Investigation of IgG4-positive cells in idiopathic multicentric Castleman disease and validation of the 2020 exclusion criteria for IgG4-related disease.

Patients with plasma cell type idiopathic multicentric Castleman disease (PC-iMCD) often show elevated serum IgG4 levels and IgG4-positive cell infiltration in tissues due to overproduction of interleukin-6, and may meet the diagnostic criteria for IgG4-related disease (IgG4-RD). Although PC-iMCD has been listed as a major exclusion disease for IgG4-RD, distinguishing between these diseases is challenging due to a lack of highly specific diagnostic biomarkers. In 2020, we proposed exclusion criteria of IgG4-RD mimickers. In this paper, we validated the accuracy of the criteria in excluding one of the mimickers, PC-iMCD, from IgG4-RD. Validation was performed on 57 PC-iMCD patients (39 presenting lymph node lesions and 19 with lung lesions) and 29 IgG4-RD patients (22 presenting lymph node lesions and seven with lung lesions). According to our results, 20.5% of the PC-iMCD patients with lymph node lesions and 42.1% of those with lung lesions met the diagnostic criteria for IgG4-RD. All these patients with PC-iMCD were excluded from a diagnosis of IgG4-RD by the proposed criteria. Additionally, 6.9% of IgG4-RD patients met the exclusion criteria. Thus, if the exclusion criteria are met, diagnosis should be made based on a combination of findings including organ distribution of disease, response to steroid therapy, and other pathological findings.

Nishikori A ，Nishimura MF ，Nishimura Y ，Notohara K ，Satou A ，Moriyama M ，Nakamura S ，Sato Y ... -  《-》

Immunoglobulin G4-related disease and idiopathic multicentric Castleman's disease: confusable immune-mediated disorders.

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.

Sasaki T ，Akiyama M ，Kaneko Y ，Takeuchi T ... -  《-》

Pulmonary Manifestations of Plasma Cell Type Idiopathic Multicentric Castleman Disease: A Clinicopathological Study in Comparison with IgG4-Related Disease.

Nishimura MF ，Igawa T ，Gion Y ，Tomita S ，Inoue D ，Izumozaki A ，Ubara Y ，Nishimura Y ，Yoshino T ，Sato Y ... -  《Journal of Personalized Medicine》

Utility of renal biopsy in differentiating idiopathic multicentric Castleman disease from IgG4-related disease.

Idiopathic multicentric Castleman disease (iMCD) is a subtype of human herpesvirus type 8 (HHV-8)-related Castleman disease that causes multi-organ damage, including kidney damage due to polyclonal lymphoproliferation and interleukin (IL)-6-induced cytokine storm. However, its renal pathological findings are unclear. We report the case of a woman in her 80 s who was diagnosed with iMCD based on renal pathological findings. Five years ago, hypergammaglobulinemia was detected, and her renal function declined. Renal biopsy revealed plasma cells infiltrating the stroma. Immunostaining revealed numerous IgG4-positive plasma cells. The serum IgG4 level was high, and she was initially diagnosed with IgG4-related disease (IgG4-RD) and treated with steroids. However, the therapeutic effect was poor. On re-examination, computed tomography revealed lymphadenopathy around the aorta and spleen. Renal histopathology showed numerous IL-6-positive plasma cells. Anemia and C-reactive protein (CRP) positivity persisted despite steroid administration. HHV-8 was negative, and polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes syndrome was not suspected. Thus, iMCD was diagnosed. Based on previous reports, there is no significant difference in IgG4 levels between iMCD and IgG4-RD, and IgG4-positive plasma cell infiltrates were observed in iMCD-affected organs. Therefore, it may be difficult to distinguish iMCD from IgG4-RD. In this case, high-serum IL-6 and CRP were observed, which are usually not seen in IgG4-RD but are common findings in iMCD, leading to the diagnosis. Patients with deep lymphadenopathy may be diagnosed with iMCD based on renal pathological findings. Renal biopsy is recommended for patients with suspected iMCD and decreased renal function.

Kawanishi M ，Kamei F ，Sonoda H ，Oba M ，Fukunaga S ，Egawa M ，Koyama T ，Sato Y ，Tanabe K ，Ito T ... -  《-》

Comparison of clinical and pathological features of lung lesions of systemic IgG4-related disease and idiopathic multicentric Castleman's disease.

The lung lesion [immunoglobulin (Ig)G4-L] of IgG4-related disease (IgG4-RD) is a condition that occurs together with IgG4-RD and often mimics the lung lesion [idiopathic multicentric Castleman's disease (iMCD-L)] of idiopathic multicentric Castleman's disease (iMCD). Because no clinical and pathological studies had previously compared features of these diseases, we undertook this comparison with clinical and histological data. Nine patients had IgG4-L (high levels of serum IgG4 and of IgG4+ cells in lung specimens; typical extrapulmonary manifestations). Fifteen patients had iMCD-L (polyclonal hyperimmunoglobulinaemia, elevated serum interleukin-6 levels and polylymphadenopathy with typical lymphadenopathic lesions). Mean values for age, serum haemoglobin levels and IgG4/IgG ratios were higher in the IgG4-L group and C-reactive protein levels were higher in the iMCD-L group. All IgG4-RD lung lesions showed myxomatous granulation-like fibrosis (active fibrosis), with infiltration of lymphoplasmacytes and scattered eosinophils within the perilymphatic stromal area, such as interlobular septa and pleura with obstructive vasculitis. All 15 lung lesions of iMCD, however, had marked accumulation of polyclonal lymphoplasmacytes in lesions with lymphoid follicles and dense fibrosis, mainly in the alveolar area adjacent to interlobular septa and pleura without obstructive vasculitis. Although both lesions had lymphoplasmacytic infiltration, lung lesions of IgG4-RD were characterized by active fibrosis with eosinophilic infiltration within the perilymphatic stromal area with obstructive vasculitis, whereas lung lesions of iMCD had lymphoplasmacyte proliferating lesions mainly in the alveolar area adjacent to the perilymphatic stromal area. These clinicopathological features may help to differentiate the two diseases.

Terasaki Y ，Ikushima S ，Matsui S ，Hebisawa A ，Ichimura Y ，Izumi S ，Ujita M ，Arita M ，Tomii K ，Komase Y ，Owan I ，Kawamura T ，Matsuzawa Y ，Murakami M ，Ishimoto H ，Kimura H ，Bando M ，Nishimoto N ，Kawabata Y ，Fukuda Y ，Ogura T ，Tokyo Diffuse Lung Diseases Study Group ... -  《-》