Exploring the depths of IgG4: insights into autoimmunity and novel treatments.

IgG4 subclass antibodies represent the rarest subclass of IgG antibodies, comprising only 3-5% of antibodies circulating in the bloodstream. These antibodies possess unique structural features, notably their ability to undergo a process known as fragment-antigen binding (Fab)-arm exchange, wherein they exchange half-molecules with other IgG4 antibodies. Functionally, IgG4 antibodies primarily block and exert immunomodulatory effects, particularly in the context of IgE isotype-mediated hypersensitivity reactions. In the context of disease, IgG4 antibodies are prominently observed in various autoimmune diseases combined under the term IgG4 autoimmune diseases (IgG4-AID). These diseases include myasthenia gravis (MG) with autoantibodies against muscle-specific tyrosine kinase (MuSK), nodo-paranodopathies with autoantibodies against paranodal and nodal proteins, pemphigus vulgaris and foliaceus with antibodies against desmoglein and encephalitis with antibodies against LGI1/CASPR2. Additionally, IgG4 antibodies are a prominent feature in the rare entity of IgG4 related disease (IgG4-RD). Intriguingly, both IgG4-AID and IgG4-RD demonstrate a remarkable responsiveness to anti-CD20-mediated B cell depletion therapy (BCDT), suggesting shared underlying immunopathologies. This review aims to provide a comprehensive exploration of B cells, antibody subclasses, and their general properties before examining the distinctive characteristics of IgG4 subclass antibodies in the context of health, IgG4-AID and IgG4-RD. Furthermore, we will examine potential therapeutic strategies for these conditions, with a special focus on leveraging insights gained from anti-CD20-mediated BCDT. Through this analysis, we aim to enhance our understanding of the pathogenesis of IgG4-mediated diseases and identify promising possibilities for targeted therapeutic intervention.

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.

Immunoglobulin G4-related disease presenting with nephrotic syndrome due to minimal change disease: a case report.

BACKGROUND: Immunoglobulin G4-related disease is an inflammatory disease affecting multiple organs including the kidney. Immunoglobulin G4-related kidney disease most commonly manifests as a tubulointerstitial nephritis and is associated with glomerular disease in a proportion of cases. Membranous nephropathy is the most frequent glomerular lesion. Herein, we report the first documented case of immunoglobulin G4-related disease presenting with nephrotic syndrome owing to minimal change disease. CASE PRESENTATION: A 67-year-old South Asian male presented to our service with systemic upset and leg swelling. He had heavy proteinuria (urine protein:creatinine ratio 1042 mg/mmol) and was hypoalbuminemic (17 g/L) and hypercholersterolemic (9.3 mmol/L), consistent with the nephrotic syndrome. His serum creatinine was 140 µmol/L, and he was hypocomplementemic (C3 0.59 g/L, C4 < 0.02 g/L) with raised immunoglobulin G4 subclass levels (5.29 g/L). Kidney biopsy demonstrated minimal change disease alongside a plasma-cell-rich tubulointerstitial nephritis with strong positive staining for immunoglobulin G4. A diagnosis of minimal change disease in the setting of immunoglobulin G4-related disease was made. He was commenced on oral prednisolone at 60 mg daily but suffered infectious complications, including necrotizing fasciitis within 3 weeks of starting treatment, ultimately resulting in his death 52 days after initial presentation. CONCLUSION: This case highlights the potential for immunoglobulin G4-related disease to be associated with a spectrum of glomerular pathologies including minimal change disease. It adds to the differential diagnosis of secondary causes of minimal change disease, and moreover, aids as an important reminder of the potential complications of high-dose steroids used in its treatment.

The clinical outcomes and healthcare resource utilization in IgG4-related disease: a claims-based analysis of commercially insured adults in the United States.

OBJECTIVES: IgG4-related disease (IgG4-RD) can affect nearly any organ and is often treated with glucocorticoids, which contribute to organ damage and toxicity. Comorbidities and healthcare utilization in IgG4-RD are poorly understood. METHODS: We conducted a cohort study using claims data from a United States managed care organization. Incident IgG4-RD cases were identified using a validated algorithm; general population comparators were matched by age, sex, race/ethnicity, and index date. The frequency of 21 expert-defined clinical outcomes associated with IgG4-RD or its treatment and healthcare-associated visits and costs were assessed 12 months before and 36 months after the index date (date of earliest IgG4-RD-related claim). RESULTS: There were 524 cases and 5,240 comparators. Most cases received glucocorticoids prior to (64.0%) and after (85.1%) the index date. Nearly all outcomes, many being common glucocorticoid toxicities, occurred more frequently in cases vs comparators. During follow-up, the largest differences between cases and comparators were seen for gastroesophageal reflux disease (prevalence difference: +31.2%, p< 0.001); infections (+17.3%, p< 0.001); hypertension (+15.5%, p< 0.01); and diabetes mellitus (+15.0%, p< 0.001). The difference in malignancy increased during follow-up from +8.8% to + 12.5% (p< 0.001). 17.4% of cases used pancreatic enzyme replacement therapy during follow-up. Over follow-up, cases were more often hospitalized (57.3% vs 17.2%, p< 0.01) and/or had an ER visit (72.0% vs 36.7%, p< 0.01); all costs were greater in cases than comparators. CONCLUSIONS: Patients with IgG4-RD are disproportionately affected by adverse outcomes, some of which may be preventable or modifiable with vigilant clinician monitoring. Glucocorticoid-sparing treatments may improve these outcomes.

The "great imitator": IgG4-related disease of the oral cavity. Two case reports and scoping review.

This study aimed to review the lesser-known intraoral manifestations of immunoglobulin G4-related disease (IgG4-RD). In this paper we report an unprecedented case of oral IgG4-RD mimicking angiolymphoid hyperplasia with eosinophilia (ALHE), and another case presenting as plasma cell gingivitis. We then performed a scoping review of published cases of IgG4-RD involving the oral cavity. The following data were collected for each case: age, sex, intraoral site(s) involved, clinical appearance, imaging features, serum IgG4 values, histopathology, treatment, and follow-up duration. Fifty-one cases of oral IgG4-RD were published in literature. The hard palate and jaw bones were the two main locations reported, while the histological identification of a IgG4/IgG plasma cells ratio ≥40% was fundamental for diagnosis. Conversely, the pathological features of storiform fibrosis and obliterative phlebitis were not common. Future reports regarding oral IgG4-RD should report clear adherence to the recognized international diagnostic criteria of the disease.

Laminin 511-E8, an autoantigen in IgG4-related cholangitis, contributes to cholangiocyte protection.

Background & Aims: IgG4-related cholangitis (IRC) is the hepatobiliary manifestation of IgG4-related disease. Anti-laminin 511-E8 autoantibodies have been identified in its pancreatic manifestation. Laminin 511-E8 promotes endothelial barrier function, lymphocyte recruitment, and cholangiocyte differentiation. Here, we investigate anti-laminin 511-E8 autoantibody presence in IRC, and mechanisms via which laminin 511 may contribute to cholangiocyte protection. Methods: Anti-laminin 511-E8 serum autoantibody positivity was assessed by ELISA. RNA sequencing and RT-qPCR were performed on human H69 cholangiocytes treated with recombinant laminin 511-E8. H69 cholangiocytes were subjected to shRNA knockdown targeting genes encoding laminin 511 (LAMA5, LAMB1, LAMC1) or treated with recombinant laminin 511-E8. Cholangiocellular bile acid influx was quantified radiochemically using 22,23-3H-glycochenodeoxycholic acid (GCDC). GCDC-induced apoptosis was determined by Caspase-3/7 assays. Cholangiocellular barrier function was assessed by FITC-Dextran permeability assays. Immunofluorescent staining of laminin 511 and claudin 1 was performed on extrahepatic bile duct tissue of control and anti-laminin 511-E8 positive individuals with IRC. Results: Seven out of 52 individuals with IRC had autoantibodies against laminin 511-E8. Recombinant laminin 511-E8 led to differential expression of genes involved in secretion, barrier function, and inflammation. Knockdown of laminin 511 constituents increased toxic bile acid permeation and GCDC-induced apoptosis. Laminin 511-E8 treatment decreased toxic bile acid permeation and dose-dependently alleviated GCDC-induced apoptosis. LAMA5 and LAMC1 knockdown increased transepithelial permeability. Laminin 511-E8 treatment reduced transepithelial permeability and prevented T lymphocyte-induced barrier dysfunction. Laminin 511 and claudin 1 staining patterns appeared altered in anti-laminin 511-E8 positive individuals with IRC. Conclusions: Laminin 511-E8 is an autoantigen in subsets of individuals with IRC. Laminin 511 enhances cholangiocellular barrier function and protects cholangiocytes against T lymphocyte-induced barrier dysfunction, toxic bile acid permeation and bile acid-induced apoptosis. Impact and implications: A subset of patients with IgG4-related cholangitis (IRC) has autoantibodies against laminin 511-E8. In human cholangiocytes, laminin 511 protects against (T lymphocyte-induced) epithelial barrier dysfunction and hydrophobic bile acids. Laminin 511 and claudin 1 staining may be altered in extrahepatic bile ducts of patients with IRC who are anti-laminin 511-E8 positive. This makes it tempting to speculate that a decreased epithelial barrier function with attraction of immune cells and impaired bicarbonate secretion as a result of dysfunction of laminin 511 by autoantibody binding could potentially be a common systemic pathogenic mechanism in a subset of patients with IgG4-RD.

IgG4 autoantibodies and autoantigens in the context of IgG4-autoimmune disease and IgG4-related disease.

Immunoglobulins are an essential part of the humoral immune response. IgG4 antibodies are the least prevalent subclass and have unique structural and functional properties. In this review, we discuss IgG4 class switch and B cell production. We review the importance of IgG4 antibodies in the context of allergic responses, helminth infections and malignancy. We discuss their anti-inflammatory and tolerogenic effects in allergen-specific immunotherapy, and ability to evade the immune system in parasitic infection and tumour cells. We then focus on the role of IgG4 autoantibodies and autoantigens in IgG4-autoimmune diseases and IgG4-related disease, highlighting important parallels and differences between them. In IgG4-autoimmune diseases, pathogenesis is based on a direct role of IgG4 antibodies binding to self-antigens and disturbing homeostasis. In IgG4-related disease, where affected organs are infiltrated with IgG4-expressing plasma cells, IgG4 antibodies may also directly target a number of self-antigens or be overexpressed as an epiphenomenon of the disease. These antigen-driven processes require critical T and B cell interaction. Lastly, we explore the current gaps in our knowledge and how these may be addressed.

IgG4-Related Disease Complicated with Diffuse and Chronic Gastrointestinal Inflammation Leading to Small Intestinal Perforation.

Immunoglobulin (Ig) G4-related disease (IgG4-RD) is a systemic inflammatory disease characterized by elevated serum IgG4, IgG4+ cell infiltration, storiform fibrosis, and obliterative phlebitis. While IgG4-RD can affect various organs, gastrointestinal tract involvement is less common. Here, we report a 70-year-old female with IgG4-RD complicated with diffuse and chronic gastrointestinal inflammation which led to small intestinal perforation. She had been suffering from anorexia, abdominal pain, vomiting, and diarrhea, and hospitalized due to recurrent ileus. Consequently, she was referred due to small intestinal perforation required for surgical intervention. Pathology revealed acute and chronic inflammation with massive IgG4+ plasmacytes infiltration into mucosa of the small intestine, and ischemic change secondarily caused by chronic inflammation. Random biopsies from the mucosa of stomach, duodenum, ileum, and colon, also revealed diffuse and massive IgG4+ plasmacytes infiltration in stomach, duodenum, small intestine, and colon. She was diagnosed with IgG4-RD based on the pathological findings and elevated serum IgG4 levels. Glucocorticoid rapidly ameliorated the symptoms. IgG4-RD may cause gastrointestinal manifestations and histopathological assessment should be considered, even in the absence of specific characteristics of IgG4-RD.

A Case of Castleman's Disease with a Marked Infiltration of IgG4-Positive Cells in the Renal Interstitium.

Multicentric Castleman's disease (MCD) is a benign lymphoproliferative disorder with heterogenous clinical symptoms, and involves systemic organs in addition to lymph nodes. Herein, we present the case of a 55-year-old man with MCD characterized by an extensive infiltration of IgG4+ plasma cells in the kidneys. The patient presented to our hospital with a high fever and diarrhea. On admission, laboratory analysis revealed anemia, renal dysfunction (eGFR 30 mL/min/1.73 m2), polyclonal gammopathy (IgG 7130 mg/dL), elevated serum IgG4 level (2130 mg/dL), and increased C-reactive protein (8.0 mg/dL). An enlargement of lymph nodes in the axillary, mediastinal, para-aortic, and inguinal regions was observed on abdominal computed tomography. Axillary lymph node biopsy revealed interfollicular expansion due to dense plasma cell infiltration. Renal biopsy demonstrated significant plasma cell infiltration into the tubulointerstitium. Immunohistochemical analysis showed a 40% IgG4-positive/IgG-positive plasma cell ratio, meeting the diagnostic criteria for an IgG4-related disease. Amyloid A deposition was observed along vessel walls, and immunofluorescence analysis indicated granular positivity of IgG and C3 along the glomerular capillary wall. Elevated levels of interleukin-6 (21 pg/mL) and vascular endothelial growth factor (VEGF; 1210 pg/mL) were noted. Based on these findings, and the histological finding of the lymph node biopsy, idiopathic MCD was diagnosed. Corticosteroid monotherapy was only partially effective. Subsequently, tocilizumab administration was initiated, leading to sustained remission, even after discontinuation of prednisolone. Due to the diverse responses to steroid therapy and the varying prognoses observed in MCD and IgG4-related disease, it is essential to carefully diagnose MCD by thoroughly assessing the organ distribution of the disease, its response to steroid therapy, and any additional pathological findings.

IgG4-related disease: an update on pathology and diagnostic criteria with a focus on salivary gland manifestations.

Immunoglobulin G4-related disease (IgG4-RD) is a multi-organ disorder characterized by a highly variable clinical presentation depending on the affected organ/s, extent of tumefactive fibroinflammatory lesions, and associated functional impairment. The disease pursues a chronic, relapsing, often asymptomatic course and hence may pose a significant diagnostic challenge. Diagnostic delay can lead to progressive fibrosis and irreversible organ damage resulting into significant morbidity and even mortality. Given its broad clinical spectrum, physicians of all specialties may be the first clinicians facing this diagnostic challenge. Outside the pancreatobiliary system, the head and neck represents the major site of IgG4-RD with variable organ-specific diffuse or mass-forming lesions. In up to 75% of cases, elevated serum IgG4 levels are observed, but this figure possibly underestimates the fraction of seronegative cases, as the disease manifestations may present metachronously with significant intervals. Together with negative serology, this can lead to misdiagnosis of seronegative cases. A standardized nomenclature and diagnostic criteria for IgG4-RD were established in 2012 and revised in 2020 facilitating scientific research and expanding the range of diseases associated with IgG4 abnormalities. In addition to orbital pseudotumor, dacryoadenitis, Riedel thyroiditis, sinonasal manifestations, and rare miscellaneous conditions, IgG4-related sialadenitis is one of the most frequent presentations in the head and neck region. However, controversy still exists regarding the relationship between sialadenitis and IgG4-RD. This review focuses on the clinicopathological features of IgG4-related sialadenitis and its contemporary diagnostic criteria.

IgG4-related disease of the ureter mimicking malignant ureter tumor: a case report and experience sharing.

Background: Immunoglobulin G4-related disease (IgG4-RD) is an autoimmune disease that can affect any organ or tissue in the body, and is characterized by intensive infiltration of IgG4-positive plasma cells, and elevated serum IgG4 levels. IgG4-RD causes renal impairment of unknown pathogenesis that may progress to kidney failure. However, few case of IgG4-RD mimicking malignant ureter tumor leading to severe hydronephrosis. Case Description: This report describes a 38-year-old male patient who was hospitalized for sudden waist pain. Enhanced abdominal computed tomography (CT) revealed a mass involving the right ureter. He presented to the urologist with severe right hydronephrosis. Urinalysis revealed occult blood (3+), and atypical cells were observed in urine cytology, raising the possibility of a ureteral malignancy. After that, the patient underwent diagnostic ureteroscopy instead of direct nephroureterectomy and was found not to have any malignancy. The patient received laparoscopic partial ureteral resection and anastomosis. Histologically, there were observations of IgG4-positive plasma cell infiltration exceeding 10 cells per high-power field, as well as a high ratio of IgG4-positive/IgG-positive cells exceeding 40%. And histopathology revealed ureteral IgG4-related disease, with no evidence of urothelial carcinoma. Conclusions: IgG4-RD has previously been reported in lesions involving the ureters, but misdiagnosis and subsequent radical nephroureterectomy can cause lifelong regret for the patient in having lost one side of the urinary tract. To avoid such misdiagnoses, clinicians should consider IgG4-RD as a potential condition.

Clinical patterns and risk factors for multiorgan involvement in IgG4-Related disease patients.

Background: IgG4-related disease with multiorgan involvement predicts higher disease activity, thus, it is necessary to identify whether IgG4-related disease involves multiple organs at the early stage. To further clarify the clinical characteristics and risk factors for IgG4-related disease with multiorgan involvement, we conducted an observational study. Methods: We retrospectively analysed the clinical data of 160 patients who were primarily diagnosed with IgG4-related disease at the First Affiliated Hospital of Zhengzhou University from January 2015 to January 2021. According to the number of involved organs, patients were divided into two groups: multiorgan involvement and nonmultiorgan involvement. Patients were divided into a multiorgan group and a nonmultiorgan group according to multiple organ involvement. Results: There were 82 cases identified with multiorgan involvement and 78 cases diagnosed with no multiorgan involvement in this series. Most cases were elderly and male (p > 0.05). The most frequently affected organs in IgG4-RD were the lymph nodes (50.6 %), pancreas (38.7 %) and salivary glands (35.6 %). Multivariate analysis showed that eosinophilia, IgG4>2*ULN, lymph node involvement, salivary gland involvement and lung involvement were independent risk factors for multiorgan involvement (p < 0.05). Conclusions: The main issues in clinical practice are how to accurately diagnose the disease and screen the more vulnerable organs.

Resolution of Macular Edema secondary to rituximab after intravitreal dexamethasone: A case report and a review of the literature.

PURPOSE: to report a case of bilateral macular edema (ME) secondary to Rituximab infusions in a woman affected by IgG4-Related Disease and to review of prior cases of ME related to Rituximab. OBSERVATIONS: ME completely resolved after Intravitreal Dexamethasone Implant (IDI). CONCLUSIONS AND IMPORTANCE: ME is a rare complication after Rituximab infusions and very few cases are reported in the literature. Usually, ME occurs a few weeks after systemic administration and is probably related to a local release of cytokines. It resolves with oral, subtenon or intravitreal steroids. Our case is the first showing that IDI is a safe and effective treatment in ME secondary to Rituximab. Rituximab is not required to be discontinued if treatment for ME is started.

Efficacy and Safety of Inebilizumab in IgG4-Related Disease: Protocol for a Randomized Controlled Trial.

INTRODUCTION: Immunoglobulin G4-related disease (IgG4-RD) is a debilitating multiorgan disease characterized by recurring flares leading to organ dysfunction, decreased quality of life, and mortality. Glucocorticoids, the standard of care for IgG4-RD, are associated with substantial treatment-related toxicity. Inebilizumab, an antibody directed against CD19, mediates the rapid and durable depletion of CD19+ B cells thought to be involved in IgG4-RD pathogenesis. We describe the first international, prospective, double-blind, placebo-controlled trial to evaluate the safety and efficacy of B-cell depletion for flare prevention in IgG4-RD (MITIGATE). METHODS: The study was designed by an international panel of physicians with expertise in IgG4-RD. Critical trial design decisions included the selection of participants, definition of clinically meaningful primary and secondary endpoints, accommodation of standard of care, and development of flare diagnostic criteria. The study is approved for conduct in 22 countries. PLANNED OUTCOMES: The primary efficacy endpoint is time from randomization to the occurrence of the first centrally adjudicated and investigator-treated disease flare during the 1-year randomized controlled period. A set of novel, organ-specific flare diagnostic criteria were developed specifically for this trial, incorporating symptoms and signs, laboratory findings, imaging study results, and pathology data. MITIGATE aims to accrue 39 flares for the primary endpoint, which provides sufficient power to detect a relative risk reduction of 65% in the inebilizumab group. It is anticipated that enrollment of 160 participants will achieve this goal. Additional endpoints include safety, annualized flare rate, flare-free complete remission, quality-of-life measures, and cumulative glucocorticoid use. MITIGATE represents the first randomized, double-blind, placebo-controlled trial of any treatment strategy conducted in IgG4-RD. Data from this study will provide insights into the natural history and pathophysiology of IgG4-RD and the efficacy and safety of B-cell depletion as a therapeutic avenue. TRIAL REGISTRATION: NCT04540497.

Severe Aortic Valvular Incompetence From IgG4-Related Disease: An Unusual Entity.

IgG4-related disease (IgG4-RD) is a new clinical entity characterized by lymphoplasmacytic lesions rich in IgG4-positive plasma cells. Myocardial involvement is extremely rare and not a typical cardiovascular manifestation of IgG4-RD. We report a rare case of IgG4-RD-associated myocardial mass causing severe aortic incompetence, successfully treated with surgery and corticosteroids. (Level of Difficulty: Intermediate.).

Research progress on the clinical application and mechanism of iguratimod in the treatment of autoimmune diseases and rheumatic diseases.

Autoimmune diseases are affected by complex pathophysiology involving multiple cell types, cytokines, antibodies and mimicking factors. Different drugs are used to improve these autoimmune responses, including nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, antibodies, and small molecule drugs (DMARDs), which are prevalent clinically in the treatment of rheumatoid arthritis (RA), etc. However, low cost-effectiveness, reduced efficacy, adverse effects, and patient non-response are unattractive factors driving the development of new drugs such as iguratimod. As a new disease-modifying antirheumatic drug, iguratimod has pharmacological activities such as regulating autoimmune disorders, inflammatory cytokines, regulating immune cell activation, differentiation and proliferation, improving bone metabolism, and inhibiting fibrosis. In recent years, clinical studies have found that iguratimod is effective in the treatment of RA, SLE, IGG4-RD, Sjogren 's syndrome, ankylosing spondylitis, interstitial lung disease, and other autoimmune diseases and rheumatic diseases. The amount of basic and clinical research on other autoimmune diseases is also increasing. Therefore, this review systematically reviews the latest relevant literature in recent years, reviews the research results in recent years, and summarizes the research progress of iguratimod in the treatment of related diseases. This review highlights the role of iguratimod in the protection of autoimmune and rheumatic bone and related immune diseases. It is believed that iguratimod's unique mode of action and its favorable patient response compared to other DMARDs make it a suitable antirheumatic and bone protective agent in the future.

Compromiso oftálmico en enfermedad relacionada con IgG4 / Ophthalmic involvement in IgG4-related disease

Resumen Introducción: la enfermedad oftálmica relacionada con IgG4 (EOR-IgG4) presenta una frecuencia del 11-59%. Pocos estudios describen las disparidades con los pacientes con ER-IgG4 extraoftálmica (NO EOR-IgG4). Objetivos: describir las características clínicas, imagenológicas, anatomopatológicas, resultados de laboratorio y tratamiento de la EOR-IgG4, y compararlas con las de los pacientes NO EOR-IgG4. Materiales y métodos: se realizó un estudio descriptivo sobre una cohorte de 54 pacientes con ER-IgG4. Se reclutaron 16 pacientes con EOR-IgG4 y 38 con NO EOR-IgG4. Se compararon ambos grupos. Resultados: la EOR-IgG4 predominó en mujeres. El 75% presentó afectación oftálmica bilateral. El antecedente de asma se asoció al grupo NO EOR-IgG4 (p=0,018). Los pacientes con EOR-IgG4 presentaron niveles séricos menores de IgE e IgG total, y la glándula lagrimal fue la estructura más afectada. Predominó el infiltrado linfoplasmocitario y eosinofílico, siendo la fibrosis estoriforme más frecuente que la no estoriforme en el grupo EOR-IgG4. Conclusiones: si bien los resultados fueron similares a lo reportado previamente, en discordancia con otras series, encontramos asociación negativa entre el asma y los niveles de IgG total sérica en los pacientes EOR-IgG4.

Abstract Introduction: IgG4-related ophthalmic disease (IgG4-ROD) presents a frequency of 11-58.8%. Few studies describe the disparities with patients with extraophthalmic IgG4-related disease (NOT IgG4-ROD). Objectives: describe the clinical, imaging, pathological characteristics, laboratory results, and treatment of IgG4-ROD characteristics; and compare them with those of the NOT IgG4-ROD patients. Materials and methods: a descriptive study was carried out on a cohort of 54 patients with ER-IgG4. 16 patients with IgG4-ROD and 38 with NOT IgG4-ROD were recruited. The data was analyzed with the SPSS Statistics 19 software. Results: IgG4-ROD predominated in women. 75% presented bilateral ophthalmic involvement. A history of asthma was associated with the NOT IgG4-ROD group (p=0,018). Patients with IgG4-ROD presented lower serum levels of IgE and total IgG, and the lacrimal gland was the most affected structure. Lymphoplasmacytic and eosinophilic infiltrates predominated, with storiform fibrosis being more frequent than non-storiform in the IgG4-ROD group. Conclusions: although the results were similar to those previously reported, in disagreement with other series, we found a negative association between asthma and serum total IgG levels with EOR-IgG4 patients.

IgG4-related retroperitoneal fibrosis: A case report of a challenging disease.

Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a multi-organ immune-mediated fibroinflammatory disorder that may imitate malignancy, infectious or any other inflammatory disorder. IgG4-related retroperitoneal fibrosis (IgG4-RPF) is a rare form of IgG4-RD, diagnosis of which is often relied on radiological technology. Herein, we describe a case of 60 year old male, presenting with low back pain and weight loss for a period of 2 months and 15 days. Imaging studies showed a retroperitoneal tumorous mass along with bilateral hydroureteronephrosis, which was later confirmed to be IgG4-related retroperitoneal fibrosis on the basis of extensive histopathological analysis. Immunosuppressive therapy resulted in a decrease in fibrosis and restoration of renal function.

Differential sensitivity of the 2020 revised comprehensive diagnostic criteria and the 2019 ACR/EULAR classification criteria across IgG4-related disease phenotypes: results from a Norwegian cohort.

BACKGROUND: We investigated sensitivity of the 2020 Revised Comprehensive Diagnostic Criteria (RCD) and the 2019 ACR/EULAR classification criteria across the four identified IgG4-related disease (IgG4-RD) phenotypes: "Pancreato-Hepato-Biliary", "Retroperitoneum and Aorta", "Head and Neck-limited" and "Mikulicz' and Systemic" in a well-characterized patient cohort. METHODS: We included adult patients diagnosed with IgG4-RD after comprehensive clinical assessment at Oslo University Hospital in Norway. We assigned patients to IgG4-RD phenotypes based on pattern of organ involvement and assessed fulfillment of RCD and 2019 ACR/EULAR classification criteria. Differences between phenotype groups were analyzed using one-way ANOVA for continuous variables, and contingency tables for categorical variables. RESULTS: The study cohort included 79 IgG4-RD patients assigned to the "Pancreato-Hepato-Biliary" (22.8%), Retroperitoneum and Aorta" (22.8%) "Head and Neck-limited" (29.1%), and "Mikulicz' and Systemic" (25.3%) phenotype groups, respectively. While 72/79 (91.1%) patients in total fulfilled the RCD, proportion differed across phenotype groups and was lowest in the "Retroperitoneum and Aorta" group (66.7%, p < 0.001). Among the 57 (72.2%) patients meeting the 2019 ACR/EULAR classification criteria, proportion was again lowest in the "Retroperitoneum and Aorta" group (27.8%, p < 0.001). CONCLUSION: The results from this study indicate that IgG4-RD patients having the "Retroperitoneum and Aorta" phenotype less often fulfill diagnostic criteria and classification criteria than patients with other IgG4-RD phenotypes. Accordingly, this phenotype is at risk of being systematically selected against in observational studies and randomized clinical trials, with potential implications for patients, caregivers and future definitions of IgG4-RD.

Coronary artery involvement in a patient with IgG4-related disease.

Immunoglobulin G4-related disease (IgG4-RD) is a chronic fibro-inflammatory disorder of obscure etiology characterized by significant infiltration of IgG4-positive plasma cells toward several organs. Coronary artery involvement is rarely seen in IgG4-RD patients; thereby, we aim to outline the noninvasive imaging findings of this rare case. Cardiac magnetic resonance (CMR) and coronary computed tomography angiography (CCTA) from a 15-year-old female diagnosed with IgG4-RD via histopathological assessment of orbital biopsy, were analyzed. CMR showed a severely reduced left ventricular ejection fraction and akinesia of the basal to mid-lateral, anterior, and septal walls. Inflammation of the basal to apical lateral wall and subendocardial infarction of the basal to apical lateral and mid inferoseptal walls were also evident. CCTA findings showed stenosis in branches of the left main artery (LM), left anterior descending artery (LAD), and right coronary artery (RCA), aortitis, and aortic wall thickening. After courses of proper treatment with prednisolone, Cellcept, and adalimumab, follow-up CMR showed significant improvement in LV systolic function and resolution of inflammation. Although IgG4-RD is an uncommon cause of coronary artery disease, it can cause lethal complications such as myocardial infarction. Hence, clinicians should be aware of cardiac complications in these patients.