Immunoglobulin G4-related disease (IgG4-RD) is a systemic inflammatory disease characterized by the infiltration of IgG4-positive plasma cells and fibrosis in organs throughout the body. IgG4-RD involvement in the gastrointestinal (GI) tract (IgG4-related GI disease; IgG4-GID) is rare, and the disease concept remains unclear. Generally, IgG4-GID has been reported with morphological changes, including ulcers, strictures, and submucosal tumors. Here, we report a case of IgG4-GID with persistent diarrhea and abdominal pain in which typical endoscopic findings were absent. This case suggests the unidentified clinical features of IgG4-GID.

A 60-year-old female with a BRCA2 mutation and a history of breast cancer presented with diffuse abdominal pain and elevated liver enzymes. Imaging revealed a porta-hepatis mass, prompting consideration of hilar cholangiocarcinoma or breast cancer metastasis. Further investigation including biopsy and 18F-fluorodeoxyglucose positron emission tomography/computed tomography findings were inconsistent with malignancy, leading to investigation of non-neoplastic causes. Elevated IgG4 levels suggested IgG4-related disease, a mass-forming fibroinflammatory condition. This case demonstrates IgG4-related disease exclusively impacting the portal vein and underscores the importance of considering IgG4-related disease in the differential diagnosis of hepatic masses.

A 77-year-old man presented with right inguinal lymphadenopathy and swollen parotid and submandibular glands bilaterally. Histopathology revealed germinal center B-cell type diffuse large B-cell lymphoma (DLBCL) in the inguinal lymph node. Lymphocyte and plasma cell infiltration in the submandibular gland with elevated serum IgG4 levels (13 g/L) prompted a diagnosis of IgG4-related disease (IgG4-RD). Systemic chemotherapy for DLBCL led to shrinkage of the lymph nodes and disappearance of the submandibular gland swelling, as confirmed by fluorodeoxyglucose-positron emission tomography/computed tomography. Although concomitant IgG4-RD and lymphoma have been reported, their simultaneous diagnosis is rare; therefore, a biopsy of all involved organs is crucial in cases with unusual organ involvement.

An asymptomatic 75-year-old man who underwent transverse colon cancer surgery two years previously presented with retroperitoneal fibrosis (RPF) around the ventral sacral and right external iliac artery and vein on abdominal computed tomography (CT) during a routine surveillance visit. We assumed cancer recurrence or immunoglobulin G4 (IgG4)-related disease (RD), but although generic tumor markers and IgG4 levels were normal, soluble interleukin 2 receptor (sIL-2R) was elevated at 569 U/mL (reference: 122-496 U/mL). No diagnosis was made at this time, and the patient was followed up. He subsequently developed edema of both lower extremities. Abdominal enhanced CT showed an enlarged RPF without invasion of surrounding organs and with a delayed contrast effect, and positron emission tomography-CT showed fluorodeoxyglucose accumulation in the same area but a lower standardized uptake value (SUV) than at the time of transverse colon cancer diagnosis. Although generic tumor markers and IgG4 levels remained within the reference range, sIL-2R was further elevated to 1100 U/mL. An open biopsy and histopathology showed a high IgG4/IgG-positive cell ratio and infiltration of IgG4-positive plasma cells. The patient was finally diagnosed with IgG4-RD RPF. In cases of RPF after colorectal cancer surgery, the combined findings of elevated sIL-2R, lack of infiltration into surrounding organs, and lower SUV values ​​than at the cancer site could provide useful information to aid the diagnosis of IgG4-RD RPF.

A 20-year-old man was presented with ulcerative gastritis and duodenitis complicated by pyloric stenosis. Helicobacter pylori infection was excluded, and the lesions did not respond to treatment with proton pump inhibitors. No other parts of the intestinal tract showed signs of inflammation. Histopathological review showed signs of chronic inflammation with granuloma formation. A tentative diagnosis of isolated upper gastrointestinal (UGI) Crohn\'s disease was performed. However, additional work-up revealed significantly positive IgG4 staining as well as elevated IgG4 serum levels. Since granulomatous disease is unlikely in IgG4-related disease, an eventual diagnosis of overlapping IgG4-related disease and Crohn\'s disease (CD) was performed. Treatment with systemic steroids and anti-TNF in combination with azathioprine led to rapid symptomatic improvement. In this article, we review the available literature on IgG4-related gastroduodenitis, granulomatous gastritis, and upper GI CD. We suggest the possibility that IgG4-infiltration may be a marker of severely active inflammatory bowel disease rather than a separate disease entity.

IgG4-related disease is a rare fibroinflammatory disorder characterized by the infiltration of IgG4-rich plasma cells. Herein, we report a case of IgG4-related disease of the subcutaneous tissue with atypical MRI findings and difficulties in the histopathological examination using needle biopsy. Based on the clinical presentation and MRI findings, the patient was diagnosed with a benign myxoid or cystic tumor. Additionally, histopathological findings from a needle biopsy suggested a myxoma. Therefore, the correct diagnosis of IgG4-related disease was not made preoperatively. The resected specimens confirmed IgG4-related disease with an IgG4/IgG ratio > 80%. Previous reports have shown that the MRI findings of IgG4-related disease mimic both malignancy and inflammation; surprisingly, the features of subcutaneous IgG-related disease, including tail sign, unclear border, and heterogeneous enhancement, were similar to those found in sarcoma. Therefore, histopathological findings are needed for a correct diagnosis. Furthermore, careful examination is essential because the neoplasm and inflammation may overlap with IgG4-related disease, and needle biopsy is not fully reflective of the tumor. As is highlighted in the present case, IgG4-related disease is often misdiagnosed; therefore, clinicians should adequately recognize that even if the histopathological findings in biopsy were consistent with those observed in the MRI, misdiagnosis may occur.

A 76-year-old woman with persistent diarrhea was referred to our hospital. She had purpura, peripheral eosinophilia (18,177/μL), and an elevated serum IgG4 level (819 mg/dL). Abdominal computed tomography revealed massive ascites and bowel edema. A skin biopsy of the purpura revealed leukocytoclastic vasculitis with prominent eosinophilic infiltration. Biopsies of the gastrointestinal mucosa revealed dense eosinophilic infiltration, indicating eosinophilic gastroenteritis (EG) associated with the hypereosinophilic syndrome. The number of IgG4-positive cells increased in the duodenal mucosa; however, the diagnostic criteria for IgG4-related disease (IgG4-RD) were not met. Whether or not EG with ascites is a manifestation of IgG4-RD warrants further investigation.

BACKGROUND: To investigate the potential utility of quantitative parameters obtained by 18F-fibroblast activation protein inhibitor positron emission tomography/computed tomography ([18F]AlF-NOTA-FAPI-04 PET/CT) in the assessment of organ involvement and disease activity in IgG4-related disease (IgG4-RD).
METHODS: This study enrolled patients who underwent [18F]AlF-NOTA-FAPI-04 PET/CT scans at the Department of Rheumatology, The First Affiliated Hospital, Zhejiang University School of Medicine from August 2021 to August 2022. The PET/CT images of the included patients were re-evaluated by PET center technicians, and the maximal standardized uptake value (SUVmax), metabolic lesion volume (MLV), and total lesion FAPI (TL-FAPI) were used to evaluate the involved organs and tissues that abnormally accumulated [18F]AlF-NOTA-FAPI-04. The clinical and laboratory data of patients are also systematically collected and analyzed.
RESULTS: Among the patients included in this study, 12 patients met the IgG4-RD classification criteria established by the American College of Rheumatology in 2019. Among them, 8 were males and 4 were females, with an average age of 59.3 ± 11.5 years. 50% of IgG4-RD patients were found with more organ involvement on PET/CT than physical examination, ultrasonography, and computed tomography. IgG4 levels (Rho = 0.594, p = 0.042) and IgG4-RI (Rho = 0.647, p = 0.023) were significantly positively correlated with TL-FAPI. After linear regression analysis, only TL-FAPI showed a predictive value of RI (R2 = 0.356, B = 0.008, p = 0.041).
CONCLUSIONS: [18F]AlF-NOTA-FAPI-04 PET/CT is a useful tool for identifying asymptomatic organ involvement and assessing disease activity. The TL-FAPI as an indicator was positively correlated with IgG4-RD disease activity.

IgG4-related tubulointerstitial nephritis (IgG4-related TIN) is the prevalent clinical manifestation of IgG4-related diseases (IgG4-RD). However, there are limited cases of IgG4-RD occurring with membranous nephropathy (MN) in the absence of phospholipase A2 receptor (PLA2R). There have been no indications of treatment using Tripterygium wilfordii. This study reported a rare case of IgG4-RD with PLA2R-associated MN without any of the distinct IgG4-related TIN. The patient was treated effectively with T. wilfordii. A 71-year-old patient was admitted to the medical facility after presenting with a 1 month history of edema and 8 months of albuminuria. The renal biopsy tissue examination confirmed the presence of MN (phase II) in the absence of pathological manifestations of IgG4-related TIN. Immunohistochemistry identified PLA2R++ (granular capillaries). The serum PLA2R antibody titer was 1:180 (1:20). The patient met the diagnosis with IgG4-RD. Over 8 years of follow-up, the patient was effectively treated with low-dose hormones and T. wilfordii, without any adverse effects. This MN is considered a unique form of IgG4-RD, regardless of whether PLA2R antibodies are present or not. Research suggests that T. wilfordii could be a promising option for elderly people with IgG4-related MN, as it has been found to have fewer adverse effects.

OBJECTIVE: To identify genes that could provide clues leading to the discovery of drugs to treat IgG4-related disease (IgG4-RD).
METHODS: Submandibular gland tissue bulk RNAseq analysis of 45 cases with a definite diagnosis of IgG4-RD was integrated with Visium spatial transcriptome analysis of 2 cases to identify pathogenic genes expressed in tertiary lymphoid tissues.
RESULTS: Bulk RNAseq and pathway analyses showed upregulation of cell cycle and T cell-related signals in IgG4-RD. Spatial transcriptome analysis identified the cluster corresponding to germinal centers and the top 38 common genes that showed significant variations in expression compared with other clusters. The top 20 genes were extracted by comparing the bulk RNAseq data. Network analysis identified CDK1 as the ge most strongly associated of the top 20 genes.
CONCLUSIONS: The CDK1 gene may be a regulator of the pathogenesis of IgG4-RD and provide clues for drug discovery.