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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 -
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 -
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 -
Clinical Ophthalmology (Auckland, N.Z.) 2022To report clinical, serological, and histopathological findings in Egyptian patients with dacryoadenitis associated with ImmunoglobulinG4-related disease (IgG4-RD).
PURPOSE
To report clinical, serological, and histopathological findings in Egyptian patients with dacryoadenitis associated with ImmunoglobulinG4-related disease (IgG4-RD).
METHODS
We retrospectively revised medical records of patients presented to Al-Azhar University Hospitals with lacrimal gland (LG) swelling between June 2016 and February 2022. We included patients with definite IgG4-related disease (IgG4-RD) diagnosis and excluded those with possible, probable, or unlikely IgG4-RD based on The Japanese Ministry of Health, Labour, and Welfare's 2011 guidelines.
RESULTS
Sixteen cases were included in the study (Fourteen females and two males, mean age 39.2±12.2 years); Seven cases met the criteria of Mikulicz disease, and nine cases met full clinical, serological, and histopathological criteria. Mean reported serum IgG was 1792.5 ± 313.7 (range 1063-2134) mg/dl, mean serum IgG4 was 576.25±215.3 (range 112-841) mg/dl, and mean Serum IgG4/IgG ratio was 31.9 ± 12.4%. The mean number of IgG4+ plasma cells/HPF was 74 ± 21.2, and the mean IgG4+ plasma cell percentage was 55 ± 9.7%. Serum IgG4 level showed a positive correlation to tissue IgG4+plasma cell percentage, while serum IgG4/IgG ratio positively correlated to both percentage and number of IgG4+plasma cells. Steroids had a good initial response, but recurrences were common.
CONCLUSION
A considerable proportion of patients with lacrimal gland swelling fall within the range of IgG4-RD. Proper diagnosis requires clinical, serological, and histopathologic correlation. Patients require long follow-up periods.
PubMed: 36039106
DOI: 10.2147/OPTH.S378583 -
Arthritis Research & Therapy Sep 2023We investigated sensitivity of the 2020 Revised Comprehensive Diagnostic Criteria (RCD) and the 2019 ACR/EULAR classification criteria across the four identified...
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.
Topics: Humans; Immunoglobulin G4-Related Disease; Norway; Phenotype
PubMed: 37670401
DOI: 10.1186/s13075-023-03155-y -
Medicine Dec 2022IgG4-related diseases cause lesions in various organs throughout the body. In otorhinolaryngology, IgG4-related Mikulicz's disease is suspected and diagnosed based on... (Review)
Review
RATIONALE
IgG4-related diseases cause lesions in various organs throughout the body. In otorhinolaryngology, IgG4-related Mikulicz's disease is suspected and diagnosed based on the presence of lesions of the head and neck, salivary and lacrimal gland enlargement, and bilateral sinus opacity concentrated on the maxillary sinuses. However, in some cases, it is necessary to consider about differentiation between IgG4-related Mikulicz's disease and Sjögren syndrome.
PATIENT CONCERNS AND DIAGNOSIS
A 75-years-old male patient visited our hospital with bilateral otitis media with effusion, which was resistant to conservative treatment. Other symptoms at presentation included enlarged bilateral submandibular and sublingual glands marked oral dryness, severe decrease in saliva secretion (1 mL/10 minutes), and dry eyes. We conducted a Schirmer's and fluorescent dye tests, both of which were positive. High serum IgG4 levels were observed, and although the Sjögren syndrome (SS)-A/SS-B antibodies were negative, marked hypolacrimation and tear secretion were observed. Therefore, a detailed examination considering both IgG4-related Mikulicz's disease and SS was conducted. Salivary gland scintigraphy performed prior to the salivary gland biopsy revealed a marked decrease in uptake, which satisfied the diagnostic criteria for SS; however, it was difficult to diagnose IgG4-related disease based on the diagnostic definition.
INTERVENSIONS
Although a definitive diagnosis of SS was made, the persistent otitis media with effusion that was resistant to conservative treatment and bilateral mixed hearing loss were confirmed. As mixed hearing loss is considered an otological symptom of IgG4-related disease, oral steroid treatment was administered.
OUTCOME
Thereafter, marked recovery of hearing and reduced swelling and induration of the bilateral parotid and submandibular glands were observed. Clinically, IgG4-related Mikulicz's disease was strongly suspected, but a definite diagnosis of SS was made.
LESSONS
In the absence of an IgG4-related Mikulicz's disease diagnosis, careful differentiation between IgG4-related Mikulicz's disease and 2 diseases and their diagnostic criteria was essential.
Topics: Male; Humans; Aged; Sjogren's Syndrome; Mikulicz' Disease; Immunoglobulin G4-Related Disease; Hearing Loss, Mixed Conductive-Sensorineural; Otitis Media with Effusion; Immunoglobulin G
PubMed: 36596084
DOI: 10.1097/MD.0000000000032617 -
Clinical and Experimental Rheumatology Dec 2023Recent studies have implicated cytotoxic CD4 and CD8 T cells in primary Sjögren's syndrome (pSS) and IgG4-related disease (IgG4-RD), but their association with immune...
OBJECTIVES
Recent studies have implicated cytotoxic CD4 and CD8 T cells in primary Sjögren's syndrome (pSS) and IgG4-related disease (IgG4-RD), but their association with immune aging and organ-specific clinical features remain unclear. CX3CR1 is expressed on cytotoxic CD4 and CD8 T cells. The aim of this study was to determine associations of peripheral CX3CR1+CD4 and CX3CR1+CD8 T cells with aging and clinical features.
METHODS
Whole blood samples were freshly obtained from consecutive patients with active, treatment-naïve pSS (n=57), IgG4-RD (n=54), and healthy individuals (n=40) and analysed by flow cytometry for CX3CR1+CD4 and CX3CR1+CD8 proportions. Associations of those T cells with aging and clinical features were determined.
RESULTS
CX3CR1+CD4 and CX3CR1+CD8 T cells selectively expressed perforin and granzyme B. Proportions of CX3CR1+CD4 and CX3CR1+CD8 T cells were significantly higher in pSS and IgG4-RD than in healthy individuals. Higher proportions of CX3CR1+CD8 T cells were associated with aging in pSS and IgG4-RD but not in healthy individuals. Sex differences were not associated with proportions of CX3CR1+CD8 T cells. Furthermore, patients with pSS with interstitial lung disease showed higher proportions of CX3CR1+CD8 T cells than those without interstitial lung disease. IgG4-RD patients with retroperitoneal fibrosis and/or aortitis exhibited higher proportions of CX3CR1+CD8 T cells compared with those with Mikulicz's disease. Moreover, proportions of CX3CR1+CD8 T cells were decreased following glucocorticoid treatment in paralleled with clinical improvements in IgG4-RD.
CONCLUSIONS
CX3CR1+CD8 T cells might be involved in immune aging and distinct clinical phenotypes of patients with pSS or IgG4-RD.
Topics: Humans; Male; Female; Sjogren's Syndrome; Immunoglobulin G4-Related Disease; CD8-Positive T-Lymphocytes; Aging; Lung Diseases, Interstitial; CX3C Chemokine Receptor 1
PubMed: 37812481
DOI: 10.55563/clinexprheumatol/kfsd65 -
Journal of the Korean Association of... Feb 2020Immunoglobulin G4 (IgG4)-related dacryoadenitis and sialoadenitis (IgG4-DS) are part of a multiorgan fibroinflammatory condition of unknown etiology termed IgG4-related... (Review)
Review
Immunoglobulin G4 (IgG4)-related dacryoadenitis and sialoadenitis (IgG4-DS) are part of a multiorgan fibroinflammatory condition of unknown etiology termed IgG4-related disease (IgG4-RD), which has been recognized as a single diagnostic entity for less than 15 years. Histopathologic examination is critical for diagnosis of IgG4-RD. CD4+ T and B cells, including IgG4-expressing plasma cells, constitute the major inflammatory cell populations in IgG4-RD and are thought to cause organ damage and tissue fibrosis. Patients with IgG4-RD who have active, untreated disease exhibit significant increase of IgG4-secreting plasmablasts in the blood. Considerable insight into the immunologic mechanisms of IgG4-RD has been achieved in the last decade using novel molecular biology approaches, including next-generation and single-cell RNA sequencing. Exploring the interactions between CD4+ T cells and B lineage cells is critical for understanding the pathophysiology of IgG4-RD. Establishment of pathogenic T cell clones and identification of antigens specific to these clones constitutes the first steps in determining the pathogenesis of the disease. Herein, the clinical features and mechanistic insights regarding pathogenesis of IgG4-RD were reviewed.
PubMed: 32158675
DOI: 10.5125/jkaoms.2020.46.1.3 -
Cells Sep 2023Prolactin-inducible protein (PIP), also referred to as gross cystic disease fluid protein 15 (GCDFP-15), has been a trending topic in recent years due to its potential... (Review)
Review
Prolactin-inducible protein (PIP), also referred to as gross cystic disease fluid protein 15 (GCDFP-15), has been a trending topic in recent years due to its potential role as a specific marker in breast cancer. PIP binds to aquaporin-5 (AQP5), CD4, actin, fibrinogen, β-tubulin, serum albumin, hydroxyapatite, zinc α2-glycoprotein, and the Fc fragment of IgGs, and the expression of PIP has been demonstrated to be modulated by various cytokines, including IL4/13, IL1, and IL6. PIP gene expression has been extensively studied due to its captivating nature. It is influenced by various factors, with androgens, progesterone, glucocorticosteroids, prolactin, and growth hormone enhancing its expression while estrogens suppress it. The regulatory mechanisms involve important proteins such as STAT5A, STAT5B, Runx2, and androgen receptor, which collaborate to enhance PIP gene transcription and protein production. The expression level of PIP in breast cancer is dependent on the tumor stage and subtype. Higher expression is observed in early-stage tumors of the luminal A subtype, while lower expression is associated with luminal B, basal-like, and triple-negative subtypes, which have a poorer prognosis. PIP expression is also correlated with apocrine differentiation, hormone receptor positivity, and longer metastasis-free survival. PIP plays a role in supporting the immune system's antitumor response during the early stages of breast cancer development. However, as cancer progresses, the protective role of PIP may become less effective or diminished. In this work, we summarized the clinical significance of the PIP molecule in breast cancer and its potential role as a new candidate for cell-based therapies.
PubMed: 37759471
DOI: 10.3390/cells12182252