IgG4-Related Disease: A Review of Persistent Challenges in the Pathogenesis, Diagnosis, and Approaches to Treatment

Introduction

In human serum, immunoglobulin G4 (IgG4) is the least abundant subclass of IgG [1]. The main roles of IgG4 include activation of the antibody-dependent immune effector response and a blocking effect on either the immune response or on the IgG4 target protein [1]. The normal serum levels of IgG4 range from <10 mg/dL to 140 mg/dL, but levels <200 mg/dL have been identified in healthy individuals without active inflammatory disease [2]. Also, IgG4 levels increase in a non-specific way in the immune response to allergens and parasites, autoimmune responses, and malignancy [1].

In 2001, Hamano and colleagues described 20 patients in Japan with autoimmune sclerosing pancreatitis and high serum levels of IgG4, which they identified as IgG4-related disease [3]. IgG4-related disease, also known as IgG4-related systemic disease, is an idiopathic, chronic, fibro-inflammatory disease characterized by the infiltration of tissues and organs by T and B lymphocytes, IgG4-secreting plasma cells, and varying degrees of fibrosis, which typically responds to oral steroid therapy [3,4]. Since 2001, there have been several reported cases with and without high IgG4 levels and with diverse organ involvement that could have also been cases of submandibular sialadenitis, Riedel’s thyroiditis, idiopathic retroperitoneal fibrosis, Mikulicz syndrome, and autoimmune pancreatitis, with similar histopathology, including the presence of IgG4-positive plasma cells [4,5]. The diagnosis of IgG4-related disease remains challenging due to the diverse clinical presentations and lack of clear diagnostic guidelines [6]. Serum and tissue levels of IgG4 are not specific, and the existence of this as a specific disease rather than an immunological association remains controversial, and the diverse manifestations of IgG4-related disease can make diagnosis difficult to establish [5,6]. Although any solid organ can be affected, there are four main clinical presentations: head and neck disease, hepatobiliary and pancreatic disease, retroperitoneal fibrosis, and systemic disease [7]. Also, IgG4-related disease includes spontaneous remissions even without treatment [8]. This article aims to review the current status and future developments in understanding the pathogenesis of IgG4-related disease, which may lead to more specific diagnosis and treatment options.

Epidemiology and Clinical Presentation of IgG4-Related Disease

IgG4-related disease is characterized by a chronic fibroinflammatory infiltrate in organs and tissues, with diverse manifestations that mimic a wide range of immune, autoimmune, and inflammatory conditions, which can complicate diagnosis [6]. Delays in the development of diagnostic criteria and the complexity of checklists for multiple approaches to diagnosis underscore that this is a disease of exclusion but with an as-yet-unidentified cause, unknown pathogenesis, and no specific diagnostic biomarkers [6]. Although most organs can be affected, seven typical presentations are most common. Table 1 summarizes the clinical presentations, which include autoimmune pancreatitis, salivary gland involvement (Mikulicz disease), renal disease, biliary disease (sclerosing cholangitis), ophthalmic disease, respiratory disease, and retroperitoneal fibrosis (Table 1) [9–15].

IgG4-related disease is reported to present in patients in their fifth to seventh decades of life, with few pediatric cases [16,17]. Most cases have a male predominance, including pancreaticobiliary disease and retroperitoneal disease, whereas IgG4-related disease limited to the head and neck most commonly affects women [6]. Population studies to identify the incidence of IgG4-related disease are limited. However, a claims-based analysis from the USA conducted between 2015 and 2019, identified an incidence of between 0.78 and 1.39 per 100,000 person-years [16,17]. In Japan, the incidence of pancreatic disease was estimated to be higher at 3.1 per 100,000 persons) using different methods [18]. Patients with a diagnosis of IgG4-related disease and other fibroinflammatory diseases may have a reduced life expectancy, probably due to irreversible organ damage and complications from steroid therapy [17].

Criteria for the Diagnosis of IgG4-Related Disease

Diagnostic criteria and disease classification depend on understanding the causes and pathogenesis of the disease, as well as relying on associated disease biomarkers. The persistent lack of clarity regarding these factors has caused delays in attempts to classify IgG4-related disease for diagnostic and disease monitoring purposes. More than a decade after the first description of cases of IgG4-related disease, diagnostic classification guidelines began to be developed from groups in Japan, the US, and Europe. In 2011, a team organized by the Ministry of Health, Labor and Welfare (MHLW) of Japan published the first comprehensive diagnostic criteria for IgG4-related disease, also known as the Japanese Comprehensive Clinical Diagnostic (CCD) [19]. These diagnostic criteria were updated in 2020 (Table 2) [20]. The 2020 revised comprehensive diagnostic criteria for IgG4-related disease comprise three domains: clinical and radiological features, serological diagnosis, and histopathology, which now include three further criteria, including the histological identification of storiform fibrosis and obliterative phlebitis (Table 2) [20]. However, none of the criteria described are diagnostic for any specific chronic inflammatory disease, which is a significant challenge for the identification of IgG4-related disease [1,5]. Therefore, it still may be argued that the histological and serological features of IgG4-related disease reflect an epiphenomenon associated with plasma cell production of IgG4 from one or more unidentified factors (Table 2) [20].

In 2019, the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) formulated the 2019 ACR/EULAR IgG4-Related Disease Classification Criteria for international use (Table 3) [21]. The ACR and EULAR investigators, comprising 86 international multispecialty physicians, reviewed the existing literature and evaluated 1,086 cases to develop a 3-step classification process for IgG4-related disease [21]. The first criterion was the demonstration that the case involved at least one of 11 possible organs with a characteristic presentation [21]. Second, exclusion criteria are applied; 32 clinical, laboratory, imaging, and histopathologic items must be evaluated [21]. Third, eight weighted inclusion criteria are required, including clinical findings, laboratory results, imaging assessments, and histopathology results [21]. However, although patients with IgG4-related disease frequently present with simultaneous lesions in several organs, the ACR/EULAR classification criteria were developed for patients with the ten most commonly involved organs, including pancreas, bile ducts, orbits, lacrimal glands, major salivary glands, kidney, aorta, retroperitoneum, meninges, and thyroid gland, and excluded organs less frequently affected, to maximize the specificity of the criteria (Table 3) [21]. The ACR/EULAR classification criteria have also defined exclusion criteria as initial criteria to eliminate patients with infections, malignancies, hematological diseases, and immunological diseases (Table 3) [21]. The exclusion criteria include the identification of specific autoantibodies, such as anti-dsDNA, anti-SSA/Ro, or anti-SSB/La, and antibodies to MPO-ANCA or PR3-ANCA (Table 3) [21]. The primary aim of classification criteria is to enhance diagnosis to allow the most appropriate patient management. Therefore, current classification criteria should be validated for sensitivity and specificity in large-scale and prospective clinical studies.

Pathogenesis: Role of B Cells and T Cells

The histopathology of the fibroinflammatory response in IgG4-related disease predominantly features B lymphocytes, IgG-positive and IgG4-positive plasma cells, T lymphocytes, and lymphoid follicle formation with germinal centers and antigen-presenting cells, suggesting a local antigen-driven immune response and the development of acquired lymphoid tissue [4]. However, the antigens and immune factors in cases identified as IgG4-related disease have not been identified [4]. Fibrosis is a consequence of chronic inflammation, and obliterative phlebitis is also a non-specific histological finding in inflammation [4]. An increase in serum immunoglobulins, including IgG4, are present in this and other chronic inflammatory diseases [22]. All these characteristics are reduced following steroid therapy and during remission and increase during active disease [22].

Two T cell subsets have been identified in IgG4-related disease. Specifically, circulating follicular T helper cells, which express programmed cell death protein 1, are expanded in IgG4-related disease, correlating with disease severity and serum IgG4 concentrations [22]. Circulating follicular T helper cells produce IL-4, which is involved in class-switching of B cells to both IgG4 and IgE and oligoclonal expansion of IgG4-positive B cells [22].

The clonal expansion of both plasmablasts and CD4-positive cytotoxic T lymphocytes in patients with IgG4-related disease supports an antigen-driven fibroinflammatory response, possibly to local autoantigens [4,7]. Triggers for disease onset, whether T cells and B cells are responding to the same antigenic drive, and the role of IgG4 are fundamental knowledge gaps in understanding the pathogenesis of IgG4-related disease [4,7]. Antigen-specific IgG4 antibodies have been identified in other diseases, including muscle-specific tyrosine kinase myasthenia gravis, pemphigus vulgaris, primary membranous nephropathy, and chronic inflammatory demyelinated polyradiculoneuropathy, but not in IgG4-related disease [4,7]. In IgG4-related disease, irreversible organ damage occurs because fibrosis is not a reversible condition. Also, fibrosis and active inflammation can have a mass effect on organs and adjacent tissues. The pancreas is commonly associated with end-stage fibrosis, with up to 60% of patients presenting with exocrine or endocrine damage at the time of diagnosis, likely due to the indolent nature of the disease in the organ [4,7]. There is also the risk of developing both diabetes and exocrine pancreatic insufficiency [4,7].

Diagnosis: Laboratory and Imaging Findings

The 2019 ACR/EULAR Classification Criteria for IgG4-related disease provide a framework for evaluating patients who may have IgG4-related disease and also provide a guide for excluding this diagnosis (Table 3) [21]. According to these diagnostic guidelines, IgG4-related disease should be considered when a patient presents with a mass lesion or fibrosis in a characteristic organ, such as the pancreas, salivary glands, orbit, bile ducts, kidneys, lung, retroperitoneum, or thyroid gland (Tables 1, 3) [21]. In most cases, biopsy and histopathology support a possible diagnosis of IgG4-related disease (Table 3) [21]. However, lesion location, procedural risk, or patient preference may prevent biopsy diagnosis. The diagnosis requires clinicopathological correlation as there is no single diagnostic marker. Imaging and laboratory tests are used to evaluate IgG4-related disease and exclude mimics. Radiographic findings may reveal organ enlargement or a mass. High serum IgG4 levels may be present. However, serum IgG4 is neither sensitive nor specific for IgG4-related disease [5]. Additional laboratory findings may include eosinophilia, increased levels of IgE, hypergammaglobulinemia, and hypocomplementemia [21]. Some laboratory tests can help to exclude IgG4-related disease, such as ANCA-associated vasculitis, as anti-Ro, anti-La, anti-MPO, and anti-PR3 antibody testing will be negative (Table 3) [21].

Diagnosis: Histopathology

Tissue biopsy and histopathology are required to support a diagnosis of IgG4-related disease and to exclude other causes of mass-like lesions, such as malignancy (Table 3) [21]. The histopathological features of IgG4-related disease include a lymphoplasmacytic infiltrate containing IgG4-positive plasma cells and CD4-positive T cells, often accompanied by fibrosis described as having a ‘storiform’ pattern, and obliterative phlebitis [4]. Obliterative phlebitis involves the destruction of small veins and venules and obstruction of the vessel lumen with lymphocytes and collagen [4]. It must be distinguished from necrotizing vasculitis, which includes necrosis, neutrophil infiltrates, and micro-abscesses [4].

Immunohistochemistry is used to identify IgG-positive and IgG4-positive plasma cells in IgG4-related disease (Table 3) [21]. However, the number of these cells that are required to support the diagnosis remains unclear. Although an infiltrate of ≥50 IgG4-positive plasma cells per high-power field (hpf) and/or an IgG4 to IgG plasma cell ratio of >40% has been identified as supporting the diagnosis, there is no consensus on this. Furthermore, the histopathology of local lymph nodes is not helpful, as the presence of IgG4-positive plasma cells in lymph nodes is not specific to IgG4-related disease [5].

Differential Diagnoses

Because the identification of IgG4-positive plasma cells in a tissue biopsy is not diagnostic for IgG4-related disease, and there is no specific disease biomarker, this condition is a disease of exclusion with a wide range of differential diagnoses [5]. Establishing a diagnosis can be even more challenging when a biopsy is not possible. The serum IgG4 concentration is a crucial component in assessing IgG4-related disease; however, it is not specific to IgG4-related disease [5]. For example, recent studies have shown that serum IgG4 testing has a positive predictive value of 34% at a level greater than 135 mg/dL [22]. For patients with pancreatic disease, the positive predictive value was 36% at a level greater than 140 mg/dL [23]. Even with very high serum levels of IgG4, at five times the normal level, the positive predictive value was 73%, indicating that 27% of patients with very high serum levels had an alternative diagnosis [23]. These diagnostic problems will persist until the pathogenesis of IgG4-related disease is understood and specific disease biomarkers are identified.

Disease Biomarkers

The laboratory tests used to diagnose IgG4-related disease are also used to monitor disease activity but are standard and non-specific, including serum IgG4 and IgE levels, complement levels (C3 and C4), and peripheral eosinophil counts (Table 4) [21]. Measurement of serum IgG4 levels is the most frequently used test. If elevated at baseline, the IgG4 concentration typically decreases after steroid treatment begins [24]. However, serum IgG4 might not normalize and can remain elevated even in the absence of disease activity [24]. In patients with hypocomplementemia, elevated IgE concentrations or peripheral eosinophilia at baseline might indicate disease activity [24]. Other organ-specific disease markers may help identify disease activity or tissue damage, such as alkaline phosphatase in cases of cholangitis. However, these diagnostic problems will persist until the pathogenesis of IgG4-related disease is understood and more specific disease biomarkers are identified.

Treatment of Acute Disease and Management of Remissions

For patients diagnosed with IgG4-related disease, the primary treatment aims are to reduce disease activity and prevent irreversible tissue and organ damage. Remission of any chronic inflammatory disease occurs when inflammation is resolved, but end-stage fibrosis does not respond to treatment. Currently, glucocorticoids are first-line therapy for IgG4-related disease [8]. However, glucocorticoid treatment may result in a brief response and is associated with toxicities and long-term side effects, including diabetes [8]. Conventional disease-modifying antirheumatic drugs (DMARDs) can be combined with glucocorticoids for induction therapy [8]. Some retrospective studies and case series have identified the effectiveness of including more powerful immune-suppressing drugs, such as azathioprine (AZT), methotrexate (MTX), and rituximab, an anti-CD20 therapeutic monoclonal antibody that depletes peripheral B cells. [8]. However, there are still no studies to compare the efficacy of steroid-sparing drugs. Until the pathogenesis of IgG4-related dsease is clearly understood, recruitment to and evaluation of controlled clinical trial data and treatment outcomes will challenge effective patient management and the development of evidence-based treatment guidelines.

Periaortic Chronic Inflammation, Retroperitoneal Fibrosis, and Chronic Periaortitis

Periaortic chronic inflammation and fibrosis, with or without aortic dilatation and ureteric involvement, is included in the current classification of IgG4-related disease involving the retroperitoneum [4,21]. Cases of IgG4-related disease have been predominantly described in middle-aged to elderly men, who also have an increased incidence of atherosclerosis of the aorta and coronary arteries [3,4]. IgG4-related disease is characterized by a lymphoplasmacytic cell infiltrate that could be driven by local antigenic stimulation [7]. However, as the causes and pathogenesis of IgG4-related disease remain unclear, concerns have arisen that the use of this term to replace established terminology for diseases is leading to confusion. The conditions of periaortic and retroperitoneal fibrosis highlight this predicament [15].

In the 1980s, chronic periaortitis was described, based on histopathological and imaging findings, as the triad of aortic atherosclerosis, medial thinning, and adventitial chronic inflammation consisting of lymphoplasmacytic infiltrates, lymphoid follicles, and varying degrees of fibrosis, with and without aortic dilatation [25,26]. Chronic periaortitis associated with aneurysm formation has also been termed ‘inflammatory aneurysm’ [25]. Without aortic dilatation, the term ‘idiopathic retroperitoneal fibrosis’ has been used, but the imaging and histopathology findings are the same [25]. In chronic periaortitis, the antigen driving the local immune response was identified as modified or oxidized low-density lipoprotein [27]. Also, in chronic periaortitis, with or without aortic dilatation, the predominant plasma cell-derived immunoglobulin is IgG [25,28]. The condition of chronic periaortitis, with or without aortic dilatation, underscores the importance of accurate terminology and diagnosis.

Future Directions

This article has highlighted significant knowledge gaps and areas that require further study. The pathogenesis of IgG4-related disease remains unknown, including the role of IgG4, target antigens, the role of complement, and the roles of T cells and B cells. This major knowledge gap means that there is currently no animal model of IgG4-related disease. Until clinical trial data become available, safe and effective non-steroidal treatments have not been identified, including B cell-targeted therapies and therapies to control fibrosis and tissue damage. Current gaps in understanding the disease pathogenesis have limited the identification of more specific diagnostic and disease activity biomarkers beyond circulating IgG4, IgE, eosinophils, and complement. Some patients with IgG4-related disease have a predominantly fibrotic disease that does not respond to current treatments. There is a lack of imaging biomarkers and methods to evaluate the extent and progression of fibrosis, a crucial disease mechanism that targeted therapies could control.

Conclusions

Although cases of IgG4-related disease have been reported for almost 25 years, specific diagnostic tests and therapies for this enigmatic condition are still awaited. The IgG4 molecule does not drive this disease, and its role remains unclear. It is also unclear why specific anatomical sites are more commonly affected, including the salivary glands, lungs, kidneys, orbit and lacrimal glands, pancreas and biliary system, and the retroperitoneum. Also, specific diagnostic tests are still required. Several ongoing clinical trials are currently underway, which may lead to more targeted treatment options. However, effective treatments will rely on specific diagnostic biomarkers, which require a clearer understanding of the cause and pathogenesis of IgG4-related disease.