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  • Writer's pictureThe Rare360 Editorial Team

Unravelling IgG4-Related Disease: From Diagnosis to Treatment

Updated: Jan 16

Team of doctors engaged in a lively discussion while gathered around a laptop.

Immunoglobulin G4-related disease (IgG4-RD) is a chronic immune-mediated fibroinflammatory disorder characterized by tumor-like masses and/or painless enlargement of multiple organs. This condition arises from the dense tissue infiltration of immune cells and expansion of the extracellular matrix, resulting in tissue scarring. Typically, IgG4- RD affects one or more organs; the 11 organs that typically are affected include the pancreas, bile ducts, lacrimal glands, orbital tissues, salivary glands, lungs, kidneys, retroperitoneal tissues, aorta, meninges, and thyroid gland. Most patients have multiorgan involvement at the time of diagnosis but tend to have one dominant phenotype.

The recognition of IgG4-related disease (IgG4-RD) began in 1961 when it was first described in the pancreas. However, it was not identified as a unified systemic disorder until 2003, with definitive confirmation in 2010. The condition is considered a rare disease due to its recent identification and its ability to affect multiple organs and links to a number of previously unrelated inflammatory diseases that were thought to impact only one organ.

Furthermore, IgG4 represents the least prevalent of the four subclasses of IgG antibodies. In IgG4-RD, there is an abnormal accumulation of immune cells that produce IgG4, as well as other related cells, in specific organs, resulting in damage. This atypical buildup can give rise to a range of symptoms and organ dysfunction, making the condition intricate and uncommon to both diagnose and treat. The serum IgG4 level often shows elevation, though not consistently, with symptomatology contingent on the organs affected. While the majority of diagnosed patients are middle-aged to older men, this disorder can impact individuals of any age and gender.

Understanding the Prevalence and Demographics of IgG4-Related Disease

The prevalence and incidence of IgG4-related disease (IgG4-RD) have been studied in the USA. The incidence of IgG4-RD increased from 2015 to 2019, likely indicating increased awareness of the disease. Between 2015 and 2019 in the USA, the incidence rate of IgG4-RD was recorded at 1.20 per 100,000 person-years, with a point prevalence of 5.3 per 100,000 individuals as of January 1, 2019.

Regarding the age and gender distribution, the average age of patients diagnosed with IgG4-RD was 56.5 years, with a predominance of females (57.6%) and white individuals (66.0%) in the USA. However, it’s important to note that IgG4-RD is currently thought to affect middle-aged and older people with a male-to-female ratio that ranges from 1.6:1 for head and neck manifestations to 4:1 for other sites of organ involvement. In the case of IgG4-related orbital disease (IgG4-ROD), this condition tends to occur in a younger group of patients (55 years versus 58-69 years) and affects men and women fairly equally (1.3:1). Additionally, IgG4-ROD is often associated with salivary gland lesions and higher serum IgG4 levels.

The prevalence of IgG4-RD varies among different countries. In Japan, the prevalence of IgG4-RD is estimated to range from 2.63–10.2 cases per million population, with an annual incidence of 336–1300 new cases. In 2019, within the commercially insured population in the USA, the recorded incidence rate and point prevalence were 1.39 per 100,000 person-years and 5.3 per 100,000, respectively. It's important to highlight that global awareness of IgG4-RD has grown significantly since its recognition as a unified disease entity just 15 years ago.

Exploring the Clinical Presentation of IgG4-Related Disease

IgG4-related disease (IgG4-RD) represents a captivating clinical spectrum encompassing various conditions, including entities previously known as Mikulicz's disease (MD), autoimmune pancreatitis (AIP), interstitial nephritis, prostatitis, and retroperitoneal fibrosis. The clinical presentation of IgG4-RD is intricately linked to the specific organs it affects. The most commonly affected organs in IgG4-RD include the pancreas (resulting in autoimmune pancreatitis), bile ducts (leading to sclerosing cholangitis), retroperitoneum (causing retroperitoneal fibrosis), salivary glands (inducing sclerosing sialadenitis), and lacrimal glands (resulting in dacryoadenitis).

Common Symptoms Associated with IgG4-RD

  • General Symptoms: IgG4-RD may present with general symptoms such as swollen lymph nodes and weight loss. Weight loss is especially prevalent when multiple organs are involved or when pancreatic enzyme production for digestion is insufficient. Fever is an unusual symptom in IgG4-RD and should prompt consideration of alternative diagnoses.

  • Organ-Specific Symptoms: Symptoms are organ-specific and vary based on the affected organs. For instance, pancreatic involvement often manifests as autoimmune pancreatitis (type 1, IgG4-related), which can present as an obstructive pancreatic mass, leading to painless jaundice and diffuse pancreatic enlargement, acute pancreatitis with abdominal pain and nausea, or smouldering chronic pancreatitis with pancreatic atrophy, exocrine pancreatic insufficiency, and/or overt diabetes mellitus.

  • Other Symptoms: Some individuals with IgG4-RD may experience mild symptoms like fatigue and loss of appetite for months or even years before seeking medical attention. Additional common symptoms encompass eye swelling or lumps, pain, vision loss, redness, skin lumps, and rashes.

Navigating the Diagnostic Landscape of IgG4-Related Disease

The diagnosis of IgG4-related disease (IgG4-RD) primarily relies on biopsy results that reveal enhanced infiltration by IgG4-positive plasma cells, storiform fibrosis, obliterative phlebitis and moderate eosinophilia, all of which are frequently observed in the affected tissues of these patients [14]. A high presence of IgG4-positive plasma cells in tissue serves as a hallmark for IgG4-RD diagnosis, even when serum IgG4 levels fall below the defined threshold.

IgG4-related disease (IgG4-RD) is diagnosed using a combination of methods:

  • Biopsy: A biopsy is usually needed for doctors to distinguish IgG4-RD from other causes of enlarged organs and/or swollen lymph nodes. The biopsy results show enhanced infiltration by IgG4-positive plasma cells, storiform fibrosis, obliterative phlebitis and moderate eosinophilia, all of which are frequently observed in the affected tissues of these patients.

  • Blood Tests: Blood tests usually show evidence of inflammation and raised IgG4 levels can support the diagnosis but are not specific enough by themselves. Serum protein electrophoresis and IgG subclasses are helpful as initial tests.

  • Imaging: Imaging can also be used to distinguish IgG4-RD from other causes of enlarged organs and/or swollen lymph nodes.

Given the diverse anatomical areas in which IgG4-RD can manifest, its diagnosis typically necessitates a multidisciplinary approach. A team of specialists from various fields collaborates in the evaluation and management of patients, including experts from:

  • Gastroenterology

  • Rheumatology

  • Ophthalmology

  • Pulmonary-Critical Care

  • Hematology/Oncology

  • Internal Medicine

  • Nephrology

  • Endocrinology

In some cases, when a pathologist suspects IgG4-RD, patients may be referred to a specialist. This specialist will conduct a comprehensive review of the patient's medical history, perform a physical examination, provide patient education about the disease, and may recommend blood tests or collaborate with a pathologist to review biopsy specimens for confirmation of the diagnosis.

Managing IgG4-Related Disease: Treatment and Prognosis

The treatment of IgG4-related disease (IgG4-RD) primarily revolves around reducing inflammation and inducing disease remission, with the goal of preserving organ function while minimizing the adverse effects of therapy. Here are some common treatment options:

  • Glucocorticoids: The majority of patients respond to glucocorticoids, particularly in the early stages of disease. However, most patients experience disease flares during or after glucocorticoid tapers.

  • Rituximab: This medication modifies the immune system’s activity and is often used in combination with corticosteroids. It may also be required for patients who do not respond to glucocorticoids or who experience disease flares during or after glucocorticoid tapers.

  • Immunosuppressive Agents: These are usually considered as glucocorticoid-sparing agents, although adequate controlled studies on their efficacy are lacking.

  • Surgery or Radiotherapy: These may be necessary in case of serious organ damage.

Recent research indicates that the landscape of IgG4-RD treatment is poised for significant evolution in the next 3 to 5 years. There is optimism surrounding three promising drugs—inebilizumab, rilzabrutinib, and elotuzumab—currently in development. The growing understanding of IgG4-RD's underlying pathophysiology is paving the way for the identification of novel therapeutic targets and potential personalized treatment approaches.

Prognosis of IgG4-Related Disease

The prognosis of IgG4-related disease is variable and hinges on disease severity and existing organ damage, particularly in vital organs like the kidneys, pancreas, aorta, and liver. Early diagnosis often allows for effective control of inflammation, preventing further damage. However, if left unrecognized, IgG4-RD can progress to end-stage organ failure and potentially fatal outcomes. Sustained courses of corticosteroid treatment are frequently necessary to maintain remission, as the disease tends to relapse in the majority of patients.

While the overall prognosis of IgG4-RD appears favorable, there is a lack of long-term follow-up studies. Data concerning the disease's prognosis is crucial, especially when considering the introduction of intensive immunosuppressive therapies.

Conclusion: Navigating the Complex Terrain of IgG4-Related Disease

In conclusion, IgG4-related disease (IgG4-RD) is a multifaceted clinical entity that challenges our understanding of immune-mediated disorders. This chronic fibroinflammatory condition, characterized by tumor-like masses and organ enlargement, has emerged as a significant medical concern. It intricately weaves its path through various organs, affecting the pancreas, bile ducts, lacrimal glands, orbital tissues, salivary glands, lungs, kidneys, retroperitoneal tissues, aorta, meninges, and thyroid gland, often presenting as one dominant phenotype.

The journey of recognizing IgG4-RD began in the 1960s, and over the past few decades, it has evolved into a unified systemic disorder. Despite its relatively recent identification, its impact on multiple organs and its association with formerly disparate inflammatory conditions have earned it the classification of a rare disease. The atypical accumulation of IgG4-producing immune cells within specific organs contributes to a complex clinical presentation, making diagnosis and treatment challenging.

Understanding the prevalence and demographics of IgG4-RD sheds light on the evolving landscape of this condition. Incidence rates have risen in recent years, reflecting increased awareness. While it appears to predominantly affect middle-aged and older individuals, IgG4-ROD manifests differently, impacting a younger cohort and displaying a more balanced gender distribution as well.

The diagnostic journey involves a multidisciplinary approach, with biopsy, blood tests, and imaging playing pivotal roles. Expertise from gastroenterologists, rheumatologists, ophthalmologists, pulmonologists, hematologists/oncologists, internists, nephrologists, and endocrinologists collaborates to unravel the complexity of IgG4-RD.

Treatment strategies primarily aim to reduce inflammation, induce remission, and protect organ function. Glucocorticoids, rituximab, immunosuppressive agents, and surgical or radiotherapeutic interventions constitute the armamentarium. Excitingly, the horizon holds promise, with emerging drugs set to revolutionize IgG4-RD management.

The prognosis of IgG4-RD remains variable, hinging on disease severity and the extent of organ damage. Early diagnosis is pivotal in averting organ failure, but long-term studies are still needed to unravel the mysteries of this enigmatic disorder.

In traversing the complex terrain of IgG4-RD, one finds a dynamic interplay of science, medicine, and hope. As our understanding continues to evolve, so too does our ability to provide timely diagnosis and effective treatment for those affected by this remarkable clinical entity.

























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