Comment on: HHV-8-negative multicentric Castleman disease patients with serological, histopathological and imaging features of IgG4-related disease: reply

DearEditor, We thank Akiyama et al. for their interest in our case report and their thoughts [1] on the diagnostic process to differentiate idiopathic multicentric Castleman disease (iMCD) with elevated serum IgG4 levels and marked tissue infiltrating IgG4-positive plasma cells (an IgG4-related disease mimicker) from true IgG4-related disease (IgG4-RD). We agree with their comment that distinguishing iMCD from IgG4-RD is sometimes very difficult. Our cases highlighted that not only elevated serum IgG4 levels and marked tissue infiltrating IgG4-positive plasma cells but also the renal findings on computed tomography (CT) can be very similar between these two diseases in some cases, making it even more difficult to differentiate iMCD and IgG4-RD [2]. However, not all patients with iMCD have elevated serum IgG4 levels. For instance, cases of the thrombocytopenia, anasarca, fever, reticulin fibrosis, organomegaly (TAFRO) subtype of iMCD typically have normal or mildly elevated immunoglobulin levels with normal IgG4 proportions. In Akiyama et al.’s analysis of 45 cases of IgG4-RD and 33 cases of iMCD, serum IgG4 levels were evaluated in only six patients with iMCD [3]. Because iMCD patients with normal serum IgG4 levels or slightly elevated serum IgG4 levels (less than 2x the upper limit of normal) are not usually confused with IgG4-RD, the clinically significant issue is to recognize the existence of iMCD patients with highly elevated serum IgG4 levels who may be misdiagnosed as having IgG4-RD. First, an iMCD patient is suspected to have IgG4-RD triggered by hypergammaglobulinemia or highly elevated serum IgG levels. Then, if the serum IgG4 level is found to be very high, the diagnosis of IgG4-RD is highly suspected rather than iMCD despite the true diagnosis being iMCD. The two cases we reported highlight this challenging differential diagnosis as the two diseases share very similar features serologically, histopathologically and radiologically. The serum IgG4 level of patient 1 in our case was 4.6 times higher than the upper limit of the normal serum IgG4 level, and patient 2’s level was 5.5 times higher. Moreover, serum IgG4/IgG ratio was 13% in patient 2, which exceeds the upper limit of normal of 8%.

Among the rare cases that demonstrate features of both iMCD and IgG4-RD, the most important points in clinical practice to look out for are response to glucocorticoids, serum CRP levels and extra-nodal involvement. Because glucocorticoid responsiveness is usually very good in IgG4-RD and CRP tends to drop significantly, ‘no objective response to glucocorticoids’ was adopted as one item in the exclusion criteria of the 2019 ACR/EULAR classification criteria for IgG4-related disease [4]. In cases where there is limited response to glucocorticoids, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and iMCD should be considered. Persistently elevated serum CRP level prior to therapy is another very useful serological finding to rule out IgG4-RD. We previously analysed 334 patients with IgG4-RD and found their serum CRP levels to be <1.0 mg/dl in 90% of patients [5]. Another item in the classification tree: ‘involved orbits, lacrimal glands, salivary glands or pancreas’ is also very important because only one of 33 iMCD patients had any such lesions, while 89% of IgG4-RD patients had at least one of them [3]. All iMCD patients have enlarged lymph nodes with characteristic histopathology and occasionally extra-nodal involvement of organs such as lungs and kidneys. Lastly, we have observed ‘atopic history’ in both iMCD and IgG4-RD, so we believe more data are needed to determine the role of this item in the classification tree. Based on our anecdotal experience and retrospective data, we agree with Akiyama et al.’s classification tree but would like to see further data related to atopic history.

Finally, we thank Akiyama et al. for their suggestion about the pathogenetic difference between IgG4-RD and iMCD, and completely agree that interleukin (IL)-6 plays a critical role in iMCD, while IL-4 is very important in IgG4-RD. However, because not all patients with iMCD have highly elevated serum IgG4, the difference between iMCD with and without highly elevated serum IgG4 might be of some significance. Because iMCD patients with highly elevated serum IgG4 sometimes have highly elevated serum IgE levels [6], and IL-4 is also associated with class switch to IgE, IL-4 might also be implicated in the pathogenesis of iMCD with highly elevated serum IgG4. Further analysis will be needed to clarify the differences in the molecular mechanisms underlying iMCD with and without highly elevated serum IgG.

Acknowledgement

We thank John Gelblum for his critical reading of the manuscript.

Funding: No specific funding was received from any public, commercial or not-for-profit sectors to carry out the work described in this manuscript.

Disclosure statement: D.C.F. has received research funding from Janssen Pharmaceuticals and EUSA Pharma for the ACCELERATE natural history registry. The other authors have declared no conflicts of interest.

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