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

IgG4-Related Disease: Diagnostic Criteria and Treatment

The diagnosis of IgG4-related disease requires a combination of clinical presentation, imaging findings, serology, and histopathology—with tissue diagnosis being the gold standard—followed by first-line corticosteroid therapy and consideration for maintenance immunosuppression given the high relapse rate.

Diagnostic Criteria

Serological Criteria

Elevated serum IgG4 levels support but cannot definitively diagnose IgG4-RD. 1

• Serum IgG4 is elevated in 50-80% of patients with IgG4-RD 1
• Serum IgG4 >4× upper limit of normal is highly specific for IgG4-related sclerosing cholangitis 2
• An IgG4/IgG1 ratio >0.24 improves specificity for distinguishing IgG4-SC from PSC 1, 2
• Blood IgG4/IgG RNA ratio >5% by quantitative PCR has excellent sensitivity (94%) and specificity (99%), though not widely available 1
• Critical caveat: Elevated serum IgG4 alone is insufficient for diagnosis, as 9-15% of PSC patients also have elevated levels 1

Histopathological Criteria (Gold Standard)

Tissue diagnosis should be pursued whenever possible to distinguish IgG4-RD from malignancy and other inflammatory conditions. 1

The diagnostic triumvirate includes: 3

1. Dense lymphoplasmacytic infiltrate
2. Storiform-type fibrosis
3. Obliterative phlebitis

Specific quantitative criteria:

• >10 IgG4-positive plasma cells per high-power field in biopsy specimens 1
• IgG4+/IgG+ plasma cell ratio >40% provides additional diagnostic evidence 1, 2, 3, 4

Imaging Criteria

Non-invasive imaging with CT, MRI/MRCP is the cornerstone of evaluation. 1

• Cross-sectional imaging identifies organ involvement (pancreas, kidneys, retroperitoneum, biliary tree) 1
• PET scanning may identify fluorodeoxyglucose uptake at distant sites (salivary/lacrimal glands) characteristic of multisystem disease 1
• For IgG4-related sclerosing cholangitis, MRCP demonstrates four characteristic biliary patterns 1:
  • Type 1: Lower common bile duct stenosis (often with pancreatitis)
  • Type 2a: Intrahepatic stenosis with prestenotic dilatation
  • Type 2b: Intrahepatic stenosis with peripheral duct pruning
  • Type 3: Hilar and lower common bile duct stenosis
  • Type 4: Hilar stenosis only

Comprehensive Diagnostic Approach

The 2020 revised comprehensive diagnostic criteria consist of three domains: 5

1. Clinical and radiological features
2. Serological diagnosis (serum IgG4 >135 mg/dL per Japanese criteria) 4
3. Pathological diagnosis (including storiform fibrosis and obliterative phlebitis) 5

Integration of all findings is essential, as no single test is definitive 2, 6

Treatment Options

First-Line Therapy: Corticosteroids

Corticosteroids are the first-line treatment for active IgG4-RD. 1

Dosing regimen: 6

• Initial dose: Prednisolone 0.6 mg/kg/day orally for 2-4 weeks
• Taper gradually to maintenance dose of 2.5-5 mg/day over 2-3 months
• Monitor response through clinical improvement (resolution of jaundice, normalization of liver biochemistry) and radiological findings (resolution of mass lesions) 1

Important caveat: Serum IgG4 levels often fall with steroid treatment but should not be used to monitor or plan further treatment 1

Maintenance Immunosuppression

All patients with IgG4-RD should be considered for continued immunosuppressive therapy due to the high relapse rate. 1, 7

• Relapse occurs in at least 60% of patients after steroid cessation, particularly with multiorgan involvement 1, 7
• A randomized study showed lower relapse rates at 3 years with maintenance prednisolone 5-7.5 mg (23%) versus steroid withdrawal (58%) 1

Options for maintenance therapy:

• Azathioprine (typically 2 mg/kg/day) with or without low-dose steroids 1
• Mercaptopurine 1
• Mycophenolate 1
• Maintenance prednisolone 5-7.5 mg daily 1

Steroid cessation should be attempted within 3 years given the elderly patient population and risk of steroid-related complications 6

Second-Line Therapy: Rituximab

Rituximab is the preferred treatment for steroid-refractory disease or disease that flares on steroid withdrawal. 1, 7

• >95% of patients with IgG4-RD respond to rituximab (anti-CD20 monoclonal antibody) 1, 7
• Particularly indicated for patients with multisystem or complex disease 1, 7
• Dosing: 2 infusions of 1000 mg rituximab 15 days apart, repeated every 6 months for maintenance 7
• Appropriate premedication should be used to minimize infusion reactions 7

Management Algorithm

1. Confirm diagnosis through combination of serology, imaging, and tissue biopsy whenever possible 1
2. Initiate corticosteroids (prednisolone 0.6 mg/kg/day) for active disease 1, 6
3. Assess response at 4-8 weeks with repeat imaging; lack of improvement suggests incorrect diagnosis or fibrotic phase 1
4. Taper to maintenance therapy over 2-3 months 6
5. Add immunomodulator (azathioprine, mycophenolate) or maintain low-dose steroids for relapse prevention 1
6. Switch to rituximab for steroid-refractory disease, relapse, or multisystem involvement 1, 7

Specialist Referral

Patients with complex IgG4-SC, suspected malignancy, or multiorgan involvement should be referred to specialist centers. 1

This ensures appropriate diagnosis, optimal management planning, and potential enrollment in clinical trials 1

Critical Pitfalls to Avoid

• Do not diagnose based on elevated serum IgG4 alone—9-15% of PSC patients have elevated levels 1
• Do not rely on brush cytology for definitive diagnosis of IgG4-SC 1
• Exclude malignancy before diagnosing IgG4-RD, as up to 8% of presumed hilar cholangiocarcinoma cases are actually IgG4-SC 1
• Do not use serum IgG4 levels to monitor treatment response—clinical and radiological improvement are the appropriate endpoints 1
• Recognize that IgG4-positive plasma cells occur in other conditions including ANCA-related vasculitis, chronic infections, and malignancies 3