IgG4-related disease with nasopharyngeal malignancy-like manifestations.

Background: 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. Case summary: 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. Conclusion: 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.

Pathogenic roles of follicular helper T cells in IgG4-related disease and implications for potential therapy.

IgG4-related disease (IgG4-RD) is a recently described autoimmune disorder characterized by elevated serum IgG4 levels and tissue infiltration of IgG4+ plasma cells in multiple organ systems. Recent advancements have significantly enhanced our understanding of the pathological mechanism underlying this immune-mediated disease. T cell immunity plays a crucial role in the pathogenesis of IgG4-RD, and follicular helper T cells (Tfh) are particularly important in germinal center (GC) formation, plasmablast differentiation, and IgG4 class-switching. Apart from serum IgG4 concentrations, the expansion of circulating Tfh2 cells and plasmablasts may also serve as novel biomarkers for disease diagnosis and activity monitoring in IgG4-RD. Further exploration into the pathogenic roles of Tfh in IgG4-RD could potentially lead to identifying new therapeutic targets that offer more effective alternatives for treating this condition. In this review, we will focus on the current knowledge regarding the pathogenic roles Tfh cells play in IgG4-RD and outline potential therapeutic targets for future clinical intervention.

A Case of IgG4 Related Lung Disease.

BACKGROUND: IgG4-related disease (IgG4-RD) is an immune-mediated systemic inflammatory fibrotic disease, which is a relatively rare and novel disease that can involve multiple organs or tissues, with variable clinical manifestations, and for which pulmonary involvement has been reported relatively infrequently. METHODS: Here we report a case of pulmonary infection that was initially suspected and received anti-inflammatory treatment, but the symptoms did not improve. CT examination indicated progression of the pulmonary lesion, and the nature of the lesion could not be determined by tracheoscopy and bronchoalveolar lavage. The diagnosis of IgG4 related lung disease (IgG4-RLD) was confirmed by percutaneous lung biopsy. A joint literature analysis was conducted to improve clinicians' understanding of this disease. RESULTS: The patient's history, symptoms, signs and relevant examination results were analyzed. The final diagnosis was IgG4-RLD. CONCLUSIONS: When the clinical symptoms and imaging manifestations of the patients are consistent with IgG4-RLD, pathological examination can be appropriately performed to clarify the nature of the lesions. More consideration should be given to the possibility of disease diagnosis to avoid misdiagnosis and underdiagnosis, and proper treatment should be given at an early stage.

Sex as a predictor of clinical phenotype and determinant of immune response in IgG4-related disease: a retrospective study of patients fulfilling the American College of Rheumatology-European League Against Rheumatism classification criteria.

BACKGROUND: IgG4-related disease is a multiorgan fibroinflammatory disease considered to have an autoimmune origin. Case series describing individual organ involvement have suggested differences in phenotypic expression between males and females. We aimed to characterise differences in IgG4-related disease manifestations between male and female patients in a large single-centre cohort. METHODS: In this retrospective, single-centre cohort study, patients were recruited from the Massachusetts General Hospital Rheumatology Clinic (Boston, MA, USA) and classified according to the American College of Rheumatology-European Alliance of Associations for Rheumatology (ACR-EULAR) classification criteria. Only patients satisfying the ACR-EULAR classification criteria were included in the study. Data on age at diagnosis, organ involvement at baseline, treatment status, and pre-treatment laboratory values were collected. Circulating plasmablasts and B-cell subsets were quantitated by flow cytometry. Active disease was defined by an IgG4-related disease Responder Index score of more than 0. Laboratory values were analysed for patients who were untreated at baseline and had active IgG4-related disease. The main outcomes were assessed in all participants with available data. FINDINGS: Of the 564 participants enrolled in the Massachusetts General Hospital Rheumatology Clinic IgG4-related disease Registry, 328 fulfilled ACR-EULAR classification criteria and were included between January, 2008, and May, 2023. There was a strong male predominance (male:female ratio 2·2:1) with 226 (69%) males and 102 (31%) females, which contrasted markedly with our general rheumatology clinic population (0·4:1; p<0·001). The male predominance increased with each decade of life starting at age 40 years. On average, male patients were 5·5 years older at diagnosis than female patients (63·7 years vs 58·2 years; p=0·0031). We observed male patients to have higher ACR-EULAR classification criteria scores at baseline with a median score of 35·0 (IQR 28·0-46·0), compared with 29·5 (25·0-39·0) for females (p=0·0010). The proportion of male patients with pancreatic and renal involvement was almost double the proportion observed in female patients (50% of the male patients had pancreatic involvement, compared with about 26% of the female patients; p<0·0001). Male patients were more likely to have serological abnormalities at baseline. The distribution of IgG4 values differed significantly between male an female sexes, favouring higher values in males. We found that male patients with IgG4-related disease were more likely to have active B-cell responses in the blood as defined by plasmablast expansions. INTERPRETATION: IgG4-related disease is unusual among autoimmune diseases in that it is more likely to affect males than females and to present with a striking sex-dependent organ distribution and degree of B-cell response. These findings highlight important variation between IgG4-related disease and other conditions generally believed to have an autoimmune basis. Most autoimmune diseases, by contrast to IgG4-related disease, demonstrate pronounced predilections for affecting females more frequently than males. Hypotheses surrounding the cause and pathophysiology of this condition need to consider this unusual sex distribution among patients with IgG4-related disease. FUNDING: National Institutes of Health, National Institute of Allergy and Infectious Diseases, Rheumatology Research Foundation, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

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.

Rapid progression of a coronary artery aneurysm caused by IgG4-related disease.

BACKGROUND: IgG4-related disease (IgG4-RD) is a recently recognized fibro-inflammatory disorder that can affect almost any organ. IgG4-RD has also been reported in coronary arteries as periarteritis. IgG4-related coronary periarteritis may cause coronary artery aneurysms, and IgG4-related coronary artery aneurysms (IGCAs) are life-threatening. We describe a case of a patient with IGCA that highlights the usefulness and limitations of various IGCA evaluation modalities and provides insight into disease pathophysiology. CASE SUMMARY: A 60-year-old man with IgG4-RD diagnosed 2 years before and with IGCA at the proximal right coronary artery (RCA) on coronary angiography (CAG) 9 months prior to admission to the hospital presented with acute coronary syndrome. Emergent CAG revealed the rapid progression of IGCA at the RCA, an obstruction of the diagonal branch, and stenosis of the left anterior descending artery (LAD) and the high lateral branch (HL). The patient underwent percutaneous coronary intervention for the diagonal branch. The RCA aneurysm was resected and bypassed with a saphenous vein graft (SVG); coronary bypass grafting (left internal mammary artery to LAD and SVG to HL) was performed. Pathological findings showed inflammatory cell infiltration and disruption of the elastic plate. CONCLUSION: IGCAs require careful follow-up with computed tomography scans for early detection of aneurysmal enlargement.

Recent advances in IgG4-related autoimmune pancreatitis.

The incidence of IgG4-related autoimmune pancreatitis (IgG4-AIP) is high in Asia and other countries, and unnecessary treatment is often undertaken due to both missed diagnosis and misdiagnosis in clinical practice. Although IgG4-AIP has attracted increasing attention, the details of IgG4-AIP pathogenesis and systemic immune response, including its relationship to tumor pathogenesis, are still unclear. In recent years, research on serum immunological detection, pathological features, clinical manifestations, diagnosis and treatment measures for IgG4-AIP has gradually increased. It is of great importance to summarize and discuss the latest progress regarding IgG4-AIP disease.

Proliferative features of IgG4-related disease.

IgG4-related disease is an immune-mediated disease that can lead to substantial morbidity and organ damage. Capable of affecting nearly any organ system or anatomic site, and showing considerable overlap in clinical presentation with various other diseases, IgG4-related disease often poses a diagnostic challenge for clinicians. Furthermore, there are no diagnostic biomarkers with high specificity for IgG4-related disease, and histopathological examination is nuanced and requires clinical correlation for accurate diagnosis. Therefore, it is crucial for clinicians to recognise the clinical phenotypes of IgG4-related disease. The disease is generally considered to have predominantly fibrotic and proliferative (or inflammatory) manifestations, with distinct clinical, serological and histopathological findings associated with each manifestation. However, the fibrotic and proliferative manifestations of this disease frequently occur together, thereby blurring this dichotomous distinction. In this Series paper, we provide a detailed overview of the clinical manifestations typical of the proliferative features of IgG4-related disease, with an emphasis on the diagnostic evaluation and differential diagnosis of each proliferative disease manifestation. In addition, we summarise the immune mechanisms underlying IgG4-related disease, suggest a framework for how to approach management and monitoring after the diagnosis is established, and highlight current unmet needs for patient care surrounding this disease.

Fibrotic phenotype of IgG4-related disease.

A prompt response to glucocorticoids is a clinical hallmark of IgG4-related disease. However, manifestations characterised by prominent tissue fibrosis on histological examination can be less responsive to glucocorticoid therapy than other types of IgG4-related disease. These manifestations include retroperitoneal fibrosis, fibrosing mediastinitis, Riedel thyroiditis, orbital pseudotumor, and hypertrophic pachymeningitis, among others. To explain this discrepancy, a preliminary distinction into proliferative and fibrotic phenotypes of IgG4-related disease has been proposed on the basis of clinical presentation, pathological features, and response to immunosuppressive therapy. Implications of this classification for patient management remain an important area of investigation. In this Series paper, we aim to dissect the pathophysiology of tissue fibrosis in IgG4-related disease and discuss how clinicians should approach the management of fibrotic manifestations of IgG4-related disease based on the most recent diagnostic and therapeutic developments.

Immunohistological analysis reveals IgG1-dominant immunophenotype of tubulointerstitial nephritis unassociated with IgG4-related diseases.

PURPOSE: Tubulointerstitial nephritis (TIN) has various etiologies, including IgG4-related disease (IgG4-RD), autoimmune diseases, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), and others. IgG4-positive plasma cell infiltration can occasionally be found in TIN unrelated to IgG4-RD. Therefore, there may be problems with usage of IgG4 immunostaining to differentiate between TIN with and TIN without IgG4-RD. This study aimed to compare the proportion of plasma cells that are positive for each IgG subclass and to clarify the predominant IgG subclass trends and clinical characteristics associated with IgG4-RD and non-IgG4-related interstitial nephritis. METHODS: The study enrolled 44 cases of TIN: 6 of IgG4-RD, 8 of autoimmune disease, 9 of AAV, and 21 of unknown disease group. In addition to clinical characteristics, IgG subclass composition of interstitial plasma cells was evaluated among 4 groups by immunohistochemistry. RESULTS: IgG1 was the predominant IgG subclass in TIN unrelated to IgG4-RD. In the IgG4-RD group, the IgG subclass rate was high in both IgG1 and IgG4. The rate of average IgG4-positive cells was significantly lower in the autoimmune disease group and unknown disease group compared with the IgG4-RD group. CONCLUSION: The present study revealed IgG1-dominant immune profiles of TIN unrelated to IgG4-RD. Further investigation is required to elucidate the clinicopathological differences between IgG1-dominant and IgG4-dominant groups in IgG4-RD.

Una inusual causa de estrechez de la vía aérea laringotraqueal / An unusual cause of laryngotracheal airway narrowing

La enfermedad relacionada con inmunoglobulina (Ig) G4 es una enfermedad de reciente conocimiento que puede comprometer cualquier órgano teniendo preferencias por ciertas regiones del cuerpo, donde la región de cabeza y cuello es uno de sus principales puntos afectados, pudiendo comprometer tanto la órbita, glándulas salivales, glándulas lagrimales, glándula tiroides, cavidades paranasales, hueso temporal, faringe y laringe. Este último órgano es infrecuentemente comprometido, solo existiendo 12 casos registrados en la literatura antes de la publicación de este escrito. Presentamos un caso de una mujer de 49 años con historia de disnea frente a esfuerzo, diagnosticándose una estenosis subglótica la cual fue manejada quirúrgicamente con una reconstrucción laringotraqueal. En el estudio histopatológico se evidenció histología compatible con enfermedad relacionada con IgG4, por lo que se inició tratamiento médico con corticotera- pia oral por un lapso de 2 meses en conjunto con inmunología. Paciente luego de 4 años de seguimiento, no ha presentado recaídas, manteniendo un lumen subglótico adecuado.

Immunoglobulin (Ig) G4-related disease is a medical condition of recent knowledge that can compromise any organ, having preferences for certain regions of the body, where the head and neck region is one of the main affected points, being able to affect orbit, salivary glands, lacrimal glands, thyroid gland, paranasal cavities, temporal bone, pharynx and larynx. The latter is infrequently compromised, with only 12 cases registered in the literature before the publication of this writing. We present a case of a 49-year-old woman with a history of exertional dyspnea, diagnosed with a sub- glottic stenosis which was managed surgically with laryngotracheal reconstruction. The histopathological study revealed histology compatible with IgG4-related disease, so medical treatment with oral corticosteroid therapy was started for a period of 2 months in conjunction with immunology. After 4 years of follow-up, the patient has not presented relapses, maintaining an adequate subglottic lumen.

Reducing relapse through maintenance steroid treatment can decrease the cancer risk in patients with IgG4-sclerosing cholangitis: Based on a Japanese nationwide study.

OBJECTIVE: IgG4-related sclerosing cholangitis (IgG4-SC) is recognized as a benign steroid-responsive disease; however, little is known about the risk of development of cancer in patients with IgG4-SC and about how to counter this risk. DESIGN: We conducted a retrospective review of the data of 924 patients with IgG4-SC selected from a Japanese nationwide survey. The incidence, type of malignancy, and risk of malignancy in these patients were examined. Then, the standardized incidence ratio (SIR) of cancer in patients with IgG4-SC was calculated. RESULTS: Relapse was recognized in 19.7% (182/924) of patients, and cancer development was noted in 15% (139/924) of patients. Multivariate analysis identified only relapse as an independent risk factor for the development of cancer. In most of these patients with pancreato-biliary cancer, the cancer developed within 8 years after the diagnosis of IgG4-SC. The SIR for cancer after the diagnosis of IgG4-SC was 12.68 (95% confidence interval [CI] 6.89-8.79). The SIRs of cancers involving the biliary system and pancreas were 27.35 and 18.43, respectively. The cumulative survival rate was significantly better in the group that received maintenance steroid treatment (MST) than in the group that did not; thus, MST influenced the prognosis of these patients. CONCLUSION: Among the cancers, the risk of pancreatic and biliary cancers is the highest in these patients. Because of the elevated cancer risk, surveillance after the diagnosis and management to prevent relapse are important in patients with IgG4-SC to reduce the risk of development of cancer.

The Role of Symptom Duration and Serologic Factors in the Relapse of IgG4-Related Ophthalmic Disease following Surgery: A Retrospective Cohort Study.

IgG4-related disease (IgG4-RD) affects multiple organs and is characterized by immune-mediated inflammation and fibrosis; IgG-RD affecting orbital tissue is known as IgG4-related ophthalmic disease (IgG4-ROD). This research is aimed at exploring whether symptom duration and common serologic factors, such as IgG, IgE, and eosinophils, are potential risk factors for IgG4-ROD patient relapse after surgery and identifying possible causes of the positive correlation between symptom duration and relapse. This retrospective cohort study included 40 IgG4-ROD patients after surgery. Auxiliary inspection results were obtained before surgery and during follow-up, and relapse risk factors were identified based on previous studies. We used the Spearman rank correlation test to reveal the relationship between symptom duration and relapse time and identified the optimal cutoff value for symptom duration by X-tile. Then, we divided the patients into the long-duration and short-duration groups. Kaplan-Meier survival analyses and log-rank tests were performed to identify the relationship between symptom duration and relapse using X-tile software. Finally, we studied the relationship between previously studied relapse risk factors and symptom duration. The survival curves of the long-duration and short-duration groups were obviously different, and the baseline serum IgG, IgE, and eosinophil levels and asthma concomitant rate were significantly different between the long-duration and short-duration groups. Furthermore, the baseline serum IgG (r = 0.485, P = 0.002), IgE (r = 0.350, P = 0.037), and eosinophil (r = 0.6535, P < 0.0001) levels were positively correlated with symptom duration. Our study shows that IgG4-ROD symptom duration is significantly positively correlated with relapse rate and negatively correlated with relapse time. Symptom duration was positively correlated with serum baseline IgG4, IgE, and eosinophil levels and asthma history, which were potential risk factors for disease relapse. We recommended that IgG4-ROD patients with symptom durations greater than 96 months continue to receive maintenance steroid therapy longer than 1 year postsurgery to reduce the relapse rate.

Immunoglobulin G4-related disease and idiopathic multicentric Castleman's disease: confusable immune-mediated disorders.

IgG4-related disease (IgG4-RD) and idiopathic multicentric Castleman's disease (iMCD) are both rare systemic immune-mediated disorders. However, the pathogenesis differs markedly between the two diseases and differing therapeutic strategies are adopted: IgG4-RD is treated using a moderate dose of glucocorticoids or rituximab, while iMCD therapy involves an IL-6-targeted approach. Nonetheless, some clinical features of IgG4-RD and iMCD overlap, so differential diagnosis is sometimes difficult, even though the classification and diagnostic criteria of the diseases require careful exclusion of the other. The key findings in IgG4-RD are high IgG4:IgG ratio, allergic features and germinal centre expansion involving T follicular helper cells, while iMCD involves polyclonal antibody production (high IgA and IgM levels), sheet-like mature plasma cell proliferation and inflammatory features driven by IL-6. The distribution of organ involvement also provides important clues in both diseases. Particular attention should be given to differential diagnosis using combined clinical and/or pathological findings, because single features cannot distinguish IgG4-RD from iMCD. In the present review, we discuss the similarities and differences between IgG4-RD and iMCD, as well as how to distinguish the two diseases.

Overexpression of IgG2 in patients resembling IgG4-related disease with normal IgG4.

IgG4-Related Disease (IgG4-RD) results from tissue infiltration by IgG4-expressing plasma cells and lymphocytes, leading to fibrosis and organomegaly. Clinical presentation is remarkably variable according to organ involvement, and high IgG4 serum concentration, initially considered a diagnostic hallmark of IgG4-RD, tends to be forgone as an indispensable criterion for its diagnosis; it can indeed be absent in some patients, highlighting the diversity of presentation of this dysimmune condition. Nevertheless, elevation of IgG4 serum concentration in suggestive settings remains an argument in favour of IgG4-RD, and while other IgG subclasses can be elevated, this biological feature lacks any diagnostic value. We retrospectively studied 9 patients (5 females, 4 males, 31-81 years old) for whom a diagnosis of IgG4-RD had been considered, based on clinical, imaging or histological criteria, but appeared to display abnormally high serum IgG2 while IgG4 levels were normal. Increased serum IgG1 in one case and increased IgG3 in another one were also noticed. Immunohistochemical analyses of intracellular immunoglobulins could be performed on tissue lymph node biopsies from 2 patients, which demonstrated strong infiltration with IgG2-expressing plasma cells. Thus, overexpression of IgG2 subclass may highlight cases of dysimmune disorders resembling IgG4-RD, although the disease trigger might be different, notably infectious. We suggest measuring all serum IgG subclass levels in patients with features consistent with IgG4-RD.