What is the treatment approach for IgG4 (Immunoglobulin G4) disease?

Treatment of IgG4-Related Disease

Corticosteroids are the first-line treatment for active IgG4-related disease, with oral prednisolone 40 mg daily for 2-4 weeks followed by gradual taper over 8-12 weeks, and all patients should be considered for continued immunosuppressive therapy given the high relapse rate of at least 60%. 1

Initial Treatment Approach

First-Line Corticosteroid Therapy

• Start oral prednisolone at 0.6 mg/kg/day (typically 40 mg daily) for 2-4 weeks to induce remission 1, 2
• Gradually taper by 5 mg weekly over approximately 8-12 weeks to reach a maintenance dose of 2.5-5 mg/day over 2-3 months 1, 2
• Monitor clinical response through resolution of symptoms (jaundice, organ dysfunction) and radiological improvement (mass lesions, organ enlargement) at weeks 4-8 1
• Lack of objective radiological improvement by weeks 4-8 suggests either incorrect diagnosis or fibrotic, non-inflammatory disease phase 1

Important Monitoring Caveat

• Serum IgG4 levels often fall with steroid treatment but should NOT be used to monitor treatment response or guide further therapy 1
• Clinical and radiological parameters are the primary measures of treatment efficacy 1

Maintenance and Relapse Prevention

High Relapse Risk

• At least 60% of patients relapse after steroid cessation, with higher rates in those with multiorgan involvement 1
• A randomized study showed maintenance prednisolone 5-7.5 mg resulted in 23% relapse at 3 years versus 58% with steroid withdrawal 1

Maintenance Immunosuppression Strategy

• All patients with IgG4-RD, particularly those with multiorgan involvement, should be considered for continued immunosuppressive therapy 1
• European and North American practice typically introduces an immunomodulator (azathioprine 2 mg/kg/day, mercaptopurine, or mycophenolate) with additional steroids if relapse occurs or high relapse risk exists 1
• Japanese experts favor maintenance steroid treatment based on lower relapse rates 1
• No clear consensus exists on whether to maintain low-dose steroids alongside azathioprine 1

Second-Line and Refractory Disease

Rituximab for Treatment Failure

• Rituximab (anti-CD20 monoclonal antibody) achieves >95% response rates in IgG4-RD and is the preferred treatment for steroid-refractory disease 1
• Indications for rituximab include:
  • Failure to respond to first- or second-line treatment 1
  • Disease flares on steroid withdrawal 1
  • Multisystem or complex disease 1
  • Need for steroid-sparing therapy in relapsing disease 3
• B-cell depletion therapy is effective even when immunomodulatory drugs have failed 2

Relapse Management

• For relapsed disease, re-administration or dose increase of steroids is effective 2
• Addition of immunomodulatory drugs like azathioprine is appropriate for relapsed cases 2

Specialist Referral Indications

Patients with complex IgG4-related disease and those with suspected malignancy should be referred to specialist multidisciplinary teams 1

Rationale for Specialist Management

• Complexity of diagnosis and treatment planning requires experienced centers 1
• Differentiation from malignancy is critical to avoid unnecessary surgery 2
• Multiorgan involvement necessitates coordinated multidisciplinary care 4
• Recruitment into clinical trials is important given limited evidence base 1

Critical Clinical Pitfalls

Avoid These Common Errors

• Do not rely on serum IgG4 levels alone for diagnosis or treatment monitoring 1
• Do not assume lack of radiological improvement at 4-8 weeks means treatment failure—consider fibrotic phase or misdiagnosis 1
• Do not discontinue all immunosuppression after initial response—relapse rates exceed 60% 1
• Be aware that elderly patients are at high risk for steroid-related complications; cessation should be attempted within 3 years when possible 2

Organ-Specific Considerations

• Ocular manifestations (episcleritis, papilledema) require urgent treatment to prevent permanent vision damage 4
• Pancreatic involvement may lead to exocrine insufficiency requiring enzyme replacement 1
• Coordination with relevant specialists (rheumatology, gastroenterology, ophthalmology) is essential 4

Treatment Algorithm Summary

1. Confirm diagnosis with histopathology showing >10 IgG4+ plasma cells per high-power field, storiform fibrosis, and obliterative phlebitis 1, 2
2. Initiate prednisolone 40 mg daily for 2-4 weeks 1
3. Taper by 5 mg weekly over 8-12 weeks 1
4. Assess response at 4-8 weeks with clinical and radiological parameters 1
5. Plan maintenance therapy with either low-dose steroids (5-7.5 mg) or immunomodulator 1
6. If steroid-refractory or relapsing, initiate rituximab 1
7. Refer complex cases to specialist centers 1