https://orcid.org/0000-0001-5075-8977
DearEditor, We read the article by Kawano et al. with great interest [1]. They reported the two cases of human herpesvirus-8-negative/idiopathic multicentric Castleman disease (MCD) with serological, histopathological and radiological features of IgG4-related disease (IgG4-RD). Both cases presented with serum IgG4 elevation (625 mg/dl in case 1 and 738 mg/dl in case 2), IgG4-positive plasma cell infiltration (IgG4/IgG 32% in case 1 and IgG4/IgG 25% in case 2) in renal biopsies, and the radiological findings of IgG4-related kidney disease (renal pelvic wall thickening in case 1 and multiple low-density lesions in case 2). Obviously, MCD is an important mimicker of IgG4-RD. However, whereas the 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-RD requires the exclusion of MCD [2], its exclusion is sometimes difficult because laboratory data and clinical presentations such as serum IgG4 levels, IgG4-positive plasma cell infiltration and kidney involvements cannot distinguish between IgG4-RD and MCD, as were shown in the article by Kawano et al. [1]. Furthermore, there is no specific diagnostic marker for IgG4-RD or MCD. Therefore, clinically applicable tools have been desired to make accurate diagnosis of IgG4-RD or MCD.
To solve the clinical problem, we have previously proposed a classification tree for distinguishing IgG4-RD and MCD for daily clinical practice use (Fig. 1A) [3]. In that study, we compared the clinical characteristics of biopsy-proven IgG4-RD and MCD cases in a large cohort and extracted clinical components that could efficiently distinguish the two diseases. As a result, the combination of ‘orbits, lacrimal glands, salivary glands or pancreas involvement, atopic history, or non-involvement of lymph node’ and ‘C-reactive protein (CRP) ≤0.8 mg/dl or IgA ≤330 mg/dl’ yielded the probability of 97.8% in IgG4-RD and 3.0% in MCD. Then, we made the ‘2017 classification tree’ with those components and validated the usefulness for distinguishing IgG4-RD and MCD in another cohort [3]. As the two cases by Kawano et al. were representative confusing ones, we applied them to our 2017 classification tree. Their atopic history was not available in the report, but both cases had apparently elevated serum IgA (949 mg/dl in case 1 and 777 mg/dl in case 2) and CRP (5.4 mg/dl in case 1 and 5.1 mg/dl in case 2) levels, indicating that they could be classified into MCD (Fig. 1A). These results suggest that the ‘2017 classification tree’ is useful to differentiate between IgG4-RD and MCD in clinically difficult cases.
Distinct clinical and pathological features between IgG4-related disease and multicentric Castleman disease
‘2017 classification tree’ for distinguishing IgG4-related disease (IgG4-RD) and multicentric Castleman disease (MCD) (A), and the scheme of the distinct pathogenesis between IgG4-RD and MCD (B).
Underlying pathogenesis of IgG4-RD and MCD is fundamentally different (Fig. 1B). Serum IgG4 elevation and the differentiation of IgG4-positive plasma cells are induced by IL-4-producing follicular helper type 2 T (Tfh2) cells in IgG4-RD, while those features are induced by hyper IL-6 in MCD (Fig. 1B) [4, 5]. In fact, patients with MCD showed the distinct elevation of serum IL-6 compared with IgG4-RD [6]. MCD, but not IgG4-RD, presents with elevated levels of serum IgA and CRP because IL-6 is a pro-inflammatory cytokine that elicits polyclonal B-cell maturation and differentiation. On the other hand, IL-4-producing Tfh2 cells induce IgG4-specific class switching, resulting in no significant elevation of serum IgA [4, 5]. Glucocorticoid is highly effective in IgG4-RD, while MCD shows the resistance to glucocorticoid treatment [7]. Furthermore, a recent study reported the efficacy of dupilumab (IL-4 receptor blockade) in IgG4-RD, while tocilizumab (IL-6 receptor blockade) is well known to be effective in MCD [8]. Thus, the differentiation between IgG4-RD and MCD is critical for appropriate treatment approach. In this regard, the ‘2017 classification tree’ can contribute to the accurate diagnosis of IgG4-RD or MCD. Further external validation is needed to recognize the strength and weakness of the ‘2017 classification tree’.
Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript.
Disclosure statement: 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 Inc., Bristol–Myers K.K., Chugai Pharmaceutical Co, Ltd, Daiichi Sankyo Co., Ltd, Takeda Pharmaceutical Co., Ltd, Teijin Pharma Ltd, AbbVie GK, Asahi Kasei Pharma Corp., Mitsubishi Tanabe Pharma, Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., AbbVie GK, Nippon Kayaku Co. Ltd, Janssen Pharmaceutical K.K., Taiho Pharmaceutical Co., Ltd, and Pfizer Japan Inc. The other authors have declared no conflicts of interest.
Data availability statement
Data are available upon reasonable request by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). All data relevant to the study are included in the article.
Comments