Immunoglobulin G4 (IgG4) fights viruses and bacteria. However, sometimes it targets the body itself. “This then leads to inflammation, the healing of which the body is unable to keep under control,” explained Ulf Müller-Ladner, MD, PhD, chairperson of the German Society of Internal Medicine (DGIM).
At the DGIM annual press conference, Müller-Ladner, who is also director of the Department of Rheumatology and Clinical Immunology at the Kerckhoff Clinic in Bad Nauheim, explained how IgG4 inflammation is triggered throughout the body and what therapeutic options are available.
IgG4-associated inflammation can affect one or more organs or the surrounding connective tissue and cause fibrosis. As a result of fibrosis, the organ gradually loses function and is eventually transformed completely into scarred connective tissue.
“In the case of IgG4-associated inflammation, these fibroses have a histological structure, but extracting a sample is not possible from every affected organ,” said Müller-Ladner. Liver, bile ducts, blood vessels, skin, eyes, or even the central nervous system — practically every organ system can be affected by these inflammatory reactions.
IgG4-associated diseases have likely been around for some time, but it is only in the past 10 years that awareness has grown that, despite various manifestations, “they are all one and the same disease,” said Müller-Ladner.
IgG4-associated chronic, inflammatory, fibrosing diseases were only classified together as a single entity in the past few years. In terms of pathophysiology, B lymphocytes, IgG4-positive plasma cells, follicular T-helper cells, cytotoxic CD4-positive T cells, and macrophages work together and trigger an inflammatory reaction, which then encourages fibroblasts to overproduce connective tissue.
Beware Inexplicable Inflammation
It is estimated that 1 in 100,000 people suffer from the disease, but the number of incorrectly categorized patients may be significantly higher.
The diagnostic challenge lies in the fact that IgG4-associated inflammation occurs in almost every organ. It can cause different symptoms, depending on the organ affected.
Müller-Ladner provided the following take-home message: “Every inexplicable inflammation event and every organ dysfunction, especially if associated with an increase in connective tissue, could be an IgG4-associated disease. Keeping this in mind is the key to recovery.”
With most people, the inflammation persists for many years before any symptoms of the disease develop. Highly acute courses of progression are also possible.
Classic symptoms, such as fever, are not so characteristic of the latent inflammatory reaction, and according to classification criteria published by specialist rheumatology societies, they are an exclusion criterion. This is true with respect to the differential diagnosis for vasculitis, which also occurs throughout the body.
Histology Is Key
Blood levels of IgG4 and imaging are not always enough to confirm the diagnosis. In such cases, the histology is often a crucial factor in making a definitive diagnosis. Dominant organs in IgG4-associated diseases are the pancreas, the liver, the gallbladder, the intestines, the retroperitoneum, large blood vessels, the kidneys, the heart, the brain, saliva, tear ducts, as well all of the body’s connective tissue.
The kidneys play host to inflammation in the connective tissue and space-occupying masses in particular. “If the pancreas is affected, the signs can vary from diffuse swelling to the onset of diabetes mellitus. In contrast, if the aorta is affected, then the inflammation is characterized through a thickening of the vessel walls, aneurysms, and the corresponding circulation disorders,” said Müller-Ladner.
Because of the long period before the diagnosis is made, more than 50% of patients exhibit irreversible organ damage at the time of diagnosis, he added.
Glucocorticoids and Immunosuppressants
Despite therapeutic intervention, the disease can have a fatal outcome, even if the patient is young, said Müller-Ladner. Glucocorticoids are the current therapy of choice. The dose is more than 0.5 mg of prednisolone equivalent per kg of body weight. “This usually leads to a rapid improvement in the inflammation. Subsequently, every organ is thoroughly diagnosed to assess the severity of the disease and to plan further treatment steps.”
In the long term, proven immunosuppressants, such as azathioprine, mycophenolate, leflunomide, and methotrexate, can be used, just as for many other chronic inflammatory diseases. Cyclophosphamide or cyclosporine is used more rarely, owing to their side effect profiles.
Because of the B-cell dominance, B-cell-depleting therapy with rituximab is currently a highly effective therapeutic option but one that must be applied for, because such use is off label. “If the body responds well to the medication, organ function often recovers,” said Müller-Ladner.