What is IgG4 (Immunoglobulin G4)-related disease?

IgG4-Related Disease (IgG4-RD)

IgG4-related disease (IgG4-RD) is a recently described multisystem fibroinflammatory disorder characterized by the presence of IgG4-positive lymphoplasmacytic infiltrates in affected organs, often accompanied by elevated serum IgG4 levels, storiform fibrosis, and obliterative phlebitis. 1, 2

Definition and Pathophysiology

• IgG4-RD is an immune-mediated chronic condition with an allergic background, where upregulated responses of T helper 2 and T regulatory cells and their cytokines play a major role in disease progression 3
• The disease is characterized by three key histopathological features:
  • Dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells
  • Storiform-type fibrosis (swirling "basket-weave" pattern)
  • Obliterative phlebitis (venous occlusion) 4, 2
• The exact etiology remains unclear with no known pathogenic role of the IgG4 molecule itself identified 4

Epidemiology

• IgG4-RD predominantly affects middle-aged to elderly male patients 3
• The true prevalence is unknown as the disease has only recently been recognized as a unified condition 2

Clinical Manifestations

IgG4-RD can affect virtually any organ system, with the most common presentations including:

• Pancreas: Type 1 autoimmune pancreatitis (IgG4-related pancreatitis) 1, 5
• Biliary tract: IgG4-related sclerosing cholangitis (IgG4-SC), classified into four types based on location of biliary involvement 1
• Salivary and lacrimal glands: Enlargement leading to sicca syndrome (Mikulicz disease) 3, 6
• Orbital disease and exophthalmos 2
• Retroperitoneal fibrosis 2, 5
• Kidneys: Tubulointerstitial nephritis 2
• Lymphadenopathy 3
• Skin: Multiple manifestations including cutaneous plasmacytosis, pseudolymphoma, and various eruptions 6
• Other organs: Lungs, aorta, upper airways, thyroid gland, meninges, heart, and mesenterium 3

Clinical Presentation

• Patients may present with symptomatic organ swelling, dysfunction, or incidental findings on imaging 3
• IgG4-SC specifically may present with:
  • Obstructive jaundice (77% of cases in one series) 1
  • Often associated with pancreatic involvement (91% of jaundice cases) 1
  • May develop in 24-39% of patients previously diagnosed with IgG4-related pancreatitis 1
• About 30-50% of patients are atopic or have mild eosinophilia 3
• Disease course can be indolent but may progress to organ damage; in IgG4-SC, progression to cirrhosis occurs in 7.7-9% of patients, and some require liver transplantation 1

Diagnostic Approach

Laboratory Testing

• Serum IgG4 levels are elevated in 50-80% of patients 1
• While elevated serum IgG4 supports the diagnosis of clinically suspected IgG4-RD, it cannot be relied upon for making a definite diagnosis 1
• An IgG4/IgG1 ratio >0.24 may improve specificity in distinguishing IgG4-SC from PSC (primary sclerosing cholangitis) 1
• Serum IgG4 >4x upper limit of normal appears highly specific for IgG4-SC 1

Imaging

• Cross-sectional imaging may reveal other organ manifestations of IgG4-RD, helping differentiate from mimics 1
• MRCP (magnetic resonance cholangiopancreatography) findings in IgG4-SC include:
  • Long strictures with prestenotic dilatations
  • Absence of peripheral duct pruning
  • Lack of biliary pseudodiverticulae 1
• 18F-fluorodeoxyglucose positron emission tomography/computed tomography can map inflammation sites, evaluate disease extent, guide biopsy decisions, and monitor treatment response 3

Histopathology

• A pathological diagnosis should be pursued in cases of suspected IgG4-RD, as this allows distinction from disease mimics including PSC and cholangiocarcinoma 1
• Key histopathological findings include:

  • 10 IgG4-positive plasma cells per high power field in affected tissues

  • IgG4+/IgG+ plasma cell ratio >40% 1
• Tissue can be obtained through:
  • Endoscopic ampullary biopsies (positive in 53-80% of IgG4-related pancreatitis)
  • Fluoroscopically guided endobiliary biopsies
  • Visually directed cholangioscopic biopsies 1

Differential Diagnosis

• Primary sclerosing cholangitis (PSC) - key differences include:
  • Higher prevalence of inflammatory bowel disease in PSC (70%) vs. IgG4-SC (5.6%)
  • Predominance of pancreatic disease in IgG4-SC
  • Extra-gastrointestinal involvement in IgG4-SC 1
• Cholangiocarcinoma 1
• Other causes of secondary sclerosing cholangitis 1
• Rosai-Dorfman-Destombes disease (RDD) - some forms of extranodal RDD may have increased IgG4-positive plasma cells, but typically have lower IgG4/IgG ratios (<40%) compared to IgG4-RD 1

Treatment

• Glucocorticoids are the first-line treatment and are usually efficacious 2
• A characteristic feature of IgG4-RD is prompt clinical and radiographic response to steroid treatment, unlike PSC which typically does not respond to steroids 1
• Relapse may occur in >40% of cases after initial response 1
• B-cell depletion with rituximab is effective in steroid-resistant disease or as a steroid-sparing agent for relapsing disease 2, 5
• Early steroid therapy helps prevent tissue fibrosis, parenchymal extinction, and severe functional impairments in affected organs 4

Prognosis

• Despite its relapsing-remitting course, patients generally have an excellent prognosis 5
• Death from IgG4-RD is rare, though increased morbidity, malignancy, and mortality compared to age-matched controls has been reported 1, 5
• Intense fibrosis can lead to permanent organ damage and insufficiency 5