IgG4-related disease (IgG4-RD) is a chronic, systemic, immune-mediated fibroinflammatory condition characterized by tissue infiltration with IgG4-positive plasma cells, storiform fibrosis, and often elevated serum IgG4 levels. This condition can affect nearly any organ system, including the pancreas, salivary glands, lacrimal glands, kidneys, lungs, and lymph nodes.

Diagnosis relies on a combination of clinical presentation, serological markers (especially serum IgG4 levels), imaging, and histopathological confirmation. Importantly, the disease often responds well to corticosteroid therapy, though relapses are common, necessitating long-term monitoring and sometimes immunosuppressive treatment.

What is IgG4?

IgG4 (Immunoglobulin G4) is one of the four subclasses of IgG, which is a type of antibody produced by the immune system to help fight infections. Antibodies (also called immunoglobulins) recognize and bind to specific foreign substances like bacteria, viruses, or allergens to help neutralize or eliminate them.

There are four IgG subclasses in humans: IgG1, IgG2, IgG3, and IgG4. Each has slightly different roles in immune function. Among them:

• IgG1 is the most common and is highly active in fighting infections.
• IgG4, on the other hand, is the least abundant (making up less than 5% of total IgG) and behaves differently.

Unique Features of IgG4:

• It is less effective at triggering inflammation compared to the other IgG subclasses.
• It can switch its binding arms, creating antibodies that are “functionally monovalent,” meaning they are less able to cross-link and activate immune responses.
• IgG4 is often associated with long-term exposure to antigens, such as in allergies or chronic immune stimulation.

In healthy people, IgG4 plays a regulatory or protective role in dampening excessive immune responses. However, in IgG4-related disease (IgG4-RD), this normally mild antibody is produced in abnormally high amounts and is associated with inflammation and fibrosis in various tissues.

What are IgG4-related diseases?

IgG4-related diseases (IgG4-RD) are a group of rare immune-mediated conditions where the body produces too much IgG4 antibody, leading to inflammation and tissue damage in various organs. This can cause swelling, masses, or fibrosis (scarring) in organs like the pancreas, salivary glands, kidneys, lungs, and more.

Though often mistaken for cancer or infection, IgG4-RD usually responds well to steroid treatment if diagnosed early.

Mechanisms of IgG4-related diseases

Although the exact pathogenesis remains incompletely understood, IgG4-RD is thought to involve both humoral and cellular immune mechanisms, with regulatory T cells and cytokines like IL-10 and TGF-β playing key roles. If left untreated, it may lead to progressive organ dysfunction due to fibrosis.

Originally recognized in the context of autoimmune pancreatitis, IgG4-RD is now understood to be a unified clinical entity encompassing a wide range of organ-specific disorders, such as Mikulicz’s disease, Riedel’s thyroiditis, and retroperitoneal fibrosis, among others.

Common IgG4-related diseases

Here’s a short list of common IgG4-related diseases (by organ or system):

• Pancreas: Autoimmune pancreatitis (Type 1)
• Salivary & Lacrimal Glands: Mikulicz’s disease
• Thyroid: Riedel’s thyroiditis
• Lungs: IgG4-related lung disease
• Kidneys: IgG4-related tubulointerstitial nephritis
• Biliary Tract: IgG4-related sclerosing cholangitis
• Retroperitoneum: Retroperitoneal fibrosis (Ormond’s disease)
• Aorta: IgG4-related aortitis/periaortitis
• Lymph nodes: IgG4-related lymphadenopathy
• Central Nervous System: Hypertrophic pachymeningitis

Urologic IgG4-related diseases

Here’s a quick summary of urologic diseases associated with IgG4-related disease (IgG4-RD):

1. IgG4-related retroperitoneal fibrosis
   • Fibrous tissue forms around the ureters, possibly causing ureteral obstruction and hydronephrosis.
2. IgG4-related tubulointerstitial nephritis (TIN)
   • Inflammation and fibrosis in the kidneys’ tubules and interstitial tissue. May lead to renal dysfunction.
3. IgG4-related prostatitis
   • Rare, but can cause prostate enlargement, urinary symptoms, and mimics prostate cancer.
4. IgG4-related ureteritis
   • Inflammation and thickening of the ureter wall, potentially leading to obstruction or hydronephrosis.

These conditions may present with flank pain, lower urinary tract symptoms, or renal impairment, and are often misdiagnosed as malignancy or infection. Early diagnosis and treatment (usually corticosteroids) are key to preventing permanent damage.

Common symptoms

Here’s a short list of common symptoms of IgG4-related disease, depending on the organ involved:

• Painless swelling or masses in affected organs
• Dry mouth or dry eyes (salivary/lacrimal gland involvement)
• Abdominal pain or jaundice (pancreas or bile ducts)
• Flank pain or kidney dysfunction
• Urinary symptoms (if prostate or ureters involved)
• Weight loss, low-grade fever, or fatigue
• Lymph node enlargement

Symptoms vary widely depending on which organ is affected. Many cases are discovered incidentally or mistaken for cancer or infection.

Diagnosis

Here’s a short summary of the diagnosis process for IgG4-related disease (IgG4-RD):

1. Clinical signs
   • Organ swelling, masses, or dysfunction
2. Blood tests
   • Elevated serum IgG4 levels (but not always present)
3. Imaging
   • CT, MRI, or PET scans show organ enlargement or fibrosis
4. Biopsy (key for diagnosis)
   • IgG4-positive plasma cell infiltration
   • Storiform fibrosis and obliterative phlebitis
5. Exclusion of other diseases
   • Rule out cancer, infection, or other autoimmune conditions

Accurate diagnosis often requires a combination of clinical, radiologic, serologic, and histopathologic findings.

Treatment of IgG4-related diseases

Here’s a short summary of the treatment for IgG4-related diseases:

1. First-line treatment:
   • Corticosteroids (e.g., prednisone)
     → Reduce inflammation and swelling
     → Most patients respond well
2. Steroid-sparing agents (for relapses or long-term use):
   • Azathioprine, mycophenolate mofetil, or methotrexate
3. Biologic therapy (for resistant or recurrent cases):
   • Rituximab (anti-CD20 monoclonal antibody)
4. Supportive care:
   • Monitoring for organ function (e.g., kidneys)
   • Treating complications (e.g., relieving ureteral obstruction)

Prognosis

Here’s a short summary of the prognosis for IgG4-related disease (IgG4-RD):

• Generally good with early diagnosis and treatment
• Most patients respond well to corticosteroids
• Relapses are common and may require long-term treatment
• Delayed treatment can lead to permanent organ damage due to fibrosis
• Rarely life-threatening, but organ function must be monitored

Summary

IgG4-related disease (IgG4-RD) is a rare, chronic immune-mediated condition characterized by inflammation and fibrosis in various organs. It involves infiltration by IgG4-positive plasma cells and often elevated serum IgG4 levels.

• Organs affected: Pancreas, salivary glands, kidneys, lungs, retroperitoneum, prostate, and more
• Symptoms: Swelling, masses, organ dysfunction, often mimicking cancer or infection
• Diagnosis: Clinical features, blood tests (IgG4), imaging, and biopsy
• Treatment: Corticosteroids (first-line), immunosuppressants, or rituximab for relapses
• Prognosis: Good with early treatment, but relapses are common

Prof. Dr. Emin ÖZBEK

Urologist

Istanbul- TURKIYE