Immunoglobulin G4-related disease (IgG4-RD) is a chronic condition driven by the immune system. It is identified by inflammation and fibrous tissue buildup, often forming masses that can be mistaken for tumors. This process can affect single or multiple organs, such as the pancreas, salivary glands, kidneys, and bile ducts, potentially leading to organ damage if not addressed.
The disease gets its name from Immunoglobulin G4, a subtype of antibody found in high numbers within affected tissues. However, the precise function of these IgG4 antibodies in the disease process is not fully understood. Many individuals may not experience clear symptoms for months or years, resulting in a delayed diagnosis while damage quietly progresses.
Primary Goals of IgG4-RD Treatment
The primary aim of treating IgG4-related disease is to induce and maintain remission by suppressing the immune system’s attack on the body’s tissues. This halts the inflammatory process and the accompanying fibrosis, a form of scarring that can become permanent. By controlling the disease activity, physicians work to prevent irreversible organ damage and maintain a better quality of life.
Another objective is the preservation of organ function. As the disease causes swelling and fibrous tissue to build up, it can impair the normal operation of organs. Medical therapy seeks to reduce these tumor-like masses, thereby relieving pressure and restoring the organ’s ability to function as it should.
First-Line Glucocorticoid Therapy
The standard initial treatment for active IgG4-RD involves a class of drugs called glucocorticoids, with prednisone being the most frequently used. These medications are powerful anti-inflammatory agents that work broadly to suppress the immune system activity driving the disease. This approach is highly effective for most patients at controlling the initial presentation and producing a rapid improvement in symptoms.
Treatment begins with a high induction dose to quickly bring inflammation under control, often 30 to 40 mg of prednisone daily. This high-dose phase is maintained for two to four weeks. Following this, the dose is slowly reduced in a process known as tapering, where physicians decrease the dose by 5 mg every one to two weeks. This aims to find the lowest effective dose that keeps the disease in remission.
Prolonged use of glucocorticoids is associated with a wide range of side effects that are a significant consideration. These can include:
- Weight gain
- Mood swings
- Sleep disturbances
- Bone density loss (osteoporosis)
- An increased risk of diabetes
- High blood pressure
- A greater susceptibility to infections
Managing Relapses and Reducing Steroid Dependence
A significant challenge in managing IgG4-RD is that the disease frequently relapses as the glucocorticoid dose is tapered or stopped. Because of the substantial side effects of long-term steroid use, a primary goal is to transition to alternative medications that can maintain remission. These drugs are referred to as “steroid-sparing” agents because they allow for the reduction or elimination of prednisone.
The leading second-line therapy is a B-cell depleting drug called rituximab. This medication is a monoclonal antibody that targets a protein called CD20 on the surface of B-cells. By removing these cells from circulation, rituximab disrupts the inflammatory process. This approach is effective for many patients who relapse or do not respond to steroids.
In certain situations, other immunosuppressive drugs may be considered to help control the disease. Medications such as azathioprine and mycophenolate mofetil are sometimes used as maintenance therapies. These drugs work by more broadly suppressing the immune system and are often employed when rituximab is not suitable or available. Their use is based on clinical experience and small studies.
Newer and Investigational Therapies
Research into IgG4-RD is exploring new treatments that target different components of the immune system. One area involves therapies that focus on the CD19 protein. The drug inebilizumab is a monoclonal antibody that targets CD19, which is present on a broader range of B-cells, including plasmablasts that actively produce antibodies.
Another avenue of investigation is aimed at the internal signaling pathways within immune cells. A class of drugs known as Bruton’s tyrosine kinase (BTK) inhibitors is being evaluated in clinical trials. These medications, such as zanubrutinib and rilzabrutinib, work by blocking a molecule involved in the activation of B-cells.
Other biologic drugs are also being studied for their potential effectiveness. Therapies that block specific inflammatory messengers, or cytokines, such as IL-4, are being explored. Many of these newer treatments are still in the clinical trial phase and are not yet available for general use.
Monitoring Treatment Efficacy and Long-Term Care
Ongoing management is a central part of care for individuals with IgG4-RD, as the disease has a tendency to relapse. Physicians closely monitor a patient’s response to therapy through a combination of regular check-ups, laboratory tests, and imaging studies. These follow-ups allow for adjustments to treatment and the early detection of any returning disease activity.
Blood tests are a routine part of long-term monitoring. Serum IgG4 levels are checked regularly alongside other markers of inflammation, such as the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Although serum IgG4 levels decrease with effective treatment, they do not always return to normal, and a relapse can occur even when levels are low.
Periodic imaging, such as CT or PET scans, plays an important role in tracking the disease. These scans allow doctors to visually assess the size of any tumor-like masses and the degree of inflammation in affected organs. Comparing scans helps determine how well a treatment is working.
Because relapses are common, many patients require some form of long-term maintenance therapy to keep the disease under control. This might involve a low dose of a glucocorticoid or a steroid-sparing agent like rituximab administered at regular intervals. Continuous, long-term follow-up with a specialist is necessary to manage the chronic nature of the condition.