Understanding IgG4-Related Disease: Why It Matters for Patients With Complex and Overlapping Symptoms

At the European Alliance of Associations for Rheumatology (EULAR) 2025, which is the largest European based rheumatology research conference annually, Leila shared an important update on IgG4-related disease (IgG4-RD) as part of the “Go With Us!” to Conferences program. Even though IgG4-RD is not classified as an autoimmune or autoinflammatory arthritis, it comes up often in our community because it is frequently misdiagnosed as conditions like Sjögren’s, lupus, sarcoidosis, or rheumatoid arthritis. In some cases, it is even mistaken for cancer.

This overlap is exactly why IgG4-RD was included in AiArthritis’ Mystery Patient Guide, a resource designed to support people who remain undiagnosed or misdiagnosed for long periods of time. For many patients, learning about IgG4-RD can be the missing piece that finally helps explain a confusing set of symptoms.

What is IgG4-related disease?

IgG4-RD is a rare but serious inflammatory condition that can affect many organs throughout the body. It is known for causing inflammation, tissue enlargement, and fibrosis, which is a type of scarring that can permanently damage organs.

Commonly affected areas include:

• Pancreas
• Salivary glands
• Kidneys
• Lungs
• Lymph nodes

Because it can involve so many systems, IgG4-RD often looks like other autoimmune or inflammatory diseases. This is one reason diagnosis is so challenging and delays are common.

Learn more about IgG4-RD and download the symptom tracker.

A major milestone: the first FDA-approved treatment

One of the most exciting updates from EULAR was confirmation that Inebilizumab (Uplizna) is now FDA approved for IgG4-RD. This is a significant breakthrough, as there were previously no approved treatments specifically for this disease.

Inebilizumab is a B-cell depleting therapy, which fits into a broader theme seen across EULAR this year. Many emerging treatments for inflammatory diseases focus on B-cell pathways.

In a phase three trial:

• Nearly 60% of patients achieved flare-free, steroid-free remission by week 52
• Flare risk was significantly reduced
• Steroid use decreased
• Remission was maintained across sex, age, race, and geographic groups
• No major safety concerns were identified

This is especially meaningful given that IgG4-RD is more common in men overall, but appears more frequently in Asian women compared to other female populations. Seeing consistent results across groups is encouraging.

Another therapy on the horizon is Ruznilomab, a PD-1 blocker currently studied in phase two trials. After a short steroid taper, about 70% of patients remained flare-free for one year, with minimal side effects reported so far. While still under investigation, it represents another promising option.

Why treatment variety matters

One recurring message from this session was the importance of having multiple treatment mechanisms available. Not every therapy works for every patient, and some treatments lose effectiveness over time. Having options allows care to be adjusted as the disease evolves.

This reflects a broader shift toward personalized medicine, where treatment decisions are guided by the individual patient’s disease features, symptoms, and response history rather than a single standard approach.

Understanding “SACQ” patients: treating the person, not the lab numbers

A key concept discussed was SACQ, which stands for serologically active, clinically quiescent.

This describes patients who:

• Have high IgG4 levels on lab testing
• Feel well and have no active symptoms

Importantly, these patients did not show higher relapse risk as long as steroids were tapered slowly. The takeaway here is critical: high IgG4 levels alone should not drive treatment decisions.

IgG4 levels can be confusing. Despite the name of the disease, elevated IgG4 is often a result of the disease process, not the cause of symptoms. Many patients assume that high IgG4 automatically means active disease, but that is not always true.

This is why clinicians are urged to treat how the patient feels and functions, not just what the labs show.

Why diagnosis is so difficult

IgG4-RD is often diagnosed using biopsies, a process called histology, where tissue is examined under a microscope. However, relying on histology alone can be misleading.

A study from Romania found that 60% of suspected IgG4-RD cases were misdiagnosed when histology was used in isolation. Many of those patients were later found to have conditions like lymphoma, sarcoidosis, or vasculitis.

At the same time, patients with those diseases can be misdiagnosed as having IgG4-RD because IgG4-positive cells appear in tissue samples.

The lesson here is that no single test is enough. Accurate diagnosis requires:

• Symptoms
• Lab results
• Imaging
• Histology
• Clinical judgment

All of these pieces must be considered together.

Why this matters for patients

For patients, these updates carry several important messages:

• IgG4-RD is real, rare, and often overlooked
• Misdiagnosis can go both ways, delaying proper care
• FDA-approved treatment now exists in the U.S., with more likely coming
• High lab numbers do not always mean active disease
• Personalized care is essential

Most importantly, increased awareness can shorten the time patients spend without answers. For those who fall into the “mystery patient” category, learning about IgG4-RD may open the door to more accurate testing, better treatment, and improved quality of life.

If you or someone you care for has complex symptoms that do not quite fit a known diagnosis, resources like the Mystery Patient Guide can be a powerful starting point. Sometimes, progress begins with simply knowing what questions to ask next.

Learn more about IgG4-RD disease and the “Go With Us!” to Conferences program.