https://orcid.org/0000-0001-9720-0698
Abstract
IgG4-related disease (IgG4-RD) and idiopathic multicentric Castleman’s disease (iMCD) are both rare systemic immune-mediated disorders. However, the pathogenesis differs markedly between the two diseases and differing therapeutic strategies are adopted: IgG4-RD is treated using a moderate dose of glucocorticoids or rituximab, while iMCD therapy involves an IL-6-targeted approach. Nonetheless, some clinical features of IgG4-RD and iMCD overlap, so differential diagnosis is sometimes difficult, even though the classification and diagnostic criteria of the diseases require careful exclusion of the other. The key findings in IgG4-RD are high IgG4:IgG ratio, allergic features and germinal centre expansion involving T follicular helper cells, while iMCD involves polyclonal antibody production (high IgA and IgM levels), sheet-like mature plasma cell proliferation and inflammatory features driven by IL-6. The distribution of organ involvement also provides important clues in both diseases. Particular attention should be given to differential diagnosis using combined clinical and/or pathological findings, because single features cannot distinguish IgG4‐RD from iMCD. In the present review, we discuss the similarities and differences between IgG4-RD and iMCD, as well as how to distinguish the two diseases.
Clinical features of IgG4-related disease and multicentric Castleman’s disease overlap.
The pathogenesis and treatment approach of IgG4-related disease and multicentric Castleman’s disease are totally different.
Using several clinical/pathological findings is important to distinguish IgG4-related disease from multicentric Castleman’s disease.
Introduction
IgG4-related disease (IgG4-RD) is a novel clinical entity of fibroinflammatory disease that is characterized by IgG4+ cell infiltration, storiform fibrosis and obliterative phlebitis in organs [1, 2]. These findings are often accompanied by increased levels of serum IgG4 [3, 4]. In 2001, Hamano et al. [5] reported that high levels of serum IgG4 were observed in sclerosing pancreatitis (autoimmune pancreatitis). In 2003, autoimmune pancreatitis patients with extrapancreatic involvement such as bile ducts, salivary glands and lymph nodes were reported and the concept of IgG4-related autoimmune disease was proposed [6]. Subsequently, various cases with IgG4+ cell infiltration in affected organs and increased levels of IgG4 in serum were reported and the term ‘IgG4-RD’ was approved internationally [7–9]. Importantly, IgG4-RD presents with tumour-like swelling, so it must be differentiated from malignancy or other autoimmune diseases [10]. The worldwide prevalence of IgG4-RD has not been described, but an increase in the number of patients is expected. Because IgG4-RD presents with a variety of symptoms and organ involvement, undiagnosed patients often first present to specialists other than rheumatologists.
Multicentric Castleman’s disease (MCD) is a systemic lymphoproliferative disorder that sometimes causes mass lesions in the lungs, kidneys and other extranodal sites, causing multiple organ dysfunction. The first case of Castleman’s disease was described in 1954 as a lymph node lesion with unique histological findings [11]. Later, patients with more than one affected organ were reported as having MCD in 1978 [12]. Recently, MCD has been further subdivided into human herpesvirus 8 (HHV-8)-associated MCD, idiopathic MCD (iMCD) and TAFRO (thrombocytopenia, anasarca, myelofibrosis, renal dysfunction and organomegaly) MCD [13]. Although the detailed mechanisms of iMCD are still unknown, the pathogenesis is likely driven by IL-6 [14], which has multifaceted effects that mediate plasmacytosis, antibody production [15] and the inflammatory response in haematopoietic cells [16], as well as proliferation and hypertrophy in non-haematopoietic cells [17]. Thus iMCD demonstrates increased levels of serum IgG4, abundant IgG4+ cell infiltration in affected organs and tumour-like swelling.
The clinical and laboratory features of IgG4-RD and iMCD overlap while the treatment approaches based on their pathogenesis are completely different. The classification and diagnostic criteria of IgG4-RD and iMCD require careful differentiation of the two diseases [10, 13]; however, distinguishing between them is often difficult because few differential methods have been established [18–25]. In the present review we summarize the similarities and differences between IgG4-RD and iMCD and discuss a promising approach to distinguish between these two diseases.
Epidemiology
No global epidemiological information is available regarding IgG4-RD and iMCD, but some studies have provided limited epidemiological characteristics. The prevalence of type 1 autoimmune pancreatitis (IgG4-related pancreatitis), an IgG4-RD subset, is estimated at 2.2/100 000 people in Japan [26]. As IgG4-RD involves many other organs, the prevalence of IgG4-RD is expected to be higher. IgG4-RD occurs at 50–60 years of age [27–29]. Overall susceptibility is almost equal between the genders, but the susceptibility of each IgG4-RD phenotype differs: cases limited to the head and neck are more frequent in females (80%) while those involving other organs are less common in females (30%) [30, 31].
Regarding MCD, ∼1650 cases are diagnosed in the USA every year, regardless of HHV-8 status [32], but the global prevalence is not well known. Notably, the incidence of MCD is extremely high in HIV-infected patients (4.3/10 000 person-years) [33], as immunocompromised patients with HIV are often co-infected with HHV-8 and are therefore prone to HHV-8-associated MCD. Almost 40% of MCD cases occur in females and the median age at diagnosis is ∼50 years [32], which is slightly younger than that of IgG4-RD.
Pathogenesis
Roles of cytokines in IgG4-RD and iMCD
Over the last 2 decades, significant progress has been made in understanding the pathogenesis of these two diseases. The mechanisms of serum IgG4 elevation and IgG4+ cell infiltration in each are completely different: in IgG4-RD, specific IgG4 class-switching is induced by IL-4 [33, 34], while in iMCD the increased serum IgG4 and IgG4+ cell populations result from polyclonal B cell expansion induced by IL-6 [14].
IL-4, a key cytokine in IgG4-RD, is a type 2 inflammatory cytokine. Some patients with IgG4-RD have allergic characteristics, such as a history of atopic dermatitis, allergic rhinitis and asthma. In addition, IL-4 can lead to fibrosis through direct effects on fibroblasts [35] and alternative activation of M2 macrophages [36, 37], which contribute to fibrotic changes in IgG4-RD. Follicular T helper (Tfh) cells [38–40], Th2 cells [41], basophils [42] and innate lymphoid cells [43] are thought to be sources of IL-4 in IgG4-RD.
In iMCD, IL-6 is thought to be the culprit cytokine, as elevation of serum IL-6 is observed in almost all patients with iMCD and IL-6-targeted therapy is very effective in this disease [44]. IL-6 directly stimulates B cells to differentiate into plasma cells and promote polyclonal antibody production [45]. IL-6 also affects haematopoietic cells and the liver, causing anaemia, thrombocytosis and inflammatory features such as fever, weakness, fatigue, weight loss and elevated serum CRP levels. With regards to HHV-8-associated MCD, a viral homologue of IL-6 in HHV-8 is causative for the disease [46, 47]. Immunohistochemical analysis of IL-6 expression in the lymph nodes and lungs of patients with iMCD indicated that B cells in the germinal centres (GCs) and interfollicular areas were the main source [48, 49].
IL-21 is another intriguing cytokine, the levels of which differ markedly between IgG4-RD and iMCD; IL-21 expression in GCs, provided by Tfh cells [50], is significantly higher in IgG4-RD than in iMCD [51]. IL-21 is essential for GC formation and B cell expansion in GCs [52–54], which are frequently observed in IgG4-RD but not in iMCD. Synergistically with IL-4, IL-21 also enhances IgG4 class-switching [55] and promotes differentiation of plasmablasts, plasma cells and Tfh cells [34, 56, 57], as well as the cytotoxic function of CD8+ T lymphocytes (CTLs), which are also characteristics of IgG4-RD [56, 57].
Other cytokines involved in the pathogenesis of IgG4-RD are IL-13, IL-10 and TGF-β. IL-13 is another type 2 inflammatory cytokine and overlaps biological effects with IL-4, including IgG4 class-switching and fibrosis. Interestingly, the IL-13 receptor consists of the IL-13 receptor α subunit and the IL-4 receptor α subunit [58], which is one possible explanation for sharing the effects between IL-4 and IL-13. IL-10 and TGF-β from regulatory T cells [59] contribute to the fibrosis in IgG4-RD. Roles of IL-13, IL-10 and TGF-β in iMCD are not well known.
Roles of B cells in IgG4-RD and iMCD
Anti-CD20 B cell depletion therapy is effective in patients with both IgG4-RD and iMCD [32, 60–62], thus B cell lineages likely have an important role in both diseases. In IgG4-RD, the involvement of memory B cells [63], CD21low B cells [41], plasmablasts [64, 65] and plasma cells [65] has been reported, as has loss of B regulatory cells [66]. In addition, although T cells do not express CD20, T cells are depleted after anti-CD20 therapy [67] in IgG4-RD, implying that the impaired role of accumulated B cells as antigen-presenting cells may also hamper T cell maturation. A recent study indicated that plasmablasts express collagen and directly contribute to fibrogenesis in IgG4-RD [68]. Antibody production plays an important role in B cells; to date, prohibitin [69], galectin-3 [70], laminin-511 [71] and annexin A11 [72] have been reported as autoantigens in the disease. However, the pathogenicity of IgG4 in IgG4-RD remains controversial. We previously discovered that ovalbumin (OVA)-specific IgG4 enhances the effect of OVA-specific CTLs in mice expressing OVA (RIP-mOVA mice), suggesting that antigen-specific IgG4 promotes CTL cytotoxicity in IgG4-RD [73]. Similarly, the injection of serum IgG4 from patients with IgG4-RD into neonatal mice can destroy the pancreas [74]. However, when injected together, serum IgG1 and IgG4 from the patients resulted in less destruction than IgG1 alone [74]. Therefore a more detailed delineation of the function of IgG4 is needed to better understand the disease mechanism of IgG4-RD.
In iMCD, expansion of CD5+ B cells and plasma cells occurs in affected organs. CD5 expression on B cells is regulated by IL-6 [75] and CD5+ B cells are expanded in the mantle zones. B cell follicles and GCs regress in the lymph nodes of patients with iMCD [76, 77]. Abundant mature plasma cells, the differentiation of which is promoted by IL-6 [78], are observed in the interfollicular area of the lymph nodes [79]. Interestingly, IL-6 can directly bind to CD5 and such binding on B cells activates the JAK-STAT pathway, even without IL-6R expression [75]. This may contribute to the differentiation into plasma cells. Autoantibodies such as anti-nuclear antibodies are observed in some cases [13], but there is little evidence about the pathogenic function of these autoantibodies.
Roles of T cells in IgG4-RD and iMCD
There is evidence that T cells play a pathogenic role in both diseases but the types of T cells differ. In IgG4-RD, CD4+SLAMF7+ CTLs and CD57+CD28−CD8+ CTLs are dominant and clonally expanded in the inflamed tissue [80, 81]. CD4+SLAMF7+ CTLs and CD57+CD28−CD8+ CTLs highly express cytotoxic molecules, such as granzyme A, granzyme B and perforin, suggesting that they contribute to tissue damage.
In iMCD, HLA-DR+CD38+CD8+ CTLs are expanded and the CD4+:CD8+ T cell ratio is decreased in the blood [82]. Although the function of HLA-DR+CD38+CD8+ CTLs in iMCD remains unclear, their number is reduced by IL-6-targeted treatment, suggesting that they are involved in disease activity [82]. Moreover, Wang et al. [83] reported that HLA-DR+CD38+CD8+ CTLs had highly activated characteristics in fatal inflammatory conditions and may contribute to disease pathogenesis in iMCD.
Allergic history is associated with IgG4-RD but not with iMCD [84]. However, the involvement of Th2 cells in IgG4-RD remains controversial. GATA3+ memory Th2 cells are only associated with allergic history in IgG4-RD, not with IgG4-RD itself [85]. In addition, we found that CXCR3−CCR6−CXCR5+ Th2-like Tfh (Tfh2) cells were specifically increased in IgG4-RD but not in iMCD [2, 38, 39]. CXCR3−CCR6−CXCR5+ Tfh2 cells can produce IL-4 and IL-21, which leads to IgG4 class-switching and plasmablast differentiation. IL-4+ Tfh cells, which are similar in phenotype, are dominant at the affected sites in IgG4-RD [40]. Patients with IgG4-RD have significantly more and larger ectopic GCs at the affected sites than those with iMCD, probably because Tfh cells are a CD4+ T cell subset that activates B cells to form GCs [79]. Considering that Tfh cells contribute to the pathogenesis of allergic diseases [86, 87], an increased proportion of Tfh cells may be associated with the high frequency of allergic history in IgG4-RD. Observation of lymph node pathology showed that CXCR5+CD40L+ Tfh-like cells increased in the GCs of IgG4-RD but decreased in MCD [88], providing further evidence for the contribution of Tfh cells in the pathogenesis of IgG4-RD but not iMCD (Figs 1 and 2).
Pathogenesis of IgG4-RD and iMCD
Lymph nodes are frequently involved in patients with IgG4-RD or iMCD and they are the main sources of IgG4 and IgG4+ cells. However, the process by which IgG4 and IgG4+ cells are generated differs between the two diseases. (a) Tfh2 cells migrate into GCs and Tfh2-derived IL-4 and IL-21 promote the differentiation of IgG4+ plasmablasts/plasma cells. IL-21 supports GC expansion and CD8+ CTL cytotoxic function. Infiltration of eosinophils is also a unique pathological observation in IgG4-RD. (b) In iMCD, dysregulation of IL-6 production facilitates the development of CD5+ B cells in the non-GC area, resulting in the expansion of the non-GC area and regression of the GC area. CD5 on B cells activates the pathway downstream of IL-6, even without the IL-6 receptor, through direct binding of CD5 to IL-6. IL-6-stimulated B cells differentiate into IgG4+ plasma cells, IgA+ plasma cells and IgM+ plasma cells. Sheet-like mature plasma cell proliferation is also a specific pathological finding in iMCD.
Comparison of histopathological findings of lymph node biopsies between IgG4-RD and iMCD
Haematoxylin and eosin staining showed many hyperplastic GCs in IgG4-RD, whereas atrophic GCs were observed in iMCD. IgG4+ cells can be observed in both IgG4-RD and iMCD. CD20+ B cells are present inside and outside of hyperplastic GCs and all CD138+ plasma cells exist outside of GCs in IgG4-RD. In iMCD, GCs in CD20+ B cells are atrophic and surrounded by a sheet-like proliferation of CD138+ plasma cells. CD3+ T cells are present inside and outside of hyperplastic GCs in IgG4-RD, whereas they are scant in iMCD.
Clinical manifestations
Symptoms and affected organs
Both IgG4-RD and iMCD demonstrate increased levels of serum IgG4, infiltration of IgG4+ cells into the inflamed tissue and tumour-like swelling. For this reason, to distinguish IgG4-RD from iMCD, clinicians must understand the differences in clinical presentation. We previously investigated the clinical characteristics of 45 patients with IgG4-RD and 33 with iMCD. Atopic history was observed in almost 70% of the IgG4-RD cases but in <30% of patients with iMCD [84]. In contrast, fever and other inflammatory symptoms such as weight loss, weakness and fatigue were more common in iMCD than in IgG4-RD [10, 32]. Furthermore, the distribution of organ involvement differs between IgG4-RD and iMCD. For example, paravertebral band-like soft tissue has been reported as a specific finding in IgG4-RD [10, 89]. Involvement of exocrine glands, such as the lacrimal glands, salivary glands or pancreas, only occurs in IgG4-RD, while iMCD always involves lymphadenopathy and can be excluded if lymphadenopathy is not observed. Therefore organ involvement distribution is quite important to distinguish between IgG4-RD and iMCD. Since IgG4-RD and iMCD form mass lesions in the lungs and retroperitoneal area, imaging evaluation is recommended [9]. CT is useful to examine organ involvement distribution in a whole body (Figs 3 and 4). Additionally, fluorodeoxyglucose PET-CT detects the affected organs more sensitively than conventional CT [90, 91]. However, as it is not so rare that IgG4-RD and iMCD present with atypical clinical presentations, clinicians must carefully distinguish these two diseases by combining clinical, serological and pathological findings.
Representative CT images of IgG4-RD
(a) Hypertrophic pachymeningitis. (b) Bilateral swelling of the lacrimal glands. (c) Swelling of extraocular muscles. (d) Bilateral swelling of submandibular glands. (e) Multiple mediastinal lymphadenopathy. (f) Peribronchovascular and septal thickening. (g) Thickening of the perilymphatic interstitium. (h) Paravertebral band-like soft tissue in the thorax. (i) Diffuse wall thickening and stenosis of coronary arteries. (j) Thickening of the pericardium. (k) Diffuse pancreas enlargement with capsule-like rim and bilateral renal cortex low-density areas. (l) Renal pelvis mass. (m) Mediastinal mass. (n) Retroperitoneum mass. (o) Abdominal aneurysm with diffuse thickening of the aortic wall. (p) Diffuse wall thickening of the iliac arteries.
Representative CT images of iMCD
(a–c) Lymphadenopathy. (d, e) Nodules and thickening of the perilymphatic interstitium and bronchial wall at numerous sites in the lungs. (f) Splenomegaly.
Biomarkers
Serological biomarkers are another important tool for distinguishing IgG4-RD from iMCD. As the positivity of serum IgG4 elevation in iMCD is 73.3%, estimated from case reports and cohort studies [20–22, 24, 25, 48, 51, 79, 84, 92–94] (Supplementary Table 1, available at Rheumatology online), serum IgG4 levels are not helpful to distinguish between IgG4-RD and iMCD. Alternatively, several studies have highlighted serum IL-6 elevation in iMCD but not in IgG4-RD [79, 95, 96]. High levels of IL-6 are also associated with higher levels of CRP, ESR, IgG, IgA, IgM and IgE, and there are lower levels of haemoglobin and albumin in iMCD than in IgG4-RD [84]. In contrast, eosinophil counts and the IgG4:IgG ratio are higher in patients with IgG4-RD [84]. Soluble IL-2 receptor is a biomarker in both IgG4-RD and iMCD [82, 97, 98], but the levels tend to be higher in iMCD [84]. Among these biomarkers, CRP [area under the curve (AUC) 0.96, cut-off 0.8 mg/dl, sensitivity 88.8%, specificity 93.9%] and IgA (AUC 0.96, cut-off 330 mg/dl, sensitivity 93.2%, specificity 93.9%) are the most useful biomarkers to distinguish between IgG4-RD and iMCD. However, even though these biomarkers have high sensitivity and specificity, IgG4-related aortitis/periaortitis, one of the clinical entities of IgG4-RD, can present with increased levels of IL-6 [99] and inflammatory markers [100–102], meaning that these biomarkers are not definitive to separate IgG4-RD and iMCD completely. In IgG4-RD, serum IgG4 levels at baseline correlate with the number of affected organs, and re-elevation of serum IgG4 levels during treatment reflects disease relapse [103, 104]. Recent studies have identified the following biomarkers for IgG4-RD: serum galectin-3, a member of the lectin family [105]; eotaxin-3 [106], a chemokine for eosinophil migration; and CCL18 [106, 107], a promoting factor for collagen production in fibroblasts [108]. Another eotaxin, CCL11, might be useful for screening of retroperitoneal fibrosis in IgG4-RD [109]. One study of blood proteomics revealed that NPS-PLA2, an acute phase reactant, is a biomarker for iMCD [110].
Histological features
Histological analyses have also revealed similarities and differences between IgG4-RD and iMCD. In histological analysis of lymph nodes, IgG4+ plasma cell infiltration is observed in both IgG4-RD and iMCD. Alternatively, eosinophil and Tfh cell infiltration is more frequently observed in IgG4-RD, whereas IgA+ cells are characteristically observed in iMCD [79, 88, 95]. On a different note, sheet-like mature plasma cell infiltration and hemosiderin deposition in lymph nodes are more frequently observed in iMCD than in IgG4-RD [111]. One clinicopathological study of lung lesions revealed that characteristics of fibrosis are different between these two diseases; the type of fibrosis observed in IgG4-RD is storiform fibrosis, whereas iMCD presents amyloid-like hyalinized fibrosis [48]. Based on the knowledge that IL-6 is a pathogenic driver of iMCD but not most of IgG4-RD, IL-6 expression might be useful to distinguish between IgG4-RD and iMCD. One histological analysis of lungs reported the utility of IL-6 immunostaining to distinguish these two diseases [48]. However, the other histological study of lung lesions did not confirm the overexpression of IL-6 in iMCD [24]. Therefore, further analysis of the utility of IL-6 expression to distinguish between in IgG4-RD and iMCD is needed. The biomarkers and histological findings of IgG4-RD and iMCD are summarized in Table 1.
Summary of different characteristics between IgG4-RD and iMCD
| Characteristics | IgG4-RD | iMCD |
|---|---|---|
| Clinical | ||
| Atopic history | Often | Normal |
| Exocrine gland involvementa | Often | Rare |
| Lymph node involvement | Sometimes | All |
| Biomarkers | ||
| CRP | Normal | High |
| Haemoglobin | Normal | Low |
| Platelet | Normal | High |
| Albumin | Normal | Low |
| IgG4:IgG ratio | High | Normal |
| IgA | Normal | High |
| IgM | Normal | High |
| IL-6 | Normal | High |
| Histology | ||
| GC expansion | Often | Sometimes |
| Mature plasma cells with sheet-like proliferation | Rare | Often |
| Hemosiderin deposition | Rare | Often |
| IgA+ cells | Rare | Abundant |
| Characteristics | IgG4-RD | iMCD |
|---|---|---|
| Clinical | ||
| Atopic history | Often | Normal |
| Exocrine gland involvementa | Often | Rare |
| Lymph node involvement | Sometimes | All |
| Biomarkers | ||
| CRP | Normal | High |
| Haemoglobin | Normal | Low |
| Platelet | Normal | High |
| Albumin | Normal | Low |
| IgG4:IgG ratio | High | Normal |
| IgA | Normal | High |
| IgM | Normal | High |
| IL-6 | Normal | High |
| Histology | ||
| GC expansion | Often | Sometimes |
| Mature plasma cells with sheet-like proliferation | Rare | Often |
| Hemosiderin deposition | Rare | Often |
| IgA+ cells | Rare | Abundant |
Exocrine gland involvement, lacrimal glands, salivary glands or pancreas.
Summary of different characteristics between IgG4-RD and iMCD
| Characteristics | IgG4-RD | iMCD |
|---|---|---|
| Clinical | ||
| Atopic history | Often | Normal |
| Exocrine gland involvementa | Often | Rare |
| Lymph node involvement | Sometimes | All |
| Biomarkers | ||
| CRP | Normal | High |
| Haemoglobin | Normal | Low |
| Platelet | Normal | High |
| Albumin | Normal | Low |
| IgG4:IgG ratio | High | Normal |
| IgA | Normal | High |
| IgM | Normal | High |
| IL-6 | Normal | High |
| Histology | ||
| GC expansion | Often | Sometimes |
| Mature plasma cells with sheet-like proliferation | Rare | Often |
| Hemosiderin deposition | Rare | Often |
| IgA+ cells | Rare | Abundant |
| Characteristics | IgG4-RD | iMCD |
|---|---|---|
| Clinical | ||
| Atopic history | Often | Normal |
| Exocrine gland involvementa | Often | Rare |
| Lymph node involvement | Sometimes | All |
| Biomarkers | ||
| CRP | Normal | High |
| Haemoglobin | Normal | Low |
| Platelet | Normal | High |
| Albumin | Normal | Low |
| IgG4:IgG ratio | High | Normal |
| IgA | Normal | High |
| IgM | Normal | High |
| IL-6 | Normal | High |
| Histology | ||
| GC expansion | Often | Sometimes |
| Mature plasma cells with sheet-like proliferation | Rare | Often |
| Hemosiderin deposition | Rare | Often |
| IgA+ cells | Rare | Abundant |
Exocrine gland involvement, lacrimal glands, salivary glands or pancreas.
Combined differentiation approach
Importantly, IgG4‐RD cannot be completely distinguished from iMCD, even if the cases satisfy some of the features in Table 1. For instance, among the biomarkers, CRP is the most useful for distinguishing between IgG4-RD and iMCD [84], but some IgG4-RD cases, especially those involving aortic aneurysms/periaortitis, present with increased levels of serum CRP [100–102]. Therefore careful diagnosis that considers various clinical, serological and pathological findings is necessary to distinguish IgG4-RD from iMCD. As such, pathological information is crucial for diagnosis; however, a recent large Chinese IgG4-RD prospective study revealed that 2.8% (15/534 patients) fulfilled the pathological features of iMCD [94]. In addition, tissue biopsy is sometimes difficult because of the location of the affected sites. In this context we have proposed a classification algorithm for IgG4-RD and iMCD that uses five simple distinguishing features: involvement of orbits, lacrimal glands, salivary glands or pancreas; atopic history; non-involvement of lymph nodes; CRP ≤0.8 mg/dl; and IgA ≤330 mg/dl [84]. These components were extracted in an overview of almost 80 IgG4-RD or iMCD cases with definitive diagnoses and preliminary validation showed high accuracy for differential diagnosis between IgG4-RD and iMCD [84, 112].
Treatment
Although IgG4-RD and iMCD have similar clinical and pathological features, their treatment approaches differ markedly. One multicentre retrospective study revealed that <40 mg/day of glucocorticoids achieved remission in 98% of patients with IgG4-RD [113], whereas only a quarter of patients with iMCD responded to high-dose glucocorticoids [32]. To decrease the harmful side effects of continuous glucocorticoids, targeted molecular drugs have been considered as a practical and useful treatment option in both diseases (Fig. 5). Rituximab therapy, which depletes B cells, is effective to treat both diseases, but the remission rates are different: 97% in IgG4-RD [60] and 63% in iMCD [32]. Abatacept, a cytotoxic T-lymphocyte antigen-4 fusion protein, reduces the number of Tfh cells [114] and shows good clinical response in some patients with IgG4-RD [115, 116]. With regards to cytokine-targeted therapies, dupilumab, a monoclonal antibody against the IL-4 receptor α subunit, may be effective in IgG4-RD treatment [117]. In contrast, the IL-6-targeted therapeutics tocilizumab and siltuximab lead to remission in nearly 90% of patients with iMCD. Considering IgG4-related aortitis/periaortitis present with high levels of IL-6 and inflammatory markers [100–102], IL-6-targeted therapeutics might be effective against IgG4-related aortitis/periaortitis [118]. In patients with anti-IL-6-refractory iMCD, the mammalian target of rapamycin (mTOR) inhibitor sirolimus, which can suppress CTL activity and inflammatory lymphadenopathy [119], is a candidate drug that has been investigated in a clinical trial (NCT03933904).
Molecular targeted approach to IgG4-RD and iMCD
A molecular targeted approach has been implemented to avoid the various side effects of glucocorticoids. The efficacy of such treatment provides valuable information about the underlying disease mechanisms. In IgG4-RD, abatacept (Tfh cell targeting), rituximab (B cell targeting) and dupilumab (IL-4 receptor targeting) are effective. It follows that there is a Tfh–IL-4–IgG4+ plamsablast/plasma cell axis. Distinct from this, siltuximab (IL-6 targeting), tocilizumab (IL-6 receptor targeting) and sirolimus (mTOR targeting) can be used to treat iMCD. The efficacy of rituximab in iMCD is lower than in IgG4-RD, suggesting that the IL-6–mTOR pathway is important in both B cells and CD8 T cells in iMCD.
Conclusions
Both IgG4-RD and iMCD exhibit similar clinical symptoms, with high serum IgG4 levels and IgG4+ plasma cell infiltration at the affected sites, whereas the pathogenesis, responsive molecules and treatment differ markedly between the two diseases. However, the partial similarities in such rare diseases make diagnosis very challenging. Combined clinical, serological and pathological features are useful, sometimes with information on treatment response.
Acknowledgements
M.A.’s work is supported by Japan Society for the Promotion of Science KAKENHI grant 21K16292.
Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article.
Disclosure statement: T.S. and M.A. report no conflicts of interest relevant to this article. Y.K. has received grants or speaker fees from AbbVie, Astellas, Ayumi, Bristol-Myers Squibb, Chugai, Eisai, Eli Lilly, Hisamitsu, Jansen, Kissei, Pfizer, Sanofi, Takeda, Tanabe-Mitsubishi and UCB. T.T. has received research grants or speaking fees from Astellas Pharma, Bristol-Myers K.K., Chugai Pharmaceutical, Daiichi Sankyo, Takeda Pharmaceutical, Teijin Pharma, AbbVie GK, Asahi Kasei Pharma, Mitsubishi Tanabe Pharma, AstraZeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., AbbVie GK, Nippon Kayaku, Janssen Pharmaceutical K.K., Taiho Pharmaceutical and Pfizer Japan.
Data availability statement
Data are available upon reasonable request to the corresponding author.
Supplementary data
Supplementary data are available at Rheumatology online.
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