What is IgG4-related disease and what are the diagnosis and treatment pathways?
Dr Emanuel Della Torre is a leading authority on immunoglobulin G4-related disease (IgG4-RD), having helped to define what the disease is. Here he explains what the disease is, discusses its diagnosis and treatment pathways, and introduces the Red Flags project, which aims to bring this underdiagnosed condition to the attention of general practitioners
Written by Geoff Case, digital editor, RARE Revolution Magazine
Interview with Dr Emanuel Della Torre, assistant professor of rheumatology at Università Vita-Salute San Raffaele, Milan, Italy, who leads the IgG4-related disease clinic at San Raffaele Hospital
The first description of IgG4-related disease (IgG4-RD) was only about 20 years ago, Emanuel says. “Probably IgG4-RD was around in the medical literature for years, but we were unable to recognise it as a unique disease.” Now, however, many different conditions are thought to be included within the spectrum of IgG4-RD.
IgG4 itself is a subtype of immunoglobulin (immunoglobulin G4)—an antibody that the body makes to protect us against disease. “[Antibodies] are produced by our immune system to target specific molecules (antigens) that belong to viruses and bacteria,” Emanuel explains. In autoimmune diseases like IgG4-RD, the antibodies that should protect us against infection harm us instead by targeting our own (‘self’) molecules. “Although IgG4 antibodies in patients with IgG4-RD seem capable of recognising ‘self’ structures, it is still unclear whether IgG4 antibodies are intrinsically harmful,” Emanuel says. “On the other hand, it is now clear that IgG4-producing cells (B cells) collect in an organ, or organs, and the tissue there becomes inflamed.”
Typically, a tumour-like lump appears (called a tumefactive lesion), and this may cause problems, such as blood vessels becoming obstructed. Gradually, the inflamed tissue becomes fibrotic (thickened and scar-like), affecting the way the organ works. It can affect one or more organs and, if two or more organs are affected, they may be affected at the same time or at different times.
The four main types of IgG4-related disease1
◾pancreato-biliary (group 1) – this affects the pancreas, bile ducts and liver
◾retroperitoneum/aortitis (group 2) – the large blood vessels entering the heart
◾head and neck limited (group 3) – the head and neck
◾Mikulicz/systemic (group 4) – this affects multiple organs together
Emanuel explains how there may be different disease mechanisms causing each type, but more work needs to be done to understand this better.
The disease is a chronic (long-lasting) one. Typically, the disease flares up before a quiet period (remission) when symptoms reduce, but then there are further flares (relapses). “Unfortunately, we don’t know what the cause is,” Emanuel says, “so that’s why it’s extremely challenging to intercept the flares and maintain remission.”
There is still no blood serum testing tool that is accurate enough to make a diagnosis of IgG4-related disease, so a doctor needs to consider radiological imaging, blood tests, and the patient’s signs and symptoms together. “The most important thing is to get a tissue biopsy (sample) whenever we can, because we want to be sure that [the lump] is not cancer.” Examining the tissue sample under a microscope may reveal signs of fibrosis and B cells, and these are part of the criteria for diagnosing IgG4-RD.
Unlike most other autoimmune diseases, IgG4-related disease is more common in males than in females. “The disease more preferentially affects males, with a ratio that reaches four males to one female.”2 The exception to this is IgG4-RD that affects the head and neck, in which similar numbers of males and females are affected. The disease mainly affects older individuals, “typically, males from the age of 45 to 50 years”,3 and it’s rare to see adolescents with IgG4-RD.
There are risk factors that may increase somebody’s chance of developing the disease, including cigarette smoke, Emanuel says. Being in close contact with contaminants such as metals and toxic powders in the workplace over a long period is a risk factor for IgG4-RD,4 in particular for pancreato-biliary and retroperitoneal disease. “There is a high prevalence of manual labourers and tradespeople at our centre.”
With IgG4-related disease, as with most autoimmune diseases, there are drugs that can be used to treat the symptoms of the disease but no drugs, currently, to treat its cause.
There are drugs to help prevent collagen being deposited in the organs (during fibrosis), but these drugs need to be used quickly. “Once the collagen is deposited, there is no treatment that helps clean it up. If we get there too late and the fibrosis is already established, then unfortunately, the organ’s function can be compromised in total or at least in part.”
“We use glucocorticoids as the first-line therapy,” Emanuel says, “but this may come with a number of side effects, such as weight gain, insomnia, hyperglycaemia, increased blood pressure, cataracts and osteoporosis.5 He explains how this may put patients in a difficult position: “If the treatment is not well-accepted, patients may have concerns about [taking] their treatment”, but without it their risk of relapse increases. “Every relapse is like a new blow to the affected organ and risks the worsening of symptoms.”
In recent years, drugs targeting B cells have been used as another treatment approach. Typically given by intravenous infusion, these clear the body of B cells for about six months, after which they come back. “This approach was a big change,” Emanuel says, explaining how it confirmed the crucial role of these cells within the disease process. With this step forward in understanding, treatments may potentially be developed in the future to specifically target the way the B cells work, without depleting them.
“IgG4-RD may not be such a rare disease. If you put all the organs together that can be affected, the prevalence of the disease may increase markedly.”
Emanuel believes that IgG4-RD is underdiagnosed—so much so that it may not be considered rare for much longer. But “general practitioners are probably still not aware of it,” he warns.
As the coordinator of the IgG4-RD working group, he leads the efforts of the European Reference Network on connective tissue and musculoskeletal diseases (ERN ReCONNET) to bring together patients who have IgG4-RD and clinicians who have expertise in managing their condition. In particular, he acknowledges the excellent work of Ilaria Galetti, who has worked so hard to make this happen. The first Italian meeting, fully dedicated to patients with IgG4-RD, will take place in Milan on 7 October 2023, and it is hoped that it will help raise the profile of the disease.
“It’s going to be an entire day in which we will discuss the pathogenesis of IgG4-RD and the most recent updates on diagnosis, clinical manifestation and treatment options. Patients will be at the centre of the event; we will have a roundtable with patient representatives to discuss their unmet needs.”
The Red Flags project is an ongoing effort within the ERN ReCONNET IgG4-RD working group. It aims to identify “red flags” to help general practitioners recognise the disease. The project will share “a few very easy tips” to help doctors diagnose the disease so they can promptly refer patients for further care.
Emanuel is also organising the fifth International Symposium on IgG4-RD in Milan (4–6 April 2024) that will gather specialists and experts from all over the world to discuss the most recent updates in the diagnosis, management and treatment of IgG4-RD.
Editor’s note: The first patient meeting took place, as scheduled, on 7 October 2023, after this article was written.
 Lanzillotta M, Campochiaro C, Mancuso G, et al. Clinical phenotypes of IgG4-related disease reflect different prognostic outcomes. Rheumatology (Oxford). 2020;59(9):2435-2442. doi:10.1093/rheumatology/keaa221
 Floreani A, Okazaki K, Uchida K, Gershwin ME. IgG4-related disease: Changing epidemiology and new thoughts on a multisystem disease. J Transl Autoimmun. 2020;4:100074. Published 2020 Dec 19. doi:10.1016/j.jtauto.2020.100074
 Pathogenesis and clinical manifestations of IgG4-related disease – UpToDate. Accessed August 28, 2023. https://www.uptodate.com/contents/pathogenesis-and-clinical-manifestations-of-igg4-related-disease
 Hubers LM, Schuurman AR, Buijs J, et al. Blue-collar work is a risk factor for developing IgG4-related disease of the biliary tract and pancreas. JHEP Reports. 2021;3(6):100385. doi:10.1016/j.jhepr.2021.100385
 List of Glucocorticoids + Uses, Types & Side Effects. Drugs.com. Accessed September 28, 2023. https://www.drugs.com/drug-class/glucocorticoids.html
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