What are the diagnostic criteria and treatment options for IgG4-related disease (Immunoglobulin G4-related disease)?

Diagnosis and Management of IgG4-Related Disease

The diagnosis of IgG4-related disease (IgG4-RD) requires a combination of characteristic histopathological findings, imaging features, elevated serum IgG4 levels, and response to steroid therapy, with histopathological confirmation being the gold standard for definitive diagnosis. 1

Diagnostic Criteria

Clinical Presentation

• Obstructive jaundice (occurs in up to 77% of patients with IgG4-SC) 2
• Multi-organ involvement (pancreas, biliary tract, salivary glands, orbits, kidneys, retroperitoneum) 1
• Pancreatic exocrine insufficiency 2
• Tumefactive lesions in multiple sites 3

Laboratory Findings

• Elevated serum IgG4 levels (>135 mg/dL) - present in 50-80% of patients 2, 4
• Important caveats:
  • Normal levels in 20-50% of patients 1
  • IgG4/IgG1 ratio >0.24 improves specificity 2
  • Serum IgG4 >4x upper limit of normal is highly specific 2
• Blood IgG4/IgG RNA ratio >5% by PCR (94% sensitivity, 99% specificity) 2, 1
• Other laboratory abnormalities:
  • Peripheral eosinophilia
  • Hypergammaglobulinemia
  • Elevated serum IgE levels
  • Hypocomplementemia 5

Imaging Features

• MRI/MRCP (first-line imaging modality): 1
  • Diffuse pancreatic enlargement
  • Capsule-like peripheral rim
  • Long pancreatic duct stricture
  • Multifocal stricturing
  • Lack of upstream pancreatic duct dilatation
• CT: Useful for assessing other organ involvement 1
• PET scanning: Identifies multisystem involvement 1

Histopathological Examination (Gold Standard)

• Essential features: 1, 3
  • Dense lymphoplasmacytic infiltrate enriched with IgG4+ plasma cells

  • 10 IgG4+ plasma cells per high power field

  • IgG4+/IgG+ plasma cell ratio >40%
  • Storiform fibrosis (except in bone marrow and lymph nodes)
  • Obliterative phlebitis (except in bone marrow and lymph nodes)

Diagnostic Approach

1. Initial Laboratory Testing:

   • Complete blood count with differential
   • Comprehensive metabolic panel
   • Erythrocyte sedimentation rate and C-reactive protein
   • Quantitative immunoglobulin levels (IgG, IgG subclasses)
   • Calculate IgG4/IgG1 ratio 2, 1

2. Imaging Studies:

   • MRI/MRCP for pancreaticobiliary evaluation
   • CT for assessment of other organ involvement
   • Consider PET scan for multisystem evaluation 1

3. Tissue Biopsy (essential for definitive diagnosis):

   • For biliary involvement: Endoscopic ampullary biopsies (positivity rate 53-80%)
   • For pancreatic involvement: EUS-guided core biopsy preferred over FNA
   • Look for characteristic histopathological features 1, 3

4. Differential Diagnosis:

   • Primary sclerosing cholangitis (PSC)
   • Cholangiocarcinoma
   • Pancreatic cancer
   • Lymphoma
   • Multicentric Castleman disease 2, 6

5. Distinguishing IgG4-SC from PSC: 2

   • PSC: Higher prevalence of IBD (~70% vs 5.6%)
   • IgG4-SC: Predominance of pancreatic disease and extra-gastrointestinal involvement
   • IgG4-SC: Rapid response to steroid therapy

Treatment

First-Line Therapy: Corticosteroids

• Regimen: Oral prednisolone 40 mg daily for 2-4 weeks, subsequently reduced by 5 mg every week over 8-12 weeks 2
• Assessment: Evaluate clinical response and radiological improvement at 4-8 weeks
• Response: Rapid clinical and radiographic response is characteristic of IgG4-RD 2, 1
• Caution: Lack of response suggests incorrect diagnosis or fibrotic phase of disease 1

Maintenance and Relapse Management

• Relapse rate: 40-60% after cessation of steroid treatment 2, 1, 7
• Options for relapsed/refractory disease:
  • Re-administration or dose increase of steroids 7
  • Immunomodulators (azathioprine, mycophenolate, mercaptopurine) 2, 7
  • Rituximab (anti-CD20 antibody) - effective even when immunomodulatory drugs fail 7, 6

Treatment Duration

• Maintenance therapy is common in Japan
• Consider cessation within 3 years to minimize steroid-related complications in elderly patients 7

Monitoring and Prognosis

• Short-term outcomes with steroid therapy are generally good
• Long-term outcomes less clear due to relapse, fibrosis, and associated malignancy 7
• Elevated serum IgG4 at diagnosis correlates with:
  • More active disease
  • Increased inflammatory markers
  • Hypocomplementemia
  • Greater number of affected organs
  • More extensive organ involvement
  • Treatment resistance
  • Shorter time to relapse 4

Pitfalls to Avoid

• Relying solely on serum IgG4 levels for diagnosis
• Failing to obtain histopathological confirmation
• Misdiagnosing IgG4-RD as malignancy or vice versa
• Inadequate exclusion of malignancy (IgG4-RD can be associated with or mimic various cancers)
• Underestimating relapse risk after steroid cessation 1