IgG4-related Disease Concomitant with Diffuse Large B-cell Lymphoma.

A 77-year-old man presented with right inguinal lymphadenopathy and swollen parotid and submandibular glands bilaterally. Histopathology revealed germinal center B-cell type diffuse large B-cell lymphoma (DLBCL) in the inguinal lymph node. Lymphocyte and plasma cell infiltration in the submandibular gland with elevated serum IgG4 levels (13 g/L) prompted a diagnosis of IgG4-related disease (IgG4-RD). Systemic chemotherapy for DLBCL led to shrinkage of the lymph nodes and disappearance of the submandibular gland swelling, as confirmed by fluorodeoxyglucose-positron emission tomography/computed tomography. Although concomitant IgG4-RD and lymphoma have been reported, their simultaneous diagnosis is rare; therefore, a biopsy of all involved organs is crucial in cases with unusual organ involvement.

Efgartigimod Successfully Ameliorated Acute Exacerbation of Myasthenia Gravis with Anti-muscle-specific Kinase Antibodies.

We herein report two patients with anti-muscle-specific kinase (MuSK) antibody-positive myasthenia gravis who experienced rapid deterioration of weakness, particularly respiratory muscle weakness, necessitating non-invasive positive pressure ventilation (NIPPV) and were treated with efgartigimod. After treatment initiation, a rapid reduction in IgG levels and recovery from clinical symptoms were observed. NIPPV was no longer required two to three weeks after the first infusion of efgartigimod. These findings suggest that the reduction of IgG levels using efgartigimod is a good treatment option in patients with myasthenia gravis positive for anti-MuSK antibodies, even during the acute phase of the disease.

IgG4 porta-hepatis pseudotumor mimicking a hilar cholangiocarcinoma.

A 60-year-old female with a BRCA2 mutation and a history of breast cancer presented with diffuse abdominal pain and elevated liver enzymes. Imaging revealed a porta-hepatis mass, prompting consideration of hilar cholangiocarcinoma or breast cancer metastasis. Further investigation including biopsy and 18F-fluorodeoxyglucose positron emission tomography/computed tomography findings were inconsistent with malignancy, leading to investigation of non-neoplastic causes. Elevated IgG4 levels suggested IgG4-related disease, a mass-forming fibroinflammatory condition. This case demonstrates IgG4-related disease exclusively impacting the portal vein and underscores the importance of considering IgG4-related disease in the differential diagnosis of hepatic masses.

IgG4-related pleural disease diagnosed by thoracoscopic pleural biopsy: A case report.

Here we report a rare case of immunoglobulin G4 (IgG4)-related pleural disease diagnosed using a thoracoscopic pleural biopsy. A 66-year-old man was admitted to our hospital with right-dominant bilateral pleural effusions and gradually worsening dyspnoea. Chest radiographs revealed right-dominant pleural effusions, while chest computed tomography showed bilateral pleural effusions without parenchymal lesions. Although the bilateral pleural effusions were exudative with an increased number of lymphocytes, the definitive diagnosis was initially elusive. High IgG4 levels in the serum and pleural effusions were observed. A pathological evaluation of a right pleural biopsy specimen collected via video-assisted thoracoscopic surgery showed fibrosis-associated lymphoplasmacytic infiltration, 45-60 IgG4-positive plasma cells per high-power field, and an IgG4/immunoglobulin G ratio of 40%. Consequently, the patient was diagnosed with IgG4-related pleural disease. The bilateral pleural effusions improved after corticosteroid therapy.

Case report and review of literature: IgG4-gastroduodenitis in upper GI Crohn's disease: two separate entities or just a marker of disease severity?

A 20-year-old man was presented with ulcerative gastritis and duodenitis complicated by pyloric stenosis. Helicobacter pylori infection was excluded, and the lesions did not respond to treatment with proton pump inhibitors. No other parts of the intestinal tract showed signs of inflammation. Histopathological review showed signs of chronic inflammation with granuloma formation. A tentative diagnosis of isolated upper gastrointestinal (UGI) Crohn's disease was performed. However, additional work-up revealed significantly positive IgG4 staining as well as elevated IgG4 serum levels. Since granulomatous disease is unlikely in IgG4-related disease, an eventual diagnosis of overlapping IgG4-related disease and Crohn's disease (CD) was performed. Treatment with systemic steroids and anti-TNF in combination with azathioprine led to rapid symptomatic improvement. In this article, we review the available literature on IgG4-related gastroduodenitis, granulomatous gastritis, and upper GI CD. We suggest the possibility that IgG4-infiltration may be a marker of severely active inflammatory bowel disease rather than a separate disease entity.

Diagnostic Approach to IgG4-Related Retroperitoneal Fibrosis After Colorectal Cancer Surgery in a Patient With Normal IgG4 Levels: A Case Report.

An asymptomatic 75-year-old man who underwent transverse colon cancer surgery two years previously presented with retroperitoneal fibrosis (RPF) around the ventral sacral and right external iliac artery and vein on abdominal computed tomography (CT) during a routine surveillance visit. We assumed cancer recurrence or immunoglobulin G4 (IgG4)-related disease (RD), but although generic tumor markers and IgG4 levels were normal, soluble interleukin 2 receptor (sIL-2R) was elevated at 569 U/mL (reference: 122-496 U/mL). No diagnosis was made at this time, and the patient was followed up. He subsequently developed edema of both lower extremities. Abdominal enhanced CT showed an enlarged RPF without invasion of surrounding organs and with a delayed contrast effect, and positron emission tomography-CT showed fluorodeoxyglucose accumulation in the same area but a lower standardized uptake value (SUV) than at the time of transverse colon cancer diagnosis. Although generic tumor markers and IgG4 levels remained within the reference range, sIL-2R was further elevated to 1100 U/mL. An open biopsy and histopathology showed a high IgG4/IgG-positive cell ratio and infiltration of IgG4-positive plasma cells. The patient was finally diagnosed with IgG4-RD RPF. In cases of RPF after colorectal cancer surgery, the combined findings of elevated sIL-2R, lack of infiltration into surrounding organs, and lower SUV values ​​than at the cancer site could provide useful information to aid the diagnosis of IgG4-RD RPF.

Submandibular gland tissue RNAseq and spatial transcriptome analyses in IgG4-related disease.

OBJECTIVE: To identify genes that could provide clues leading to the discovery of drugs to treat IgG4-related disease (IgG4-RD). METHODS: Submandibular gland tissue bulk RNAseq analysis of 45 cases with a definite diagnosis of IgG4-RD was integrated with Visium spatial transcriptome analysis of 2 cases to identify pathogenic genes expressed in tertiary lymphoid tissues. RESULTS: Bulk RNAseq and pathway analyses showed upregulation of cell cycle and T cell-related signals in IgG4-RD. Spatial transcriptome analysis identified the cluster corresponding to germinal centers and the top 38 common genes that showed significant variations in expression compared with other clusters. The top 20 genes were extracted by comparing the bulk RNAseq data. Network analysis identified CDK1 as the ge most strongly associated of the top 20 genes. CONCLUSION: The CDK1 gene may be a regulator of the pathogenesis of IgG4-RD and provide clues for drug discovery.

Preclinical efficacy of peanut-specific IgG4 antibody therapeutic IGNX001.

BACKGROUND: Existing therapeutic strategies are challenged by long times to achieve effect and often require frequent administration. Peanut allergic individuals would benefit from a therapeutic that provides rapid protection against accidental exposure within days of administration while carrying little risk of adverse reactions. OBJECTIVE: Guided by the repertoire of human IgE monoclonal antibodies (mAbs) from allergic individuals, we sought to develop a treatment approach leveraging the known protective effects of allergen-specific IgG4 antibodies. METHODS: We applied our single-cell RNA sequencing SEQ SIFTER™ platform to whole blood samples from peanut allergic individuals to discover IgE mAbs. These were then class-switched by replacing the IgE constant region with IgG4 while retaining the allergen-specific variable regions. In vitro mast cell activation tests (MATs), basophil activation tests (BATs), enzyme-linked immunosorbent assays (ELISAs), and an in vivo peanut allergy mouse model were used to evaluate the specificity, affinity, and activity of these recombinant IgG4 mAbs. RESULTS: We determined that human peanut-specific IgE mAbs predominantly target immunodominant epitopes on Ara h 2 and Ara h 6 and that recombinant IgG4 mAbs effectively blocked these epitopes. IGNX001, a mixture of two such high-affinity IgG4 mAbs, provided robust protection against peanut-mediated mast cell activation in vitro as well as against anaphylaxis upon intragastric peanut challenge in a peanut allergy mouse model. CONCLUSION: We developed a peanut-specific IgG4 antibody therapeutic with convincing preclinical efficacy starting from a large repertoire of human monoclonal IgE antibodies from demographically and geographically diverse individuals. These results warrant further clinical investigation of IGNX001 and underscore the opportunity for the application of this therapeutic development strategy in other food and environmental allergies.

The role of tissue IgG4 levels in steroid therapy in patients with idiopathic granulomatous mastitis.

Idiopathic granulomatous mastitis (IGM) is a benign, chronic inflammatory lesion of the breast. Immunoglobulin G4 (IgG4) associated disease is rare in the breast. In our study, we aimed to evaluate the efficacy of steroid treatment on IgG4 levels in tissue in patients diagnosed with IGM. Between 2008 and 2017, 55 patients diagnosed with IGM in our clinic were included in the study. Demographic, clinical, microbiologic and histopathologic characteristics, treatment modality and recovery time were evaluated retrospectively. Patients were divided into 3 groups according to tissue IgG4 levels: negative (Group I), infrequently and slightly positive (Group II), and highly positive (Group III). Group I patients had a complete response rate of 77.8%. In the rest of the patients (22.2%), insufficient response was detected from the beginning of the treatment. In Group II, the response rate was 91.3% and the permanent success rate after treatment was 87.0%. Although group III patients had a complete response at the beginning (95.65%), they relapsed in a short period of time (26.1%) after discontinuation of steroid treatment. At least one steroid-related side effect was observed in 47 (85.8%) patients in all groups. There is no consensus on the dose and duration of immunosuppressive treatment in IGM. In this study, responses to steroid treatment according to IgG4 concentration in pathologic breast tissue and recurrences after the end of treatment were determined. We think that high IgG4 concentration in the tissue is associated with recurrence and other immunosuppressive drugs should be added as maintenance after steroid treatment.

A human monoclonal antibody based immunoenzymetric assay to measure Fel d 1 concentrations in cat hair and pelt allergenic extracts.

In the United States, 19 allergen extracts of different specificities are standardized, which means that their potencies are determined in comparison to a US reference standard. For cat allergen extracts, potency is determined by measuring Fel d 1 content expressed in in Fel d 1 units, and with a unitage that correlates with skin test reactions (bioequivalent allergy units or BAU). Currently, Fel d 1 content is measured with a radial immunodiffusion (RID) assay that uses polyclonal sheep antisera to detect the allergenic protein by producing a white precipitin line in agar gel. However, the RID is considered cumbersome, and the polyclonal sera may qualitatively vary among animals and may recognize epitopes irrelevant to human allergic disease. In this report, we describe a quantitative two-site immunoenzymetric assay (IEMA) for Fel d 1 that uses immobilized capture and soluble biotin-labeled detection Fel d 1-specific human IgE monoclonal antibodies (mAb) that have been class-switched to IgG4. Together, they sandwich Fel d 1 molecules from extracts. Using purified natural Fel d 1 as a calibrator, the historically reported ∼4 micrograms Fel d 1/Fel d 1 unit assignment was directly measured in this mAb-based IEMA at 3.12 ± 0.24 micrograms of Fel d 1 per Fel d 1 unit. This IEMA appears to be equivalent to RID in the measurement of biological potencies of commercial cat hair and cat pelt extracts marketed in the United States.

Volume-Based Quantitative Measurement of [18F]AlF-NOTA-FAPI-04 PET/CT Uptake Reflects the Disease Activity of IgG4-Related Disease.

BACKGROUND: To investigate the potential utility of quantitative parameters obtained by 18F-fibroblast activation protein inhibitor positron emission tomography/computed tomography ([18F]AlF-NOTA-FAPI-04 PET/CT) in the assessment of organ involvement and disease activity in IgG4-related disease (IgG4-RD). METHODS: This study enrolled patients who underwent [18F]AlF-NOTA-FAPI-04 PET/CT scans at the Department of Rheumatology, The First Affiliated Hospital, Zhejiang University School of Medicine from August 2021 to August 2022. The PET/CT images of the included patients were re-evaluated by PET center technicians, and the maximal standardized uptake value (SUVmax), metabolic lesion volume (MLV), and total lesion FAPI (TL-FAPI) were used to evaluate the involved organs and tissues that abnormally accumulated [18F]AlF-NOTA-FAPI-04. The clinical and laboratory data of patients are also systematically collected and analyzed. RESULTS: Among the patients included in this study, 12 patients met the IgG4-RD classification criteria established by the American College of Rheumatology in 2019. Among them, 8 were males and 4 were females, with an average age of 59.3 ± 11.5 years. 50% of IgG4-RD patients were found with more organ involvement on PET/CT than physical examination, ultrasonography, and computed tomography. IgG4 levels (Rho = 0.594, p = 0.042) and IgG4-RI (Rho = 0.647, p = 0.023) were significantly positively correlated with TL-FAPI. After linear regression analysis, only TL-FAPI showed a predictive value of RI (R2 = 0.356, B = 0.008, p = 0.041). CONCLUSIONS: [18F]AlF-NOTA-FAPI-04 PET/CT is a useful tool for identifying asymptomatic organ involvement and assessing disease activity. The TL-FAPI as an indicator was positively correlated with IgG4-RD disease activity.

Treatment Outcomes of Patients with Orbital Inflammatory Diseases: Should Steroids Still Be the First Choice?

Objective: To clarify the therapy response in orbital inflammatory diseases (OID), we analyzed the treatment effects of steroid therapy, the use of disease-modifying antirheumatic drugs (DMARDS), and biologicals in our tertiary referral center cohort. Methods: We collected the clinical and demographic data of all patients treated for non-specific orbital inflammation (NSOI) (n = 111) and IgG4-ROD (n = 13), respectively at our center from 2008 to 2020 and analyzed them with descriptive statistics. NSOI were sub-grouped according to the location into either idiopathic dacryoadenitis (DAs) (n = 78) or typical idiopathic orbital myositis (n = 32). Results: Mean age at first clinical manifestation was significantly different between subgroups (IOI: 49.5 ± 18, IgG4-ROD: 63.2 ± 14, p = 0.0171). Among all examined OID, 63 patients (50%) achieved full remission (FR) with corticosteroids (NSOI 53%/IgG4-ROD 31%). In contrast, classic myositis showed a significantly higher response (76%). Disease-modifying drugs (DMARDS) for myositis accomplished only 33% FR (NSOI 57%) and 66% did not respond sufficiently (NSOI 43%). The biologic agent (Rituximab) was significantly more efficient: 19 of 23 patients (82%) achieved full remission and only 4 (17%) did not respond fully and needed orbital irradiation or orbital decompressive surgery.

Is systemic lupus erythematosus linked to Immunoglobulin G4 Autoantibodies?

Systemic lupus erythematosus (SLE) is a systemic autoimmune disorder characterized by a hyperactive immune system with multiple abnormalities in B-cell proliferation, antibody production, T-cell regulation, and immune complex (IC) formation. In humans, Immunoglobulin (Ig) G is found in four subclasses. IgG1-IgG4, which are distinguished by both structural and biological differences. Fab-arm Exchange (FAE), specific biases in the IgG4 response repertoire, and a decreased capacity to induce effector functions mediated by interactions in the fragment crystallizable (Fc) region are just a few of the distinctive characteristics of IgG4. The recent finding of the presence of double-stranded DNA (dsDNA) and antinuclear antibody (ANA)-IgG4 has raised attention to this IgG subclass and its possible role in SLE. IgG4 was previously believed to just have anti-inflammatory effects by inhibiting immune responses, but recent studies have shown that these antibodies can also play a role in the onset and development of some clinical disorders. To consider the clinical effects of IgG4 presence, it is necessary to discuss its characteristics, which could underlie the potential role it can play in SLE. Therefore, this study aimed to comprehensively review the role of IgG4 in SLE to elucidate the collective incidence of high IgG4 levels reported in some SLE patients.

The Potential of Human Monoclonal IgE Antibodies to Establish Biological Potency and Stability of Allergen Extracts.

PURPOSE OF REVIEW: Allergenic extracts are often standardized to control for potency, either by measuring concentrations of major allergens or "overall allergenicity" by competition for IgE in pooled sera from highly allergic subjects with a reference extract. Recent developments present an opportunity to use human mAb cloned from highly allergic subjects to define potency of allergenic extracts. RECENT FINDINGS: Two recent developments present an opportunity for revising potency measurements of allergen extracts: cloning allergen specific IgE from allergic subjects and extensive epitope mapping of major allergenic proteins. Because human IgE mAb recognize biologically relevant epitopes, they present a novel opportunity to determine the potencies of allergenic extracts and may contribute to the science base for allergen standardization.

The 2023 revised diagnostic criteria for IgG4-related ophthalmic disease.

Immunoglobulin G4 (IgG4)-related disease is a clinical entity characterized by elevated serum IgG4 concentrations and infiltration of IgG4-immunopositive plasmacytes in various organs, including ophthalmic lesions. Diagnostic criteria for IgG4-related ophthalmic disease (IgG4-ROD) were established in 2014 and describe the most affected ocular adnexal tissues such as lacrimal glands, trigeminal nerves and extraocular muscles, but do not mention optic neuropathy, the most severe indication of ophthalmic lesions. We reviewed published case reports of optic neuropathy in IgG4-related disease (n = 44), and in many cases, decreased visual acuities recovered well following treatment such as systemic corticosteroids, rituximab, and orbital surgery. However, some patients did not recover, especially when pretreatment visual acuities were as low as light perception or less. Herein, we propose a 2023 revised diagnostic criteria for IgG4-ROD, which include a reminder not to overlook optic neuropathy. The 2014 diagnostic criteria specify mucosa-associated lymphoid tissue (MALT) lymphoma as an important differential diagnosis for the relationship between IgG4-ROD and orbital lymphoma. The 2023 revision directs physicians' attention toward lymphomas other than MALT lymphoma, considering that the 2014 criteria might have placed too much emphasis on MALT lymphoma.

Dry Crusty Nose: Not Just Rhinosinusitis! Hidden IgG4-related Disease Without IgG4 Level Rise.

IgG4-related disease (IgG4-RD) is a fibro-inflammatory condition that can affect various organs. Localized sinonasal IgG4-RD is a rare condition characterized by bone and soft-tissue invasion. In this report, we present a case of a patient initially diagnosed with chronic rhinosinusitis, who underwent endoscopic sinus surgery and was later found to have biopsy proven IgG4-related sinonasal disease despite having normal serum levels of IgG4, resulting in erosion of the right lamina papyracea.

Anti-TNF therapy impairs both short- and long-term IgG responses after repeated vaccination.

BACKGROUND: Recently, it has been questioned whether vaccination of patients with inflammatory (auto)immune diseases under anti-tumor necrosis factor (TNF) treatment leads to impaired vaccine-induced immune responses and protection against breakthrough infections. However, the effects of TNF blockade on short- and long-term immune responses after repeated vaccination remain unclear. Vaccination studies have shown that initial short-term IgG antibodies (Abs) carry highly galactosylated and sialylated Fc glycans, whilst long-term IgG Abs have low levels of galactosylation and sialylation and are most likely generated by long-lived plasma cells (PCs) derived primarily from the germinal center (GC) response. Thus, IgG Fc glycosylation patterns may be applicable to distinguish short- and long-term vaccine responses after repeated vaccination under the influence of anti-TNF treatment. METHODS: We used COVID-19 vaccination as a model to investigate vaccine-induced IgG subclass levels and Fc glycosylation patterns, B cell subsets, and effector functions of short- and long-term Ab responses after up to three vaccinations in patients on anti-TNF or other immunosuppressive treatments and in healthy individuals. Using TriNetX, a global healthcare database, we determined the risk of SARS-CoV-2 breakthrough infections in vaccinated patients treated with anti-TNF or other immunosuppressive drugs. RESULTS: Anti-TNF treatment reduced the long-term abundance of all anti-S IgG subclasses with low levels of galactosylation and sialylation. Re-activation of potential memory B cells initially generated highly galactosylated and sialylated IgG antibodies, which were progressively reduced after each booster dose in anti-TNF-treated patients, especially in the elderly. The reduced short- and long-term IgG (1) levels in anti-TNF-treated patients correlated with diminished functional activity and an increased risk for the development of COVID-19. CONCLUSIONS: The data suggest that anti-TNF treatment reduces both GC-dependent long-lived PCs and GC-dependent memory B cell-derived short-lived PCs, hence both the long- and short-term IgG subclass responses, respectively, after repeated vaccination. We propose that anti-TNF therapy, especially in the elderly, reduces the benefit of booster vaccination.

[FAPI-PET-CT for quantification of the tissue response in rheumatic diseases]. / FAPI-PET/CT zur Quantifizierung der Gewebeantwort bei rheumatischen Erkrankungen.

Fibroblast activation protein (FAP) is mainly found on the surface of activated fibroblasts but is not expressed on the surface of inactive fibroblasts. Selective FAP inhibitors (FAPI), which are coupled to a radioactive tracer, can be used to quantify profibrotic and proinflammatory fibroblasts in patients using FAPI positron emission tomography (PET) computed tomography (CT). Following initial applications in neoplastic diseases, FAPI-PET/CT is also increasingly being applied in rheumatological diseases. The first studies have shown that in patients with systemic sclerosis (SSc) FAPI accumulates in actively fibrotically remodeled pulmonary and myocardial areas, that a high FAPI accumulation is associated with the risk of short-term progression and that this accumulation in the lungs regresses after successful treatment. In cases of immunoglobulin 4 (IgG4)-associated diseases (IgG4 rheumatic disease, RD), the FAPI signal correlates with the histological accumulation of activated fibroblasts and a poorer response to treatment to inhibit inflammation. Fibroblasts in chronically inflamed tissue, such as patients with inflammatory joint diseases, vasculitis or myositis, also express FAP and can be quantified by FAPI-PET/CT. The treatment-induced change of the phenotype from a destructive IL-6+/MMP3+THY1+ fibroblast subtype to an inflammation inhibiting CD200+DKK3+ subtype can be mechanistically demonstrated using FAPI-PET/CT. These studies provide indications that FAPI-PET/CT enables quantification of the tissue response in patients with fibrosing and chronic inflammatory diseases and can be used for patient stratification; however, further studies are essential for validation of the use of FAPI-PET/CT as a molecular imaging marker.

Clinical Significance of IgG4 Serum Concentration in Graves' Disease.

Elevated immunoglobulin G4 (IgG4) serum antibodies are an important feature of IgG4-related disease. However, IgG4 antibodies can play a role in autoimmune thyroid disorders. In this study, we aimed to evaluate the impact of serum IgG4 levels on clinical features of Graves' disease (GD). We recruited 60 patients with GD (48 patients without thyroid eye disease, 12 patients with moderate-to-severe Graves' orbitopathy [GO], and 25 healthy control subjects). The prevalence of high IgG4 serum concentration was 4.2% among GD patients without GO and 33.33% in patients with moderate-to-severe GO. The group with GO had significantly higher median IgG4 levels (87.9 mg/dL) than the control group (41.2 mg/dL, P = 0.034) and the GD without GO group (30.75 mg/dL, P < 0.001). Patients with thyroid nodules had lower IgG4 levels than patients without thyroid nodules, but the difference was not statistically significant (35.7 [24.8; 41.53] mg/dL vs. 43 [30.1; 92.7] mg/dL, P = 0.064). IgG4 as a diagnostic tool for moderate-to-severe GO had the following parameters: area under the curve (AUC): 0.851 (P < 0.001), at the cut-off value of 49 mg/dL, negative predictive value: 100%, positive predictive value: 48%, sensitivity: 100%, specificity: 73%. There were no significant differences between the high and normal IgG4 groups in thyroid hormones, antithyroid antibodies, and ultrasound features. Serum IgG4 levels are associated with some of the clinical features of GD and can help in the diagnostic process of the disease. More research is needed to better understand the pathophysiology of IgG4 involvement in GD.