Immunoglobulin G4 -related gastrointestinal disease associated with type 1 autoimmune pancreatitis: A case report.

Immunoglobulin G4 (IgG4)-related diseaseis a systemic inflammatory condition of unknown etiology characterized by increases in serum IgG4 and in the number of IgG4-positive cells in affected tissues. One of the commonly involved locations is the pancreas; this condition is known as type 1 autoimmune pancreatitis (AIP). Type 1 AIP, which shows a biliary stricture in the intrapancreatic bile duct, can be misdiagnosed as a malignancy due to similar cholangiography findings and clinical presentation. In rare cases complicated by post-bulbar duodenal ulcers, differentiating between type 1 AIP and malignancies is even more difficult. An 81-year-old male was referred to our hospital for the treatment of a pancreatic head mass and obstructive jaundice. Serological and radiological findings were consistent with both type 1 AIP and a malignancy. Gastroduodenoscopy revealed a post-bulbar duodenal ulcer with endoscopic features that evoked malignant duodenal invasion. Although biopsies were negative for malignant cells, subsequent bleeding from the lesion suggested the progression of malignancy, which led to surgical resection. Pancreatoduodenectomy and pathological examination indicated that type 1 AIP was present. Simultaneously, the involvement of IgG4-related disease in the ulcerative lesion was suggested. To our knowledge, this is the first reported case of type 1 AIP complicated by post-bulbar duodenal ulcers, which was misdiagnosed as malignancy and considered an IgG4-related gastrointestinal disease associated with type 1 AIP.

Immunoglobulin G4-related disease manifesting as peripheral neuropathy: A rare clinical symptom due to rare autoimmune disease.

Background: Nervous system involvement in immunoglobulin G4-related disease (IgG4-RD) has been rarely reported. Case Description: 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. Conclusion: This report highlights a rare case of IgG4-RD involving nerve roots that neurosurgeons should consider.

Sinonasal immunoglobulin G4-related disease: a case report of an atypical and rare entity.

BACKGROUND: Immunoglobulin G4-related disease is marked by extensive inflammation and fibrosis of an unknown autoimmune component, with an overall incidence ranging from 0.78 to 1.39 per 105 person-years. Sinonasal immunoglobulin G4-related disease is atypical and exceedingly uncommon in the existing literature, frequently manifesting clinically as chronic rhinosinusitis, epistaxis, and facial pain. CASE PRESENTATION: This report describes a 25-year-old Iraqi female who has been suffering from symptoms of chronic rhinosinusitis for 8 years. Despite undergoing several surgeries, there has been no improvement in her symptoms. A tissue biopsy that revealed dense lymphoplasmocytosis with noticeable plasma cell infiltration, storiform fibrosis, and obliterative angitis, along with positive immunohistochemical staining for Immunoglobulin G4 plasma cells, finally confirmed the diagnosis of sinonasal immunoglobulin G4-related disease. The patient responded well to oral prednisolone and methotrexate treatments. CONCLUSIONS: The main objective of the current report is to raise awareness among physicians about the significance of promptly identifying and diagnosing this rarity, thus preventing the adverse consequences linked to delayed diagnosis and treatment initiation.

Immunoglobulin G4 disease-related retroperitoneal fibrosis: A series of five cases.

Immunoglobulin G4 (IgG4)-related disease has the potential to impact any part of the body, including the walls of large- and medium-sized blood vessels and the ureters. While histopathologic examination is currently the standard method for identifying organ involvement and diagnosing IgG4-related disease (IgG4-RD), obtaining biopsy or surgical samples from vessel or ureteral walls is challenging. Given that patients may display only mild symptoms, non-invasive imaging plays a vital role in both diagnosing and managing IgG4-related diseases. Multidetector CT scans are valuable in establishing the primary diagnosis, identifying anatomical landmarks and assessing their relationships. Involvement of the genitourinary organs, such as the ureter, bladder, urethra, and male and female reproductive organs in IgG4-RD, is infrequent when compared to kidney involvement. The imaging findings may include the presence of a localised mass within or surrounding the affected organ or a generalised enlargement of the organ. This report includes cross-sectional images of five cases of IgG4-RD involving large- and medium-sized blood vessels (the aorta and superior mesenteric artery) and the ureters. Contribution: This case series provides insight into the various imaging appearances of IgG4-related retroperitoneal organ involvement and helps differentiate it radiologically from retroperitoneal fibrosis.

Combinational elastography prior to pericardiectomy to assess liver condition in patients with constrictive pericarditis.

A 68-year-old man was diagnosed with pericarditis associated with immunoglobulin G4-related disease and was administered prednisolone 2 years prior to presentation. During the process of tapering off from prednisolone 1 year later, edema of the lower legs and pleural effusion worsened. He gradually developed dyspnea on exertion, and laboratory examinations revealed elevated liver enzyme levels. Diuretics were administered; however, the symptoms did not resolve. Transthoracic echocardiography and cardiac catheterization revealed findings consistent with those of constrictive pericarditis. Pericardiectomy was considered and the perioperative risks due to possible recovery from liver dysfunction were discussed. Combinational elastography was subsequently performed. The results indicated the absence of liver fibrosis, suggesting that liver dysfunction was attributable to liver congestion; thus, the liver dysfunction was considered reversible. Subsequently, pericardiectomy was performed. Given that constrictive pericarditis can lead to liver dysfunction due to congestion, the perioperative risk is often controversial when considering surgical interventions. Learning objective: Combinational elastography may be useful in the preoperative evaluation of patients with cardiac diseases complicated by liver dysfunction to distinguish liver fibrosis, understand the pathogenesis of liver dysfunction, and determine subsequent treatment strategies.

Immunoglobulin G4-related disease mimicking an appendiceal neoplasm: a case report.

Immunoglobulin G4-related disease (IgG4-RD) is a fibroinflammatory condition characterized by chronic activation of the immune system and a tendency to form tumorous lesions. IgG4-RD is frequently characterized by the presence of tumor-like masses affecting multiple organs and is easily mistaken for a malignant neoplasm. However, IgG4-RD affecting the appendix is extremely rare, with only seven cases reported previously. We report the case of a woman in her early 60s who presented with insidious abdominal pain and radiological findings mimicking appendiceal neoplasms. After diagnosing appendiceal neoplasms, surgery was performed. The patient had a serum IgG4 concentration of <1.35 g/L, which did not satisfy one of the three revised comprehensive diagnostic criteria for IgG4-RD. A pathological examination was conducted, and the patient was diagnosed with appendiceal IgG4-RD. To the best of our knowledge, there have been no previously reported cases of IgG4-RD affecting the appendix in patients with low serum IgG4 concentrations. This report may prove beneficial for the future understanding of IgG4-RD and for the revision of diagnostic and treatment strategies.

IgG4-related disease-rare but you should not forget it.

Immunoglobulin G4-related disease is a systemic immune-mediated disease with insidious evolution characterized by fibroinflammatory lesions over virtually any organ system. Despite the remarkable progression of knowledge, its etiology remains undefined. Due to its relapse-remitting pattern, it could accumulate irreversible damage, increasing comorbidities and mortality. This paper emphasizes key concepts for diagnosing and treating patients with this condition.

Utilizing Immunoglobulin G4 Immunohistochemistry for Risk Stratification in Patients with Papillary Thyroid Carcinoma Associated with Hashimoto Thyroiditis.

BACKGRUOUND: Hashimoto thyroiditis (HT) is suspected to correlate with papillary thyroid carcinoma (PTC) development. While some HT cases exhibit histologic features of immunoglobulin G4 (IgG4)-related disease, the relationship of HT with PTC progression remains unestablished. METHODS: This cross-sectional study included 426 adult patients with PTC (≥1 cm) undergoing thyroidectomy at an academic thyroid center. HT was identified based on its typical histologic features. IgG4 and IgG immunohistochemistry were performed. Wholeslide images of immunostained slides were digitalized. Positive plasma cells per 2 mm2 were counted using QuPath and a pre-trained deep learning model. The primary outcome was tumor structural recurrence post-surgery. RESULTS: Among the 426 PTC patients, 79 were diagnosed with HT. With a 40% IgG4 positive/IgG plasma cell ratio as the threshold for diagnosing IgG4-related disease, a cutoff value of >150 IgG4 positive plasma cells per 2 mm2 was established. According to this criterion, 53% (43/79) of HT patients were classified as IgG4-related. The IgG4-related HT subgroup presented a more advanced cancer stage than the IgG4-non-related HT group (P=0.038). The median observation period was 109 months (range, 6 to 142). Initial assessment revealed 43 recurrence cases. Recurrence-free survival periods showed significant (P=0.023) differences, with patients with IgG4 non-related HT showing the longest period, followed by patients without HT and those with IgG4-related HT. CONCLUSION: This study effectively stratified recurrence risk in PTC patients based on HT status and IgG4-related subtypes. These findings may contribute to better-informed treatment decisions and patient care strategies.

Robot-assisted thoracoscopic resection of a posterior mediastinal tumor with immunoglobulin G4-related disease: a case report.

BACKGROUND: Immunoglobulin (Ig)G4-related disease affects nearly every organ, and its clinical course varies depending on the involved organ; however, its occurrence in the mediastinum is rarely reported. CASE PRESENTATION: A 58-year-old woman presented with a posterior mediastinal tumor along the thoracic spine on imaging. Based on her elevated serum IgG4 level of 349.7 mg/dL, IgG4-related disease was suspected. Since the tumor was growing and malignancy could not be excluded, surgical resection was performed for definitive diagnosis. Robot-assisted thoracoscopic surgery was performed via the left semipronation and right thoracic approaches. The irregularly-shaped tumor was located on the level of the seventh to ninth thoracic vertebra, along the sympathetic nerve. A malignancy was not excluded based on the appearance of the tumor. The tumor had poor mobility. The sympathetic nerves, intercostal arteries, and veins were also excised. In this case, the articulated forceps, used during the robotic surgery, were useful in achieving complete tumor resection along the vertebral body. The pathological examination revealed IgG4-positive plasma infiltration, which fulfilled the criteria for IgG4-related diseases. The postoperative course was uneventful, and the patient underwent follow-up on an outpatient basis without additional medications. CONCLUSION: The clinical presentation of IgG4-related disease varies, based on the involved organs. This case was rare because the mediastinum was involved, and it emphasized the effectiveness of surgical resection.

Tubulointerstitial nephritis with IgG4-positive plasma cell infiltration and tertiary lymphoid tissue in a patient with cryoglobulinemic vasculitis: a case report.

Tertiary lymphoid tissue (TLT) develops at sites of chronic immune stimulation, including infection, autoimmune disease, transplant rejection, and cancer. Recently, TLT has been focused on an indicator for poor renal prognosis in various kidney diseases. In cryoglobulinemic vasculitis (CV), specific glomerular and vascular lesions are seen; however, tubulointerstitial lesions are usually nonspecific. We herein report the case of a 74-year-old man with idiopathic CV with rare tubulointerstitial lesions, such as tubulointerstitial nephritis (TIN) with IgG4-positive plasma cell infiltration and TLT. To our knowledge, this is the first report identifying TLT in the kidney biopsy in a patient with CV. Glucocorticoid improved the renal outcome. The association between CV and TIN with TLT remains unknown.

Diagnostic Dilemma: IgG4-Related Sclerosing Mesenteritis Mimicking an Abdominal Malignancy Enveloping the Superior Mesenteric Artery.

Sclerosing mesenteritis, a rare fibroinflammatory disease affecting the mesentery, presents a diagnostic challenge due to its varied clinical manifestations and unknown etiology. We present a case of a 50-year-old female presenting with epigastric pain and weight loss, initially suspected of abdominal malignancy. Imaging revealed a mesenteric mass, and histopathological examination confirmed dense lymphoplasmacytic infiltrate with storiform fibrosis, along with elevated serum IgG4 levels, indicative of IgG4-related sclerosing mesenteritis. Treatment with thalidomide and prednisolone resulted in significant mass regression and symptom improvement. Our case highlights the importance of considering sclerosing mesenteritis in the differential diagnosis of abdominal masses and suggests a potential therapeutic approach for this rare condition. Further research is warranted to elucidate its pathogenesis and optimize management strategies.

Type one autoimmune pancreatitis based on clinical diagnosis: A case report.

BACKGROUND: Autoimmune pancreatitis (AIP) is a rare form of autoimmune-mediated pancreatitis, which is easily misdiagnosed as pancreatic cancer and thus treated surgically. We studied the diagnosis and treatment of a patient with type 1 AIP recently admitted to our hospital, and reviewed the literature to provide a reference for clinical diagnosis of AIP. CASE SUMMARY: The chief complaint was yellowing of the body, eyes and urine for 21 d. The patient's clinical presentation was obstructive jaundice and imaging suggested pancreatic swelling. It was difficult to distinguish between inflammation and tumor. Serum immunoglobulin G4 (IgG4) was markedly elevated. IgG4 is an important serological marker for type 1 AIP. The patient was diagnosed with AIP, IgG4-related cholangitis, acute cholecystitis and hepatic impairment. After applying hormonal therapy, the patient's symptoms improved significantly. At the same time, imaging suggested that pancreatic swelling subsided, and liver function and other biochemical indicators decreased. The treatment was effective. CONCLUSION: In patients with pancreatic swelling, the possibility of AIP should be considered.

Immunoglobulin G4-related Autoimmune Pancreatitis and Hypopituitarism Following Immune Checkpoint Inhibitor Therapy: A Case Report.

A 70-year-old man underwent nephrectomy for renal cell carcinoma followed by 3 cycles of pembrolizumab as adjuvant chemotherapy. Three months later, he complained of appetite loss. He was diagnosed with secondary adrenal insufficiency and pancreatic tumor. Amylase and immunoglobulin G (IgG) 4 levels were normal. The differential diagnosis poses challenges in distinguishing pancreatic cancer, renal cell carcinoma metastasis, and autoimmune pancreatitis, necessitating tumor resection surgery. A histological examination revealed IgG4-related sclerosing pancreatitis. Postoperatively, there was no recurrence of pancreatitis. It is essential to consider the potential development of IgG4-related diseases after the administration of immune checkpoint inhibitors.

Viral DNA in submandibular gland tissue with an inflammatory disorder.

Background: The etiology behind different types of chronic sialadenitis (CS), some of which exhibit IgG4 overexpression, is unknown. Further, IgG4-related disease (IgG4-RD) commonly affects the submandibular gland, but its relationship to IgG4-overexpressing CS, and the antigen triggering IgG4 overexpression, remain unknown. Materials and Methods: By qPCR, we assessed the presence of 21 DNA-viruses causing IgG4 overexpression in submandibular gland tissue from patients with IgG4-positive and IgG4-negative CS. Healthy submandibular glands and glands with sialolithiasis without CS were used as controls. We examined the distribution of HHV-7, HHV-6B and B19V DNA, within virus PCR-positive tissues with RNAscope in-situ hybridization (RISH). Results: We detected DNA from seven viruses in 48/61 samples. EBV DNA was more prevalent within the IgG4-positive samples (6/29; 21%) than the IgG4-negative ones (1/19; 5.3%). B19V DNA was more prevalent within the IgG4-negative samples (5/19; 26%) than the IgG4-positive ones (4/29; 14%). The differences in virus prevalence were not statistically significant. Of the IgG4-RD samples (n = 3) one contained HHV-6B DNA. RISH only showed signals of HHV-7. Conclusions: None of the studied viruses are implicated as triggering IgG4-overexpression in CS. Although our results do not confirm viral etiology in the examined conditions, they provide valuable information on the prevalence of viruses in both diseased and healthy submandibular gland tissue.

Understanding autoimmune pancreatitis: Clinical features, management challenges, and association with malignancies.

In this editorial we comment on the article by Jaber et al. Autoimmune pancreatitis (AIP) represents a distinct form of pancreatitis, categorized into AIP-1 and AIP-2, characterized by obstructive jaundice, lymphoplasmacytic infiltrate, and fibrosis. AIP-1, associated with elevated immunoglobulin G4 (IgG4) levels, exhibits higher relapse rates, affecting older males, while AIP-2 is less common and linked to inflammatory bowel disease. AIP is considered a manifestation of IgG4-related systemic disease, sharing characteristic histological findings. Steroids are the primary treatment, with emerging biomarkers like interferon alpha and interleukin-33. AIP poses an increased risk of various malignancies, and the association with pancreatic cancer is debated. Surgery is reserved for severe cases, necessitating careful evaluation due to diagnostic challenges. AIP patients may have concurrent PanINs but display favorable long-term outcomes compared to pancreatic cancer patients. Thorough diagnostic assessment, including biopsy and steroid response, is crucial for informed surgical decisions in AIP.

Two Surgical Cases of Colorectal Cancer in Patients With Immunoglobulin G4-Related Disease.

Immunoglobulin G4-related disease (IgG4RD) is a relatively new disease concept that is most common in Asia. It is a systemic chronic lymphoproliferative disease that is diagnosed by mass formation or thickened lesion, a high serum IgG4 level (≥135 mg/dL), and confirmation of lymphocytes and plasma cells by histopathological examination. The precise mechanism of this disease remains elusive; however, distinguishing IgG4RD from malignancy proves challenging due to its manifestation of swollen lymph nodes and retroperitoneal thickening and fibrosis. Malignancy is also 3.5 times more likely in cases with IgG4RD. In this study, we report two cases of colorectal cancer in patients with IgG4RD who underwent surgery. In both cases, excising the tumor from the retroperitoneal posed a challenge, and swollen lymph nodes were observed without evidence of cancer metastasis. We believe that these are very informative cases, and we report the cases with a literature review of IgG4RD.

Neurological Involvement in a Portuguese Cohort of IgG4-Related Disease.

INTRODUCTION: Neurological involvement in immunoglobulin G4-related disease (IgG4-RD) is increasingly recognized. Its diagnosis can be challenging due to clinical mimics and difficulty in obtaining nervous system biopsies. The aim of this study was to describe a cohort of neurological IgG4-RD patients. METHODS: Patients were recruited from a neuroimmunology tertiary center. Clinical, laboratory, neuroimaging and histological data were reviewed. RESULTS: Fifteen patients (60% women), with a median age of 53 years (48.5 - 65.0) were included: 13 (86.7%) classified as possible IgG4-RD, one (6.7%) as probable and one (6.7%) as definitive. The most common neurological phenotypes were meningoencephalitis (26.7%), orbital pseudotumor (13.3%), cranial neuropathies (13.3%), peripheral neuropathy (13.3%), and longitudinally extensive transverse myelitis (LTEM) (13.3%). Median serum IgG4 concentration was 191.5 (145.0 - 212.0) mg/dL. Seven in 14 patients had CSF pleocytosis (50.0%) and oligoclonal bands restricted to the intrathecal compartment, while most cases presented elevated CSF proteins (64.3%). Magnetic resonance imaging abnormalities included white matter lesions in four (26.7%), hypertrophic pachymeningitis in two (13.3%), and LETM in two (13.3%). Two patients had biopsy-proven IgG4-RD in extra-neurological sites. CONCLUSION: This study highlights the phenotypical variability of the neurological IgG4-RD. Biopsy inaccessibility reinforces the importance of new criteria for the diagnosis of this subset of patients.

Unmet needs in biomarkers for autoimmune pancreatitis diagnosis.

Autoimmune pancreatitis (AIP) is a rare chronic autoimmune disorder. The diagnosis of AIP mainly depends on histopathology, imaging and response to treatment. Serum immunoglobulin 4 (IgG4) is used only as collateral evidence in diagnostic criteria for AIP because of its moderate sensitivity. Serum IgG4 levels are normal in 15%-37% of type 1 AIP and most of type 2 AIP patients. In these patients, the indeterminate imaging and histopathology may lead to the difficulty in definitive diagnosis of AIP. Therefore, discovery of new biomarkers is important for AIP diagnosis. Here, we provide some views on the progression and challenges in identifying novel serological biomarkers in AIP diagnosis.

Radiology domain in the diagnosis of IgG4-RD according to the 2019 American College of Rheumatology and European League Against Rheumatism classification.

OBJECTIVES: To evaluate the performance of radiology-related inclusion criteria of the 2019 ACR-EULAR classification system in the diagnosis of IgG4-related disease (IgG4-RD). METHODS: This retrospective single-institution study included patients who received a diagnosis of IgG4-RD between January 2010 and December 2020. Two abdominal radiologists independently reviewed baseline imaging studies and scored radiology findings according to the 2019 ACR-EULAR classification criteria. Additional scores were assigned based on serological, histopathological, and immunostaining features. RESULTS: Seventy-four patients (58 males and 16 females) with a mean age of 59.3 ± 13.9 years diagnosed with IgG4-RD were included. 51/74 (68.9%) were classified as having IgG4-RD according to the 2019 ACR-EULAR classification criteria. To reach a score ≥ 20 in these 51 patients, the radiology domain was sufficient in 20/51 (39.2%) and adding the serology domain was required for another 20/51 (39.2%). The remaining 11/51 patients (21.6%) required the histopathology and immunostaining domains. Radiological involvement of two or more organs at presentation was significantly associated with a score of ≥ 20 and seen in 43/51 (84.3%) compared to 5/23 (21.7%) of the non-classified group (p < 0.001). The group classified as having IgG4-RD showed a significantly higher proportion of elevated IgG4 levels (39/51, 76.5%) than the non-classified group (8/23, 34.8%) (< 0.001). CONCLUSION: The study findings support the effectiveness of the radiology-related inclusion criteria of the 2019 ACR-EULAR classification system in diagnosing IgG4-RD. Combining radiology and serology domains achieved the cut-off in 80% of IgG-RD patients, enabling non-invasive diagnosis. The classification of IgG4-RD was significantly associated with multi-organ involvement, particularly affecting the pancreas and biliary system. CRITICAL RELEVANCE STATEMENT: This study is the first to evaluate the diagnostic performance of the radiology domain in the 2019 ACR-EULAR classification criteria. The study results confirm its utility and potential to enable non-invasive diagnosis when combined with serological testing in a significant proportion of patients. KEY POINTS: • A significant proportion of patients can be diagnosed with IgG4-RD using the radiology and serology domains exclusively. • Multi-organ involvement is significantly associated with classifying patients as IgG4-RD, with the pancreas and biliary system most frequently affected. • A high level of inter-reader agreement in the scoring of the radiology domain supports its reliability.