-
Respirology (Carlton, Vic.) Feb 2023Immunoglobulin G4-related disease (IgG4-RD) is a recently described rare systemic fibroinflammatory disease with an estimated incidence of less than 1 in 100,000 persons... (Review)
Review
Immunoglobulin G4-related disease (IgG4-RD) is a recently described rare systemic fibroinflammatory disease with an estimated incidence of less than 1 in 100,000 persons per year. The disease can affect virtually any organ and is characterized by unifying histopathological findings. Recently, four subgroups of patients have been characterized: hepatobiliary, head and neck, Mikulicz syndrome and retroperitoneal fibrosis, who illustrate the mainly abdominal and ENT tropism of the disease. Yet, thoracic involvement is not uncommon. It can be detected in up to 30% of patients with systemic IgG4-RD and is the exclusive manifestation of the disease in about 10% of cases. Clinical symptoms are nonspecific and may include dyspnoea, cough or chest pain. Chest CT findings are heterogeneous and primarily include peribronchovascular thickening, nodules, ground-glass opacities and lymphadenopathy. There is no specific diagnostic test for IgG4-RD thoracic involvement, which may mimic malignancy or vasculitis. Therefore, a cautious approach is needed to make an accurate diagnosis: a search for extra-thoracic manifestations, elevated serum IgG4 levels, circulating levels of plasmablasts and pathologic evidence of disease is warranted. Although very suggestive, neither the presence of a polyclonal IgG4 lymphoplasmacytic infiltrate, storiform fibrosis or obliterative phlebitis are sufficient to confirm the histological diagnosis. Steroids are recommended as first-line therapy. Rituximab or disease-modifying antirheumatic drugs may be used in relapsed or rare cases of steroid-refractory disease. In this review, we summarize current knowledge regarding the pathophysiology, epidemiology, diagnostic modalities (clinical-biological-imaging-histopathology) and treatment of IgG4-RD thoracic involvement.
Topics: Humans; Immunoglobulin G4-Related Disease; Lymphadenopathy; Fibrosis; Plasma Cells; Immunoglobulin G
PubMed: 36437514
DOI: 10.1111/resp.14422 -
Annals of the Rheumatic Diseases Mar 2019IgG4-related disease (IgG4-RD) is a heterogeneous, multiorgan condition of unclear aetiology that can cause organ failure. Difficulty recognising IgG4-RD contributes to...
OBJECTIVE
IgG4-related disease (IgG4-RD) is a heterogeneous, multiorgan condition of unclear aetiology that can cause organ failure. Difficulty recognising IgG4-RD contributes to diagnostic delays. We sought to identify key IgG4-RD phenotypes.
METHODS
We used two cross-sectional studies assembled by an international, multispecialty network of IgG4-RD specialists who submitted 765 cases to derive and replicate phenotypic groups. Phenotype groups of disease manifestations and key covariate distributions across the identified groups were measured using latent class analysis.
RESULTS
In the derivation cohort (n=493), we identified four groups with distinct manifestations: Group 1 (31%), Pancreato-Hepato-Biliary disease; Group 2 (24%), Retroperitoneal Fibrosis and/or Aortitis; Group 3 (24%), Head and Neck-Limited disease and Group 4 (22%), classic Mikulicz syndrome with systemic involvement. We replicated the identification of four phenotype groups in the replication cohort. Compared with cases in Groups 1, 2 and 4, respectively, cases in Group 3 were more likely to be female (OR 11.60 (95% CI 5.39 to 24.98), 10.35 (95% CI 4.63 to 23.15) and 9.24 (95% CI 3.53 to 24.20)) and Asian (OR 6.68 (95% CI 2.82 to 15.79), 7.43 (95% CI 2.97 to 18.56) and 6.27 (95% CI 2.27 to 17.29)). Cases in Group 4 had a higher median serum IgG4 concentration (1170 mg/dL) compared with groups 1-3 (316, 178 and 445 mg/dL, respectively, p<0.001).
CONCLUSION
We identified four distinctive IgG4-RD phenotypes according to organ involvement. Being Asian or female may predispose individuals to head and neck-limited disease. These phenotypes serve as a framework for identifying IgG4-RD and studying its aetiology and optimal treatment.
Topics: Adult; Americas; Aortitis; Asia; Asian People; Cross-Sectional Studies; Digestive System Diseases; Europe; Female; Humans; Immunoglobulin G; Immunoglobulin G4-Related Disease; Male; Middle Aged; Mikulicz' Disease; Otorhinolaryngologic Diseases; Phenotype; Racial Groups; Retroperitoneal Fibrosis
PubMed: 30612117
DOI: 10.1136/annrheumdis-2018-214603 -
Taiwan Journal of Ophthalmology 2018Immunoglobulin G4-related disease (IgG4-RD) is a recently recognized inflammatory disease of unknown etiology. It characterized by distinctive histopathological... (Review)
Review
Immunoglobulin G4-related disease (IgG4-RD) is a recently recognized inflammatory disease of unknown etiology. It characterized by distinctive histopathological appearance of dense IgG4-positive lymphoplasmacytic infiltrates, storiform fibrosis, and obliterative phlebitis in one or more organs, simultaneously or subsequently. In cases of ocular adnexal involvement, unique clinicohistopathological features were delineated by recent studies, and IgG4-related ophthalmic disease (IgG4-ROD) is generally recognized as the disease name. A significant proportion of previous labeled idiopathic orbital inflammations and Mikulicz's disease are now consistent with a diagnosis of IgG4-ROD. Increasing studies have accumulated regarding its epidemiology, diagnosis, clinical features, treatment, and the association between lymphoma. In this review, we summarize our present understanding of IgG4-ROD.
PubMed: 29675343
DOI: 10.4103/tjo.tjo_12_17 -
Circulation May 2024Empagliflozin reduces the risk of heart failure (HF) events in patients with type 2 diabetes at high cardiovascular risk, chronic kidney disease, or prevalent HF... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Empagliflozin reduces the risk of heart failure (HF) events in patients with type 2 diabetes at high cardiovascular risk, chronic kidney disease, or prevalent HF irrespective of ejection fraction. Whereas the EMPACT-MI trial (Effect of Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients With Acute Myocardial Infarction) showed that empagliflozin does not reduce the risk of the composite of hospitalization for HF and all-cause death, the effect of empagliflozin on first and recurrent HF events after myocardial infarction is unknown.
METHODS
EMPACT-MI was a double-blind, randomized, placebo-controlled, event-driven trial that randomized 6522 patients hospitalized for acute myocardial infarction at risk for HF on the basis of newly developed left ventricular ejection fraction of <45% or signs or symptoms of congestion to receive empagliflozin 10 mg daily or placebo within 14 days of admission. In prespecified secondary analyses, treatment groups were analyzed for HF outcomes.
RESULTS
Over a median follow-up of 17.9 months, the risk for first HF hospitalization and total HF hospitalizations was significantly lower in the empagliflozin compared with the placebo group (118 [3.6%] versus 153 [4.7%] patients with events; hazard ratio, 0.77 [95% CI, 0.60, 0.98]; =0.031, for first HF hospitalization; 148 versus 207 events; rate ratio, 0.67 [95% CI, 0.51, 0.89]; =0.006, for total HF hospitalizations). Subgroup analysis showed consistency of empagliflozin benefit across clinically relevant patient subgroups for first and total HF hospitalizations. The need for new use of diuretics, renin-angiotensin modulators, or mineralocorticoid receptor antagonists after discharge was less in patients randomized to empagliflozin versus placebo (all <0.05).
CONCLUSIONS
Empagliflozin reduced the risk of HF in patients with left ventricular dysfunction or congestion after acute myocardial infarction.
REGISTRATION
URL: https://www.clinicaltrials.gov; Unique identifier: NCT04509674.
Topics: Humans; Glucosides; Benzhydryl Compounds; Heart Failure; Male; Female; Myocardial Infarction; Aged; Middle Aged; Double-Blind Method; Sodium-Glucose Transporter 2 Inhibitors; Hospitalization; Treatment Outcome; Stroke Volume
PubMed: 38581389
DOI: 10.1161/CIRCULATIONAHA.124.069217 -
JMA Journal Mar 2019Immunoglobulin G4-related disease (IgG4-RD) is a recently established systemic disease that is characteristically associated with elevated serum immunoglobulin G4 (IgG4)... (Review)
Review
Immunoglobulin G4-related disease (IgG4-RD) is a recently established systemic disease that is characteristically associated with elevated serum immunoglobulin G4 (IgG4) levels and believed to be caused by autoimmune mechanisms. The clinical features of IgG4-RD include (i) systemic distribution, (ii) imaging findings of swelling, nodules, and/or wall thickening, (iii) high serum IgG4 levels, (iv) abundant IgG4-bearing plasma cell infiltration and fibrosis in affected organs, (v) a favorable response to corticosteroid therapy, and (vi) coexistence with other IgG4-RD manifestations simultaneously or in a metachronous fashion. The concept of IgG4-RD was established based on the culmination of specific discoveries. Specifically, a close association between autoimmune pancreatitis (AIP) and high serum IgG4 levels, massive IgG4-bearing plasma cell infiltration in pancreatic tissues affected by AIP, and systemic other organ involvements in AIP with similar IgG4-bearing plasma cell features opened the gateway from AIP to IgG4-RD. The systemic distribution of IgG4-RD seems to be capable of affecting every organ, causing well-established members including AIP, lacrimal and salivary gland lesions such as Mikulicz's disease, respiratory diseases, sclerosing cholangitis, kidney diseases, and retroperitoneal fibrosis. IgG4-RD has been diagnosed worldwide, and international collaboration efforts on the disease have led to consensus publications on its nomenclature, pathology findings, and management approach. The algorithms developed for the comprehensive diagnostic criteria for IgG4-RD have remarkably increased detection sensitivity. Oral glucocorticoids are the first-line agents for remission induction, and certain patients with high disease activity may benefit from maintenance therapy afterwards. Originally, IgG4-RD had been considered reversible and to have a good prognosis; however, long-term afflictions sometimes result in transition to advanced-stage conditions with dysfunction and/or complicating malignancy. The immunological abnormalities in IgG4-RD have been reported in both innate and adaptive immune systems; however, it remains unclear whether IgG4 has a pathogenic role or a protective one in disease onset and progression.
PubMed: 33681509
DOI: 10.31662/jmaj.2018-0017 -
Reumatologia 2020According to a new concept for the classification and division of autoimmune diseases, Mikulicz's disease and Küttner's tumor belong to immunoglobulin G4-related... (Review)
Review
According to a new concept for the classification and division of autoimmune diseases, Mikulicz's disease and Küttner's tumor belong to immunoglobulin G4-related diseases (IgG4-RD) and fulfil their diagnostic criteria. The aim of this study was to summarize the new classification concepts of IgG4-RD in the head and neck area and to review their clinical, histopathological and serologic criteria and the methods used in the diagnostic workup with respect to their advantages, limitations and differentiative value. The PubMed, Web of Science, Google Scholar, and Scopus databases were searched for articles published between 2009 and 2019 using the following key words: IgG4-related diseases, Mikulicz's disease, Küttner's tumor, salivary glands, xerostomia. Results of the review of the literature revealed that Mikulicz's disease and Küttner's tumor fulfil the same diagnostic criteria but may manifest different clinical symptoms which determine the choice of the different diagnostic tools.
PubMed: 32921832
DOI: 10.5114/reum.2020.98437 -
Cells Feb 2023Diverse immune cell subsets have been described in IgG4-related disease (IgG4-RD). If there is a different immunophenotype according to clinical phenotype and activity...
Diverse immune cell subsets have been described in IgG4-related disease (IgG4-RD). If there is a different immunophenotype according to clinical phenotype and activity status is not known. Levels of IL-4-, IL-13-, IL-5-, and IL-21-producing CD4 T cells (Th2 subsets), CD4 cytotoxic T lymphocytes (CD4CTLs), T helper 9 cells, T follicular helper cells (Tfh; Tfh1/Tfh2/Tfh17/Tf regulatory [Tfr]), Foxp3 regulatory T cells, Type 1 regulatory T cells (Tr1), T helper 3 regulatory cells (Th3), IL-10-producing regulatory B cells (Bregs), IL-10-expressing regulatory plasmacytoid dendritic (pDC IL-10) cells, and M1 and M2 monocytes were determined by flow cytometry in 43 IgG4-RD patients and 12 controls. All immune subsets were higher in patients vs. controls. CD4/IL-4, CD4/IL-5, CD4CTLs, Tfh2, Tfh17, Tfr, and M1 monocyte cell number was different among IgG4-RD clinical phenotypes. The pancreato-hepato-biliary phenotype was characterized by a higher CD4CTLs, Tfh17, Tfh2, and Tfr and lower M1 cell number. An increased CD4CTLs and Th3 cell number distinguished the head and neck-limited phenotype, while the retroperitoneal/aortic and Mikulicz/systemic phenotypes were characterized by increased Th2 subsets. Tfh17, Tr1, Th3, pDC, M1, and M2 monocytes were augmented in active patients. In summary, the clinical heterogeneity of IgG4-RD might be driven by the participation of different immunophenotypes and, consequently, by a different fibroinflammatory process.
Topics: Humans; Interleukin-10; Immunoglobulin G4-Related Disease; Interleukin-4; Interleukin-5; Phenotype
PubMed: 36831337
DOI: 10.3390/cells12040670 -
Reumatologia Clinica 2017IgG4-related disease is the term used to refer to a condition characterized by a lymphoplasmacytic infiltrate, fibrosis and an increased number of IgG4+ cells present in... (Review)
Review
IgG4-related disease is the term used to refer to a condition characterized by a lymphoplasmacytic infiltrate, fibrosis and an increased number of IgG4+ cells present in tissue, in most cases, with an elevated serum IgG4 level. This disease frequently affects the pancreas, salivary glands and lymph nodes, but can involve almost any tissue. Its etiology and the exact role of the different inflammatory cells in the damage to the target organ is still unclear. As yet, there is no international consensus about diagnostic criteria for the disease, but there are important advances in its treatment and in the quest to achieve remission. We include a review of the history, possible pathogenesis, clinical manifestations, diagnostic approach and available therapeutic approaches.
Topics: Autoimmune Diseases; Biomarkers; Global Health; Humans; Immunoglobulin G; Incidence; Prevalence
PubMed: 27329319
DOI: 10.1016/j.reuma.2016.05.009 -
Head and Neck Pathology Mar 2015IgG4 related disease of the head and neck region represents one of the more common manifestations of IgG4 related disease. Involvement of the submandibular and parotid... (Review)
Review
IgG4 related disease of the head and neck region represents one of the more common manifestations of IgG4 related disease. Involvement of the submandibular and parotid glands, the orbit and thyroid represent some of the more common sites involved by IgG4 related disease. Eosinophilic angiocentric fibrosis, Mikulicz disease and Riedel thyroiditis are also members of the family of IgG4 related disease. Clinically, the disease is characterized by tumefactive lesions, often multicentric, that show a swift response to immunosuppressive therapy. An elevated serum IgG4 represents the only validated blood based biomarker. However, elevated serum IgG4 is detected in only half the patients with this disease. Histology continues to represent the gold standard for the diagnosis of IgG4 related disease: storiform-type fibrosis and obliterative phlebitis constitute characteristic features of this disease. A definitive diagnosis of IgG4 related disease also requires the presence of elevated numbers of IgG4 positive plasma cells as well as an IgG4 to IgG ratio of greater than 40 %. In isolation, elevated numbers of IgG4 positive plasma cells represents a non-specific feature, detected in a variety of other inflammatory as well as neoplastic diseases. Attention to the clinical context, histological features, as well as an elevated IgG4 to IgG ratio is critical to avoiding overdiagnosis of IgG4 related disease.
Topics: Head; Humans; Immunoglobulin G; Neck
PubMed: 25804380
DOI: 10.1007/s12105-015-0620-6 -
Clinical and Experimental Immunology Aug 2015Immunoglobulin G4-related disease (IgG4-RD) is a fibroinflammatory condition that derives its name from the characteristic finding of abundant IgG4(+) plasma cells in... (Review)
Review
Immunoglobulin G4-related disease (IgG4-RD) is a fibroinflammatory condition that derives its name from the characteristic finding of abundant IgG4(+) plasma cells in affected tissues, as well as the presence of elevated serum IgG4 concentrations in many patients. In contrast to fibrotic disorders, such as systemic sclerosis or idiopathic pulmonary fibrosis in which the tissues fibrosis has remained largely intractable to treatment, many IgG4-RD patients appear to have a condition in which the collagen deposition is reversible. The mechanisms underlying this peculiar feature remain unknown, but the remarkable efficacy of B cell depletion in these patients supports an important pathogenic role of B cell/T cell collaboration. In particular, aberrant T helper type 2 (Th2)/regulatory T cells sustained by putative autoreactive B cells have been proposed to drive collagen deposition through the production of profibrotic cytokines, but definitive demonstrations of this hypothesis are lacking. Indeed, a number of unsolved questions need to be addressed in order to fully understand the pathogenesis of IgG4-RD. These include the identification of an antigenic trigger(s), the implications (if any) of IgG4 antibodies for pathophysiology and the precise immunological mechanisms leading to fibrosis. Recent investigations have also raised the possibility that innate immunity might precede adaptive immunity, thus further complicating the pathological scenario. Here, we aim to review the most recent insights on the immunology of IgG4-RD, focusing on the relative contribution of innate and adaptive immune responses to the full pathological phenotype of this fibrotic condition. Clinical, histological and therapeutic features are also addressed.
Topics: Adaptive Immunity; B-Lymphocytes; Cell Communication; Collagen; Gene Expression; Granuloma, Plasma Cell; Humans; Immunity, Innate; Immunoglobulin G; Inflammation; Mikulicz' Disease; Retroperitoneal Fibrosis; T-Lymphocytes, Regulatory; Th2 Cells
PubMed: 25865251
DOI: 10.1111/cei.12641