1 INTRODUCTION

Immunoglobulin G4-related disease (IgG4-RD) is a systemic disorder with characteristic clinicopathological features, including sclerosing lesions with storiform fibrosis, obliterative phlebitis, elevated serum IgG4 levels, and infiltration of IgG4-positive cells in the organs. IgG4-RD may affect nearly every organ of the body. Moreover, it predominantly affects middle-aged and elderly men.^1-7

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic inflammation of small vessels accompanied by ANCAs in the serum. It has three clinicopathological phenotypes: granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA), and microscopic polyangiitis (MPA).^8-11

Despite being distinct disease entities with different etiological mechanisms, AAV and IgG4-RD share similarities regarding clinical, serological, and histopathological manifestations, leading to diagnostic challenges owing to their propensity to mimic each other. On the one hand, AAV, similar to IgG4-RD, is a systemic disorder affecting multiple organs, such as the orbital region, sinuses, lungs, kidneys, and meninges.^12-14 On the other hand, ANCA appears to be a hallmark of AAV, whereas IgG4-RD is typically characterized by the presence of IgG4-positive cells. However, some previous reports indicate that some patients with AAV may exhibit IgG4 positivity; similarly, some patients with IgG4-RD can also present with ANCA.^15-19 In this review, we aimed to comprehensively analyze the clinical features and laboratory and pathological characteristics of IgG4-RD and AAV to elucidate their similarities and differences.

2 ETIOLOGY

Both AAV and IgG4-RD are associated with immune system abnormalities; however, their exact causes are not yet fully understood, although recent research has identified smoking as a triggering factor for both. Smokers are at an increased risk of developing IgG4-RD, particularly in women and those with retroperitoneal fibrosis or a normal serum IgG4 level.^{20, 21} Additionally, Lin et al.²² and Chen et al.²³ have reported a frequent history of allergies among patients with IgG4-RD. A recent genome-wide association study in 850 Japanese patients identified the HLA-DRB1 and FCGR2B regions as IgG4-RD susceptibility loci, indicating a potential genetic predisposition.²⁴ In IgG4-RD, antigen-driven interactions between B and CD4⁺ T cells are crucial. Two distinct subtypes of CD4 T cells, CD4 follicular T-helper cells and CD4 cytotoxic T lymphocytes are associated with IgG4-RD, of which CD4 cytotoxic T lymphocytes appear to play a crucial role in IgG4-RD development as their interaction with B cells is crucial for the onset of IgG4-RD and its related fibrotic processes.^{25, 26}

Apart from smoking, several environmental factors, such as silicon dioxide and staphylococcus aureus, have been identified as contributors to the etiology of AAV.^{10, 27, 28} Furthermore, numerous drugs have been associated with AAV, including propylthiouracil, hydrazine, and minocycline.^29-32 Similar to IgG4-RD, AAV appears to have a genetic component. Studies have shown a strong association between AAV and the class II major histocompatibility complex genes. GPA with proteinase 3-ANCA is particularly associated with the HLA-DP region, whereas MPA with myeloperoxidase-ANCA shows a strong association with the HLA-DQ region.²⁷

3 DEMOGRAPHIC FEATURES

IgG4-RD has been reported across nearly all ethnic groups, with an estimated annual incidence of 2.8–10.8 per million persons annually and a prevalence of approximately 1 per 600,000 inhabitants.³³ The prevalence of AAV is 300–421 per million people. In addition, GPA is less frequently observed in East Asian nations or areas, whereas it predominantly affects populations of European descent. Conversely, MPA is prevalent in Asian countries, such as China and Japan.¹⁰ IgG4-RD is more commonly diagnosed in male patients, with a prevalence estimated between 54% and 80%, whereas AAV appears to be more prevalent among female patients.^{33, 34}

4 ORGAN INVOLVEMENT

A literature search of PubMed was conducted from January 1, 2010 to June 30, 2024. Publications describing IgG4-RD or AAV. Select the cross-sectional studies meeting the diagnostic criteria, providing a detailed description of organ damage, and the number of patients participating in the study is more than 90. Eight cross-sectional studies involving 2690 patients were included.

Both IgG4-RD and AAV are systemic diseases with overlapping affected organs. MPA is prevalent in Asian countries, such as China and Japan.¹⁰ IgG4-RD typically affects the pancreas, salivary glands, lacrimal glands, kidneys, and lymph nodes. AAV primarily targets small-to-medium-sized blood vessels, with GPA often involving the upper respiratory tract, lungs, and kidneys, whereas MPA frequently affects the kidneys and lungs^{22, 35-41} (Tables 1–2). Therefore, patients can exhibit various clinical manifestations, depending on the organs involved.

For patients with IgG4-RD, the most prevalent symptom is the swelling of the salivary, lacrimal glands, and pancreas. Rare manifestations include pituitary inflammation, skin involvement, sclerosing thyroiditis, orchitis, mediastinal fibrosis, and colitis. Notably, there are differences in the organs involved between male and female patients with IgG4-RD.¹ Although IgG4-RD is less prevalent in females, sialadenitis and dacryoadenitis frequently develop when female patients get the disease.⁴² Compared with IgG4-RD, there are no significant sex-based differences in the incidence of AAV; however, patients with AAV are more prone to experiencing manifestations affecting the lungs, upper airways, kidneys, nervous system, eyes, and skin.

The cardiovascular system can be affected by both IgG4-RD and AAV, with notable differences in tissue predilection and clinical presentation. Compared with AAV, which primarily affects the small blood vessels, IgG4-RD mainly affects the large and medium-sized arteries,⁴³ with the aorta being the most frequently affected, followed by the iliac and coronary arteries.^{44, 45} Periarterial inflammation is the most common cardiovascular complication of IgG4-RD, affecting 10%–40% of patients, with the aorta involved in 88% of these cases.^{46, 47} Patients with thoracic involvement typically present with nonspecific symptoms, such as dyspnea or cough, which are also observed in AAV.⁴⁸ Since AAV mainly affects the capillaries, adjacent arterioles, and venules, it predominantly targets major organs that are rich in capillaries, such as the kidneys and lungs. Researchers have reported a low incidence of acute coronary syndrome in patients with AAV. A Korean cohort study reported an incidence rate of 2.7% for acute coronary syndrome, with non-ST-segment elevation myocardial infarction being the most common type observed in Korean patients with AAV.⁴⁹

IgG4-RD that impacts the digestive system is a systemic fibroinflammatory condition primarily identified by its hallmark features: autoimmune pancreatitis and IgG4-associated cholangitis. Patients may exhibit gastrointestinal symptoms such as jaundice, abdominal discomfort, and the presence of pancreatic and hepatic masses that can be indistinguishable from malignancies.⁵⁰ Compared with IgG4-RD, AAV often causes damage to the nervous system, especially the peripheral nervous system, often manifesting as recurrent mononeuropathies, mononeuritis multiplex, or symmetric polyneuropathy owing to ischemia caused by vasculitis of the vasa nervorum.⁵¹

Although both IgG4-RD and AAV are systemic diseases affecting multiple organs, they exhibit different systemic manifestations. First, patients with AAV are more likely to experience fever than those with IgG4-RD. Kawashima et al.³⁴ found that 61.6% of patients with GPA experienced fever, whereas fever in patients with IgG4-RD was rare. Moreover, weight loss is a common symptom of AAV.^{38, 41, 52}

5 LABORATORY CHARACTERISTICS

Most patients with IgG4-RD exhibit elevated serum IgG4 levels. However, an increased IgG4 level is not a specific marker for IgG4-RD.²² Malignant tumors, autoimmune disorders, multicentric Castleman disease, chronic hepatitis, and allergy diseases have all been associated with elevated serum IgG4 levels. Importantly, elevated serum IgG4 levels have been observed in patients with AAV.^{53, 54} In contrast, IgG4 levels vary and correlate with the number of affected organs, inflammation, and other factors. Wallace et al.³⁷ found that, compared with patients having IgG4-RD with normal serum IgG4 levels, those with elevated IgG4 levels were older, had more organ involvement, lower complement protein levels, higher absolute eosinophil count, and higher IgE levels. Furthermore, patients with IgG4-RD with pancreatic involvement are more likely to exhibit elevated serum IgG4 levels. Another study indicated that patients with IgG4-RD with aortitis/periaortitis and periarteritis exhibit a higher erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, and IgA level and lower serum IgG4 and IgE levels than those without these complications.⁵⁵ Hence, Umehara et al.⁵⁶ mentioned the drawbacks of using serum IgG4 levels to identify IgG4-RD, noting that a cut-off level of >135 mg/dL results in low sensitivity and specificity. Failure to understand and effectively utilize the diagnostic indications of serum IgG4 levels in clinical practice can lead to either overdiagnosis or delayed diagnosis.^57-59

However, IgG4⁺ plasmablasts correlate well with the disease activity. Serum IgG4 levels are positively correlated with inflammatory indicators, such as ESR and CRP, making them valuable for predicting the activity and relapse of IgG4-RD.^{18, 19, 22, 37} Notably, the levels of inflammatory markers, including CRP and serum complement proteins, differ between the IgG4-RD and AAV. In ANCA-associated renal vasculitis, CRP is not only a prognostic inflammatory marker, but it may also play a role in renal damage by interacting with the complement protein system.⁶⁰ Kawashima et al.³⁴ found that CRP levels were significantly elevated in patients with GPA than in those with IgG4-RD. In a cohort study conducted by Yamada et al.,³⁶ low C3 was observed in 34.7% of patients with IgG4-RD, with this frequency varying based on the organs involved. The affected organs associated with low serum C3 levels are the kidneys, lungs, and pancreas. Over 50% of patients with kidney lesion have hypocomplementemia, whereas the overall prevalence of hypocomplementemia in the population with IgG4-RD is approximately 30%.³⁶ In contrast, most patients with AAV do not exhibit decreased plasma C3 and C4 levels. However, recent findings suggest that the alternative complement pathway produces C5a, which primes neutrophils and activates the alternative complement pathway, thereby leading to the pathogenesis of AAV.^{9, 61}

6 PATHOLOGY

Owing to the limitations in serological and imaging findings, the definitive diagnosis of IgG4-RD still relies on histopathological examination. The identification of IgG4-RD is largely dependent on histopathological findings that reveal an increased presence of IgG4-positive plasma cells, characteristic patterns of fibrosis known as storiform, the narrowing or blockage of small veins referred to as obliterative phlebitis, and a moderate increase in eosinophils, which are commonly found in the tissues of individuals with the condition.^{3, 62} A notable hallmark of IgG4-RD is the significant presence of IgG4-positive plasma cells in the tissue, even when serum IgG4 concentrations fall below the cut-off level. The number of IgG4-positive plasma cells differs among organs, and the consensus statement on pathology emphasizes tissue IgG4 cell counts in each organ for the diagnosis of IgG4-RD. However, tissue IgG4 positive cells should be supplemented with IgG4⁺/IgG⁺ plasma cell ratios of >40% to diagnose IgG4-RD.⁵⁶

Fibrinoid necrosis and inflammation of small vessels, occasionally accompanied by thrombosis, are hallmarks of acute injury in all forms of AAV. The various forms of AAV exhibit histopathological differences despite sharing many characteristics. These characteristics are absent from MPA, unlike granulomas in GPA or prominent eosinophilic infiltrates in EGPA, which are other distinguishing characteristics. In the studies by Perugino et al.,⁶³ no arterial stenosis caused by primary IgG4-associated vasculitis was observed, presenting a significant distinction from other types of large-vessel vasculitis, especially giant cell arteritis and large-vessel vasculitis. Unlike AAV, which primarily affects the inner elastic membrane, the cellular infiltration in IgG4-RD arteritis mainly involves the outer membrane, with less involvement of the middle and inner membranes.^{10, 63}

Owing to the differences in their pathophysiology and underlying mechanisms, IgG4-RD and AAV have significant pathological distinctions, even when they affect similar organs. For example, IgG4-related kidney disease may present as tubulointerstitial nephritis (characterized by rich plasma cell infiltration accompanied by dilated interstitial fibrosis and IgG4-positive plasma cell proliferation), membranous glomerulonephropathy and other rare glomerular lesions, acute renal failure, pyelitis, and hydronephrosis.^{35, 64} However, segmental necrosis of the glomerular capillary loops, with little to no immunoglobulin or complement deposition—referred to as “pauci-immune” focal necrotizing (and crescentic) glomerulonephritis—is the hallmark disease of AAV.¹⁰

7 TREATMENT

Glucocorticoid therapy has been proven to be the most effective initial treatment for both IgG4-RD and AAV. Most patients with IgG4-RD receive glucocorticoid therapy alone or in combination with immunosuppressive drugs, and typically improve within 3 months. IgG4-RD often responds well to steroid therapy alone (achieving response rates of 97%–100%), whereas AAV typically requires the concomitant use of immunosuppressants. It is notable that immunosuppressive drugs could reduce disease relapse in IgG4-RD.⁶⁵ Alongside glucocorticoids and immunosuppressants, biologics (such as rituximab) are increasingly being integrated into clinical practice.^{2, 10, 22, 26} Rituximab is useful for treating relapses in patients with IgG4-RD and AAV, as well as induction therapy.^{66, 67} For both of these two diseases, there are some novel treatment strategies, such as Obinutuzumab, monoclonal antibodies targeting CD19, and anti-CD19 directed Chimeric Antigen Receptor T-Cell Immunotherapy (CAR-T) therapies.¹¹

8 DISCUSSION

Both IgG4-RD and AAV are immune-mediated conditions characterized by multiorgan involvement, potentially resulting in permanent organ injury or death if left untreated. We aimed to comprehensively analyze the clinical features and laboratory and pathological characteristics of IgG4-RD and AAV to elucidate their similarities and differences (Tables 1 and 3).

Upon reviewing retrospective cohort studies, AAV was found to be frequently accompanied by fever and weight loss. Furthermore, compared with IgG4-RD, which often affects the salivary glands, lacrimal glands, and pancreas, AAV tends to affect the upper respiratory tract, lungs, and kidneys. Furthermore, compared with AAV, IgG4-RD is associated with lower serum CRP levels and a higher likelihood of hypocomplementemia. According to the 2019 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) IgG4-RD criteria,⁶⁸ the exclusion criteria include fever, no objective response to glucocorticoids, positive antineutrophil cytoplasmic antibody, positive SSA/Ro or SSB/La antibody, positive double-­stranded DNA, RNP, or Sm antibody, other disease-­specific autoantibody, cellular infiltrates suggesting malignancy and so on. Nonetheless, according to the 2019 ACR/EULAR IgG4-RD criteria,⁶⁸ 2022 ACR/EULAR classification criteria of GPA,⁶⁹ MPA,⁷⁰ and EGPA,⁷¹ pinpointing a conclusive diagnosis of IgG4-RD or AAV necessitates thorough integration of clinical and pathological data, as standalone clinical observations and lab tests are frequently inadequate for differentiating these conditions from others, such as neoplastic, inflammatory, and infectious diseases.

The coexistence of AAV and IgG4-RD (overlap syndrome) has also been reported.⁷² Notably, overlap syndrome predominantly affects patients with GPA.^{73, 74} Individuals who suffer from both IgG4-RD and AAV exhibit symptoms that largely overlap with those seen in AAV patients. In a study conducted by Ma et al.,⁷⁵ they examined the clinical and pathological traits of 10 individuals diagnosed with both conditions. Renal biopsies indicated the presence of features typical for IgG4-RD, such as lymphoplasmacytic infiltration in the renal interstitium, storiform fibrosis, and the infiltration of IgG4-positive plasma cells. Each patient was found to have glomerulonephritis characterized by crescents, and in seven cases, there was segmental necrosis of the glomerular capillary walls, indicative of renal damage commonly associated with AAV. However, these individuals exhibited more pronounced inflammatory markers compared to those affected solely by IgG4-RD. For such patients, there is no consensus regarding whether it is an overlap syndrome or a distinct disease entity. The emergence of such patients presents a significant diagnostic challenge for clinicians. Indeed, several unresolved issues need to be addressed to comprehensively understand the pathogenesis of AAV and IgG4-RD. Given the complexity and diagnostic challenges associated with such patients, further research is required to improve our understanding and the diagnosis of these conditions.

9 CONCLUSIONS

Although clinical studies have suggested similarities between AAV and IgG4-RD, there are also significant differences. Pinpointing a conclusive diagnosis of IgG4-RD or AAV necessitates thorough integration of clinical and pathological data. Given the complexity and diagnostic challenges associated with these patients, further research is required to improve our understanding and the diagnosis of these conditions.

AUTHOR CONTRIBUTIONS

Yanying Liu, Wenhuan Zeng, and Mingxin Bai were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published.

CONFLICT OF INTEREST STATEMENT

Yanying Liu is a member of the Rheumatology & Autoimmunity editorial board and is not involved in the peer-review process of this article. The remaining authors declare no conflict of interest.

ETHICS STATEMENT

Not applicable.