Understanding the disease

For years IgG4-RD hid in plain sight by looking like other diseases, until doctors connected the clue. Now awareness is growing.

From confusion to clarity: A short history of IgG4‑related disease

In medicine, some conditions are hidden for years before we recognize them. IgG4-related disease (IgG4-RD) is one of those diseases. For more than a century, physicians carefully documented unusual swellings of salivary glands, pancreas, lymph nodes, or tissues around the eyes, never realizing the problems in those disparate organs were caused by a single underlying condition.

Today, we understand IgG4-RD as a systemic (body-wide) immune-mediated disease that causes inflammation and scarring (fibrosis). But reaching this understanding required decades of observation, breakthroughs in Japan and worldwide, and the courage to rethink old assumptions.

Whether you’re learning about IgG4‑RD for the first time or trying to better understand the condition, this short history shows how we got here—and why care is better today.

The discovery of IgG4-related disease brings understanding to light

A Japanese physician once described IgG4-RD as “a black crow flying through a dark night,” a disease that was present but long unseen. In this short film, Dr. John Stone—a Harvard Medical School professor, rheumatologist at Massachusetts General Hospital, and the Executive Chairman of the IgG4ward! Foundation—provides a brief look into the history of IgG4-RD.

Join Dr. Stone as he traces the remarkable history of IgG4-RD, from early puzzling cases to the breakthroughs that finally brought this condition into the light.

Just a few years later, in 1896, Hermann Küttner documented tumor-like enlargement of the submandibular glands, swellings that were known for more than a century as a “Küttner’s tumor.”

A third German physician, Bernhard Riedel, also described yet another manifestation of IgG4-RD—“Riedel’s thyroiditis” — in the 1890s. These cases puzzled physicians for generations, because no single disease seemed to connect them.

The modern story began in Japan. In 2001, Dr. Hideaki Hamano, Department of Internal Medicine/Gastroenterology at Shinshu University School, and colleagues discovered that patients with a mysterious form of autoimmune pancreatitis (AIP) had strikingly elevated blood levels of the antibody IgG4.

By 2003, Dr. Terumi Kamisawam of Tokyo Metropolitan Komagome Hospital and collaborators linked AIP to similar findings in other organs, postulating a systemic, “autoimmune” disease process.

Researchers began to recognize that many previously “separate” disorders—Riedel’s thyroiditis, Mikulicz’s disease, Küttner’s tumor, retroperitoneal fibrosis—were actually different faces of one disease family.

Global collaboration accelerated rapidly. Japan and the U.S. formed the earliest research networks, followed by Europe, Canada, and beyond. A major milestone arrived in 2011, when international experts at the first International Symposium on IgG4-RD, held in Boston, agreed on the name “IgG4-related disease” and published formal a consensus document on disease nomenclature.

The first International Symposium on IgG4-related disease brought together more than 130 delegates at Massachusetts General Hospital, including more than 100 from Japan, helping to launch a global community of collaboration that continues today.

Since then, researchers have continued to refine the understanding of the disease’s immune mechanisms, clinical patterns, and treatment strategies. What once seemed rare and mysterious is now recognized as a global condition—still challenging, but far better understood. But one major gap remained: patients had nowhere to turn for trusted, accessible education. This need ultimately seeded the creation of patient-centered foundations and this very learning program.

Timeline: The history of IgG4-related disease

Early clues (late 1800s–1970s)

1892 — Mikulicz’s syndrome

Symmetric swelling of lacrimal and salivary glands first described.

1896 — Küttner’s tumor

Tumor-like enlargement of the submandibular glands documented.

1977 — Early fibrosis research

Histologic descriptions identify stages of fibrosis in Küttner’s tumor—later recognized as classic IgG4-RD patterns.


Modern discovery (1990s–2003)

1995 — Concept of autoimmune pancreatitis 

Japanese researchers propose a distinct form of pancreatitis later linked to IgG4-RD.

2001 — Key breakthrough

Elevated serum IgG4 identified in autoimmune pancreatitis.

2003 — Extrapancreatic disease recognized

Kamisawa et al. describe systemic involvement linked by a common pathology, revealing a unified disease.


Rapid expansion (2010s–present)

2010s–present — Improved recognition

Growing global experience reveals how often IgG4-RD mimics cancer, infections, and autoimmune conditions—sharpening diagnostic accuracy worldwide.

Naming the disease (2012)

2012 — International consensus

“IgG4-related disease” formally adopted; comprehensive diagnostic criteria published.

2010–2012 — Reclassification accelerates

Many long-standing, single-organ conditions (Mikulicz’s disease, Küttner’s tumor, Riedel’s thyroiditis, retroperitoneal fibrosis) are recognized as part of the IgG4-RD spectrum.

2012 — Global framework established

International experts adopt the name “IgG4-related disease” and publish unified diagnostic criteria.

2013–2016 — International collaboration grows

Research networks expand across Japan, the U.S., Europe, and beyond, supported by pathology exchanges and early international symposia.

2014–2024 — New treatments & clinical trials

Major clinical advances emerge, including B-cell depletion strategies (early rituximab reports in 2010; expanded studies in 2015) and the landmark MITIGATE trial published in 2024.

2023–2024 — Patient advocacy emerges

The IgG4ward Foundation and other patient-centered groups form to provide trusted education and support.

Summary

The medical understanding of IgG4-RD took decades to uncover. It emerged piece by piece—first as scattered observations in the late 19th century, then as a pancreatic mystery involving the IgG antibody, and finally as a unifying diagnosis starting in the early 2000s.

The past two decades brought a remarkable acceleration in understanding, driven by global collaboration and patient stories. This history reminds us that medical breakthroughs often begin with curiosity, careful observation, and the willingness to ask new questions.