IgG4-Related Disease Explained: From Symptoms to Treatment Options

Medically Reviewed by Dr. Sony Sherpa, (MBBS)

IgG4-related disease, or IgG4-RD for short, is a chronic immune-mediated condition driven by an abnormal immune response involving immunoglobulin G4 (IgG4) antibodies, leading to swelling, tissue thickening, and sometimes organ dysfunction.

Although considered rare, IgG4-RD is increasingly recognized worldwide due to improved diagnostic awareness. Studies suggest a prevalence of less than 1 in 100,000 individuals, with most cases occurring in middle-aged to older men. However, exact rates vary depending on geographic and population factors.

Raising awareness of IgG4-RD is crucial given its ability to mimic numerous other medical conditions. Misdiagnosis may lead to unnecessary surgeries or delayed treatment. Early recognition and proper diagnosis allow for effective management, often with corticosteroids or immunosuppressive therapy, which can protect against irreversible organ damage and improve long-term outcomes.

What Is IgG4-Related Disease?

IgG4-related disease is a systemic, immune-mediated fibroinflammatory disorder that can affect one or multiple organs. It is characterized by the infiltration of IgG4-positive plasma cells and lymphocytes into tissues, leading to inflammation, fibrosis, and organ enlargement. The disease often develops gradually and may resemble cancer, infection, or other autoimmune diseases, making early recognition essential for appropriate treatment.

Commonly affected sites include the pancreas (autoimmune pancreatitis), salivary and lacrimal glands (Mikulicz’s disease), biliary tree, kidneys, lungs, and retroperitoneum. Despite involving various organs, all manifestations share a similar pathological pattern of IgG4-positive plasma cell infiltration and storiform (whorled) fibrosis.

IgG4-Related Disease Classification Criteria

To ensure research consistency, the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) developed the IgG4-RD classification criteria in 2019. These criteria involve three main steps:

• Entry criteria—Identification of a clinical or radiologic presentation consistent with IgG4-RD in one or more organs.

• Exclusion criteria—ruling out alternative diagnoses such as malignancy, infections, or other autoimmune diseases.

• Scoring system—A weighted scoring method based on histopathology, serum IgG4 levels, imaging, and organ involvement.

• A score of ≥20 points supports classification as IgG4-RD.

Causes and Risk Factors

What Causes IgG4-Related Disease?

The exact cause of IgG4-RD is still unknown, but research indicates it arises from a combination of factors, such as immune system dysregulation, genetic predisposition, and environmental triggers.

Role of IgG4 Antibodies in the Immune System

IgG4 represents one of the four subclasses of immunoglobulin G (IgG) antibodies. Normally, IgG4 helps regulate the immune system by reducing excessive inflammation and promoting immune tolerance. In IgG4-RD, however, the immune system becomes overactive, leading to the abnormal production of IgG4 antibodies. These antibodies stimulate an inflammatory response in various organs, resulting in tissue swelling, fibrosis, and organ dysfunction.

Autoimmune and Genetic Predisposition

IgG4-RD is widely regarded by experts as an autoimmune-like disorder marked by an inappropriate immune response against the body's own tissues. Genetic factors may also play a role, as certain HLA gene variants are more common in people with the disease.

Possible Triggers

Several external factors are thought to trigger or exacerbate the condition in genetically or immunologically susceptible individuals. These include:

• Infections - Chronic or repeated infections may stimulate an abnormal immune response.

• Environmental exposures - Such as allergens or occupational irritants.

• Vaccinations - Although rare, a few case reports have described IgG4-RD occurring after vaccination, including the COVID-19 vaccine. However, these cases are extremely uncommon, and a direct causal link has not been established.

Who Is at Risk?

IgG4-RD typically affects middle-aged to older men, though women and younger individuals can also be affected. The disease can involve one or multiple organs, and risk factors for developing multi-organ involvement are still being studied.

Symptoms, Organs Affected, and Manifestations

General Symptoms

IgG4-related disease can affect almost any organ, resulting in a broad range of symptoms. In many cases, symptoms develop gradually, which can delay diagnosis. Common general signs include:

• Fatigue and unexplained weight loss

• Low-grade fever or malaise

• Swelling or lumps in affected areas

• Pain or tenderness depending on organ involvement

Red Flags and the Triad of IgG4-RD

Experts often look for characteristic combinations of clinical, serologic, and histologic findings.

On histology, a classic triad supports IgG4-RD:

• Dense lymphoplasmacytic infiltrate - A large number of immune cells collecting in the tissue, showing ongoing inflammation.

• Storiform (whorled) fibrosis - Scar-like tissue arranged in a swirling or “woven” pattern, which is typical of IgG4-RD.

• Obliterative phlebitis - Inflammation that blocks or damages small veins within the affected organ.

These features, together with increased IgG4-positive plasma cells, organ enlargement (‘tumor-like’ lesions), and — often but not always — elevated serum IgG4, should prompt evaluation for IgG4-RD.

Organs Commonly Affected and Their Manifestations

The commonly affected sites and their typical clinical presentations are listed below:

• Pancreas:

  • Condition: Autoimmune pancreatitis

  • Symptoms: Abdominal or back pain, jaundice, and digestive disturbances due to bile duct compression

• Salivary and Lacrimal Glands:

  • Condition: Mikulicz’s disease

  • Symptoms: Painless swelling of salivary (parotid, submandibular) and lacrimal glands, causing dry mouth and dry eyes

• Kidneys:

  • ​Condition: Tubulointerstitial nephritis or hydronephrosis from retroperitoneal fibrosis

  • Symptoms: Reduced kidney function, flank or back pain, and swelling due to obstructed urine flow

• Lungs:

  • Condition: Pulmonary nodules or interstitial lung disease

  • Symptoms: Chronic cough, shortness of breath, or incidental findings on imaging

• Bile Ducts and Liver:

  • Condition: IgG4-related sclerosing cholangitis

  • Symptoms: Jaundice, itching, dark urine, and pale stools from bile duct obstruction

• Brain and Central Nervous System:

  • Condition: Hypertrophic pachymeningitis or pituitary involvement

  • Symptoms: Headache, vision changes, hormonal disturbances, or cranial nerve palsies

• Retroperitoneum:

  • Condition: Retroperitoneal fibrosis

  • Symptoms: Back or abdominal pain, leg swelling, or kidney dysfunction from ureteral obstruction

• Mediastinum:

  • Condition: Mediastinitis or fibrosis around the chest cavity

  • Symptoms: Chest pain, cough, or shortness of breath due to pressure on nearby structures

• Heart and Aorta:

  • Condition: Aortitis or periaortitis

  • Symptoms: Chest or abdominal pain, aneurysm formation, or signs of vascular inflammation

• Eye and Orbit:

  • ​Condition: Orbital inflammatory disease

  • Symptoms: Bulging of the eye, double vision, or pain around the orbit

Coexisting Conditions and Differential Diagnosis

Several conditions can occur alongside IgG4-RD or closely resemble it, making diagnosis challenging. Below is an overview of commonly associated conditions, important mimics, and key diagnostic principles to help clinicians and researchers distinguish between them.

Conditions That Commonly Coexist with IgG4-RD

These are clinical or laboratory findings often observed in patients with IgG4-RD. While they may support the diagnosis, they are not diagnostic on their own and must always be interpreted in the context of imaging and histopathology findings.

• Polyclonal Hypergammaglobulinemia: Frequently reported in IgG4-RD cohorts. Patients often show elevated total IgG with a disproportionately high IgG4 fraction.
• Eosinophilia: A substantial proportion of patients exhibit peripheral eosinophilia and elevated IgE levels, reflecting an allergic or Th2-skewed immune response.
• Lymphadenopathy (IgG4-rich lymph node changes): IgG4-positive plasma cell–rich lymph nodes are a well-recognized manifestation and may occur at multiple sites.
• Hematologic Abnormalities: Conditions such as thrombocytopenia have been described but are less common. When present, they should prompt an evaluation for alternative causes.

Conditions That Mimic IgG4-RD (Important Differential Diagnoses)

Several diseases can present with similar features to IgG4-RD and must be carefully excluded through biopsy, imaging, and laboratory investigations.

• Lymphoma and Plasma Cell Neoplasms: These may present with mass lesions or lymphadenopathy. Clonality testing on biopsy helps distinguish malignant monoclonal proliferations from the polyclonal IgG4-rich infiltrates typical of IgG4-RD.

• Multicentric Castleman Disease (MCD): Shares overlapping clinical and laboratory features, such as lymph node enlargement and elevated inflammatory markers. Histopathology and overall clinical presentation are key to differentiation.

• Sarcoidosis: A multisystem granulomatous disease that can mimic the glandular or retroperitoneal involvement seen in IgG4-RD. The presence of noncaseating granulomas on biopsy and specific organ distribution patterns help confirm sarcoidosis.

• Malignancies (Pancreatic, Biliary, and Other Cancers): IgG4-RD often forms mass-like lesions, such as in autoimmune pancreatitis, which may resemble malignancy. Accurate diagnosis requires a combination of imaging, serologic testing, and tissue biopsy.

• Graves’ Orbitopathy: This thyroid-associated orbital inflammation can mimic IgG4-related orbital disease. Differentiation depends on thyroid function tests, imaging findings, and sometimes biopsy confirmation.

• Rheumatoid Arthritis and Other Autoimmune Diseases: These may occasionally overlap or present with similar systemic symptoms. Comprehensive autoimmune serology and clinicopathologic correlation are essential.

• Other Inflammatory Biliary Disorders (e.g., Primary Sclerosing Cholangitis): Must be distinguished from IgG4-related sclerosing cholangitis through imaging, histology, and serologic features.

When a patient presents with an organ mass, obstructive jaundice, progressive organ dysfunction, or atypical laboratory findings, malignancy and infection should always be ruled out first. A tissue diagnosis is often required to confirm IgG4-RD.

Diagnosis

Classification vs. Diagnostic Criteria

As discussed above, the 2019 ACR/EULAR classification criteria are widely used in research settings to standardize patient cohorts. These criteria involve specific entry and exclusion steps, along with a weighted scoring system. A score of 20 or higher supports classification as IgG4-RD. While helpful for research, these criteria are not a substitute for clinical diagnosis but improve consistency across studies.

Blood Tests

• Serum IgG4 Concentration: Elevated serum IgG4 levels are common and support the diagnosis. Meta-analyses and cohort studies report a sensitivity of approximately 85–90% with good specificity. However, elevated IgG4 levels are not entirely specific and may be normal in some biopsy-confirmed patients. The commonly used laboratory cutoff is 1.35 g/L, though results vary by assay method.

• Serum Electrophoresis and Immunofixation: In some cases, IgG4 produces a narrow band on serum protein electrophoresis that mimics a monoclonal gammopathy. Immunofixation or subclass-specific testing helps determine whether the band represents a polyclonal IgG4 response (seen in IgG4-RD) or a true monoclonal paraprotein (suggesting plasma cell neoplasm). This distinction is crucial for accurate diagnosis.

Imaging

Imaging studies, including CT, MRI, and PET-CT, help identify organ enlargement, mass-like lesions, and multisystem involvement. PET-CT is particularly useful for mapping active disease sites to guide biopsy and for monitoring treatment response. Radiologic findings, when integrated with the classification scoring system, enhance diagnostic accuracy.

Tissue Biopsy (Gold Standard)

Histopathologic examination remains the definitive diagnostic method for IgG4-RD, which may reveal the classic triad and increased numbers of IgG4-positive plasma cells, with a high IgG4:IgG ratio.

A biopsy is essential not only to confirm IgG4-RD but also to rule out malignancy or alternative causes of inflammation.

Ancillary Tests

Additional investigations are tailored to the organs involved. Examples include pancreatic imaging and enzyme studies, liver function tests, renal biopsy when kidney involvement is suspected, and endocrine assessments for pituitary disease. These organ-specific evaluations ensure accurate diagnosis and guide individualized management.

Treatment

Treatment should be initiated promptly in patients with symptomatic, organ-threatening, or active IgG4-related disease to prevent irreversible fibrosis. Glucocorticoids have historically served as the first-line therapy, with most patients showing a rapid improvement in both clinical symptoms and biochemical markers. The long-term management strategy focuses on maintaining disease control, preventing relapses, and minimizing steroid exposure to reduce side effects.

Specific Treatment Options

Corticosteroids

Glucocorticoids remain the cornerstone of induction therapy due to their rapid onset of action. Tapering schedules vary depending on disease activity and organ involvement. However, relapse is common when steroids are tapered too quickly or discontinued, emphasizing the need for individualized tapering plans and maintenance strategies.

Steroid-Sparing Immunosuppressants

Agents such as azathioprine, mycophenolate mofetil, and methotrexate are often used to maintain remission or reduce the required steroid dose. While these medications are widely used in clinical practice, their efficacy is primarily supported by observational studies and expert consensus rather than large randomized controlled trials.

B-Cell Targeted Therapy (Biologics)

Rituximab, an anti-CD20 monoclonal antibody, has strong supporting evidence from multiple cohort studies and clinical trials. It is effective in inducing remission and serves as a potent steroid-sparing option, particularly for patients who relapse or are intolerant to long-term steroid use.

Inebilizumab (Uplizna®; inebilizumab-cdon)

In a major regulatory milestone, inebilizumab, an anti-CD19 monoclonal antibody, received FDA approval for the treatment of IgG4-RD on April 3, 2025, making it the first drug specifically approved for this condition. According to regulatory reports and press releases, the pivotal MITIGATE trial demonstrated that inebilizumab significantly reduced disease flares and allowed for reduced steroid dependence. This marks an important advancement in the targeted treatment of IgG4-RD.

Local and Mechanical Measures

In certain organ-specific complications, mechanical interventions are necessary to prevent organ damage. Examples include biliary stenting for obstructive jaundice due to sclerosing cholangitis, and ureteric stenting for hydronephrosis caused by retroperitoneal fibrosis. These procedures provide immediate decompression and are often performed alongside systemic therapy.

Other Agents (Experimental or Case-Based Evidence)

Hydroxychloroquine has been described in a few case reports and small series as potentially beneficial due to its anti-inflammatory and anti-fibrotic effects. However, evidence remains limited, and it is not part of the standard treatment regimen. It may be considered only as an adjunctive option in selected patients while awaiting stronger clinical data.

Monitoring and Relapse Prevention

Ongoing monitoring is essential, as relapse is common even in well-controlled cases. Regular clinical evaluations should be complemented with laboratory testing (including serum IgG4 levels when informative) and imaging studies as indicated by organ involvement. Many patients require long-term maintenance therapy or periodic re-treatment. Utilizing organ-specific outcome measures and engaging a multidisciplinary team, including rheumatology, gastroenterology, nephrology, or hematology specialists, can significantly improve long-term disease control and patient outcomes.

Prognosis and Long-Term Management

The prognosis for IgG4-related disease is generally positive, particularly when it is identified and managed before significant fibrosis develops. Early detection offers a better chance of reversing the disease and preventing permanent organ damage.

Relapse, however, is common. Without ongoing maintenance or targeted therapy, many patients experience disease recurrence. The use of B-cell–directed therapies and steroid-sparing immunosuppressants has been shown to lower the risk of relapse and help maintain long-term remission in many cases.

Although IgG4-RD itself is not usually fatal, recent cohort studies indicate a higher risk of malignancy, particularly lymphoma and certain solid tumors, compared to the general population. This risk appears to be greatest during the first year following diagnosis, highlighting the importance of vigilant monitoring and follow-up. Overall life expectancy varies depending on the extent of organ involvement, existing comorbidities, and individual treatment response.

Supportive care plays a crucial role in long-term management. Patients should receive ongoing attention for fatigue, metabolic side effects of steroid therapy (such as diabetes and weight gain), and the psychological impact of a chronic illness. Vaccination status should be reviewed carefully, balancing the benefits and risks of immunization while on immunosuppressive therapy. Lifestyle guidance and a multidisciplinary approach, coordinating care between specialists, are essential for improving overall outcomes and quality of life.

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