Unmasking IgG4-Related Disease: Best Practices for Accurate Diagnosis and Optimal Care

IgG4-related disease (IgG4-RD) is a complex, immune-mediated condition that can affect nearly any organ system in the body, often presenting with subtle or nonspecific symptoms that can easily be mistaken for other serious conditions. As awareness of this rare disease grows, clinicians are recognizing the importance of timely diagnosis and tailored management strategies.

Dr. Matthew Baker, Associate Division Chief in the Division of Immunology and Rheumatology at Stanford University and the Co-Founder and Co-Director of the Stanford Multidisciplinary Sarcoidosis Program, spoke with ReachMD to explore the hallmark clinical features that raise suspicion for IgG4-RD, ways to differentiate it from mimicking conditions, and evolving best practices in treatment and long-term care. Dr. Baker also presented on this topic at the 2025 Congress of Clinical Rheumatology East conference in Destin, Florida.

What are some of the hallmark clinical features that raise suspicion for IgG4-related disease?

Most patients with IgG4-RD present with some form of a mass or with organ enlargement. When the affected organs are visible, such as the lacrimal glands or salivary glands, the swelling is detected relatively quickly and is noticeable to the patient and/or examining physician. However, when certain internal organs are affected, it may not come to our attention until the disease has caused enough damage to result in signs or symptoms, or until imaging is performed. Sometimes, the disease is identified incidentally when patients obtain an imaging study for other reasons, and a mass or enlarged organ is detected. For patients with pancreas involvement, it’s relatively common to present with new onset type 2 diabetes and/or pancreatic exocrine dysfunction, which results in poor absorption in the GI tract and weight loss. Depending on the exact organs involved, the presenting symptoms can differ significantly from patient to patient. 

How do you differentiate IgG4-related disease from other mimicking conditions, like malignancy, sarcoidosis, or vasculitis?

We consider IgG4-RD one of the great mimickers, as it often presents with mass lesions, multi-organ involvement, and weight loss. There’s frequently an initial concern for malignancy, and patients will often have a biopsy to rule this out. There’s no single test that allows us to make the diagnosis of IgG4-RD—it’s a combination of the clinical history, exam, labs, imaging, and histopathology. Typically, once all that information is available, we can differentiate between the other diseases on the differential. But there are certainly cases that can be difficult to tease apart. 

What are some best practices for first-line treatment in newly diagnosed patients?

First-line treatment depends on patient characteristics (age, comorbidities, etc.) and disease characteristics (organs involvement, urgent treatment indications, risk of relapse, etc.). For most patients, we start with glucocorticoids—typically prednisone—and treat with a B-cell depleting agent, such as off-label use of rituximab. We try to minimize glucocorticoid exposure as best as we can and taper once it’s safe to do so and the disease appears to be responding. The goal is to induce remission with that regimen and then maintain long term remission by monitoring the disease closely and repeating treatment as needed. 

What are the most common challenges in managing IgG4-related disease, and how can we address them?

A common challenge in managing IgG4-RD is determining the optimal treatment dose and interval between treatments for a given patient. The current practice many of us follow is to monitor patients and reactively treat with another course of B-cell depletion when the disease appears to be relapsing. It’s possible, however, that in between treatments, the disease may be active at low levels that we do not detect, leading to slowly progressive organ damage. We don’t have evidence for this now, but if we did, it would be an argument for treating patients on a more regular schedule—such as every six or 12 months—regardless of whether we can detect disease activity.