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 US 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 5240 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). Some 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 emergency room 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.

Coronary artery wall contrast enhancement imaging impact on disease activity assessment in IgG4-RD: a direct marker of coronary involvement.

BACKGROUND: Coronary artery wall contrast enhancement (CE) has been applied to non-invasive visualization of changes to the coronary artery wall in systemic lupus erythematosus (SLE). This study investigated the feasibility of quantifying CE to detect coronary involvement in IgG4-related disease (IgG4-RD), as well as the influence on disease activity assessment. METHODS: A total of 93 subjects (31 IgG4-RD; 29 SLE; 33 controls) were recruited in the study. Coronary artery wall imaging was performed in a 3.0 T MRI scanner. Serological markers and IgG4-RD Responder Index (IgG4-RD-RI) scores were collected for correlation analysis. RESULTS: Coronary wall CE was observed in 29 (94 %) IgG4-RD patients and 22 (76 %) SLE patients. Contrast-to-noise ratio (CNR) and total CE area were significantly higher in patient groups compared to controls (CNR: 6.1 ± 2.7 [IgG4-RD] v. 4.2 ± 2.3 [SLE] v. 1.9 ± 1.5 [control], P < 0.001; Total CE area: 3.0 [3.0-6.6] v. 1.7 [1.5-2.6] v. 0.3 [0.3-0.9], P < 0.001). In the IgG4-RD group, CNR and total CE area were correlated with the RI (CNR: r = 0.55, P = 0.002; total CE area: r = 0.39, P = 0.031). RI´ scored considering coronary involvement by CE, differed significantly from RI scored without consideration of CE (RI v. RI´: 15 ± 6 v. 16 ± 6, P < 0.001). CONCLUSIONS: Visualization and quantification of CMR coronary CE by CNR and total CE area could be utilized to detect subclinical and clinical coronary wall involvement, which is prevalent in IgG4-RD. The potential inclusion of small and medium-sized vessel involvements in the assessment of disease activity in IgG4-RD is worthy of further investigation.

IgG4-related cholangitis - a mimicker of fibrosing and malignant cholangiopathies.

IgG4-related cholangitis (IRC) is the major hepatobiliary manifestation of IgG4-related disease (IgG4-RD), a systemic fibroinflammatory disorder. The pathogenesis of IgG4-RD and IRC is currently viewed as multifactorial, as there is evidence of a genetic predisposition while environmental factors, such as blue-collar work, are major risk factors. Various autoantigens have been described in IgG4-RD, including annexin A11 and laminin 511-E8, proteins which may exert a partially protective function in cholangiocytes by enhancing secretion and barrier function, respectively. For the other recently described autoantigens, galectin-3 and prohibitin 1, a distinct role in cholangiocytes appears less apparent. In relation to these autoantigens, oligoclonal expansions of IgG4+ plasmablasts are present in patients with IRC and disappear upon successful treatment. More recently, specific T-cell subtypes including regulatory T cells, follicular T helper 2 cells, peripheral T helper cells and cytotoxic CD8+ and CD4+ SLAMF7+ T cells have been implicated in the pathogenesis of IgG4-RD. The clinical presentation of IRC often mimics other biliary diseases such as primary sclerosing cholangitis or cholangiocarcinoma, which may lead to inappropriate medical and potentially invalidating surgical interventions. As specific biomarkers are lacking, diagnosis is made according to the HISORt criteria comprising histopathology, imaging, serology, other organ manifestations and response to therapy. Treatment of IRC aims to prevent or alleviate organ damage and to improve symptoms and consists of (i) remission induction, (ii) remission maintenance and (iii) long-term management. Glucocorticosteroids are highly effective for remission induction, after which immunomodulators can be introduced for maintenance of remission as glucocorticosteroid-sparing alternatives. Increased insight into the pathogenesis of IRC will lead to improved diagnosis and novel therapeutic strategies in the future.

The M-ANNHEIM-AiP-Activity-Score is useful for predicting relapse in patients with type 1 autoimmune pancreatitis.

BACKGROUND/OBJECTIVES: Proper assessment of disease activity and prediction of relapse are crucial for the management of autoimmune pancreatitis (AIP). The M-ANNHEIM-AiP-Activity-Score (MAAS) has been proposed to determine disease activity and predict relapse in German and Swedish patients with AIP. MAAS is calculated using six categories: pain report, pain control, exocrine insufficiency, endocrine insufficiency, imaging, and complications. This study aimed to clarify the usefulness of MAAS to predict relapse in Japanese patients with type 1 AIP. METHODS: We retrospectively analyzed 117 patients with type 1 AIP undergoing initial and maintenance steroid treatments at our institute between April 2006 and March 2021. AIP was diagnosed according to the Japanese Diagnostic Criteria for AIP 2018. We examined the association of MAAS with relapse during and after maintenance treatment. RESULTS: MAAS (median, 8 points) at the start of the initial treatment was reduced after treatment (median, 4 points; P < 0.001). A MAAS ≥11 points at the start of the initial treatment was associated with relapse. The initial treatment-induced reduction of MAAS<60% was more frequent in patients with relapse (75.0%) than in patients without relapse (37.6%; P = 0.007). MAAS at the start of maintenance treatment was higher for patients with relapse (median, 5 points) than that for patients without relapse (median, 4 points; P = 0.007). MAAS ≥4 points at the start of maintenance treatment was associated with subsequent relapse. CONCLUSIONS: MAAS is useful for predicting relapse in patients with type 1 AIP undergoing maintenance therapy.

A case of IgG4-related interstitial nephritis with ureteral obstruction: case report and literature review.

BACKGROUND: IgG4-related disease (IgG4-RD) is a newly discovered systemic disease that can affect any organ or tissue in the body. IgG4-related kidney disease (IgG4-RKD) is relatively rare but essential to IgG4-RD. However, there are few reports of IgG4-RD mimicking malignant ureteral tumors leading to hydronephrosis. We report here a rare case of IgG4-RD involving the ureter. CASE PRESENTATION: An 87-year-old man presented to our nephrology department with anorexia, nausea, and acute kidney injury in November 2020. Urinary computed tomography (CT) examination revealed a right lower ureter mass with right renal and ureter hydronephrosis. The serum level of IgG4 was 1890 mg/dL, and the concurrently renal biopsy revealed extensive infiltration of IgG4-positive plasma cells in renal interstitium, which was diagnosed as IgG4-associated tubule-interstitial nephritis(IgG4-TIN). The renal function improved significantly after double-J tube implantation of the right ureter and moderate-dose hormone therapy. The serum IgG4 decreased to the normal range, and the right lower ureter mass almost disappeared after one year of low-dose hormone maintenance therapy. CONCLUSION: IgG4-RD can present as a mass in the renal pelvis and (or) ureter, leading to hydronephrosis. Therefore, early recognition of this disease is significant. Most patients respond well to hormonal therapy to avoid surgical treatment due to misdiagnosis as malignant tumors, causing secondary harm to patients.

Distinct disease-specific Tfh cell populations in 2 different fibrotic diseases: IgG4-related disease and Kimura disease.

BACKGROUND: How T follicular (Tfh) cells contribute to many different B-cell class-switching events during T-cell-dependent immune responses has been unclear. Diseases with polarized isotype switching offer a unique opportunity for the exploration of Tfh subsets. Secondary and tertiary lymphoid organs in patients with elevated tissue expression levels of IgE (Kimura disease, KD) and those of IgG4 (IgG4-related disease, IgG4-RD) can provide important insights regarding cytokine expression by Tfh cells. OBJECTIVE: We sought to identify disease-specific Tfh cell subsets in secondary and tertiary lymphoid organs expressing IL-10 or IL-13 and thus identify different cellular drivers of class switching in 2 distinct types of fibrotic disorders: allergic fibrosis (driven by type 2 immune cells) and inflammatory fibrosis (driven by cytotoxic T lymphocytes). METHODS: Single-cell RNA sequencing, in situ sequencing, and multicolor immunofluorescence analysis were used to investigate B cells, Tfh cells, and infiltrating type 2 cells in lesion tissues from patients with KD or IgG4-RD. RESULTS: Infiltrating Tfh cells in tertiary lymphoid organs from IgG4-RD were divided into 6 main clusters. We encountered abundant infiltrating IL-10-expressing LAG3+ Tfh cells in patients with IgG4-RD. Furthermore, we found that infiltrating AICDA+CD19+ B cells expressing IL-4, IL-10, and IL-21 receptors correlated with IgG4 expression. In contrast, we found that infiltrating IL-13-expressing Tfh cells were abundant in affected tissues from patients with KD. Moreover, we observed few infiltrating IL-13-expressing Tfh cells in tissues from patients with IgG4-RD, despite high serum levels of IgE (but low IgE in the disease lesions). Cytotoxic T cells were abundant in IgG4-RD; in contrast, type 2 immune cells were abundant in KD. CONCLUSIONS: Our analysis revealed a novel subset of IL-10+LAG3+ Tfh cells infiltrating the affected organs of IgG4-RD patients. In contrast, IL-13+ Tfh cells and type 2 immune cells infiltrated those of KD patients.

Immunoglobulin G4-Related Disease of the Intestine: A Clinicopathological Entity to Be Considered.

Background and Objectives: Immunoglobulin G4-related disease (IgG4-RD) is a recently recognized immune-mediated, systemic condition of unknown etiology, associated with fibroinflammatory lesions. Diagnosis is set in the presence of IgG4-positive plasma cell infiltration of the involved tissue and elevated serum IgG4 levels. However, approximately 30% of patients have normal serum IgG4 levels. IgG4-RD may affect several organs, including the pancreas, bile ducts, mesentery, retroperitoneum, and salivary glands, but the involvement of the gastrointestinal tract is uncommon. Materials and Methods: The case series of 4 patients with IgG4-RD involving the intestinal tract was observed in the period of 2017-2022. Colorectal and ileal biopsy specimens were stained with hematoxylin and eosin and immunohistochemical techniques using monoclonal antihuman IgG4 primary antibody. Diagnosis of IgG4-RD was based on the presence of >50 cells/ HPF and IgG4/IgG ratio >40 confirmed by two pathologists. Results: IgG4-RD was set in patients previously diagnosed as affected by Crohn's disease. Conclusions: Systematic IgG4 immunohistochemical staining should be considered in the diagnostic workup of patients with gastrointestinal strictures, mimicking Crohn's disease. The exact prevalence of the condition is likely more frequent than reported and should be defined by a large series of consecutive patients.

Expanded CD4+CXCR5-PD-1+ peripheral T helper like cells and clinical significance in IgG4-related disease.

To identify the phenotypic features and clinical significance of peripheral T helper (Tph) like cells in IgG4-RD, 54 untreated IgG4-RD patients and 57 healthy controls (HCs) were enrolled. Flow cytometry analysis, ELISA and correlation analysis were performed. Results indicated that percentages of CD4 + CXCR5-PD-1+ Tph like cells in the peripheral blood of IgG4-RD patients were significantly higher than those of HCs (2.27% ± 1.99% vs 1.12% ± 0.98%, P < 0.001). Expression of CD38, CD25, and TIGIT was higher, whereas that of CCR7, CD127 was lower in the Tph like cells from the IgG4-RD patients than in those from the HCs. The IgG4-RD patients with affected internal organs had higher circulating Tph like cell levels than those without (2.69% ±1.99% vs 1.23% ± 0.93%, respectively, P = 0.003). In addition, Tph like cells correlated with serum IgG and IgG4 and peripheral plasmablast levels which could be a promising biomarker for disease activity monitoring.

The role of PD-1/PD-Ls in the pathogenesis of IgG4-related disease.

OBJECTIVE: To investigate the role of programmed cell death protein 1 (PD-1) and its two ligands, PD-L1 and PD-L2, in the pathogenesis of IgG4-related disease (IgG4-RD). METHODS: Patients with IgG4-RD (n = 43) and healthy controls (n = 34) were recruited. Expression levels of PD-1, PD-L1 and PD-L2 in plasma, submandibular gland and T cell subsets were determined by ELISA, immunohistochemistry and flow cytometry. Naïve T cells were stimulated with or without PD-L1/PD-L2 or anti-PD-L1/anti-PD-L2 for 7 days and the proportion of CD4+CD25+ Treg cells was detected by flow cytometry. RESULTS: The expression of PD-1, PD-L1 and PD-L2 in the plasma, submandibular gland and on the surface of Treg cells was increased in IgG4-RD patients. Plasma soluble (s)PD-1 was positively correlated with serum IgG, IgG1, IgG3, IgG4, IgG4-RD responder index and numbers of organs involved, and negatively correlated with serum IgM, IgA, C3 and C4. Plasma sPD-L2 was positively correlated with serum IgG1, and plasma sPD-L1 was positively correlated with sPD-L2 and negatively correlated with C3. Stimulation of PD-L1 but not PD-L2 promoted the differentiation of naïve T cells from IgG4-RD patients into CD4+CD25+ Treg cells. CONCLUSION: Plasma concentrations of sPD-1, sPD-L1 and sPD-L2 were significantly increased in patients with IgG4-RD, and the expression of PD-1 and PD-L2 on Treg cells was upregulated. PD-1-PD-L1 can promote the differentiation of naïve T cells into Treg cells and thus participate in the pathogenesis of IgG4-RD.

Dupilumab as an adjunct treatment for a patient with steroid-dependent immunoglobulin G4-related disease complicated by asthma: a case report.

Introduction: Immunoglobulin G4-related disease (IgG4-RD) responds well to glucocorticoids but is often associated with relapses. Interleukin (IL)-4 and IL-13 are involved in the pathogenesis of IgG4-RD. We present the first case in which dupilumab was an effective adjunct treatment for a patient with steroid-dependent IgG4-RD complicated by asthma.Case study: A 57-year-old man was referred to our hospital for further investigation and treatment of proptosis with neck swelling in 2019. He developed a cough and swelling of the neck in 2016. He was diagnosed with asthma in 2017 and started receiving inhaled glucocorticoids and a long-acting beta-agonist. The patient started receiving oral prednisolone at a dose of 20 mg/day. Oral prednisolone reduced his symptoms, but he relapsed when treatment was tapered to less than 10 mg/day. He was diagnosed with IgG4-RD through a parotid gland biopsy.Results: Azathioprine was given to reduce systemic glucocorticoids. The prednisolone dose was gradually tapered to 10 mg/day, resulting in the relapse of proptosis and an asthma attack. We added dupilumab, and his asthma symptoms and proptosis improved. Serum IgG4 levels continued to decrease, and the prednisolone dose was tapered to 2 mg.Conclusion: Dupilumab might be useful as an adjunctive treatment for patients with steroid-dependent IgG4-RD complicated by asthma. Serum IgG4 levels can be used as a marker to monitor dupilumab treatment in IgG4-RD.

The prevalence of extra-salivary gland complications in immunoglobulin G4-related sialadenitis.

OBJECTIVES: To estimate the prevalence of extra-glandular lesions in patients with immunoglobulin G4-related sialadenitis (IgG4-RS). METHODS: Six electronic databases (PubMed, EMBASE, Science Direct, Scopus, Web of Science, and China National Knowledge Infrastructure) were systematically searched from the date of inception of each database to March 2021. The Strengthening the Reporting of Observational Studies in Epidemiology statement was used to conduct methodological quality assessment, and a random-effect meta-analysis model was applied to estimate the prevalence. Publication bias was visually assessed using a funnel plot and calculated via Begg's and Egger's tests. The Stata 15 software was used to perform data analysis. RESULTS: A total of 43 articles comprising 1,864 patients with IgG4-RS were considered to be eligible for this study. The pooled prevalence of extra-salivary gland lesions in IgG4-RS was 76.53% with a confidence interval (CI) of (69.39%, 83.04%). A higher prevalence was associated with studies published before or during 2015 (84.38%, CI [74.23%, 92.58%]) than those published after 2015 (68.55%, CI [58.44%, 77.88%]). Lacrimal gland involvement (54.68%, CI [45.61%, 63.60%]) and lymph node swelling (56.96%, CI [48.16%, 65.56%]) were the most frequent lesions. CONCLUSIONS: Extra-glandular lesions were common in patients with IgG4-RS. More high-quality prospective studies with less heterogeneity are required to determine the accurate prevalence.

Eruptive cherry angiomas-a novel cutaneous manifestation of immunoglobulin type gamma 4-related disease.

Immunoglobulin type gamma 4-related disease (IgG4-RD) is a fibroinflammatory condition that can have systemic and/or cutaneous manifestations. The most common cutaneous features are erythematous papules, nodules and/or plaques, typically involving the head and neck (J Am Acad Dermatol. 2016;75:197). We report a case of IgG4-RD presenting with eruptive cherry angiomas, a novel cutaneous presentation.

CD4+ and CD8+ cytotoxic T lymphocytes may induce mesenchymal cell apoptosis in IgG4-related disease.

BACKGROUND: IgG4-related disease (IgG4-RD) is an immune-mediated fibrotic disorder that has been linked to CD4+ cytotoxic T lymphocytes (CD4+CTLs). The effector phenotype of CD4+CTLs and the relevance of both CD8+ cytotoxic T lymphocytes (CD8+CTLs) and apoptotic cell death remain undefined in IgG4-RD. OBJECTIVE: We sought to define CD4+CTL heterogeneity, characterize the CD8+CTL response in the blood and in lesions, and determine whether enhanced apoptosis may contribute to the pathogenesis of IgG4-RD. METHODS: Blood analyses were undertaken using flow cytometry, cell sorting, transcriptomic analyses at the population and single-cell levels, and next-generation sequencing for the TCR repertoire. Tissues were interrogated using multicolor immunofluorescence. Results were correlated with clinical data. RESULTS: We establish that among circulating CD4+CTLs in IgG4-RD, CD27loCD28loCD57hi cells are the dominant effector subset, exhibit marked clonal expansion, and differentially express genes relevant to cytotoxicity, activation, and enhanced metabolism. We also observed prominent infiltration of granzyme A-expressing CD8+CTLs in disease tissues and clonal expansion in the blood of effector/memory CD8+ T cells with an activated and cytotoxic phenotype. Tissue studies revealed an abundance of cells undergoing apoptotic cell death disproportionately involving nonimmune, nonendothelial cells of mesenchymal origin. Apoptotic cells showed significant upregulation of HLA-DR. CONCLUSIONS: CD4+CTLs and CD8+CTLs may induce apoptotic cell death in tissues of patients with IgG4-RD with preferential targeting of nonendothelial, nonimmune cells of mesenchymal origin.

Probable IGG4 related ophthalmic disease presenting with uveitis.

We present a case of an uncommon presentation of IgG4-related ophthalmic disease (ROD). A 58-year-old female presented with unilateral acute anterior uveitis of the right eye, which progressed to scleritis with the development of an associated orbital mass despite treatment with oral glucocorticoid. Initial histopathology of an orbital biopsy was non-diagnostic and continued progression of the disease lead to complete loss of vision in the right eye. The development of uveitis in the previously unaffected left eye led to the decision for enucleation of the right globe and further orbital biopsy. Histopathology revealed features supporting IgG4-related ophthalmic disease. Oral glucocorticoid therapy failed to induce remission, and rituximab therapy was initiated, leading to a rapid resolution in her symptoms. Other cases with a similar presentation report a poor visual prognosis, highlighting the need for prompt diagnosis and treatment of uveitis associated with signs of orbital or scleral involvement.

Ossifying fibrous epulis as an IgG4-related disease of the oral cavity: a case report and literature review.

BACKGROUND: Fibrous sclerosing tumours and hypertrophic lesions in IgG4-related disease (IgG4-RD) are formed in various organs throughout the body, but disease in the oral region is not included among individual organ manifestations. We report a case of ossifying fibrous epulis that developed from the gingiva, as an instance of IgG4-RD. CASE PRESENTATION: A 60-year-old Japanese man visited the Department of Oral and Maxillofacial Surgery, Gunma University Hospital, with a chief complaint of swelling of the left mandibular gingiva. A 65 mm × 45 mm pedunculated tumour was observed. The bilateral submandibular lymph nodes were enlarged. The intraoperative pathological diagnosis of the enlarged cervical lymph nodes was inflammation. Based on this diagnosis, surgical excision was limited to the intraoral tumour, which was subsequently pathologically diagnosed as ossifying fibrous epulis. Histopathologically, the ossifying fibrous epulis exhibited increased levels of fibroblasts and collagen fibres, as well as infiltration by numerous plasma cells. The IgG4/IgG cell ratio was > 40%. Serologic analysis revealed hyper-IgG4-emia (> 135 mg/dL). The patient met the comprehensive clinical diagnosis criteria and the American College of Rheumatology and European League Against Rheumatism classification criteria for IgG4-RD. Based on these criteria, we diagnosed the ossifying fibrous epulis in our patient as an IgG4-related disease. A pathological diagnosis of IgG4-related lymphadenopathy was established for the cervical lymph nodes. Concomitant clinical findings were consistent with type II IgG4-related lymphadenopathy. CONCLUSIONS: A routine serological test may be needed in cases with marked fibrous changes (such as epulis) in the oral cavity and plasma cells, accompanied by tumour formation, to determine the possibility of individual-organ manifestations of IgG4-related disease.

IgG4-Related Chronic Sinonasal Pseudotumor with Refractory Nasal Bleeding: A Case Report.

Immunoglobulin G4-related disease (IgG4-RD) is a systemic fibro-inflammatory and idiopathic autoimmune disorder. IgG4-RD can be characterized by the presence of pseudotumors. Inflammatory pseudotumors may involve any part of a human organ. There are few reports of sinus lesions in IgG4-RD. An 82-year-old man has a history of chronic sinusitis for the last several years and no remarkable family history. Two years before disease presentation, the patient experienced intermittent nasal bleeding, stuffy nose, dizziness, and fatigue. Blood test revealed positive (160X) antinuclear antibody with a mixed speckled and nucleolar pattern, IgG level of 1370 mg/dL, and IgG4 level of 99.7 mg/dL. Computed tomography (CT) of the sinus revealed several calcifications in the sphenoid sinus. Surgical findings revealed tumor-like materials. Pathological examination of the soft tissues revealed acute and chronic granulomatous inflammation. Immunohistochemical analysis demonstrated high levels of positive-affinity markers of IgG, IgG4, and CD138 and a IgG4/IgG ratio > 40%. IgG4-RD with pseudotumor was diagnosed. The initial treatment was intravenous methylprednisolone 120 mg daily for three days and oral prednisolone 10 mg twice a day and azathioprine 50 mg daily. The efficacy of the treatment was insufficient, and nasal bleeding did not decrease. Subsequently administered intravenous rituximab 1000 mg monthly for 2 months. Following this treatment, nasal bleeding stopped. CT revealed reduction in nasal mucosal swelling compared with that in a previous scan. This report highlights that in cases with an inflammatory mass mimicking malignancy, IgG4RD should always be considered, and rituximab treatment is recommended upon failure of steroid and azathioprine therapy.

The association of smoking with immunoglobulin G4-related disease: a case-control study.

OBJECTIVE: To evaluate the association between cigarette smoking and the odds of IgG4-related disease (IgG4-RD). METHODS: We performed a case-control study of patients with IgG4-RD compared in a 1:5 ratio with age-, race- and sex-matched controls. We included cases evaluated at the Massachusetts General Hospital, a hospital within the Mass General Brigham (MGB) System. Controls were identified from the MGB Biobank. Smoking status at the date of IgG4-RD diagnosis or corresponding index date was determined. Conditional logistic regression was used to estimate the association between cigarette smoking and the odds of having IgG4-RD. RESULTS: There were 234 IgG4-RD cases and 1170 controls. The mean age (59 years), sex (62% male) and race (75% white) were well balanced. IgG4-RD cases were more likely to be current smokers compared with controls [25 (11%) vs 70 (6%); odds ratio (OR) 1.79 (95% CI 1.08, 2.95)]. This association was strongest among female cases [13 (14%) vs 19 (4%);, OR 3.79 (95% CI 1.71, 8.39)] and those with retroperitoneal fibrosis [RPF; 13 (28%) vs 13 (6%);, OR 6.93 (95% CI 2.78, 17.26)] or normal IgG4 concentrations [21 (21%) vs 21 (4%); OR 6.22 (95% CI 3.09, 12.49)]. When RPF cases were excluded, there was no longer an association between current smoking and the odds of having IgG4-RD [12 (6%) vs 57 (6%); OR 0.95 (95% CI 0.49, 1.86)]. CONCLUSION: Being a current smoker is associated with greater odds of having IgG4-RD, especially among women and those with RPF or normal IgG4 concentrations. Current smoking is the first recognized modifiable risk factor for IgG4-RD.

Synergistic effect of IgG4 antibody and CTLs causes tissue inflammation in IgG4-related disease.

IgG4-related disease (IgG4-RD) is characterized by multi-organ irreversible damage resulting from tissue-specific infiltration of IgG4+ plasma cells and cytotoxic T lymphocytes (CTLs). However, whether IgG4 antibody contributes to the inflammation remains unclear. In this study, we established a mouse model that enabled us to evaluate the pathogenic function of IgG4 antibodies in response to a tissue-specific autoantigen using recombinant ovalbumin (OVA)-specific human IgG4 monoclonal antibody (rOVA-hIgG4 mAb) and the mice expressing OVA of the pancreatic islets (RIP-mOVA mice). We found no inflammatory effect of rOVA-hIgG4 mAb transfer alone; however, co-transfer with OVA-specific CD8 CTLs (OT-I T cells) induced tissue damage with dense lymphocytic inflammation in the pancreas of RIP-mOVA mice. rOVA-hIgG4 mAb caused accumulation of conventional DC1 cells (cDC1s) in the lymphoid tissues, and the dendritic cells (DCs) activated the OT-I T cells via cross-presentation. We also revealed that the synergistic effects of CTLs and antibodies were observed in the other subclasses including endogenous antibodies if they recognized the same antigen. The transfer of OVA-specific CD4 helper T cells (OT-II T cells) into RIP-mOVA mice induced the production of anti-OVA antibody, which had a synergistic effect, through acquisition of a T follicular helper (TFH) phenotype. Moreover, using OT-II T cells deficient in Bcl6 caused lower anti-OVA antibody production and inflammation with OT-I T cells. Our results indicated that autoreactive IgG4 antibodies play an important role of the tissue-specific CTL response in IgG4-RD.

Establishment of time-resolved fluoroimmunoassay of IgG4 based on magnetic microspheres.

BACKGROUND: The abnormal increase in serum IgG4 level is an important clinical symptom of IgG4-related disease (IgG4-RD), and the detection of serum IgG4 level is a powerful tool for the diagnosis of IgG4-RD. This study was conducted to establish a simple and rapid immunoassay for the determination of human serum IgG4 levels. METHODS: Based on the competition method, a novel immunoassay was established for the determination of human serum IgG4 using a combination of time-resolved fluoroimmunoassay (TRFIA) and magnetic microspheres. IgG4 was coupled with magnetic microspheres and competed with IgG4 in the samples to bind the Eu3+ -labeled anti-IgG4 antibody. The immunocomplex was separated and washed in a magnetic field, and the fluorescence counts were measured according to the number of dissociated europium ions. RESULTS: The analytical sensitivity of IgG4-TRFIA based on magnetic microspheres was 0.006 g/L, and the detection range was 0.006-20 g/L under optimal conditions. The precision, recovery, and specificity of this immunoassay were demonstrated to be acceptable. The clinical application of IgG4-TRFIA based on magnetic microspheres was evaluated and compared with that of immunonephelometry. The results showed that the two detection methods had a good correlation, with a correlation coefficient of .9871. CONCLUSION: IgG4-TRFIA based on magnetic microspheres has the advantages of high sensitivity, wide detection range, and short analysis time and has the potential to become a useful tool for the diagnosis of IgG4-RD.

The 2020 revised comprehensive diagnostic (RCD) criteria for IgG4-RD.

IgG4-related disease (IgG4-RD) is a fascinating clinical entity first reported in this century in Japan, and includes a wide variety of diseases, such as formerly named Mikulicz's disease (MD), autoimmune pancreatitis (AIP), interstitial nephritis, prostatitis and retroperitoneal fibrosis. The Japanese IgG4 team organized by the Ministry of Health, Labor and Welfare (MHLW) of Japan has published the first criteria, comprehensive diagnostic (CD) criteria for IgG-RD 2011. Thereafter, IgG4-RD has been accepted widely and many cases have been reported from all over the world. Several problems have arisen in clinical practice, however, including the difficulty obtaining biopsy samples, and the sensitivity and specificity in cut off level of serum IgG4 and impaired immunostaining of IgG4. Given these situations, the Japanese IgG4 team has updated the 2011 comprehensive diagnostic criteria for IgG4-RD and propose the 2020 revised comprehensive diagnostic (RCD) criteria for IgG4-RD, which consists of 3 domains; 1) Clinical and radiological features, 2) Serological diagnosis and 3) Pathological diagnosis. In addition, the new pathological diagnosis is composed by three sub-items including storiform fibrosis and obliterative phlebitis.