Autoimmune diseases are commonly associated with a polygenic inheritance pattern. In rare instances, causal monogenic variants have been identified. The study by Liu et al. in this issue of the JCI provides an example of monogenic variants occurring in patients with IgG4-related disease (IgG4-RD). The authors investigated a familial cluster of IgG4-RD that consisted of an affected father and two daughters; the mother was unaffected. Genome sequencing of this quad identified a variant in IKZF1 (encoding IKAROS) and another variant in UBR4 (encoding E3 ubiquitin ligase). Both variants were present in the father and both daughters but absent in the unaffected mother. Using multidimensional profiling of immune cells and functional experiments in primary cells, the authors determined a molecular pathway contributing to T cell activation in IgG4-RD. Importantly, the characterization of these variants provides insights into pathogenic mechanisms in IgG4-RD and, potentially, other autoimmune diseases.

Immunoglobulin G4-related disease (IgG4-RD) is a systemic fibroinflammatory condition characterized by significant infiltration of immunoglobulin G4 (IgG4)-positive plasma cells within affected tissues, with or without elevated serum IgG4 levels. The prevalence of IgG4-RD remains largely undetermined due to diagnostic challenges, as the condition is frequently unrecognized or misdiagnosed. This report describes a case of a 63-year-old man who was ultimately diagnosed with this rare condition after an extensive two-year period of elusive symptoms. Initially presenting with intermittent body pains and fluctuating fever, his condition progressively evolved to include severe right orbital swelling with marked tenderness and ecchymosis, recurrent non-tender nodules on his arm, and diminished vision. A detailed review of his medical history prompted the consideration of IgG4-RD, leading to the measurement of serum human IgG4 levels, which were found to be significantly elevated at 1504 mg/L (normal range: 39.2-864 mg/L). Following his diagnosis, treatment with glucocorticoids (0.6 mg/kg for one month) was initiated, resulting in a positive clinical response. This case emphasizes the critical importance of considering less common conditions in the differential diagnosis of patients presenting with complex, multi-system symptoms.

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BACKGROUND: The heart can be involved in immunoglobulin (Ig)-G4-related disease (IgG4-RD). This study aimed to summarize the clinical features and efficacy of treatment for IgG4-RD patients with heart involvement.
METHODS: We conducted a retrospective study enrolling 42 IgG4-RD patients with heart involvement from the IgG4-RD cohorts of the Peking Union Medical College Hospital and Beijing An Zhen Hospital, from 2010 to 2022. Clinical, laboratory, radiological data were collected, and treatment responses to glucocorticoids and immunosuppressants were analyzed.
RESULTS: IgG4-related cardiac involvement is a rare part of the IgG4-RD spectrum. The incidences of coronary periarteritis and pericarditis were 1.2%(13/1075) and 3.1%(33/1075), respectively in our cohort. Valvular disease possibly related to IgG4-RD was detected in two patients. None of the patients with myocardial involvement were identified. The average age was 58.2 ± 12.8 years, with a male predominance (76.7%). Coronary artery CT revealed that mass-like and diffuse wall-thickening lesions were the most frequently observed type of coronary periarteritis. Pericarditis presented as pericardial effusion, localized thickening, calcification and mass. After treatment with glucocorticoid and immunosuppressants, all patients achieved a reduced IgG4-RD responder index score and achieved radiological remission. Two patients with coronary peri-arteritis experienced clinical relapses during the maintenance period.
CONCLUSIONS: Cardiac involvement in IgG4-RD is rare and easily overlooked since many patients are asymptomatic, and the diagnosis relies on imaging. Patients showed a satisfactory response to glucocorticoid based treatment.

Immunoglobulin (Ig) G4-related diseases are very rare diseases and are difficult to diagnose and treat. Here, we report a rare condition, an IgG4-related disease involving the bilateral renal pelvises, which was successfully treated with steroid therapy. A 64-year-old female was admitted with left flank pain and hematuria. Computed tomographic images showed irregular enhancing masses around the bilateral renal pelvises and lymph nodes in the left para-aortic area. A histopathological examination of a renal needle biopsy revealed numerous cells that were positive for IgG and more than 10 IgG4-positive cells per high-powered field. The IgG4/IgG ratio was more than 40%. Her serum IgG4 level was elevated to 1440 mg/dL, and her IgG4/IgG ratio was 82.1%. After a diagnosis of IgG4 sclerosing disease, a double-J ureteral stent was inserted and steroid therapy was performed for 20 weeks. Her symptoms dramatically improved, and the follow-up images showed a resolved state. There was no relapse of the disease for more than 6 months after the removal of the stent.

IgG4-related diseases (IgG-RDs) are a group of fibroinflammatory diseases that affect a variety of tissues, resulting in tumour-like effects and/or organ dysfunction. Monoclonal gammopathies (MGPs) are a group of disorders characterized by clonal proliferation of plasma cells or lymphoid cells resulting in the secretion of a monoclonal immunoglobulin. Cases of MGPs in IgG4-RDs coexisting with plasma cell dyscrasias and lymphoid neoplasms have been reported over the past few years. Therefore, the results of examinations of M protein in IgG4-RD patients should be interpreted with caution. Herein, we report the case of a 58-year-old male with a history of type 2 diabetes who presented with submandibular masses, anosmia, swollen lymph nodes, proteinuria, and renal impairment. Laboratory tests revealed hyperglobulinemia and elevated levels of IgG4 (124 g/L) and serum-free light chains (sFLCs). Serum protein electrophoresis (SPEP) revealed an M spike of 5.6 g/dL, and immunofixation electrophoresis (IPE) revealed biclonal IgG-κ and IgG-λ. The patient underwent bone marrow, lymph node, and kidney biopsy, which ruled out plasma cell disorders and lymphoma. He was finally diagnosed with an IgG4-RD comorbid with diabetic nephropathy. The findings in this case highlight that significant activation of B cells in IgG4-RD patients, especially those with multiorgan involvement can lead to significant hyperglobulinemia and high sFLC and IgG4 levels, which are more pronounced in the setting of renal impairment. Relatively high concentrations of polyclonal IgG4 can give rise to a focal band bridging the β and γ fractions, which may mimic the appearance of a monoclonal band on SPEP and monoclonal gammaglobulinemia in IFE. The patient experienced considerable improvement in his symptoms after rituximab combined with glucocorticoid therapy, and a monoclonal immunoglobulin was not detected.

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UNASSIGNED: Nervous system involvement in immunoglobulin G4-related disease (IgG4-RD) has been rarely reported.
UNASSIGNED: We describe an unusual case of IgG4-RD manifested as paresthesia in the right lower extremity. A 51-year-old male presented with paresthesia in the right S1-S3 regions. A neurological examination revealed peripheral neuropathy. Blood examination results were normal, barring slightly elevated IgG levels. Initial magnetic resonance imaging of the swollen right S1 and S2 nerve roots revealed lymphoma, schwannoma, and sarcoidosis. However, following the biopsy, the pathological findings were not typical of these diseases. Abdominal computed tomography revealed perirenal lesions, and IgG4-RD was suspected. The patient had a serum IgG4 level of 724 mg/dL. Additional pathological evaluations of the swollen S1 nerve revealed findings that corresponded to the diagnostic criteria for IgG4-RD. Oral steroid therapy was initiated, which improved paresthesia, and the swollen S1 nerve root gradually shrank.
UNASSIGNED: This report highlights a rare case of IgG4-RD involving nerve roots that neurosurgeons should consider.

UNASSIGNED: IgG4-related disease (IgG4-RD) was characterized by single or multiple masses in organs, which may mimic various inflammatory and malignant diseases. Here, we summarize 4 patients with aggressive manifestations of IgG4-RD that mimic nasopharynx cancer to provide some new sights for the diagnosis of IgG4-RD.
UNASSIGNED: Four patients were included in our series. The age ranged from 53 to 64 years old, and the duration of the disease ranged from 4 to 6 months. The chief complaints included headache, rhinorrhea, or diplopia. All patients had more than 10 IgG4+ plasma cells/HPF in immunohistochemistry with plasma lgG4 levels ranging from 218 mg/dL to 765 mg/dL. All of them met the diagnostic criteria of lgG4-RD.
UNASSIGNED: The described case is highly similar to the clinical manifestations of nasopharyngeal carcinoma. Although pathology is the gold standard, there are still limitations. Serological IgG4 can help confirm the diagnosis. Timely diagnosis of IgG4-RD is of great significance in preventing secondary organ damage in patients with active diseases.

Mass-forming phenotypes of IgG4-related disease (IgG4-RD) mimic malignancy and histological confirmation can be challenging. A woman in her 70s with HIV infection presented with painless obstructive jaundice and weight loss. Magnetic resonance imaging was suggestive of unresectable cholangiocarcinoma. Tumour markers and serum IgG4 were normal. Percutaneous liver biopsy was consistent with IgG4-RD inflammatory pseudotumour, with complete response to glucocorticoid therapy. Two years later, a new episode of obstructive jaundice occurred, with CT showing a solid lesion in the head of the pancreas with double duct sign and encasement of the portal vein. Re-induction therapy was tried without response. Fine-needle biopsy was consistent with pancreatic cancer. Supportive care was offered and the patient died 8 months later, with no signs of disease progression on subsequent imaging. We discuss the challenges of IgG4-RD diagnosis and treatment and the differential diagnosis between mass-forming phenotypes and malignancy, highlighting the difficulties in managing such patients.