RARE DISEASE
IgG4-related disease
IgG4-related disease
IgG4-related disease
Synonyms: IgG4-related sclerosing disease, Immunoglobulin G4-related sclerosing disease
Synonyms: IgG4-related sclerosing disease, Immunoglobulin G4-related sclerosing disease
Synonyms: IgG4-related sclerosing disease, Immunoglobulin G4-related sclerosing disease
Drug discovery
5
drugs
With orphan designations
Overview
IgG4-related disease (IgG4-RD) is a rare immune-mediated fibroinflammatory disorder characterized by tumor-like lesions, lymphoplasmacytic infiltrates rich in IgG4+ plasma cells, storiform fibrosis, and obliterative phlebitis. It affects multiple organs, including the pancreas, biliary tract, salivary glands, and kidneys, often mimicking malignancies or other systemic diseases. Diagnosis requires histopathology and elevated serum IgG4 (though nonspecific), with early glucocorticoid treatment critical to prevent irreversible fibrosis [1][3][18]. Relapses occur in ~40% of patients within 1 year [3][7].
Therapies
First-line: Glucocorticoids (0.6 mg/kg prednisone for 2–4 weeks, tapering over 3–6 months) [3][7][10]
Relapse management: Rituximab (B-cell depletion), steroid-sparing immunosuppressants (azathioprine, mycophenolate), or surgery for obstructive complications [3][16][20]
Emerging: Targeted biologics (anti-CD19/20, BTK inhibitors) in clinical trials [10][16]
Categories: rare systemic and rheumatological diseases
Research Papers
1,431 drug discovery papers about IgG4-related disease, with 2 first-in-class and 29 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,431 drug discovery papers about IgG4-related disease, with 2 first-in-class and 29 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-13 | Isolated IgG4-related lung disease: a case report.
IgG4-related disease (IgG4-RD) represents a chronic, immune-driven fibroinflammatory condition capable of affecting diverse organ systems; within this spectrum, pulmonary involvement (IgG4-RLD) remains comparatively uncommon. This case report outlines the clinical, imaging and pathological features of a patient with IgG4-related lung disease. We report a 60-year-old male patient with recurrent fever, chest pain, and cough with hemoptysis. Chest computed tomography (CT) initially showed right upper lobe lesions suggestive of pneumonia, but the patient failed to respond to multiple courses of antibiotics including levofloxacin, nemonoxacin malate, ceftizoxime, and amoxicillin. Further investigations revealed significantly elevated serum IgG4 level (266 mg/dL). Endobronchial ultrasound-guided transbronchial lung cryobiopsy (EBUS-GS-TBLC) confirmed dense lymphoplasmacytic infiltration in the lung tissue, with IgG4-positive plasma cells >50 per high powered field (HPF) and IgG4-positive/IgG-positive cell ratio >50%, consistent with the diagnosis of IgG4-related interstitial lung disease. The patient was treated with oral cyclosporine and mycophenolate mofetil, resulting in significant clinical and radiological improvement. IgG4-RLD should be considered in the differential diagnosis of patients with pulmonary lesions unresponsive to antibiotic therapy. Comprehensive evaluation including serum IgG4 measurement and targeted pathological biopsy is essential for accurate diagnosis. Early initiation of immunosuppressive therapy can effectively improve outcomes and prevent disease progression.
2026-08-11 | Treatment strategies for relapsing IgG4-RD: twelve-year experience from a prospective cohort.
Relapse is common in IgG4-related disease (IgG4-RD). While previous studies focus on treatments for active IgG4-RD, data on the management of relapsing IgG4-RD remains limited. We aimed to investigate the treatment strategies for relapsing IgG4-RD. This study analyzed data prospectively collected from an IgG4-RD cohort, including patients who experienced their first relapse and were followed for over 12 months. We compared the outcome among three groups: (1) Intensifying glucocorticoids (GC) only; (2) Intensifying immunosuppressants (IM) only; (3) Intensifying both GC and IM. The primary outcome was recurrent relapses. A decision tree model was developed to predict recurrent relapses. A total of 259 patients with IgG4-RD was included, with a male predominance (61.7%) and a median age of 54.0 years. Patients who intensified both GC and immunosuppressants (IM) (adjusted p 0.0002, HR 0.29, 95% CI: 0.16-0.52) experienced less relapses compared to those who intensified IM alone, while those who only intensified GC had a tendency to experience less relapses (adjusted p 0.0823, HR 0.51, 95% CI: 0.26-1.03). These differences were more pronounced in the subgroup with internal organ involvement. The decision tree indicated that those with an RI decrease to ≤ 2 and an IgG4 decrease ≥25% after treatment were more likely to stay free from recurrent relapses, with an AUC of 0.728 in the testing set. When treating relapse in IgG4-RD, GC-based treatment was associated with a lower hazard of recurrent relapse compared with only adjusting IMs, especially for those with internal organ involvement.
2026-08-07 | Directional Coronary Atherectomy as a Diagnostic Adjunct in Suspected IgG4-Related Coronary Artery Disease.
Immunoglobulin (Ig) G4-related disease can involve the cardiovascular system, and isolated vessel involvement is diagnostically challenging. A 79-year-old Japanese man with a history of percutaneous coronary intervention presented with exertional angina. Imaging demonstrated in-stent occlusion of the left anterior descending artery, severe distal left circumflex artery stenosis, and marked adventitial thickening of the coronary arteries and aorta. Serum IgG4 levels were markedly elevated. Directional coronary atherectomy (DCA) enabled retrieval of intimal tissue. Although the pathological findings did not fulfill formal classification criteria, tissue sampling provided supportive histopathological evidence for IgG4-related disease. Prednisolone therapy resulted in regression of adventitial thickening and reduction of nonrevascularized coronary lesions. DCA may serve as both a therapeutic strategy and an adjunctive diagnostic approach. DCA may provide supportive histopathological information when conventional biopsy is not feasible, and steroid therapy can be effective for cases of vascular involvement in IgG4-related disease.
2026-07-24 | Case Report: IgG4-related disease presenting with prominent oculomotor nerve palsy.
Immunoglobulin G4-related disease (IgG4-RD) is a systemic fibroinflammatory disorder that uncommonly involves cranial nerves. Oculomotor nerve palsy as the predominant manifestation of IgG4-RD is exceptionally rare and may elude timely diagnosis due to nonspecific symptoms. A 76-year-old man presented with a two-month history of bilateral plantar numbness and pain, followed by nausea, vomiting, and headache. The patient was hospitalized twice: first in August 2025 in the Department of Hematology, and subsequently in October 2025 in the Department of Rheumatology and Immunology. Laboratory evaluation revealed markedly elevated immunoglobulins, prompting a comprehensive workup including bone marrow aspiration, positron emission tomography-computed tomography (PET-CT), and lymph node biopsy. Histopathology demonstrated reactive lymphoid hyperplasia with abundant IgG4 + plasma cell infiltration (IgG4+ > 100 cells/HPF; IgG4/IgG ratio >40%), which established the diagnosis of IgG4-RD according to the 2019 ACR/EULAR classification criteria. During the second hospitalization, the patient developed right ptosis and diplopia, and neurological examination confirmed isolated right oculomotor nerve palsy. Contrast-enhanced brain MRI showed no structural abnormalities, and CTA, along with CSF analysis, excluded alternative etiologies such as aneurysm, neoplasm, or infection. Treatment with intravenous methylprednisolone (40 mg daily) followed by oral mycophenolate mofetil (500 mg twice daily) led to significant clinical improvement of oculomotor palsy within 4 months, with normalization of serum IgG4 levels (from a peak of 74.3 g/L to 8.94 g/L at follow-up) and reduction of inflammatory markers. IgG4-RD should be considered in the differential diagnosis of unexplained cranial neuropathies, even in the absence of radiographic abnormalities. This case highlights that neurological recovery may be gradual and require sustained immunosuppression, and underscores the importance of multidisciplinary collaboration in managing atypical manifestations of IgG4-RD.
2026-07-22 | A phase 2 trial of rilzabrutinib in IgG4-related disease.
The objective of the article is to assess the efficacy and safety of rilzabrutinib, an oral, reversible inhibitor of Bruton's tyrosine kinase, in participants with IgG4-related disease. This Phase 2a (NCT04520451) open-label, 52-week study enrolled 2 cohorts of participants with IgG4-related disease: Cohort A (participants who had failed or were intolerant to rituximab) and Cohort B (participants enrolled agnostic to rituximab history). Participants received rilzabrutinib plus a 2-to-4-week glucocorticoid (GC) taper followed by rilzabrutinib alone for up to 52 weeks. Primary endpoints were the proportion of participants without disease flare following first rilzabrutinib dose until the end of treatment and safety. This study included 27 participants (Cohort A: 13; Cohort B: 14). At the end of treatment, 70.4% (19/27) of participants were flare-free and off GCs/immunosuppressants. Disease activity (mean [SD]), measured by IgG4-related disease Responder Index, decreased by 8.3 (5.8) at week 12 in both cohorts and by 10.7 (6.3) in participants who completed 52 weeks of rilzabrutinib (14/17). Serious treatment-emergent adverse events (TEAEs) occurred in 2 participants, 1 resulting in death, but both events were judged unrelated to the study drug. The most frequent TEAEs were diarrhoea, 40.7% (11/27); coronavirus disease 2019, 18.5% (5/27); and dizziness, 18.5% (5/27). Rilzabrutinib had an acceptable safety profile in patients with IgG4-related disease who had failed/ intolerant to rituximab and who were rituximab-naïve. Most participants discontinued GCs successfully without disease flares and exhibited sustained disease activity reduction. Further investigation of this potential alternative to B-cell-depleting therapies is needed in larger, long-term, placebo-controlled trials.
antibodies
2026-08-13 | [An unusual cause for unilateral eye pain with double vision].
A 48-year-old man was diagnosed with IgG4-related disease (IgG4-RD) during an evaluation for exophthalmos and unexplained pain on the left side of his face. The diagnosis was made by ruling out all other possible conditions and was based on histopathological findings. After initiating immunosuppressive therapy with corticosteroids (GC), most of the symptoms resolved. As the GC-dose was gradually reduced, a relapse occurred, leading to two courses of Rituximab. Reflecting the success of the therapy, long-term follow-up revealed a marked radiological reduction in the retrobulbar mass and a significant clinical improvement in pain.
2026-07-30 | Case Report: Immune checkpoint inhibitor-induced IgG4-related disease mimicking renal metastatic progression: successful steroid-sparing management with rituximab.
Immune checkpoint inhibitors (ICIs) can induce a broad spectrum of immune-related adverse events (irAEs), including rare fibroinflammatory autoimmune manifestations. IgG4-related disease (IgG4-RD) has only exceptionally been described following dual ICI therapy. We report a 65-year-old man with metastatic clear cell renal carcinoma treated with nivolumab plus ipilimumab after nephrectomy. Despite initial radiologic stability, follow-up computed tomography revealed newly developed mass-like lesions in the solitary remaining kidney, raising suspicion of metastatic progression. CT-guided biopsy demonstrated subacute pyelonephritis, acute tubular injury, storiform fibrosis, and dense IgG4-positive plasma cell infiltration consistent with IgG4-RD. Because glucocorticoids were considered potentially detrimental to antitumor immune surveillance, rituximab was selected as steroid-sparing first-line therapy. Two infusions of rituximab (1000 mg each) led to radiologic stabilization/regression of renal lesions while pulmonary metastases remained under oncologic control. This case highlights IgG4-RD as a rare but clinically important underrecognized irAE of dual ICI therapy that may mimic malignant progression. Histologic confirmation is crucial, and B-cell depletion with rituximab may represent an effective treatment strategy when preservation of antitumor immunity is a priority.
2026-07-10 | From inflammatory initiation to fibrotic remodeling: mechanisms and precision therapeutic strategies in otorhinolaryngologic involvement of IgG4-related disease.
IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory disorder characterized by complex immune-mediated mechanisms and broad organ involvement that remains substantially underdiagnosed in clinical practice. The head and neck region is one of the most commonly involved anatomical domains, encompassing the major salivary glands, lacrimal glands, nasal cavity and paranasal sinuses, larynx and subglottis, thyroid gland, middle ear, orbit, and cervical lymph nodes. This review integrates current understanding of the immunopathological mechanisms underlying IgG4-RD with organ-specific clinical features and therapeutic considerations across these head and neck subregions. The core immune pathogenesis involves clonally expanded CD4+ cytotoxic T lymphocytes and activated follicular helper T cells that, within a Th2-skewed cytokine environment, promote IgG4 class-switch recombination and plasmablast expansion, driving the transition from inflammatory infiltration to progressive fibrotic remodeling. Although head and neck subtypes share this common immunopathological framework, they differ considerably in the relative balance between inflammatory and fibrotic features, clinical severity, and organ-specific risk profiles. These differences may reflect local microenvironmental factors, including epithelial characteristics, innate immune responsiveness, and the functional properties of resident stromal fibroblasts, though the precise mechanisms remain to be fully established. Therapeutically, glucocorticoids remain the standard first-line treatment for remission induction but are limited by high relapse rates after withdrawal. Rituximab has demonstrated efficacy in refractory and relapsing disease. Inebilizumab, an anti-CD19 monoclonal antibody, has shown significant benefit in a phase III randomized controlled trial. Dupilumab, which targets the IL-4/IL-13 signaling axis, has shown potential in case reports and small series, but prospective validation is required before it can be recommended as a standard therapeutic option. By mapping organ-specific immunopathological differences onto differentiated therapeutic approaches, this review aims to support a more individualized, biologically informed framework for managing IgG4-RD in the head and neck.
2026-06-30 | [Immunoglobulin G4-related retroperitoneal fibrosis: clinical, laboratory, imaging, and histopathological features in a Russian single-center cohort].
To describe a Russian cohort of patients with IgG4-related retroperitoneal fibrosis (RPF). This retrospective single-center study included 36 patients diagnosed with IgG4-related RPF according to the revised 2020 diagnostic criteria. Clinical, laboratory, instrumental, and pathomorphological data were analyzed. The cohort of 36 patients with IgG4-related RPF predominantly comprised males (4:1 ratio), with a median onset age of 52 years and median time to diagnosis of 8 months. The disease most presented with low back or lower abdominal pain (75%), renal dysfunction (44%), elevated serum IgG4>1.35 g/L (82%), and increased ESR/CRP. Urinary tract infection was detected in 44% due to frequent ureteral catheterization. Isolated retroperitoneal involvement occurred in 72% of cases, with typical infrarenal periaortitis in 58%; atypical sites included perirenal, periureteral, and presacral localizations. Biopsy (n=23) revealed lymphoplasmacytic infiltrate (100%), fibrosis (87%), IgG4+/CD138+>40% (71%), with obliterative phlebitis (26%) and tissue eosinophilia (26%) less common. Compared to international data, our findings reveal a higher prevalence of atypical localizations and concomitant urinary tract infections, necessitating their consideration in diagnostic algorithms and treatment planning for RPF patients.
2026-06-28 | Spontaneous regression of colorectal liver metastasis with coexisting IgG4-rich inflammatory pseudotumor-like changes: a case report.
Spontaneous regression of colorectal liver metastasis (CRLM) is an extremely rare phenomenon with only a few reported cases. However, the underlying mechanism remains unclear. Infection-triggered immune reactivation and inflammation have also been proposed to be potential contributors. IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory condition characterized by IgG4-positive plasma cell infiltration and fibrosis, and rarely manifests in the liver as an inflammatory pseudotumor (IPT). We herein report a rare case of a 71-year-old man with possible spontaneous regression of CRLM accompanied by coexisting IgG4-rich IPT-like changes. Eight months after the laparoscopic Hartmann's operation for rectal cancer, imaging revealed hepatic lesions in segments S5 and S7, which were diagnosed as CRLM. Partial hepatectomy revealed necrotic adenocarcinoma in the S7 lesion, with IgG4-rich IPT-like inflammatory changes. Postoperative evaluation revealed markedly elevated serum IgG4 levels and IgG4-positive plasma cell infiltration in the mediastinal lymph nodes, fulfilling the diagnostic criteria for systemic IgG4-RD. Twenty months postoperatively, the patient remained recurrence-free without adjuvant chemotherapy or steroid therapy. This case report describes the coexistence of spontaneous tumor regression and IgG4-related hepatic IPT within the same lesion and provides insight into the clinicopathological spectrum linking tumor regression and IgG4-RD.
cell therapies
2026-01-27 | Effects of anti-CD19 CAR-T cells in a murine model of IgG4-related disease.
BACKGROUND: Chimeric antigen receptor T-cell (CAR-T) therapy, an emerging immunotherapy, has shown promising efficacy in several autoimmune diseases. In this study, we conducted a preclinical evaluation of the therapeutic potential of CD19-specific CAR-T cell–mediated B-cell depletion in a mouse model that recapitulates key features of human IgG4-related disease (IgG4-RD). METHODS: B cell depletion strategies were evaluated in the LatY136F mouse model, a spontaneous murine model of IgG4-RD. Anti-CD19 CAR-T cells or control cells were transferred into LatY136F mice pretreated with total body irradiation. LatY136F mice treated with anti-CD20 monoclonal antibodies (mAb) served as the positive control group. RESULTS: CD19-targeted CAR-T cell infusion resulted in a more profound depletion of B cells and plasmablasts compared to anti-CD20 mAb treatment. This depletion was observed in peripheral blood, spleen, lacrimal glands, lungs, and pancreas in LatY136F mice. Moreover, CAR-T cell therapy significantly prolonged the survival of LatY136F mice and improved clinical symptoms compared to anti-CD20 mAb treatment. However, while CAR-T cell therapy reduced inflammation and fibrosis in the lacrimal glands and pancreas, it did not improve these conditions in the lungs. CONCLUSIONS: Our findings demonstrate that anti-CD19 CAR-T therapy effectively alleviates the progression of IgG4-RD, showing superior efficacy compared to anti-CD20 mAb in this preclinical model. These results support further investigation of CAR-T cells as a potential therapeutic option for IgG4-RD patients, with attention to potential adverse effects.
2025-12-11 | CAR T-cell therapy induces remission in multiorgan IgG4-related disease with hepatobiliary involvement.
IgG4-related disease (IgG4-RD) is a fibroinflammatory disorder in which IgG4+ B cells and T cells interact to drive chronic organ inflammation. Patients with multiorgan involvement may become refractory to standard therapy, resulting in progressive organ damage and risk of organ failure. Here, we report a patient with treatment-refractory multiorgan IgG4-RD treated with CD19-directed chimeric antigen receptor (CAR) T cells and describe the clinical and immunologic effects over more than 12 months of follow-up. A 60-year-old man with IgG4-RD involving the pancreas, hepatobiliary tract, and lungs, who was refractory to long-term immunosuppression, received autologous CD19-directed CAR T cells. Disease course was monitored longitudinally and multimodal immune profiling was performed on peripheral blood. CAR T cell therapy was well tolerated, with only grade 1 cytokine release syndrome, no neurotoxicity, and transient cytopenias without infections. Treatment induced B-cell aplasia lasting 6 months, while serum IgG4 levels normalized by month 8 and remained within the reference range thereafter. FAPI (fibroblast activation protein inhibitor) PET/CT demonstrated regression of fibroinflammatory activity, accompanied by improved lung function and quality of life. Immunosuppressive therapy was completely discontinued without disease flares for more than 12 months. B cell reconstitution consisted predominantly of naïve and transitional subsets. This was paralleled by a decline in T follicular helper cells and CD4+ cytotoxic T cells and attenuation of fibro-inflammatory and B cell-mediated signaling networks on interactome analyses. In this treatment-refractory case of multiorgan IgG4-RD, CD19-directed CAR T cell therapy induced durable, treatment-free remission with normalization of serum IgG4 and improvement across multiple clinical endpoints. Multimodal immune profiling indicates that CAR T cells can reset the B cell compartment and dampen pathogenic T cell and stromal interactions, supporting prospective evaluation of CAR T cell therapy in IgG4-RD.
2025-09-20 | Heart Transplantation in Advanced Heart Failure Due to IgG4-Related Endomyocardial Fibrosis.
IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory condition that rarely affects the heart. Cardiac manifestations include pericarditis, coronary arteritis, and myocarditis; endomyocardial fibrosis (EMF) is exceedingly rare. We report a 66-year-old man with advanced heart failure and recurrent hospitalizations due to restrictive cardiomyopathy, initially attributed to hypereosinophilia from parasitic disease. The patient developed cardiogenic shock requiring inotropes and intra-aortic balloon pump support. Imaging revealed biatrial enlargement, endocardial thickening, and subendocardial fibrosis, suggestive of EMF. Serology was positive for Trichinella spiralis IgG. Because of progressive clinical deterioration, the patient underwent urgent orthotopic heart transplantation. Histology of the explanted heart confirmed IgG4-related EMF. Posttransplant follow-up at 12 months showed preserved graft function and no recurrence. This case illustrates a rare cause of end-stage heart failure due to IgG4-RD and highlights the importance of including systemic inflammatory conditions in the differential diagnosis of restrictive cardiomyopathy. IgG4-related disease, though rare, can present as isolated endomyocardial fibrosis with features mimicking tropical EMF or hypereosinophilic cardiomyopathy. In advanced fibrotic stages with isolated cardiac IgG4-RD and cardiogenic shock, orthotopic heart transplantation may be the only lifesaving therapeutic option.
2025-04-30 | Refractory corneal melting due to IgG4-related disease: Successful management via buccal mucosal graft transplantation.
PurposeTo present the first case of isolated corneal involvement in IgG4-RD, managed successfully with oral mucosal grafting due to the destructive course of the disease.Case reportA 56-year-old female one-eyed patient was referred to our clinic with a diagnosis of unresponsive infectious corneal melting. The ophthalmologic examination revealed light perception visual acuity, intense conjunctival inflammation and an infected area of approximately 4 × 5 mm with accompanying melting. Her medical history includes a diagnosis of dry eye disease that has persisted for over a decade, multiple previous corneal transplant surgeries in the right eye with similar complaints, and subsequent evisceration surgery. Her complaints in the left eye had increased over the previous six months, and she had undergone eight instances of amniotic membrane transplantation at an external medical facility. Corneal scraping, conjunctival and corneal biopsy were performed. The histopathologic examination and elevated serum IgG4 level indicated the presence of IgG4-related disease. She was referred to the rheumatology department, where immunosuppression treatment was initiated. Oral mucosal grafting was performed to address the uncontrolled melting. At the follow-up examination, the melting was successfully controlled, the inflammation regressed, and the early hypertrophy of the oral mucosal epithelium flattened over time.ConclusionThis case highlights the potential for IgG4-related disease to manifest as atypical ocular surface involvement. Dry eye secondary to the disease can exacerbate existing findings. In such instances, preserving the integrity of the globe is of the utmost importance. Therefore, oral mucosal grafting, which is known for its durability, should be considered a viable option.
2024-12-14 | Efficacy and safety of anti-CD19 CAR-T in a mouse model of IgG4-related disease.
Dysregulated B-cell activation plays pivotal roles in IgG4-related disease (IgG4-RD), which makes B-cell depletion a potential strategy for IgG4-RD treatment. In this study, we aimed to investigate the feasibility of applying anti-CD19 chimeric antigen receptor T(CAR-T) cell therapy to IgG4-RD treatment in a mouse disease model based on LatY136F knock-in (Lat) mice. We constructed murine anti-CD19 CARs with either CD28 or 4-1BB as the intracellular costimulatory motif and evaluated the therapeutic function of the corresponding CAR-T cells by infusing them into Lat mice. Next, we assessed the safety of CAR-T infusion by evaluating the risk of cytokine release syndrome (CRS) and the antiviral capabilities in a mouse influenza infection model. Finally, we performed human anti-CD19 CAR-T manufacturing from IgG4-RD patients and evaluated its activation level and functional effects in vitro. Compared with 1D3 antibody treatment, the adoptive transfer of anti-CD19 CAR-T cells with CD28 costimulatory motif showed comparable B-cell-depletion effect in Lat mice. Furthermore, the transfer of syngeneic anti-CD19 CAR-T cells also decreased the percentage of plasma cells as well as IL-4 secreting Th cells, therefore attenuating the inflammation and fibrosis condition. CAR-T cells with CD28 costimulatory motif showed better therapeutic efficiency without the incidence of serious CRS events or increasing the risk of infection. In addition, we validated the feasibility of human CAR-T preparation in vitro from IgG4-RD patients. Taken together, these results show that anti-CD19 CAR-T therapy was effective in the treatment of a murine model of IgG4-RD, indicating its potential for clinical use in patients.
proteins
2024-01-23 | Laminin 511-E8, an autoantigen in IgG4-related cholangitis, contributes to cholangiocyte protection
IgG4-related cholangitis (IRC) is the hepatobiliary manifestation of IgG4-related disease. Anti-laminin 511-E8 autoantibodies have been identified in its pancreatic manifestation. Laminin 511-E8 promotes endothelial barrier function, lymphocyte recruitment, and cholangiocyte differentiation. Here, we investigate anti-laminin 511-E8 autoantibody presence in IRC, and mechanisms via which laminin 511 may contribute to cholangiocyte protection. Anti-laminin 511-E8 serum autoantibody positivity was assessed by ELISA. RNA sequencing and RT-qPCR were performed on human H69 cholangiocytes treated with recombinant laminin 511-E8. H69 cholangiocytes were subjected to shRNA knockdown targeting genes encoding laminin 511 (LAMA5, LAMB1, LAMC1) or treated with recombinant laminin 511-E8. Cholangiocellular bile acid influx was quantified radiochemically using 22,23-3H-glycochenodeoxycholic acid (GCDC). GCDC-induced apoptosis was determined by Caspase-3/7 assays. Cholangiocellular barrier function was assessed by FITC-dextran permeability assays. Immunofluorescent staining of laminin 511 and claudin 1 was performed on extrahepatic bile duct tissue of control and anti-laminin 511-E8 positive individuals with IRC. Seven out of 52 individuals with IRC had autoantibodies against laminin 511-E8. Recombinant laminin 511-E8 led to differential expression of genes involved in secretion, barrier function, and inflammation. Knockdown of laminin 511 constituents increased toxic bile acid permeation and GCDC-induced apoptosis. Laminin 511-E8 treatment decreased toxic bile acid permeation and dose-dependently alleviated GCDC-induced apoptosis. LAMA5 and LAMC1 knockdown increased transepithelial permeability. Laminin 511-E8 treatment reduced transepithelial permeability and prevented T lymphocyte-induced barrier dysfunction. Laminin 511 and claudin 1 staining patterns appeared altered in anti-laminin 511-E8 positive individuals with IRC. Laminin 511-E8 is an autoantigen in subsets of individuals with IRC. Laminin 511 enhances cholangiocellular barrier function and protects cholangiocytes against T lymphocyte-induced barrier dysfunction, toxic bile acid permeation and bile acid-induced apoptosis. A subset of IgG4-related cholangitis (IRC) patients has autoantibodies against laminin 511-E8. In human cholangiocytes, laminin 511 protects against (T lymphocyte-induced) epithelial barrier dysfunction and hydrophobic bile acids. Laminin 511 and claudin 1 staining may be altered in extrahepatic bile ducts of anti-laminin 511-E8 positive IRC patients. This makes it tempting to speculate that a decreased epithelial barrier function with attraction of immune cells and impaired bicarbonate secretion due to dysfunction of laminin 511 by autoantibody binding could potentially be a common systemic pathogenetic mechanism in a subset of IgG4-RD patients.
2022-05-19 | Role of eosinophilia in IgG4-related disease.
Immunoglobulin G4-related disease (IgG4-RD) is a heterogeneous immune-mediated condition that can affect almost any organ and is now being recognised with increasing frequency. Laboratory abnormalities including peripheral eosinophilia, hypergammaglobulinaemia, elevated serum IgE level, and hypocomplementaemia often provide initial clues to the diagnosis of IgG4-RD. The distinctive histopathological hallmarks of IgG4-RD are a dense lymphoplasmacytic infiltration with a high percentage of IgG4+ plasma cells, storiform fibrosis, obliterative phlebitis, and mild to moderate tissue eosinophilia. Around 20-40% of patients with IgG4-RD presented with peripheral eosinophilia and 51-86% are manifested as tissue eosinophilia. These data indicate an extensive involvement of eosinophil in IgG4-RD. Here, we review the biology of eosinophil, the discovery of eosinophilia in IgG4-RD, and its association with disease activity and relapse. We also discuss the possible functions and therapeutic potential of eosinophil in IgG4-RD.
2022-05-13 | Central Diabetes Insipidus Due to IgG4-related Hypophysitis That Required over One Year to Reach the Final Diagnosis Due to Symptoms Being Masked by Sialadenitis
Pituitary inflammation due to IgG4-related disease is a rare condition and is sometimes accompanied by central diabetes insipidus. Central diabetes insipidus produces a strong thirst sensation, which may be difficult to distinguish when complicated by salivary insufficiency. A 45-year-old man was admitted to our department for a thorough examination of his thirst and polyuria. He had suddenly developed these symptoms more than one year earlier and visited an oral surgeon. Swelling of the left submandibular gland, right parotid gland, and cervical lymph nodes had been observed. Since his IgG4 level was relatively high at 792 mg/dL and a lip biopsy showed high plasmacytoid infiltration around the gland ducts, he had been diagnosed with IgG4-related disease. He had started taking 0.4 mg/kg/day of prednisolone, and his chief complaint temporarily improved. However, since the symptom recurred, he was referred to our institution. After admission, to examine the cause of his thirst and polyuria, we performed a water restriction test, vasopressin loading test, hypertonic saline loading test and pituitary magnetic resonance imaging. Based on the findings, we diagnosed him with central diabetes insipidus due to IgG4-related hypophysitis. We increased the dose of prednisolone to 0.6 mg/kg/day and started 10 μg/day of intranasal desmopressin. His symptoms were subsequently alleviated, and his serum IgG4 level finally normalized. We should remember that IgG4-related disease can be accompanied by hypophysitis and that central diabetes insipidus is brought about by IgG4-related hypophysitis. This case report should remind physicians of the fact that pituitary inflammation due to IgG4-related disease is very rare and can be masked by symptoms due to salivary gland inflammation, which can lead to pitfalls in the diagnosis in clinical practice.
2022-03-03 | Neutralizing anti-IL-1 receptor antagonist autoantibodies induce inflammatory and fibrotic mediators in IgG4-related disease.
IgG4-related disease (IgG4-RD) is a fibroinflammatory condition involving loss of B-cell tolerance and production of autoantibodies. However, the relevant targets and role of these aberrant humoral immune responses are not defined. Our aim was to identify novel autoantibodies and autoantigen targets that promote pathogenic responses in IgG4-RD. We sequenced plasmablast antibody repertoires in patients with IgG4-RD. Representative mAbs were expressed and their specificities characterized by using cytokine microarrays. The role of anti-IL-1 receptor antagonist (IL-1RA) autoantibodies was investigated by using in vitro assays. We identified strong reactivity against human IL-1RA by using a clonally expanded plasmablast-derived mAb from a patient with IgG4-RD. Plasma from patients with IgG4-RD exhibited elevated levels of reactivity against IL-1RA compared with plasma from the controls and neutralized IL-1RA activity, resulting in inflammatory and fibrotic mediator production in vitro. IL-1RA was detected in lesional tissues from patients with IgG4-RD. Patients with anti-IL-1RA autoantibodies of the IgG4 subclass had greater numbers of organs affected than did those without anti-IL-1RA autoantibodies. Peptide analyses identified IL-1RA epitopes targeted by anti-IL-1RA antibodies at sites near the IL-1RA/IL-1R interface. Serum from patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) also had elevated levels of anti-IL-1RA autoantibodies compared with those of the controls. A subset of patients with IgG4-RD have anti-IL-1RA autoantibodies, which promote proinflammatory and profibrotic meditator production via IL-1RA neutralization. These findings support a novel immunologic mechanism underlying the pathogenesis of IgG4-RD. Anti-IL-1RA autoantibodies are also present in a subset of patients with SLE and RA, suggesting a potential common pathway in multiple autoimmune diseases.
2021-10-13 | Interleukin-35 promotes the differentiation of regulatory T cells and suppresses Th2 response in IgG4-related type 1 autoimmune pancreatitis.
IgG4-related disease (IgG4-RD) is a systemic inflammatory disease, which includes type 1 autoimmune pancreatitis (AIP). Interleukin-35 (IL-35) exhibits immunosuppressive effects in several autoimmune diseases. However, the expression of IL-35 had not been reported so far in type 1 AIP. We evaluated the association between IL-35 and several cytokines, which mediate the function of Tregs in type 1 AIP. Plasma was collected from patients with type 1 AIP, alcoholic chronic pancreatitis (ACP), and healthy controls (HC) and assayed for cytokine expression. Total mRNA separated from peripheral blood was isolated from naïve Tregs (nTregs) and effector Tregs (eTregs). EBI3 and IL-12p35 gene expressions were tested in these cells by quantitative PCR. In addition, expression of IL-35 subunits in the pancreatic tissues of patients with type 1 AIP and ACP was analyzed by immunohistochemistry. IL-35 was significantly elevated in type 1 AIP (n = 32) plasma compared with ACP (n = 16) and HC (n = 22), but IL-27 was not. We also detected many cells expressing both EBI3 and IL-12p35 in type 1 AIP tissues. Moreover, in peripheral blood lymphocyte, the percentage of nTregs and eTregs of CD4+ T cells in patients with type 1 AIP (n = 14) compared with HC (n = 15) was significantly decreased and increased, respectively. There were no significant differences of gene expression in patients with type 1 AIP and HC. This study identified elevated expression of plasma IL-35 and tissue IL-35 subunits in patients with type 1 AIP. This might lead to inflammation suppression via activated eTregs. IL-35 might be associated with this anti-inflammatory role, especially against the Th2 response through several cytokines and the differentiation of Tregs in type 1 AIP.
other
2023-10-02 | Suppressed IgG4 class switching in dupilumab- and TNF inhibitor-treated patients after repeated SARS-CoV-2 mRNA vaccination
Abstract Background Repeated mRNA vaccination against SARS-CoV-2 has been shown to induce class switching to IgG4, a non-inflammatory human antibody subclass linked to tolerance. Although poorly understood, prolonged antigenic stimulation and IL-4 signalling may be instrumental in IgG4 switching. We and others have previously shown that widely used immunosuppressive drugs such as methotrexate (MTX) and TNF inhibitors (TNFi) have a minor inhibitory impact on humoral SARS-CoV-2 mRNA vaccination responses. However, the impact of such immunosuppressive drugs on IgG4 switching is unknown. Aim To study the impact of widely used immunosuppressive drugs (TNFi, MTX, or the IL-4 receptor-blocking antibody dupilumab on IgG4 skewing upon repeated SARS-CoV-2 mRNA vaccination. Methods Antibody responses to the receptor-binding domain (RBD) of the spike protein upon repeated SARS-CoV-2 mRNA vaccination were measured in 604 individuals including patients with immune-mediated inflammatory diseases treated with TNFi and/or MTX, or dupilumab, as well as healthy controls and untreated patients. Results We observed a substantial increase in the proportion of RBD-specific IgG4 antibodies (median 21%) in healthy/untreated controls after a third mRNA vaccination. This IgG4 skewing was absent when primary vaccination was adenoviral vector-based and was profoundly reduced in both dupilumab- and TNFi-treated patients (<1%), but only moderately in patients treated with MTX (7%). Conclusion Our results imply a major role for both IL-4/IL-13 as well as TNF in IgG4 class switching. These novel findings advance our understanding of IgG4 class switch dynamics, and may benefit future mRNA vaccine strategies, humoral tolerance induction, as well as treatment of IgG4 pathologies.
2023-02-10 | Effects of Fibulin-5 Gene Silencing on Proliferation and Apoptosis of IgG4-ROD Lacrimal Gland Fibroblasts
This study is aimed at discussing the value of RNA interference technology on inhibiting lacrimal gland fibrosis in IgG4-related ocular disease (IgG4-ROD).Six patients with IgG4-ROD who came to the hospital for surgical treatment from October 2018 to August 2019 were selected, and their diseased lacrimal glands were taken for primary cell culture and fibroblast identification. High efficiency and specificity small interference RNA (siRNA) plasmid vector was constructed, its inhibitory effect on fibroblast proliferation was determined by CCK-8 assay, and the appropriate concentration was selected as the siRNA concentration for subsequent experiments. RT-PCR and Western blot detected the relative expression levels of Fibulin-5 mRNA and protein in the cells 48 hours after transfection. The apoptosis rate of each group of cells at 24 hours, 48 hours, and 72 hours after transfection was detected by flow cytometry, and the proliferation and apoptosis of cells after silencing Fibulin-5 were analyzed and compared.24 hours after transfection, there was no significant difference in the proliferation rate among the four groups (P > 0.05); 48 hours and 72 hours after Fibulin-5 siRNA transfection, the proliferation activity of the transfected cells was significantly decreased compared with the 0 nM group, and the inhibitory effect of 75 nM siRNA was the strongest. The expression of Fibulin-5 mRNA and protein in the siRNA-transfected cells was significantly decreased compared with the blank and empty vector negative siRNA groups, and the difference was statistically significant (P < 0.05). The apoptosis rate of cells in the Fibulin-5 siRNA transfection group was significantly higher than that of cells in the blank and empty vector negative siRNA groups, and the difference was statistically significant (P < 0.05).Fibulin-5 siRNA recombinant plasmid can significantly downregulate the mRNA and protein expressions of target gene Fibulin-5 and promote apoptosis after transfection into IgG4-ROD lacrimal gland fibroblasts. It is speculated that Fibulin-5 can be used as a target to effectively inhibit the fibrosis of lacrimal gland tissues by RNAi technique.
small molecules
2026-08-13 | Isolated IgG4-related lung disease: a case report.
IgG4-related disease (IgG4-RD) represents a chronic, immune-driven fibroinflammatory condition capable of affecting diverse organ systems; within this spectrum, pulmonary involvement (IgG4-RLD) remains comparatively uncommon. This case report outlines the clinical, imaging and pathological features of a patient with IgG4-related lung disease. We report a 60-year-old male patient with recurrent fever, chest pain, and cough with hemoptysis. Chest computed tomography (CT) initially showed right upper lobe lesions suggestive of pneumonia, but the patient failed to respond to multiple courses of antibiotics including levofloxacin, nemonoxacin malate, ceftizoxime, and amoxicillin. Further investigations revealed significantly elevated serum IgG4 level (266 mg/dL). Endobronchial ultrasound-guided transbronchial lung cryobiopsy (EBUS-GS-TBLC) confirmed dense lymphoplasmacytic infiltration in the lung tissue, with IgG4-positive plasma cells >50 per high powered field (HPF) and IgG4-positive/IgG-positive cell ratio >50%, consistent with the diagnosis of IgG4-related interstitial lung disease. The patient was treated with oral cyclosporine and mycophenolate mofetil, resulting in significant clinical and radiological improvement. IgG4-RLD should be considered in the differential diagnosis of patients with pulmonary lesions unresponsive to antibiotic therapy. Comprehensive evaluation including serum IgG4 measurement and targeted pathological biopsy is essential for accurate diagnosis. Early initiation of immunosuppressive therapy can effectively improve outcomes and prevent disease progression.
2026-08-11 | Treatment strategies for relapsing IgG4-RD: twelve-year experience from a prospective cohort.
Relapse is common in IgG4-related disease (IgG4-RD). While previous studies focus on treatments for active IgG4-RD, data on the management of relapsing IgG4-RD remains limited. We aimed to investigate the treatment strategies for relapsing IgG4-RD. This study analyzed data prospectively collected from an IgG4-RD cohort, including patients who experienced their first relapse and were followed for over 12 months. We compared the outcome among three groups: (1) Intensifying glucocorticoids (GC) only; (2) Intensifying immunosuppressants (IM) only; (3) Intensifying both GC and IM. The primary outcome was recurrent relapses. A decision tree model was developed to predict recurrent relapses. A total of 259 patients with IgG4-RD was included, with a male predominance (61.7%) and a median age of 54.0 years. Patients who intensified both GC and immunosuppressants (IM) (adjusted p 0.0002, HR 0.29, 95% CI: 0.16-0.52) experienced less relapses compared to those who intensified IM alone, while those who only intensified GC had a tendency to experience less relapses (adjusted p 0.0823, HR 0.51, 95% CI: 0.26-1.03). These differences were more pronounced in the subgroup with internal organ involvement. The decision tree indicated that those with an RI decrease to ≤ 2 and an IgG4 decrease ≥25% after treatment were more likely to stay free from recurrent relapses, with an AUC of 0.728 in the testing set. When treating relapse in IgG4-RD, GC-based treatment was associated with a lower hazard of recurrent relapse compared with only adjusting IMs, especially for those with internal organ involvement.
2026-08-07 | Directional Coronary Atherectomy as a Diagnostic Adjunct in Suspected IgG4-Related Coronary Artery Disease.
Immunoglobulin (Ig) G4-related disease can involve the cardiovascular system, and isolated vessel involvement is diagnostically challenging. A 79-year-old Japanese man with a history of percutaneous coronary intervention presented with exertional angina. Imaging demonstrated in-stent occlusion of the left anterior descending artery, severe distal left circumflex artery stenosis, and marked adventitial thickening of the coronary arteries and aorta. Serum IgG4 levels were markedly elevated. Directional coronary atherectomy (DCA) enabled retrieval of intimal tissue. Although the pathological findings did not fulfill formal classification criteria, tissue sampling provided supportive histopathological evidence for IgG4-related disease. Prednisolone therapy resulted in regression of adventitial thickening and reduction of nonrevascularized coronary lesions. DCA may serve as both a therapeutic strategy and an adjunctive diagnostic approach. DCA may provide supportive histopathological information when conventional biopsy is not feasible, and steroid therapy can be effective for cases of vascular involvement in IgG4-related disease.
2026-07-24 | Case Report: IgG4-related disease presenting with prominent oculomotor nerve palsy.
Immunoglobulin G4-related disease (IgG4-RD) is a systemic fibroinflammatory disorder that uncommonly involves cranial nerves. Oculomotor nerve palsy as the predominant manifestation of IgG4-RD is exceptionally rare and may elude timely diagnosis due to nonspecific symptoms. A 76-year-old man presented with a two-month history of bilateral plantar numbness and pain, followed by nausea, vomiting, and headache. The patient was hospitalized twice: first in August 2025 in the Department of Hematology, and subsequently in October 2025 in the Department of Rheumatology and Immunology. Laboratory evaluation revealed markedly elevated immunoglobulins, prompting a comprehensive workup including bone marrow aspiration, positron emission tomography-computed tomography (PET-CT), and lymph node biopsy. Histopathology demonstrated reactive lymphoid hyperplasia with abundant IgG4 + plasma cell infiltration (IgG4+ > 100 cells/HPF; IgG4/IgG ratio >40%), which established the diagnosis of IgG4-RD according to the 2019 ACR/EULAR classification criteria. During the second hospitalization, the patient developed right ptosis and diplopia, and neurological examination confirmed isolated right oculomotor nerve palsy. Contrast-enhanced brain MRI showed no structural abnormalities, and CTA, along with CSF analysis, excluded alternative etiologies such as aneurysm, neoplasm, or infection. Treatment with intravenous methylprednisolone (40 mg daily) followed by oral mycophenolate mofetil (500 mg twice daily) led to significant clinical improvement of oculomotor palsy within 4 months, with normalization of serum IgG4 levels (from a peak of 74.3 g/L to 8.94 g/L at follow-up) and reduction of inflammatory markers. IgG4-RD should be considered in the differential diagnosis of unexplained cranial neuropathies, even in the absence of radiographic abnormalities. This case highlights that neurological recovery may be gradual and require sustained immunosuppression, and underscores the importance of multidisciplinary collaboration in managing atypical manifestations of IgG4-RD.
2026-07-22 | A phase 2 trial of rilzabrutinib in IgG4-related disease.
The objective of the article is to assess the efficacy and safety of rilzabrutinib, an oral, reversible inhibitor of Bruton's tyrosine kinase, in participants with IgG4-related disease. This Phase 2a (NCT04520451) open-label, 52-week study enrolled 2 cohorts of participants with IgG4-related disease: Cohort A (participants who had failed or were intolerant to rituximab) and Cohort B (participants enrolled agnostic to rituximab history). Participants received rilzabrutinib plus a 2-to-4-week glucocorticoid (GC) taper followed by rilzabrutinib alone for up to 52 weeks. Primary endpoints were the proportion of participants without disease flare following first rilzabrutinib dose until the end of treatment and safety. This study included 27 participants (Cohort A: 13; Cohort B: 14). At the end of treatment, 70.4% (19/27) of participants were flare-free and off GCs/immunosuppressants. Disease activity (mean [SD]), measured by IgG4-related disease Responder Index, decreased by 8.3 (5.8) at week 12 in both cohorts and by 10.7 (6.3) in participants who completed 52 weeks of rilzabrutinib (14/17). Serious treatment-emergent adverse events (TEAEs) occurred in 2 participants, 1 resulting in death, but both events were judged unrelated to the study drug. The most frequent TEAEs were diarrhoea, 40.7% (11/27); coronavirus disease 2019, 18.5% (5/27); and dizziness, 18.5% (5/27). Rilzabrutinib had an acceptable safety profile in patients with IgG4-related disease who had failed/ intolerant to rituximab and who were rituximab-naïve. Most participants discontinued GCs successfully without disease flares and exhibited sustained disease activity reduction. Further investigation of this potential alternative to B-cell-depleting therapies is needed in larger, long-term, placebo-controlled trials.
antibodies
2026-08-13 | [An unusual cause for unilateral eye pain with double vision].
A 48-year-old man was diagnosed with IgG4-related disease (IgG4-RD) during an evaluation for exophthalmos and unexplained pain on the left side of his face. The diagnosis was made by ruling out all other possible conditions and was based on histopathological findings. After initiating immunosuppressive therapy with corticosteroids (GC), most of the symptoms resolved. As the GC-dose was gradually reduced, a relapse occurred, leading to two courses of Rituximab. Reflecting the success of the therapy, long-term follow-up revealed a marked radiological reduction in the retrobulbar mass and a significant clinical improvement in pain.
2026-07-30 | Case Report: Immune checkpoint inhibitor-induced IgG4-related disease mimicking renal metastatic progression: successful steroid-sparing management with rituximab.
Immune checkpoint inhibitors (ICIs) can induce a broad spectrum of immune-related adverse events (irAEs), including rare fibroinflammatory autoimmune manifestations. IgG4-related disease (IgG4-RD) has only exceptionally been described following dual ICI therapy. We report a 65-year-old man with metastatic clear cell renal carcinoma treated with nivolumab plus ipilimumab after nephrectomy. Despite initial radiologic stability, follow-up computed tomography revealed newly developed mass-like lesions in the solitary remaining kidney, raising suspicion of metastatic progression. CT-guided biopsy demonstrated subacute pyelonephritis, acute tubular injury, storiform fibrosis, and dense IgG4-positive plasma cell infiltration consistent with IgG4-RD. Because glucocorticoids were considered potentially detrimental to antitumor immune surveillance, rituximab was selected as steroid-sparing first-line therapy. Two infusions of rituximab (1000 mg each) led to radiologic stabilization/regression of renal lesions while pulmonary metastases remained under oncologic control. This case highlights IgG4-RD as a rare but clinically important underrecognized irAE of dual ICI therapy that may mimic malignant progression. Histologic confirmation is crucial, and B-cell depletion with rituximab may represent an effective treatment strategy when preservation of antitumor immunity is a priority.
2026-07-10 | From inflammatory initiation to fibrotic remodeling: mechanisms and precision therapeutic strategies in otorhinolaryngologic involvement of IgG4-related disease.
IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory disorder characterized by complex immune-mediated mechanisms and broad organ involvement that remains substantially underdiagnosed in clinical practice. The head and neck region is one of the most commonly involved anatomical domains, encompassing the major salivary glands, lacrimal glands, nasal cavity and paranasal sinuses, larynx and subglottis, thyroid gland, middle ear, orbit, and cervical lymph nodes. This review integrates current understanding of the immunopathological mechanisms underlying IgG4-RD with organ-specific clinical features and therapeutic considerations across these head and neck subregions. The core immune pathogenesis involves clonally expanded CD4+ cytotoxic T lymphocytes and activated follicular helper T cells that, within a Th2-skewed cytokine environment, promote IgG4 class-switch recombination and plasmablast expansion, driving the transition from inflammatory infiltration to progressive fibrotic remodeling. Although head and neck subtypes share this common immunopathological framework, they differ considerably in the relative balance between inflammatory and fibrotic features, clinical severity, and organ-specific risk profiles. These differences may reflect local microenvironmental factors, including epithelial characteristics, innate immune responsiveness, and the functional properties of resident stromal fibroblasts, though the precise mechanisms remain to be fully established. Therapeutically, glucocorticoids remain the standard first-line treatment for remission induction but are limited by high relapse rates after withdrawal. Rituximab has demonstrated efficacy in refractory and relapsing disease. Inebilizumab, an anti-CD19 monoclonal antibody, has shown significant benefit in a phase III randomized controlled trial. Dupilumab, which targets the IL-4/IL-13 signaling axis, has shown potential in case reports and small series, but prospective validation is required before it can be recommended as a standard therapeutic option. By mapping organ-specific immunopathological differences onto differentiated therapeutic approaches, this review aims to support a more individualized, biologically informed framework for managing IgG4-RD in the head and neck.
2026-06-30 | [Immunoglobulin G4-related retroperitoneal fibrosis: clinical, laboratory, imaging, and histopathological features in a Russian single-center cohort].
To describe a Russian cohort of patients with IgG4-related retroperitoneal fibrosis (RPF). This retrospective single-center study included 36 patients diagnosed with IgG4-related RPF according to the revised 2020 diagnostic criteria. Clinical, laboratory, instrumental, and pathomorphological data were analyzed. The cohort of 36 patients with IgG4-related RPF predominantly comprised males (4:1 ratio), with a median onset age of 52 years and median time to diagnosis of 8 months. The disease most presented with low back or lower abdominal pain (75%), renal dysfunction (44%), elevated serum IgG4>1.35 g/L (82%), and increased ESR/CRP. Urinary tract infection was detected in 44% due to frequent ureteral catheterization. Isolated retroperitoneal involvement occurred in 72% of cases, with typical infrarenal periaortitis in 58%; atypical sites included perirenal, periureteral, and presacral localizations. Biopsy (n=23) revealed lymphoplasmacytic infiltrate (100%), fibrosis (87%), IgG4+/CD138+>40% (71%), with obliterative phlebitis (26%) and tissue eosinophilia (26%) less common. Compared to international data, our findings reveal a higher prevalence of atypical localizations and concomitant urinary tract infections, necessitating their consideration in diagnostic algorithms and treatment planning for RPF patients.
2026-06-28 | Spontaneous regression of colorectal liver metastasis with coexisting IgG4-rich inflammatory pseudotumor-like changes: a case report.
Spontaneous regression of colorectal liver metastasis (CRLM) is an extremely rare phenomenon with only a few reported cases. However, the underlying mechanism remains unclear. Infection-triggered immune reactivation and inflammation have also been proposed to be potential contributors. IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory condition characterized by IgG4-positive plasma cell infiltration and fibrosis, and rarely manifests in the liver as an inflammatory pseudotumor (IPT). We herein report a rare case of a 71-year-old man with possible spontaneous regression of CRLM accompanied by coexisting IgG4-rich IPT-like changes. Eight months after the laparoscopic Hartmann's operation for rectal cancer, imaging revealed hepatic lesions in segments S5 and S7, which were diagnosed as CRLM. Partial hepatectomy revealed necrotic adenocarcinoma in the S7 lesion, with IgG4-rich IPT-like inflammatory changes. Postoperative evaluation revealed markedly elevated serum IgG4 levels and IgG4-positive plasma cell infiltration in the mediastinal lymph nodes, fulfilling the diagnostic criteria for systemic IgG4-RD. Twenty months postoperatively, the patient remained recurrence-free without adjuvant chemotherapy or steroid therapy. This case report describes the coexistence of spontaneous tumor regression and IgG4-related hepatic IPT within the same lesion and provides insight into the clinicopathological spectrum linking tumor regression and IgG4-RD.
cell therapies
2026-01-27 | Effects of anti-CD19 CAR-T cells in a murine model of IgG4-related disease.
BACKGROUND: Chimeric antigen receptor T-cell (CAR-T) therapy, an emerging immunotherapy, has shown promising efficacy in several autoimmune diseases. In this study, we conducted a preclinical evaluation of the therapeutic potential of CD19-specific CAR-T cell–mediated B-cell depletion in a mouse model that recapitulates key features of human IgG4-related disease (IgG4-RD). METHODS: B cell depletion strategies were evaluated in the LatY136F mouse model, a spontaneous murine model of IgG4-RD. Anti-CD19 CAR-T cells or control cells were transferred into LatY136F mice pretreated with total body irradiation. LatY136F mice treated with anti-CD20 monoclonal antibodies (mAb) served as the positive control group. RESULTS: CD19-targeted CAR-T cell infusion resulted in a more profound depletion of B cells and plasmablasts compared to anti-CD20 mAb treatment. This depletion was observed in peripheral blood, spleen, lacrimal glands, lungs, and pancreas in LatY136F mice. Moreover, CAR-T cell therapy significantly prolonged the survival of LatY136F mice and improved clinical symptoms compared to anti-CD20 mAb treatment. However, while CAR-T cell therapy reduced inflammation and fibrosis in the lacrimal glands and pancreas, it did not improve these conditions in the lungs. CONCLUSIONS: Our findings demonstrate that anti-CD19 CAR-T therapy effectively alleviates the progression of IgG4-RD, showing superior efficacy compared to anti-CD20 mAb in this preclinical model. These results support further investigation of CAR-T cells as a potential therapeutic option for IgG4-RD patients, with attention to potential adverse effects.
2025-12-11 | CAR T-cell therapy induces remission in multiorgan IgG4-related disease with hepatobiliary involvement.
IgG4-related disease (IgG4-RD) is a fibroinflammatory disorder in which IgG4+ B cells and T cells interact to drive chronic organ inflammation. Patients with multiorgan involvement may become refractory to standard therapy, resulting in progressive organ damage and risk of organ failure. Here, we report a patient with treatment-refractory multiorgan IgG4-RD treated with CD19-directed chimeric antigen receptor (CAR) T cells and describe the clinical and immunologic effects over more than 12 months of follow-up. A 60-year-old man with IgG4-RD involving the pancreas, hepatobiliary tract, and lungs, who was refractory to long-term immunosuppression, received autologous CD19-directed CAR T cells. Disease course was monitored longitudinally and multimodal immune profiling was performed on peripheral blood. CAR T cell therapy was well tolerated, with only grade 1 cytokine release syndrome, no neurotoxicity, and transient cytopenias without infections. Treatment induced B-cell aplasia lasting 6 months, while serum IgG4 levels normalized by month 8 and remained within the reference range thereafter. FAPI (fibroblast activation protein inhibitor) PET/CT demonstrated regression of fibroinflammatory activity, accompanied by improved lung function and quality of life. Immunosuppressive therapy was completely discontinued without disease flares for more than 12 months. B cell reconstitution consisted predominantly of naïve and transitional subsets. This was paralleled by a decline in T follicular helper cells and CD4+ cytotoxic T cells and attenuation of fibro-inflammatory and B cell-mediated signaling networks on interactome analyses. In this treatment-refractory case of multiorgan IgG4-RD, CD19-directed CAR T cell therapy induced durable, treatment-free remission with normalization of serum IgG4 and improvement across multiple clinical endpoints. Multimodal immune profiling indicates that CAR T cells can reset the B cell compartment and dampen pathogenic T cell and stromal interactions, supporting prospective evaluation of CAR T cell therapy in IgG4-RD.
2025-09-20 | Heart Transplantation in Advanced Heart Failure Due to IgG4-Related Endomyocardial Fibrosis.
IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory condition that rarely affects the heart. Cardiac manifestations include pericarditis, coronary arteritis, and myocarditis; endomyocardial fibrosis (EMF) is exceedingly rare. We report a 66-year-old man with advanced heart failure and recurrent hospitalizations due to restrictive cardiomyopathy, initially attributed to hypereosinophilia from parasitic disease. The patient developed cardiogenic shock requiring inotropes and intra-aortic balloon pump support. Imaging revealed biatrial enlargement, endocardial thickening, and subendocardial fibrosis, suggestive of EMF. Serology was positive for Trichinella spiralis IgG. Because of progressive clinical deterioration, the patient underwent urgent orthotopic heart transplantation. Histology of the explanted heart confirmed IgG4-related EMF. Posttransplant follow-up at 12 months showed preserved graft function and no recurrence. This case illustrates a rare cause of end-stage heart failure due to IgG4-RD and highlights the importance of including systemic inflammatory conditions in the differential diagnosis of restrictive cardiomyopathy. IgG4-related disease, though rare, can present as isolated endomyocardial fibrosis with features mimicking tropical EMF or hypereosinophilic cardiomyopathy. In advanced fibrotic stages with isolated cardiac IgG4-RD and cardiogenic shock, orthotopic heart transplantation may be the only lifesaving therapeutic option.
2025-04-30 | Refractory corneal melting due to IgG4-related disease: Successful management via buccal mucosal graft transplantation.
PurposeTo present the first case of isolated corneal involvement in IgG4-RD, managed successfully with oral mucosal grafting due to the destructive course of the disease.Case reportA 56-year-old female one-eyed patient was referred to our clinic with a diagnosis of unresponsive infectious corneal melting. The ophthalmologic examination revealed light perception visual acuity, intense conjunctival inflammation and an infected area of approximately 4 × 5 mm with accompanying melting. Her medical history includes a diagnosis of dry eye disease that has persisted for over a decade, multiple previous corneal transplant surgeries in the right eye with similar complaints, and subsequent evisceration surgery. Her complaints in the left eye had increased over the previous six months, and she had undergone eight instances of amniotic membrane transplantation at an external medical facility. Corneal scraping, conjunctival and corneal biopsy were performed. The histopathologic examination and elevated serum IgG4 level indicated the presence of IgG4-related disease. She was referred to the rheumatology department, where immunosuppression treatment was initiated. Oral mucosal grafting was performed to address the uncontrolled melting. At the follow-up examination, the melting was successfully controlled, the inflammation regressed, and the early hypertrophy of the oral mucosal epithelium flattened over time.ConclusionThis case highlights the potential for IgG4-related disease to manifest as atypical ocular surface involvement. Dry eye secondary to the disease can exacerbate existing findings. In such instances, preserving the integrity of the globe is of the utmost importance. Therefore, oral mucosal grafting, which is known for its durability, should be considered a viable option.
2024-12-14 | Efficacy and safety of anti-CD19 CAR-T in a mouse model of IgG4-related disease.
Dysregulated B-cell activation plays pivotal roles in IgG4-related disease (IgG4-RD), which makes B-cell depletion a potential strategy for IgG4-RD treatment. In this study, we aimed to investigate the feasibility of applying anti-CD19 chimeric antigen receptor T(CAR-T) cell therapy to IgG4-RD treatment in a mouse disease model based on LatY136F knock-in (Lat) mice. We constructed murine anti-CD19 CARs with either CD28 or 4-1BB as the intracellular costimulatory motif and evaluated the therapeutic function of the corresponding CAR-T cells by infusing them into Lat mice. Next, we assessed the safety of CAR-T infusion by evaluating the risk of cytokine release syndrome (CRS) and the antiviral capabilities in a mouse influenza infection model. Finally, we performed human anti-CD19 CAR-T manufacturing from IgG4-RD patients and evaluated its activation level and functional effects in vitro. Compared with 1D3 antibody treatment, the adoptive transfer of anti-CD19 CAR-T cells with CD28 costimulatory motif showed comparable B-cell-depletion effect in Lat mice. Furthermore, the transfer of syngeneic anti-CD19 CAR-T cells also decreased the percentage of plasma cells as well as IL-4 secreting Th cells, therefore attenuating the inflammation and fibrosis condition. CAR-T cells with CD28 costimulatory motif showed better therapeutic efficiency without the incidence of serious CRS events or increasing the risk of infection. In addition, we validated the feasibility of human CAR-T preparation in vitro from IgG4-RD patients. Taken together, these results show that anti-CD19 CAR-T therapy was effective in the treatment of a murine model of IgG4-RD, indicating its potential for clinical use in patients.
proteins
2024-01-23 | Laminin 511-E8, an autoantigen in IgG4-related cholangitis, contributes to cholangiocyte protection
IgG4-related cholangitis (IRC) is the hepatobiliary manifestation of IgG4-related disease. Anti-laminin 511-E8 autoantibodies have been identified in its pancreatic manifestation. Laminin 511-E8 promotes endothelial barrier function, lymphocyte recruitment, and cholangiocyte differentiation. Here, we investigate anti-laminin 511-E8 autoantibody presence in IRC, and mechanisms via which laminin 511 may contribute to cholangiocyte protection. Anti-laminin 511-E8 serum autoantibody positivity was assessed by ELISA. RNA sequencing and RT-qPCR were performed on human H69 cholangiocytes treated with recombinant laminin 511-E8. H69 cholangiocytes were subjected to shRNA knockdown targeting genes encoding laminin 511 (LAMA5, LAMB1, LAMC1) or treated with recombinant laminin 511-E8. Cholangiocellular bile acid influx was quantified radiochemically using 22,23-3H-glycochenodeoxycholic acid (GCDC). GCDC-induced apoptosis was determined by Caspase-3/7 assays. Cholangiocellular barrier function was assessed by FITC-dextran permeability assays. Immunofluorescent staining of laminin 511 and claudin 1 was performed on extrahepatic bile duct tissue of control and anti-laminin 511-E8 positive individuals with IRC. Seven out of 52 individuals with IRC had autoantibodies against laminin 511-E8. Recombinant laminin 511-E8 led to differential expression of genes involved in secretion, barrier function, and inflammation. Knockdown of laminin 511 constituents increased toxic bile acid permeation and GCDC-induced apoptosis. Laminin 511-E8 treatment decreased toxic bile acid permeation and dose-dependently alleviated GCDC-induced apoptosis. LAMA5 and LAMC1 knockdown increased transepithelial permeability. Laminin 511-E8 treatment reduced transepithelial permeability and prevented T lymphocyte-induced barrier dysfunction. Laminin 511 and claudin 1 staining patterns appeared altered in anti-laminin 511-E8 positive individuals with IRC. Laminin 511-E8 is an autoantigen in subsets of individuals with IRC. Laminin 511 enhances cholangiocellular barrier function and protects cholangiocytes against T lymphocyte-induced barrier dysfunction, toxic bile acid permeation and bile acid-induced apoptosis. A subset of IgG4-related cholangitis (IRC) patients has autoantibodies against laminin 511-E8. In human cholangiocytes, laminin 511 protects against (T lymphocyte-induced) epithelial barrier dysfunction and hydrophobic bile acids. Laminin 511 and claudin 1 staining may be altered in extrahepatic bile ducts of anti-laminin 511-E8 positive IRC patients. This makes it tempting to speculate that a decreased epithelial barrier function with attraction of immune cells and impaired bicarbonate secretion due to dysfunction of laminin 511 by autoantibody binding could potentially be a common systemic pathogenetic mechanism in a subset of IgG4-RD patients.
2022-05-19 | Role of eosinophilia in IgG4-related disease.
Immunoglobulin G4-related disease (IgG4-RD) is a heterogeneous immune-mediated condition that can affect almost any organ and is now being recognised with increasing frequency. Laboratory abnormalities including peripheral eosinophilia, hypergammaglobulinaemia, elevated serum IgE level, and hypocomplementaemia often provide initial clues to the diagnosis of IgG4-RD. The distinctive histopathological hallmarks of IgG4-RD are a dense lymphoplasmacytic infiltration with a high percentage of IgG4+ plasma cells, storiform fibrosis, obliterative phlebitis, and mild to moderate tissue eosinophilia. Around 20-40% of patients with IgG4-RD presented with peripheral eosinophilia and 51-86% are manifested as tissue eosinophilia. These data indicate an extensive involvement of eosinophil in IgG4-RD. Here, we review the biology of eosinophil, the discovery of eosinophilia in IgG4-RD, and its association with disease activity and relapse. We also discuss the possible functions and therapeutic potential of eosinophil in IgG4-RD.
2022-05-13 | Central Diabetes Insipidus Due to IgG4-related Hypophysitis That Required over One Year to Reach the Final Diagnosis Due to Symptoms Being Masked by Sialadenitis
Pituitary inflammation due to IgG4-related disease is a rare condition and is sometimes accompanied by central diabetes insipidus. Central diabetes insipidus produces a strong thirst sensation, which may be difficult to distinguish when complicated by salivary insufficiency. A 45-year-old man was admitted to our department for a thorough examination of his thirst and polyuria. He had suddenly developed these symptoms more than one year earlier and visited an oral surgeon. Swelling of the left submandibular gland, right parotid gland, and cervical lymph nodes had been observed. Since his IgG4 level was relatively high at 792 mg/dL and a lip biopsy showed high plasmacytoid infiltration around the gland ducts, he had been diagnosed with IgG4-related disease. He had started taking 0.4 mg/kg/day of prednisolone, and his chief complaint temporarily improved. However, since the symptom recurred, he was referred to our institution. After admission, to examine the cause of his thirst and polyuria, we performed a water restriction test, vasopressin loading test, hypertonic saline loading test and pituitary magnetic resonance imaging. Based on the findings, we diagnosed him with central diabetes insipidus due to IgG4-related hypophysitis. We increased the dose of prednisolone to 0.6 mg/kg/day and started 10 μg/day of intranasal desmopressin. His symptoms were subsequently alleviated, and his serum IgG4 level finally normalized. We should remember that IgG4-related disease can be accompanied by hypophysitis and that central diabetes insipidus is brought about by IgG4-related hypophysitis. This case report should remind physicians of the fact that pituitary inflammation due to IgG4-related disease is very rare and can be masked by symptoms due to salivary gland inflammation, which can lead to pitfalls in the diagnosis in clinical practice.
2022-03-03 | Neutralizing anti-IL-1 receptor antagonist autoantibodies induce inflammatory and fibrotic mediators in IgG4-related disease.
IgG4-related disease (IgG4-RD) is a fibroinflammatory condition involving loss of B-cell tolerance and production of autoantibodies. However, the relevant targets and role of these aberrant humoral immune responses are not defined. Our aim was to identify novel autoantibodies and autoantigen targets that promote pathogenic responses in IgG4-RD. We sequenced plasmablast antibody repertoires in patients with IgG4-RD. Representative mAbs were expressed and their specificities characterized by using cytokine microarrays. The role of anti-IL-1 receptor antagonist (IL-1RA) autoantibodies was investigated by using in vitro assays. We identified strong reactivity against human IL-1RA by using a clonally expanded plasmablast-derived mAb from a patient with IgG4-RD. Plasma from patients with IgG4-RD exhibited elevated levels of reactivity against IL-1RA compared with plasma from the controls and neutralized IL-1RA activity, resulting in inflammatory and fibrotic mediator production in vitro. IL-1RA was detected in lesional tissues from patients with IgG4-RD. Patients with anti-IL-1RA autoantibodies of the IgG4 subclass had greater numbers of organs affected than did those without anti-IL-1RA autoantibodies. Peptide analyses identified IL-1RA epitopes targeted by anti-IL-1RA antibodies at sites near the IL-1RA/IL-1R interface. Serum from patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) also had elevated levels of anti-IL-1RA autoantibodies compared with those of the controls. A subset of patients with IgG4-RD have anti-IL-1RA autoantibodies, which promote proinflammatory and profibrotic meditator production via IL-1RA neutralization. These findings support a novel immunologic mechanism underlying the pathogenesis of IgG4-RD. Anti-IL-1RA autoantibodies are also present in a subset of patients with SLE and RA, suggesting a potential common pathway in multiple autoimmune diseases.
2021-10-13 | Interleukin-35 promotes the differentiation of regulatory T cells and suppresses Th2 response in IgG4-related type 1 autoimmune pancreatitis.
IgG4-related disease (IgG4-RD) is a systemic inflammatory disease, which includes type 1 autoimmune pancreatitis (AIP). Interleukin-35 (IL-35) exhibits immunosuppressive effects in several autoimmune diseases. However, the expression of IL-35 had not been reported so far in type 1 AIP. We evaluated the association between IL-35 and several cytokines, which mediate the function of Tregs in type 1 AIP. Plasma was collected from patients with type 1 AIP, alcoholic chronic pancreatitis (ACP), and healthy controls (HC) and assayed for cytokine expression. Total mRNA separated from peripheral blood was isolated from naïve Tregs (nTregs) and effector Tregs (eTregs). EBI3 and IL-12p35 gene expressions were tested in these cells by quantitative PCR. In addition, expression of IL-35 subunits in the pancreatic tissues of patients with type 1 AIP and ACP was analyzed by immunohistochemistry. IL-35 was significantly elevated in type 1 AIP (n = 32) plasma compared with ACP (n = 16) and HC (n = 22), but IL-27 was not. We also detected many cells expressing both EBI3 and IL-12p35 in type 1 AIP tissues. Moreover, in peripheral blood lymphocyte, the percentage of nTregs and eTregs of CD4+ T cells in patients with type 1 AIP (n = 14) compared with HC (n = 15) was significantly decreased and increased, respectively. There were no significant differences of gene expression in patients with type 1 AIP and HC. This study identified elevated expression of plasma IL-35 and tissue IL-35 subunits in patients with type 1 AIP. This might lead to inflammation suppression via activated eTregs. IL-35 might be associated with this anti-inflammatory role, especially against the Th2 response through several cytokines and the differentiation of Tregs in type 1 AIP.
other
2023-10-02 | Suppressed IgG4 class switching in dupilumab- and TNF inhibitor-treated patients after repeated SARS-CoV-2 mRNA vaccination
Abstract Background Repeated mRNA vaccination against SARS-CoV-2 has been shown to induce class switching to IgG4, a non-inflammatory human antibody subclass linked to tolerance. Although poorly understood, prolonged antigenic stimulation and IL-4 signalling may be instrumental in IgG4 switching. We and others have previously shown that widely used immunosuppressive drugs such as methotrexate (MTX) and TNF inhibitors (TNFi) have a minor inhibitory impact on humoral SARS-CoV-2 mRNA vaccination responses. However, the impact of such immunosuppressive drugs on IgG4 switching is unknown. Aim To study the impact of widely used immunosuppressive drugs (TNFi, MTX, or the IL-4 receptor-blocking antibody dupilumab on IgG4 skewing upon repeated SARS-CoV-2 mRNA vaccination. Methods Antibody responses to the receptor-binding domain (RBD) of the spike protein upon repeated SARS-CoV-2 mRNA vaccination were measured in 604 individuals including patients with immune-mediated inflammatory diseases treated with TNFi and/or MTX, or dupilumab, as well as healthy controls and untreated patients. Results We observed a substantial increase in the proportion of RBD-specific IgG4 antibodies (median 21%) in healthy/untreated controls after a third mRNA vaccination. This IgG4 skewing was absent when primary vaccination was adenoviral vector-based and was profoundly reduced in both dupilumab- and TNFi-treated patients (<1%), but only moderately in patients treated with MTX (7%). Conclusion Our results imply a major role for both IL-4/IL-13 as well as TNF in IgG4 class switching. These novel findings advance our understanding of IgG4 class switch dynamics, and may benefit future mRNA vaccine strategies, humoral tolerance induction, as well as treatment of IgG4 pathologies.
2023-02-10 | Effects of Fibulin-5 Gene Silencing on Proliferation and Apoptosis of IgG4-ROD Lacrimal Gland Fibroblasts
This study is aimed at discussing the value of RNA interference technology on inhibiting lacrimal gland fibrosis in IgG4-related ocular disease (IgG4-ROD).Six patients with IgG4-ROD who came to the hospital for surgical treatment from October 2018 to August 2019 were selected, and their diseased lacrimal glands were taken for primary cell culture and fibroblast identification. High efficiency and specificity small interference RNA (siRNA) plasmid vector was constructed, its inhibitory effect on fibroblast proliferation was determined by CCK-8 assay, and the appropriate concentration was selected as the siRNA concentration for subsequent experiments. RT-PCR and Western blot detected the relative expression levels of Fibulin-5 mRNA and protein in the cells 48 hours after transfection. The apoptosis rate of each group of cells at 24 hours, 48 hours, and 72 hours after transfection was detected by flow cytometry, and the proliferation and apoptosis of cells after silencing Fibulin-5 were analyzed and compared.24 hours after transfection, there was no significant difference in the proliferation rate among the four groups (P > 0.05); 48 hours and 72 hours after Fibulin-5 siRNA transfection, the proliferation activity of the transfected cells was significantly decreased compared with the 0 nM group, and the inhibitory effect of 75 nM siRNA was the strongest. The expression of Fibulin-5 mRNA and protein in the siRNA-transfected cells was significantly decreased compared with the blank and empty vector negative siRNA groups, and the difference was statistically significant (P < 0.05). The apoptosis rate of cells in the Fibulin-5 siRNA transfection group was significantly higher than that of cells in the blank and empty vector negative siRNA groups, and the difference was statistically significant (P < 0.05).Fibulin-5 siRNA recombinant plasmid can significantly downregulate the mRNA and protein expressions of target gene Fibulin-5 and promote apoptosis after transfection into IgG4-ROD lacrimal gland fibroblasts. It is speculated that Fibulin-5 can be used as a target to effectively inhibit the fibrosis of lacrimal gland tissues by RNAi technique.
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Drug Discovery Landscape
5 orphan drug designations for IgG4-related disease, including 1 approved therapy.
5 orphan drug designations for IgG4-related disease, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
inebilizumab-cdon [Uplizna] | antibodies | FDA | 2026-05-01 | 2025-04-03 | Horizon Therapeutics Ireland DAC |
Rilzabrutinib | small molecules | EMA | 2025-08-22 | — | Sanofi B.V. |
rilzabrutinib | small molecules | FDA | 2025-04-01 | — | Sanofi US Services, Inc |
Humanised Fc-engineered monoclonal antibody against CD19 | antibodies | EMA | 2018-01-17 | — | Zenas BioPharma B.V. |
obexelimab | antibodies | FDA | 2017-05-09 | — | Zenas BioPharma (USA) LLC. |
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