochemical, and radiological response in steroid-resistant cases 6

Critical Pitfalls to Avoid

• Do not continue empiric immunosuppression without tissue diagnosis: This delays appropriate treatment if malignancy is present and exposes the patient to unnecessary toxicity
• Do not rely solely on serum IgG4: It is neither sensitive nor specific enough to make or exclude the diagnosis 1
• Do not assume steroid failure means you need more aggressive immunosuppression: It more likely indicates wrong diagnosis 1
• Do not ignore the 5mm pancreatic duct: While not severely dilated, document whether this represents improvement, stability, or progression from prior imaging

Monitoring Strategy If Diagnosis Remains Unclear

• Repeat cross-sectional imaging in 2-3 months to assess for interval change 3
• Serial CA 19-9 measurements if malignancy remains in differential
• Close clinical follow-up for development of new symptoms or signs