Clinical Performance of Immunonephelometric Assay and Chemiluminescent Immunoassay for Detection of IgG Subclasses in Chinese.

BACKGROUND: Detection of IgG subclasses (IgGSc) is vital for the diagnosis and management of disease, especially IgG4-related diseases (IgG4-RD). This study aimed to evaluate the performances of the chemiluminescent immunoassay (CLIA) for detecting IgGSc and diagnosing IgG4-RD by IgGSc. METHODS: A total of 40 individuals with IgG4-RD, 40 with primary Sjogren's syndrome (pSS), and 40 healthy controls (HCs) were enrolled. Serum samples were collected for the simultaneous detection of IgG1, IgG2, IgG3, and IgG4 by the Siemens immunonephelometric assay and the CLIA. The correlation analysis was performed, and diagnostic value was analyzed by the receiver operating characteristic (ROC) curve. RESULTS: Patients with IgG4-RD had higher IgG4 (p < 0.001) and lower IgG1 (p < 0.001) than those with pSS, and HC. The results by the Siemens immunonephelometric assay and the CLIA showed a strong correlation in detecting IgG1, IgG2, IgG3, and IgG4 (r = 0.937, r = 0.847, r = 0.871, r = 0.990, all p < 0.001, respectively). The sum of IgG1, IgG2, IgG3, and IgG4 using two assays strongly correlated with total IgG by the IMMAGE 800 (r = 0.866, r = 0.811, both p < 0.001, respectively). For discriminating IgG4-RD from pSS and HC, no significant differences were observed in CLIA IgG4 and Siemens immunonephelometric assay IgG4 (z = 0.138, p = 0.891), which provided the area under the curves (AUCs) of 0.951 (p < 0.001) and 0.950 (p < 0.001), respectively. The AUCs of CLIA IgG1 and Siemens immunonephelometric assay IgG1 in distinguishing pSS from IgG4-RD and HC were 0.761 (p < 0.001) and 0.765 (p < 0.001), respectively, with no significant differences (z = 0.228, p = 0.820). CONCLUSIONS: The CLIA and the Siemens immunonephelometric assay appeared to have good consistency with comparable diagnostic value in detecting IgGSc, especially IgG4, and IgG1 that can accurately identify IgG4-RD or pSS in clinical practice.

Posible enfermedad por IgG4 asociada con alogenosis iatrogénica. Caso clínico / Possible IgG4 disease associated with iatrogenic allogeneic disease. Case report

Presentamos un caso de paciente con alogenosis iatrogénica que tras ser intervenido quirúrgicamente, cursa con pancreatitis aguda de etiología no precisada con valores séricos elevados de inmunoglobulina 4 (IgG4). La asociación con la buena respuesta terapéutica al tratamiento esteroideo unida al antecedente de síndrome autoinmune inflamatorio sistémico inducido por adyuvantes, insuficiencia renal crónica con biopsia que reportó atrofia tubular severa con fibrosis, pseudotumores intestinales, pérdida de peso, diarrea y dolores óseos asociados, hizo pensar que el agente desencadenante de la respuesta inmunológica pudo ser el estímulo que elevó la IgG4 sérica llevando al diagnóstico de posible enfermedad relacionada con IgG4.(AU)

We present a case with iatrogenic allogenosis who, after undergoing surgery, presented acute pancreatitis of unspecified etiology with elevated serum levels of immunoglobulin 4 (IgG4). The association with a good therapeutic response to steroid treatment coupled with a history of adjuvant-induced systemic inflammatory autoimmune syndrome, insufficiency chronic kidney disease with biopsy that reported severe tubular atrophy with fibrosis, intestinal pseudotumors, weight loss, diarrhea and associated bone pain, suggested that the immunogenic agent that triggers the immune response could be the stimulus to raise serum IgG4 leading to the diagnosis of possible IgG4 disease.(AU)

The Significance of Serum IgG4/IgG and IgG4/IgG1 Ratio in the Diagnosis Value of IgG4-Related Diseases.

OBJECTIVE: Elevated serum immunoglobulin G4 (IgG4) is one of the important features of patients with IgG4-related diseases (IgG4-RD). But diagnosing these diseases using IgG4 alone is tricky because the tests can sometimes give inaccurate results. Our research is focused on studying the ratio of IgG4 to two other substances, immunoglobulin G (IgG) and immunoglobulin G1 (IgG1), in the blood. We hope this approach will lead to more accurate diagnoses of IgG4-RD. METHODS: We conducted a study on 68 patients diagnosed with IgG4-related diseases (IgG4-RD) and 160 individuals suffering from other autoimmune diseases (AID) at our hospital between June 2018 and June 2022. Eighty healthy people who underwent physical examination in our hospital at the same time were randomly selected as controls, and medical records were collected for all subjects. The serum IgG and IgG subclasses were detected, and the IgG4/IgG and IgG4/IgG1 ratios were calculated. RESULTS: We found that patients with IgG4-RD have significantly higher average levels of serum IgG4 and more elevated IgG4/IgG and IgG4/IgG1 ratios compared to individuals with other AID patients and those in good health (p < 0.001). The receiver operating characteristic (ROC) curve analysis showed that the diagnostic effectiveness area under the curve (AUC) of the serum IgG4/IgG ratio for IgG4-RD was 0.906 (95% confidence interval [CI], 0.865-0.947) and 0.921 (95% CI, 0.876-0.965) when comparing with other AID patients and healthy individuals, respectively. The optimal cut-off value for the IgG4/IgG ratio was 0.147 (with 72.1% sensitivity and 94.4% specificity) compared with AID patients and 0.129 (with 77.9% sensitivity and 96.2% specificity) compared with healthy individuals. Similarly, the AUC of the serum IgG4/IgG1 ratio for diagnosing IgG4-RD was 0.919 (95% CI, 0.882-0.956) and 0.916 (95% CI, 0.870-0.962) when compared with patients with other AID and healthy individuals, respectively. When we divided our study participants into a high IgG4/IgG ratio group (>0.129) and a normal IgG4/IgG ratio group (≤0.129) using a cut-off point of 0.129, we found through logistic regression analysis that those with a high IgG4/IgG ratio were more likely to be associated with IgG4-RD (odds ratio [OR], 31.25; 95% CI, 15.31-63.79; p < 0.001). Likewise, a high IgG4/IgG1 ratio was also significantly linked to an increased risk of IgG4-RD (OR, 36.39; 95% CI, 17.57-75.38; p < 0.001). CONCLUSIONS: The serum's IgG4/IgG and IgG4/IgG1 ratios are independently linked to IgG4-RD and are valuable in its diagnosis.

A case of pancreatic ductal adenocarcinoma concomitant with IgG4-related disease in the pancreas and the stomach.

A 75-year-old Japanese woman visited a hospital with a stomachache. The patient was diagnosed with localized mild acute pancreatitis. Blood tests revealed elevated serum IgG4 levels. Contrast-enhanced computed tomography showed a hypovascular mass, 3 cm in size, in the pancreatic body with dilation of the upstream duct. Additionally, it showed another tumorous lesion of 10 mm in size in the anterior wall of the stomach, and endoscopic examination confirmed a submucosal tumor (SMT) sized 10 mm in the anterior wall of the stomach. Endoscopic ultrasound-guided fine needle aspiration biopsy (EUS-FNAB) of the pancreas revealed an adenocarcinoma concomitant with marked IgG4-positive cell infiltration. Hence, distal pancreatectomy with local gastrectomy was performed, and the final diagnosis was concluded as pancreatic ductal adenocarcinoma (PDAC) complicated by IgG4-related diseases (IgG4-RD) in the pancreas and stomach. IgG4-RD of the digestive tract is exceedingly rare. The correlation between PDAC and autoimmune pancreatitis or malignancy and IgG4-RD is controversial. However, the clinical course and histopathological examination, in this case, provide valuable suggestive findings for further discussion.

A Tumefactive Fibroinflammatory Lesion of the Head and Neck Mimicking Immunoglobulin G4-related Disease.

A 67-year-old woman with a 5-year history of recurrent swollen eyelids and epistaxis, diagnosed as immunoglobulin G4-related diseases (IgG4-RD) based on hyper-IgG4-emia and IgG4-positive cell infiltration to the lesion, was referred to our department due to recurrent symptoms despite corticosteroid therapies. Computed tomography revealed an osteoclastic sinus mass with prominent neutrophil infiltration and necrosis that was incompatible with IgG4-RD histopathologically. Finally, she was diagnosed with a tumefactive fibroinflammatory lesion (TFIL) of the head and neck and treated with high-dose corticosteroids. Physicians should remember that TFIL can mimic IgG4-RD in the head and neck region with prominent neutrophil infiltration and necrosis.

Anti-IgLON5 disease: a novel topic beyond neuroimmunology.

Anti-IgLON5 disease is a recently defined autoimmune disorder of the nervous system associated with autoantibodies against IgLON5. Given its broad clinical spectrum and extremely complex pathogenesis, as well as difficulties in its early diagnosis and treatment, anti-IgLON5 disease has become the subject of considerable research attention in the field of neuroimmunology. Anti-IgLON5 disease has characteristics of both autoimmunity and neurodegeneration due to the unique activity of the anti-IgLON5 antibody. Neuropathologic examination revealed the presence of a tauopathy preferentially affecting the hypothalamus and brainstem tegmentum, potentially broadening our understanding of tauopathies. In contrast to that seen with other autoimmune encephalitis-related antibodies, basic studies have demonstrated that IgLON5 antibody-induced neuronal damage and degeneration are irreversible, indicative of a potential link between autoimmunity and neurodegeneration in anti-IgLON5 disease. Herein, we comprehensively review and discuss basic and clinical studies relating to anti-IgLON5 disease to better understand this complicated disorder.

IgG4 paratesticular fibrous pseudotumor: Case presentation and literature review.

PFP with IgG-4 immunostaining is a rare paratesticular tumour. Pre-operative ultrasound scan and MRI usually confirm the benign nature of the paratesticular mass avoiding the need for radical orchiectomy. The final diagnosis is based on histology of the removed paratesticular tumour. FDG PET scan plays an important role in ruling out systematic IgG4-related disease (IgG4-RD). We describe a case of multiple paratesticular fibrous pseudotumors with IgG4 immunostaining, not associated with systemic IgG4 related disease.

Ascending aortic aneurysm associated with lymphoplasmacytic thoracic aortitis mimics acute type A intramural hematoma - case report.

INTRODUCTION: Lymphoplasmacytic thoracic aortitis is still underrecognized cause of thoracic aortic aneurysm. CASE REPORT: We herein report a case of symptomatic inflammatory ascending aortic aneurysm and pericarditis diagnosed on CT scan as acute type A intramural hematoma. Patient underwent emergency supracoronary ascending aorta replacement with a prosthetic graft. Marked inflammatory thickening of aneurysm wall was the intraoperative finding. Histopathologic examination of the excised aortic tissue showed inflammation with lymphoplasmacytic pattern of aortitis. CONCLUSION: This case demonstrates that lymphoplasmacytic aortitis may mimic symptoms and radiological findings of intramural hematoma.

[Unusual forms of inflammatory diseases of the central nervous system]. / Seltene Formen der entzündlichen Erkrankungen des Zentralnervensystems.

BACKGROUND: White matter lesions of the central nervous system (CNS) are frequently encountered on magnetic resonance imaging (MRI) exams. If the morphologic findings, clinical symptoms and laboratory results are not typical for one of the more common inflammatory CNS diseases, the diagnosis may become challenging, which also means that interesting and sometime emotional discussions may arise. OBJECTIVE: While frequent causes of inflammatory CNS diseases were already discussed in a previous article, we now focus on more seldom forms and place attention on morphologic characteristics which may help to find the correct diagnosis.

Immunohistochemical analysis of pyroptosis-related protein expression in IgG4-related sialadenitis.

BACKGROUND: NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3)-induced pyroptosis is involved in the development of a variety of autoimmune diseases, but its role in IgG4-related sialadenitis (IgG4-RS) is unclear. METHODS: Salivary gland tissues from 19 patients with IgG4-RS were designated the experimental group, and peritumoral tissues from 20 patients with benign salivary gland tumours were designated the control group. The cell morphology and fibrosis in the IgG4-RS samples were observed by haematoxylin-eosin (H&E) and Masson trichrome (MT) staining. Immunohistochemical (IHC) staining was used to determine pyroptosis-related proteins (NLRP3, ASC (apoptosis-associated speck-like protein containing a CARD), Caspase-1, GSDMD (gasdermin family members, including digestive dermatin D), interleukin 1ß (IL-1ß), and interleukin 18 (IL-18)) expression levels. RESULTS: Increased lymphoid follicle proliferation, germinal centre plasma cell infiltration, and irregular fibrosis were observed in the experimental group compared with the control group. The NLRP3, ASC, Caspase-1, GSDMD, IL-1ß, and IL-18 levels were significantly higher in the experimental group than in the control group (p < 0.0001). CONCLUSION: This study suggested that pyroptosis-related proteins might be involved in IgG4-RS pathogenesis. However, the specific cellular pathway involved and whether multiple cell death pathways contribute to the occurrence of IgG4-RS still need to be further studied.

The characteristics and clinical significance of elevated serum IgG4/IgG levels in patients with Graves' disease.

PURPOSE: This study aims to further explore the clinical and laboratory characteristics of patients with GD with high serum IgG4 based on the IgG4/IgG ratio. METHODS: This study is a prospective observational study. A total of 25 normal controls and 84 people newly diagnosed with GD were enrolled in this study. Taking the IgG4/IgG ratio of 8% as the cutoff value, the experimental groups were further divided into two subgroups: the high IgG4/IgG subgroup and the normal IgG4/IgG subgroup. We evaluated the differences in clinical characteristics and laboratory parameters between the groups. RESULTS: The IgG4, IgG4/IgG, and IL-17 of the newly diagnosed GD group were significantly higher than those of the normal control group (P < 0.05). The differences in age, IL-1ß, IL-17, and eosinophil count between the high IgG4/IgG subgroup and the normal IgG4/IgG subgroup were statistically significant (P < 0.05). After ATD treatment, some patients developed allergies; the high IgG4/IgG subgroup was significantly higher than the normal IgG4/IgG subgroup (χ2 = 4.424, P = 0.035). After 3 months of ATD treatment in patients with GD, the TRAb in the normal IgG4/IgG subgroup were significantly lower than before (P < 0.05), while the difference in the high IgG4/IgG subgroup was not statistically significant (P > 0.05). CONCLUSIONS: A small portion of patients with GD harbored elevated serum IgG4/IgG levels. They are younger, have higher eosinophils, and are more prone to allergies; also, they have higher levels of cytokines IL-1ß and IL-17 and their remission is not easily attained after treatment with ATD; this could be due to the instability of the Th17/Treg cell balance.

Clinical analysis of 21 cases of IgG4-related diseases / 口腔疾病防治

Objective@# To summarize the clinical manifestations of IgG4-related diseases in the head and neck, explore treatment methods.@*Methods @#The clinical data of 21 patients diagnosed with IgG4-related diseases were retrospectively analyzed. The clinical data and the results of glucocorticoid and immunosuppressive therapy were studied retrospectively.@* Results@#All patients had swollen sclerotic masses, and CT showed irregular high-density masses with uniform enhancement in the enlarged glands. Some patients had mucosal thickening and mass-like changes in theoral cavity, nose, sinuses, throat and other tissues, and most of the patients had cervical lymphadenopathy and elevated serum IgG4 levels (≥ 1.35 g/L). Histopathological examination of affected exosine glands and affected mucosa and lymph nodes in all patients showed infiltration of lymphocytes, plasma cells and IgG4+ plasma cells. In 21 patients, the mass in the affected glands and mucosa (including head, neck and other tissues) disappeared, and the clinical symptoms were relieved after the application of glucocorticoids. However, with a reduction in glucocorticoids, the mass recurred or even worsened.@*Conclusion @#For patients with a single mass in the submandibular gland, parotid gland and other salivary glands, as well as lymph node enlargement, CT is the first choice to identify the nature of gland neoplasms. Combined with pathological examination, related auxiliary examination and peripheral blood examination are also needed to obtain a definitive diagnosis. Glucocorticoid therapy is used to achieve a good prognosis, and long-term follow-up and timely adjustment of medication regimens are required.

IgG4 related disease involving the adrenal glands: a case report / 中华泌尿外科杂志

IgG4-related diseases have a low incidence and are easily misdiagnosed as tumors in clinical treatments. A 26-year-old male patient was admitted to the hospital because of a left adrenal tumor found in health examination for more than 5 months. The tumor in the left adrenal region could be seen from abdominal CT, and the retroperitoneal laparoscopic resection of the left adrenal tumor was performed. Postoperative pathology was consistent with IgG4-related diseases, and serum IgG4 was abnormally high. After 2 months’ follow-up, serum IgG4 returned to normal, and no special discomfort.

Advances in diagnosis and treatment of IgG4-related hepatobiliary and pancreatic diseases / 临床肝胆病杂志

IgG4-related hepatobiliary and pancreatic diseases are a part of the IgG4-related disease multiorgan fibroinflammatory disorder, including IgG4-related autoimmune pancreatitis, IgG4-related sclerosing cholangitis, and IgG4-related hepatic involvement. The main pathological features include IgG4 + plasma cell/lymphocyte infiltration, storiform fibrosis, obliterative phlebitis, and eosinophil infiltration. The diagnosis of this disease is often based on the comprehensive diagnostic criteria for IgG4-related diseases and organ-specific diagnostic criteria. However, it is difficult to differentiate IgG4-related hepatobiliary and pancreatic diseases from neoplastic diseases, and novel diagnostic biomarkers are expected to improve the sensitivity and specificity of diagnosis. To date, glucocorticoids remain the first-line drug for this disease, and biological agents, especially anti-CD20 monoclonal antibody, may be an alternative therapy for patients with corticosteroid contraindication/intolerance or recurrent/refractory disease.

[Progress of IgG4 related sino-nasal diseases].

IgG4 related disease（IgG4-RD）is a newly recognized chronic fibroinflammatory disease in recent years.It is often accompanied by the significant elevation of serum IgG4 level，but the diagnostic specificity of the elevation is not high.The diagnosis is mainly based on histopathology，which is characterized by dense IgG4 positive plasma cell infiltration，storiform fibrosis and obliteran phlebitis.IgG4-RDcan involve various organs of the body，but less involve the nasal cavity and paranasal sinuses.The nasal symptoms of IgG4-RD are lack of specificity，so it is easier to be missed and misdiagnosed.PET/CT has important value in the diagnosis and differential diagnosis of the disease.We reviewed the relevant studies of IgG4-RD in nasal cavity and paranasal sinus in recent years,in order to improve the understanding of IgG4-RD in nasal cavity and paranasal sinuses and to improve the diagnosis and treatment rate.

Immunoglobulin G4-related disease of the cavernous sinus with orbit invasion - A case report.

BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) is a rare systemic disease of unknown etiology. It is characterized by tissue infiltration caused by IgG4 plasma cells and sclerosing inflammation of various body organs. At present, there are very few reported cases of IgG4-RD invasion of cavernous sinus and the orbit. CASE DESCRIPTION: A 56-year-old female with a history of rheumatoid arthritis was presented with a gradual onset of right oculomotor, abducens, and trigeminal nerve deficits. Four weeks after the onset of symptoms, the patient developed gradual visual deficit. Following this, a trial of steroids was administered to the patient. However, the treatment did not work as expected and patient's condition worsened. She progressed on to suffer complete visual loss in the right eye. Extensive work-up conducted on her turned out to be nondiagnostic. After this, the patient was referred to us for our evaluation. Neuroimaging revealed a right-sided cavernous sinus and orbital apex lesion. Given the lack of diagnosis and response to steroid treatment, we recommended surgical intervention and performed a modified pterional and pretemporal approach with extradural anterior clinoidectomy and transcavernous approach. We performed a lesion biopsy and cavernous sinus decompression, which helped in the partial recovery of visual function. The pathology report was consistent with IgG4-RD. CONCLUSION: IgG4-RD is a rare disease that occurs even less in combination with cavernous sinus and orbit invasion. The rarity of the disease and the diverse presentation of symptoms have sometimes caused delayed diagnosis and intervention. Patients who failed to respond to conservative management and patients in the fibrotic stage of the disease without other organ involvement may benefit from surgical intervention if amenable. Early suspicion, diagnosis, and intervention can facilitate better prognosis.

Ten-year epidemiological study of ocular and orbital tumors in Chiba University Hospital.

BACKGROUND: The purpose of this study is to determine the epidemiology of tumors of the ocular adnexa and orbit in Japan. METHODS: We conducted a retrospective study on the histopathological reports in the medical records of the Chiba University Hospital from April 2009 to March 2019. Three hundred and seventy two records were examined. In addition, we examined the annual changes in the major types of tumors including malignant lymphomas and IgG4-related diseases (IgG4-RDs). RESULTS: There were 270 conjunctival or eyelid tumors with 166 benign and 104 malignant. There were 102 orbital tumors with 55 benign, 47 malignant tumors, and 21 cases of IgG4-RDs. Ten cases of adenoma (2.7%), another benign tumor, was also diagnosed. The major malignant tumors were malignant lymphoma in 74 cases, sebaceous gland carcinoma (SGC) in 28 cases, basal cell carcinoma in 15 cases, and squamous cell carcinoma in 8 cases. The SGCs were the most common malignant eyelid tumor at 54%. Among the malignant lymphomas, extranodal marginal zone lymphomas of the mucosa-associated lymphoid tissue type, MALT lymphomas, was the most common at 51 cases and the second most common was the diffuse large B-cell lymphoma at 11 cases. The ratio of MALT lymphomas to that of all malignant lymphomas increased significantly with years. The serum IgG4 values were measured more often in the last 5 years (70%) than in the former 5 years (33%). CONCLUSIONS: We conclude that malignant lymphoma is a major malignant tumor in Japan and pathological biopsies should be done proactively to prevent missing IgG4-positive MALT lymphomas.

Differential diagnosis of immunoglobulin G4-related sialadenitis and Kimura's disease of the salivary gland: a comparative case series.

The aim of this study was to investigate key points for the differential diagnosis of immunoglobulin G4-related sialadenitis (IgG4-RS) and Kimura's disease (KD) involving the salivary glands. The clinical, serological, radiological, histological, and immunohistochemical features of 85 IgG4-RS cases and 52 KD cases were evaluated comparatively. Seventy-two IgG4-RS cases had enlargement of multiple salivary and/or lacrimal glands; 67 patients had bilateral submandibular gland (SMG) involvement. Unilateral parotid gland involvement (59.6%) and comorbid skin lesions (61.5%) were common in KD. Serum IgG4 was elevated in 94.1% of IgG4-RS cases versus 19.0% of KD cases (cut-off value=266.5mg/dl). KD was more commonly associated with elevated eosinophil counts (86% vs 23.1%) and elevated IgE concentrations (95.5% vs 76.6%). Storiform fibrosis, irregular lymphoid follicles, and increased IgG4-positive cells (112.9±37.6/high-power field (HPF)) were common in IgG4-RS. Acellular fibrosis, regular lymphoid follicles, IgE-positive reticular networks, increased IgE-positive cells (43.4±26.7/HPF), and tryptase-positive mast cells (29.7±13.3/HPF) were usually detected in KD. Computed tomography showed that 85.7% of KD cases involved subcutaneous fat tissue. A superficial hypoechoic and reticular pattern with multiple hypoechoic foci were the sonographic features of the SMG in IgG4-RS. Despite numerous overlapping manifestations, histopathological examination showed meaningful differences in the types of fibrosis, eosinophils, and IgG4-positive cell counts. Comprehensive evaluation of clinical, serological, radiological, and histopathological features are crucial for the differential diagnosis.

Anti-Neuronal IgG4 Autoimmune Diseases and IgG4-Related Diseases May Not Be Part of the Same Spectrum: A Comparative Study.

Background: IgG4 is associated with two emerging groups of rare diseases: 1) IgG4 autoimmune diseases (IgG4-AID) and 2) IgG4-related diseases (IgG4-RLD). Anti-neuronal IgG4-AID include MuSK myasthenia gravis, LGI1- and Caspr2-encephalitis and autoimmune nodo-/paranodopathies (CNTN1/Caspr1 or NF155 antibodies). IgG4-RLD is a multiorgan disease hallmarked by tissue-destructive fibrotic lesions with lymphocyte and IgG4 plasma cell infiltrates and increased serum IgG4 concentrations. It is unclear whether IgG4-AID and IgG4-RLD share relevant clinical and immunopathological features. Methods: We collected and analyzed clinical, serological, and histopathological data in 50 patients with anti-neuronal IgG4-AID and 19 patients with IgG4-RLD. Results: A significantly higher proportion of IgG4-RLD patients had serum IgG4 elevation when compared to IgG4-AID patients (52.63% vs. 16%, p = .004). Moreover, those IgG4-AID patients with elevated IgG4 did not meet the diagnostic criteria of IgG4-RLD, and their autoantibody titers did not correlate with their serum IgG4 concentrations. In addition, patients with IgG4-RLD were negative for anti-neuronal/neuromuscular autoantibodies and among these patients, men showed a significantly higher propensity for IgG4 elevation, when compared to women (p = .005). Last, a kidney biopsy from a patient with autoimmune paranodopathy due to CNTN1/Caspr1-complex IgG4 autoantibodies and concomitant nephrotic syndrome did not show fibrosis or IgG4+ plasma cells, which are diagnostic hallmarks of IgG4-RLD. Conclusion: Our observations suggest that anti-neuronal IgG4-AID and IgG4-RLD are most likely distinct disease entities.