IgG4-Related Disease: Manifestations and Treatment Options
IgG4-related disease (IgG4-RD) is a multisystem fibro-inflammatory disorder that most commonly affects the pancreas and biliary tract, with corticosteroids being the first-line treatment of choice. 1
Clinical Manifestations
Common Organ Involvement
- Pancreas: Type 1 autoimmune pancreatitis/IgG4-related pancreatitis (IgG4-RP) - most common manifestation 2
- Biliary tract: IgG4-related sclerosing cholangitis (IgG4-SC) - present in 59% of patients with IgG4-RD 3
- Salivary and lacrimal glands: Causing enlargement and dysfunction 4
- Orbits: Orbital inflammatory disease 4
- Retroperitoneum: Retroperitoneal fibrosis 5
- Kidneys: Tubulointerstitial nephritis 4
- Lungs: Interstitial pulmonary fibrosis 5
- Lymph nodes: Abdominal or mediastinal lymphadenopathy 5
- Aorta: Aortic aneurysm/periaortitis 5, 6
Clinical Presentation Patterns
- Symptomatic biliary obstruction: Often presenting as obstructive jaundice (77% of IgG4-SC patients) 3
- Multisystem involvement: Multiple organs affected simultaneously 5
- Incidental findings: IgG4-SC may be found incidentally in patients with manifestations in other organs 3
Hematologic Manifestations
Diagnostic Approach
Laboratory Testing
- Serum IgG4 levels: Elevated (>135 mg/dL) in 50-80% of patients, but insufficient alone for diagnosis 3, 1
- IgG4/IgG1 ratio: >0.24 improves specificity for distinguishing IgG4-SC from PSC 3, 1
- Blood IgG4/IgG RNA ratio: >5% by PCR has 94% sensitivity and 99% specificity 3, 1
- Additional tests: Complete blood count, comprehensive metabolic panel, ESR, CRP, and quantitative immunoglobulin levels 1
Imaging Studies
- MRI/MRCP: First-line imaging for pancreaticobiliary evaluation 1
- Characteristic findings: Diffuse pancreatic enlargement, capsule-like rim, long pancreatic duct stricture, multifocal stricturing
- CT: Useful for assessing other organ involvement 1
- PET scanning: Identifies multisystem involvement with 80% sensitivity and 90% specificity 1
Histopathology (Essential for Definitive Diagnosis)
- Key features: 1, 4
10 IgG4+ plasma cells per high power field
- IgG4+/IgG+ plasma cell ratio >40%
- Lymphoplasmacytic infiltration with fibrosis
- Storiform fibrosis
- Obliterative phlebitis
Treatment Options
First-Line Therapy: Corticosteroids
- Initial regimen: Oral prednisolone 40 mg (0.6 mg/kg) daily for 2-4 weeks 1, 7
- Tapering schedule: Gradual taper by 5 mg every week over 8-12 weeks 1
- Response assessment: Clinical and radiological improvement should be evaluated at 4-8 weeks 1
Maintenance Therapy
- Options: 1, 7
- Low-dose prednisolone (5-7.5 mg daily)
- Immunomodulators (azathioprine, mycophenolate mofetil, or mercaptopurine)
- Rationale: High relapse rates (60%) after steroid cessation 1
- Japanese approach: Maintenance steroids reduce relapse rate to 23% vs 58% with steroid withdrawal 1
Second-Line/Refractory Disease
- Rituximab: Anti-CD20 monoclonal antibody with >95% response rate 1
- Preferred for patients who fail first/second-line treatment
- Particularly effective for multisystem or complex disease
- Immunosuppressants: Azathioprine, mycophenolate mofetil, methotrexate as steroid-sparing agents 5
Disease Course and Prognosis
Important Differential Diagnoses
- Primary sclerosing cholangitis (PSC): Distinguished by higher prevalence of IBD (~70% vs 5.6% in IgG4-SC) 1
- Malignancies: Cholangiocarcinoma, pancreatic cancer, lymphoma 1, 7
- Other immune disorders: Multicentric Castleman disease, sarcoidosis 1, 6
Clinical Pearls and Pitfalls
- Misdiagnosis risk: In patients undergoing surgery for presumed hilar cholangiocarcinoma, 8% may actually have IgG4-SC 3
- Diagnostic challenge: Serum IgG4 can be elevated in 9-15% of PSC patients, complicating differentiation 3
- Biopsy approach: EUS-guided core biopsy is preferred over FNA for diagnosing IgG4-RD pancreatitis 1
- Steroid complications: New or worsening diabetes occurs in about 40% of treated patients 6
- Monitoring: Regular follow-up is essential due to risk of relapse and potential complications 1