What is IgG4 disease?

IgG4-Related Disease: A Multisystem Fibroinflammatory Disorder

IgG4-related disease (IgG4-RD) is a systemic immune-mediated fibroinflammatory disorder characterized by IgG4-positive lymphoplasmacytic infiltration in affected organs, often presenting with pseudotumorous lesions and typically responding well to corticosteroid therapy. 1, 2

Definition and Pathophysiology

IgG4-RD is a relatively recently described condition (first reported in 2001 and officially named in 2010) that can affect virtually any organ system in the body. Key characteristics include:

• Immune-mediated systemic disease with predominantly fibrotic and proliferative manifestations
• Dense polyclonal lymphoplasmacytic infiltrates enriched with IgG4-positive plasma cells
• Storiform fibrosis (whorled pattern) in affected tissues
• Obliterative phlebitis (vascular involvement)
• Often elevated serum IgG4 levels (>135 mg/dL in 50-80% of patients)

Clinical Manifestations

IgG4-RD can affect multiple organ systems simultaneously or sequentially:

• Pancreas: Type 1 autoimmune pancreatitis (IgG4-related pancreatitis)
• Biliary tract: IgG4-related sclerosing cholangitis (IgG4-SC), present in 59% of patients 1
• Salivary/lacrimal glands: Chronic sclerosing sialadenitis, dacryoadenitis
• Retroperitoneum: Retroperitoneal fibrosis
• Kidneys: Tubulointerstitial nephritis
• Lymph nodes: Lymphadenopathy
• Other organs: Lungs, aorta, thyroid, meninges, heart, skin, and more

Diagnostic Features

Diagnosis requires a combination of:

1. Clinical presentation: Often presents with organ enlargement or dysfunction

   • 77% of IgG4-SC patients present with jaundice 1
   • Multiorgan involvement is common

2. Laboratory findings:

   • Elevated serum IgG4 (>135 mg/dL) in 50-80% of patients
   • Polyclonal hypergammaglobulinemia
   • Eosinophilia in 30-50% of patients
   • Elevated inflammatory markers (ESR, CRP)

3. Histopathology (gold standard):

   • Dense lymphoplasmacytic infiltrate with IgG4+ plasma cells
   • IgG4+/IgG+ plasma cell ratio >40%

   • 10 IgG4+ plasma cells per high-power field

   • Storiform fibrosis (except in lymph nodes and bone marrow)
   • Obliterative phlebitis 2, 3

4. Imaging:

   • MRI/MRCP: First-line for pancreaticobiliary evaluation
   • CT: Useful for assessing other organ involvement
   • PET: Can identify multisystem involvement 2

Differential Diagnosis

Important conditions to distinguish from IgG4-RD include:

• Primary sclerosing cholangitis (PSC)
• Malignancies (pancreatic cancer, cholangiocarcinoma, lymphoma)
• Multicentric Castleman disease
• Plasma cell neoplasms
• Hypereosinophilic syndromes
• Systemic vasculitides 3, 4

Treatment

1. First-line therapy: Corticosteroids

   • Prednisolone 40 mg/day for 2-4 weeks
   • Followed by gradual taper over 8-12 weeks
   • Response should be evaluated at 4 weeks 2
   • Rapid response to steroids is characteristic and helps confirm diagnosis

2. Maintenance therapy:

   • Often necessary due to high relapse rates (30-60%)
   • Low-dose prednisolone (5-7.5 mg daily) or
   • Steroid-sparing agents: azathioprine, 6-mercaptopurine, mycophenolate mofetil 2

3. For refractory cases:

   • Rituximab (anti-CD20 monoclonal antibody) with >95% response rate
   • Preferred for patients who fail first/second-line treatment 2

Prognosis

• Generally good prognosis with early diagnosis and treatment
• Can progress slowly if untreated
• Potential for progression to cirrhosis in 7.7-9% of patients with IgG4-SC 1, 2
• Risk of relapse after treatment is 30-60% 2
• Requires long-term monitoring due to risk of recurrence

Special Considerations

• Patients with complex IgG4-SC or suspected malignancy should be referred to specialist centers 1
• In elderly patients or those with insulin-dependent diabetes, lower initial doses of prednisolone (10-20 mg/day) may be considered 2
• Endoscopic intervention may be necessary for biliary strictures that don't respond to medical treatment 2

IgG4-RD is an evolving field of study, with ongoing research to better understand its pathogenesis, improve diagnostic criteria, and develop more targeted therapies.