IgG4-Related Disease and Salivary Gland Involvement

Introduction:

IgG4-related disease (IgG4-RD) is a condition that affects multiple organs in the body, causing inflammation and the formation of tumefactive lesions. It can be known by various names such as IgG4-related systemic disease, hyper-IgG4 disease, IgG4-related autoimmune disease, IgG4-associated disease, IgG4-related sclerosing disease, and IgG4 syndrome. The most commonly affected organs are the pancreas, kidneys, orbital adnexal structures, salivary glands, and retroperitoneum. Due to its diverse presentation, patients with IgG4-RD are often misdiagnosed with malignancies or other diseases. However, a good response to treatment with systemic glucocorticosteroids can help in diagnosing the condition.

What Are the Causes of IgG4-Related Disease With Salivary Gland Involvement?

The exact reasons for IgG4-related disease with salivary gland involvement are not completely understood, and researchers are still studying how it develops. However, several factors are believed to play a part in its development:

• Autoimmune Dysfunction: IgG4-related disease is considered an autoimmune condition, where the body's immune system mistakenly attacks its own tissues. This leads to chronic inflammation and damage to the organs, including the salivary glands. The immune system produces increased levels of IgG4 antibodies, which contribute to the formation of fibrous masses and inflammation.

• Genetic Predisposition: While the specific genetic factors are not known, some individuals may have a genetic predisposition to develop the condition. Certain gene variants, particularly in the human leukocyte antigen (HLA) genes, have been associated with the disease.

• Environmental Triggers: Environmental factors may also play a role in triggering the abnormal immune response. However, the specific triggers are not yet known. It's possible that infections or exposure to certain substances in the environment could initiate the immune system's attack on healthy tissues.

• Dysregulation of Immune Cells: Certain immune cells, like regulatory T cells (Tregs) and helper T cells (Th2 cells), may be involved in the disease's development. Dysregulation of these cells could lead to the overproduction of IgG4 antibodies and the resulting inflammation and fibrosis in affected tissues, including the salivary glands.

What Are the Clinical Features of IGG4-Related Disease With Salivary Gland Involvement?

The symptoms of IgG4-related disease with salivary gland involvement are mentioned below:

• Bilateral Salivary Gland Swelling: One of the hallmark features of IgG4-related disease affecting the salivary glands is the presence of bilateral swelling. Both the parotid and submandibular salivary glands may be affected. The swelling is usually painless and gradually progresses over time.

• Dry Mouth (Xerostomia): As the inflammation and fibrosis increase, the salivary glands' functional capacity may be compromised, leading to a decrease in saliva production. This can exacerbate dry mouth symptoms and may affect oral health.

• Pain or Tenderness: While the swelling itself may be painless, some patients may experience mild pain or tenderness in the affected salivary gland area.

• Facial or Neck Masses: In some cases, the accumulation of fibrous tissue in the salivary glands can lead to the formation of pseudotumors. These masses can present as palpable lumps in the face or neck region.

• Difficulty in Chewing, Swallowing, and Speaking: The enlargement of the salivary glands and the presence of pseudotumors can exert pressure on surrounding structures, causing difficulties in chewing, swallowing, and speaking.

• Systemic Symptoms: In more advanced cases or when other organs are involved, patients may experience nonspecific systemic symptoms such as fatigue, weight loss, and fever.

How Can IgG4-Related Disease With Salivary Gland Involvement Be Diagnosed?

Salivary gland disorders can present with overlapping clinical features, making their diagnosis complex. Swelling of salivary glands may require the integration of various imaging techniques, even though biopsy remains the most reliable method for definitively diagnosing IgG4-RS.

The various diagnostic methods are the following:

• Ultrasonography (USG): This imaging technique is the most widely used due to its non-invasiveness and cost-effectiveness. It has been effective in differentiating IgG4-RD from other conditions. The recent addition of color Doppler has allowed the identification of specific features in salivary glands affected by certain conditions.

• Positron Emission Tomography (PET) Scan: This scan is an emerging diagnostic approach for IgG4-RD as it detects high concentrations of fluorine-18 labeled-fludeoxyglucose (FDG) in organ lesions. While it may not specifically differentiate between inflammatory and cancerous lesions, it proves valuable in identifying organ involvement beyond the salivary glands, including the pancreas, retroperitoneum, and periaortic tissue, which can be affected by IgG4-RD even without evident symptoms. Scans can be helpful in detecting organ involvement beyond the salivary glands, but their use should be targeted due to its cost.

• Imaging Studies: CT (computed tomography) scans and MRI (magnetic resonance imaging) can be useful in diagnosing salivary gland swelling, but they have limitations in diagnosing certain conditions like IgG4-related disease (IgG4-RD). Sialendoscopy is a promising tool for evaluating the duct system without the need for sialography, and it is useful for non-stone disorders of major salivary glands.

• Salivary Gland Biopsy: While biopsy remains crucial for diagnosis, tissue samples from different glands may show slight differences in the histological pattern. The size and location of the salivary gland swelling will determine whether a fine-needle aspiration (FNA) biopsy or an open biopsy is necessary. Biopsy of labial salivary glands is relatively easy to obtain but has low sensitivity for diagnosing IgG4-RD. In contrast, a biopsy of parotid and submandibular glands may require more invasive surgical interventions.

• Others: Researchers have proposed diagnostic criteria based on the presence of plasma cells that produce the immunoglobulin G subclass 4 (IgG4) antibodies, but further validation is needed. Western blot analysis of immunoglobulin heavy-chain gene rearrangement may be necessary in some cases.

What Is the Treatment for IgG4-Related Disease With Salivary Gland Involvement?

The treatment for IgG4-related disease with salivary gland involvement typically involves a combination of medical and, in some cases, surgical interventions. The goals of treatment are to reduce inflammation, control symptoms, prevent organ damage, and improve the patient's quality of life. The main treatment approaches include:

• Corticosteroids: Corticosteroids, such as Prednisone, are often the first-line treatment for IgG4-related disease with salivary gland involvement. These medications work to suppress the inflammatory response and reduce the number of IgG4-producing plasma cells. Corticosteroids can lead to a rapid improvement in symptoms and a reduction in the size of pseudotumors.

• Immunosuppressive Agents: In cases where corticosteroids alone are not sufficient or not well-tolerated, immunosuppressive agents may be prescribed. Drugs such as Azathioprine or Methotrexate are used to further suppress the abnormal immune response and prevent disease progression.

• Monoclonal Antibody Treatment: Tocilizumab and Rituximab are commonly used in this treatment.

  1. Rituximab, a monoclonal antibody targeting CD20-positive B cells, has shown promising results in treating refractory cases of IgG4-related disease. It is used in patients who do not respond adequately to corticosteroids or immunosuppressive agents.

  2. Tocilizumab is another targeted therapy that inhibits the interleukin-6 (IL-6) receptor, which plays a role in the inflammatory process. It has been used successfully in some cases of IgG4-related disease, including those with salivary gland involvement.

• Surgical Intervention: In certain situations, surgical intervention may be necessary. For example, if pseudotumors compress nearby structures and cause significant complications, surgery can help alleviate pressure and improve symptoms. Additionally, salivary ductal obstruction may require drainage procedures or surgical interventions.

Conclusion:

IgG4-RD is a disease that can affect different organs in the body, including the lacrimal and salivary glands. When doctors suspect this condition, they focus on distinguishing it from tumors or lymphomas (especially if there are mass lesions) and studying its presence in multiple organs using imaging techniques. Biopsy of affected organs is the most reliable way to diagnose IgG4-RD. The pathophysiology, risk factors, and ideal treatment options for IgG4-related disease are all still being studied because it is a relatively recent diagnosis. Improvements in the disease's understanding may result in better treatment options and better long-term outcomes for those who are affected.