IgG4-related disease (IgG4-RD) is a fibroinflammatory condition characterized by progressive organ damage; however, the spatial organization linking immune dysregulation to fibrotic remodeling remains incompletely understood. In this study, we performed spatial transcriptomic analysis of submandibular gland tissues from patients with IgG4-RD representing two distinct fibrosis-associated tissue states. Gene expression data were normalized and z-scored, and immune- and fibrosis-related module scores were calculated. Fibrotic niches were defined based on COL1A1 expression and fibroblast signatures, and spatial co-localization and correlation analyses were conducted. Fibrosis-high tissue regions exhibited enrichment of SPP1-expressing macrophages that co-localized with COL1A1 and fibroblast-rich areas, consistent with a spatially defined fibrotic niche. These regions were associated with increased expression of PDGFB and TGF-β–related molecules, which correlated with fibrosis-related signatures. Immune network analysis suggested remodeling of the immune microenvironment, with expansion and integration of Tph-associated populations. A preTfh-to-Tph axis became more apparent in fibrosis-high lesions, accompanied by reduced germinal center B-cell signatures and enhanced extrafollicular activation. Exhaustion-associated programs, including PDCD1 and TOX, were associated with T-cell differentiation states and SPP1-related signatures. Together, these findings identify an SPP1-associated immune–fibrotic niche and suggest a spatially coordinated relationship between immune remodeling and fibrosis in IgG4-RD. This hypothesis-generating framework provides insights into fibrosis-associated tissue remodeling and may inform future strategies for disease stratification and therapeutic targeting.
A newsletter destaca os avanços do EULAR 2026, com ênfase no estudo INDIGO sobre o obexelimabe na doença relacionada à IgG4 e no papel do metotrexato na redução da progressão para artrite reumatoide em pacientes ACPA-negativos. Além disso, discute a importância da padronização na fisioterapia para osteoartrite e o uso combinado de biomarcadores e ultrassom para triagem de doença pulmonar intersticial.
OBJECTIVE: To describe the epidemiology, organ involvement, histopathological patterns, and clinical management of immunoglobulin G4-related disease (IgG4-RD) in Stockholm County, Sweden. METHOD: Patients with an International Classification of Diseases, 10th revision, Swedish Edition (ICD-10-SE) diagnosis of IgG4-RD recorded between 2019 and 2023 were identified from the Swedish National Patient Register, encompassing all diagnoses recorded in inpatient and specialist outpatient care. Clinical data, laboratory results, histopathology reports, and treatment information were obtained through systematic medical record review. RESULTS: In total, 112 patients with a registered IgG4-RD diagnosis were identified, of which 95 diagnoses were confirmed after medical record review. The cohort was predominantly male (68%), and 60% had disease involvement of two or more organs. Elevated serum IgG4 was present in 71% of patients. The pancreas, hepatobiliary system, and kidneys were the most frequently affected organs, while salivary gland involvement was comparatively uncommon. Among patients who underwent biopsy (76%), a majority showed histopathological features supportive of IgG4-RD, although only a minority fulfilled multiple histopathological criteria. Comorbidities at the time of diagnosis were similar to those observed in the general older population, although an elevated prevalence of nasal polyposis and asthma was observed. Most patients received systemic glucocorticoids, either alone or in combination with rituximab. Overall, the prognosis was favourable, with high remission rates. CONCLUSION: IgG4-RD in Stockholm County shows a pancreatohepatobiliary-renal dominant pattern, with relatively few glandular cases compared to Asian and US cohorts. Histopathological confirmation was supportive in most biopsied patients, although many affected organs were not biopsied.
A newsletter apresenta os principais destaques do congresso EULAR 2026, abordando desde a eficácia da manutenção do alopurinol na gota até novos alvos terapêuticos para a Síndrome de Sjögren. Além das atualizações clínicas, explora como fatores psicossociais e a satisfação conjugal influenciam diretamente o prognóstico e a saúde mental de pacientes com doenças reumáticas crônicas.
Immunoglobulin-G4-related disease (IgG4-RD) is a rare recurring fibroinflammatory autoimmune condition that can affect multiple organs. Although it is gaining recognition, few studies have assessed the clinical and economic burden of this disease. This study aimed to characterize patients with IgG4-RD in the United States and describe healthcare resource utilization (HRU) and costs before and after diagnosis. This retrospective cohort study used a validated algorithm to identify commercially insured adult patients with IgG4-RD from health plan claims data obtained from the IQVIA PharMetrics Plus database (January 1, 2011, to June 30, 2022). The index date was defined as the date of the first observed IgG4-RD-related diagnosis. The baseline and study periods were defined as the 12 months before and after diagnosis, respectively. Demographic characteristics were reported on the index date. Clinical characteristics, IgG4-RD-related treatments, and all-cause HRU and healthcare costs (2022 US dollars, payer’s perspective) were reported during the baseline and study periods. A total of 295 patients with IgG4-RD were included in the study. Comorbid burden was substantial, with hypertension (31.5%), hyperlipidemia (22.4%), and type 2 diabetes (17.3%) being the most common comorbidities after diagnosis. Most patients received IgG4-RD-related treatment before (60.3%) and after (87.8%) diagnosis, with prednisone being the most common (71.5% after diagnosis). Pancreatic and biliary involvement each occurred in nearly a third of patients. Annual HRU was high before (mean of 30.4 outpatient [OP] visits; 22.7% with ≥1 inpatient [IP] admission, lasting a mean of 9.0 days) and after diagnosis (mean of 40.7 OP visits; 35.3% with ≥1 IP admission, lasting a mean of 10.6 days). Mean annual healthcare costs were 1.5 times higher after diagnosis ($69,753) than before diagnosis ($45,844), predominantly driven by increased OP and
Autoimmune rheumatic diseases (ARDs) are a diverse group of chronic disorders characterized by immune dysregulation and multi-organ inflammation. B cell receptor (BCR) signaling emerges as a shared, yet heterogeneously regulated, pathogenic axis across these diseases. This dysregulation drives B cell activation, autoantibody production, and ultimately tissue damage. Recent research highlights its involvement in both common and disease-specific mechanisms, which helps explain the wide variation in clinical features and therapeutic responses across ARDs. This review summarizes current evidence establishing BCR signaling as a central regulatory and therapeutic target in rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s syndrome, IgG4-related disease, and ANCA-associated vasculitis. It integrates mechanistic insights with recent clinical trial data on BCR signaling-targeted therapies, discussing factors that may contribute to variability in therapeutic responses and treatment limitations. Finally, we outline current challenges and future directions for precision medicine in ARDs, with a focus on biomarker-guided strategies and innovative combination therapies to improve patient outcomes.
Abstract Objectives This subgroup analysis of the MITIGATE study aimed to evaluate whether the efficacy and safety of inebilizumab in Japanese patients with IgG4-related disease are consistent with those observed in the overall trial population. Methods MITIGATE was a randomized, double-blind, placebo-controlled, phase 3 study conducted in 22 countries, and this subgroup analysis included the Japanese patients enrolled in that trial. Results In total, 27 Japanese patients (inebilizumab, N = 20; placebo, N = 7) were included in this subgroup analysis. The organs most frequently affected were the submandibular gland (66.7%), lacrimal gland (59.3%), and pancreas (51.9%). Despite the discontinuation of glucocorticoids within 8 weeks of study initiation, there were no adjudication committee-determined flares requiring treatment in the inebilizumab group. Flares were observed in four patients (57.1%) in the placebo group, with a median time to the first flare of 246.0 days. Inebilizumab reduced the annualized flare rate, increased flare-free complete remission, and lowered glucocorticoid use. Safety profiles were similar between treatment groups; most treatment-emergent adverse events were non-serious. Conclusions Inebilizumab reduced flare risk and glucocorticoid exposure, and it was well tolerated in Japanese patients with IgG4-related disease, which is consistent with the overall MITIGATE results. Trial registration NCT04540497.
A newsletter destaca que a normalização da IgG total no primeiro ano de tratamento é um preditor de recaída superior à IgG4 na Doença Relacionada à IgG4. Discute também que pacientes com vasculite anti-MPO apresentam maior risco cardiovascular e menor tempo para eventos adversos do que os anti-PR3. Por fim, aborda como a fragilidade impacta a tolerância aos corticoides na polimialgia reumática e o papel dos iSGLT2 na redução da necessidade de alopurinol.
A newsletter analisa uma meta-análise que indica benefícios significativos da metformina na redução da dor e melhora funcional em pacientes com osteoartrite de joelho. Outro destaque é a discussão sobre o mimetismo clínico entre a artrite reumatoide soronegativa e a doença por depósito de pirofosfato de cálcio (CPPD), especialmente em pacientes idosos. O conteúdo também revisa os principais avanços terapêuticos de 2025 em doenças como lúpus, esclerose sistêmica e IgG4-RD.
Objective To investigate longitudinal serum IgG dynamics in IgG4‐related disease (IgG4‐RD) after treatment and assess their prognostic value for relapse. Methods A retrospective cohort of 274 newly treated patients with IgG4‐RD was stratified into elevated IgG (n = 186) and normal IgG (n = 88) groups. Treatment responses were evaluated by covariance analysis adjusted for baseline IgG. Longitudinal IgG trends and relapse risk were analyzed using Kaplan–Meier curves and Cox regression. Results Elevated baseline IgG level was associated with more severe phenotypes, including male predominance, older age, higher responder index scores, more internal organ involvement, hypocomplementemia, and elevated erythrocyte sedimentation rate/C‐reactive protein level. IgG1 and IgG4 mainly contributed to IgG elevation. After treatment, 79.6% of patients with elevated IgG levels achieved normalization, with the greatest decline in the first year. Glucocorticoid (GC)–based regimens reduced IgG levels more effectively than GC‐sparing therapies and achieved higher normalization rates (85.2% vs 66.7%). Twelve‐month IgG normalization strongly predicted reduced relapse risk. Patients achieving IgG normalization had lower relapse rates (17.9% vs 44.1%; P = 0.001) and superior relapse‐free survival (mean 33.20 [95% CI 32.21–34.19] vs 27.71 [95% CI 24.29–31.13] months; log‐rank P < 0.001). Multivariate Cox regression confirmed failure of 12‐month IgG normalization (hazard ratio [HR] 2.67 [95% CI 1.43–4.99], P = 0.002) and treatment intensity (GCs + weak immunosuppressants [IMs]: HR 0.36, P = 0.012; GCs + potent IMs: HR 0.40, P = 0.020, vs GC‐sparing) as independent relapse determinants. Conclusion Baseline IgG elevation marks more severe IgG4‐RD phenotypes. The first treatment year achieving IgG normalization represents a critical prognostic biomarker. Failure to normalize IgG within 12 months markedly increases relapse risk. Longitudinal IgG monitoring supports risk stratification and treatment optimization.
High-resolution, high-throughput single-cell omics has transformed our understanding of autoimmune disease pathogenesis. We synthesise recent single-cell omics advances across six autoimmune diseases-systemic sclerosis, systemic lupus erythematosus, Sjögren's syndrome, ankylosing spondylitis, IgG4-related disease and rheumatoid arthritis. We further summarise translational progress in targeted therapies. We delineate core pathological networks shared across these conditions, highlight convergent mechanisms, and provide a mechanistic rationale for the clinical activity of agents such as tofacitinib and abatacept across multiple autoimmune settings. These insights support the feasibility of mechanism-informed, cross-disease targeting-deploying shared pathway interventions across distinct clinical entities. Finally, we discuss current technical and interpretative challenges and outline future directions for mechanistic discovery, target prioritisation and precision medicine.
Immunoglobulin G4-related ophthalmic disease (IgG4-ROD) is an immune-mediated ocular condition characterized by tumefactive lesions with IgG4+ plasma cell infiltration, and commonly affecting the lacrimal gland, extraocular muscles, and trigeminal nerves.The precise pathogenesis of IgG4-ROD remains unclear. Elucidating its molecular mechanisms is crucial for the development of targeted molecular therapies. To investigate the molecular pathogenesis of IgG4-ROD, we conducted a case-controlled study involving 15 patients who presented at the Second Hospital of Jilin University between 2021 and 2022. In accordance with the comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD) established in 2011, participants were stratified into three distinct cohorts based on lacrimal gland histopathological findings: confirmed IgG4-ROD, suspected IgG4-ROD, and a control group. We then utilized 4D-Fast DIA technology to acquire proteomic profiles from the lacrimal gland biopsies, with rigorous bioinformatics methodologies employed to process and interpret these data, focusing on the differential protein expression patterns across the groups, aiming to identify signaling pathways that are significantly associated with IgG4-ROD. The comparative analysis of clinical characteristics, imaging features, and histopathological findings among the control group, patients with suspected IgG4-ROD, and diagnosed patients revealed a progressive trend towards more severe pathology. Principal component analysis (PCA) and Pearson correlation heatmaps indicated that the profiles of differentially expressed proteins in lacrimal gland samples from the suspected and diagnosed groups were highly similar, suggesting that the patients from these two groups may belong to the same population. Further analysis of protein expression changes across the three groups revealed significant enrichment in pathways related to asthma, Th1 and Th2 cell differentiation, and other relevant signaling pathways. Notably, Toll-like receptor (TLR), NF-κB, Wnt, and PI3K-AKT signaling pathways were prominently activated. In the diagnosed group, proteins such as
Although immune checkpoint inhibitors (ICIs) have improved survival in head and neck squamous cell carcinoma (HNSCC), associated adverse events, such as sialadenitis, remain poorly characterized. This study aimed to define the clinicopathological features, establish the causal pathogenic mechanism, and validate a therapeutic target for ICI-associated sialadenitis. This study integrated three complementary approaches. First, a prospective cohort of 25 HNSCC patients underwent functional assessment of salivary and lacrimal glands before and after ICI therapy. Second, salivary gland tissues from separate cohorts of ICI-treated (n=30) and untreated control (n=30) patients were subjected to comprehensive analysis, including histology, multi-platform immunophenotyping (immunohistochemistry, multiplex immunofluorescence, flow cytometry), and cytokine quantification at both transcript and protein levels. Finally, a preclinical mouse model was established to confirm causality and validate the therapeutic efficacy of IL-17A blockade. Following ICI treatment, patients showed significantly reduced salivary and lacrimal secretion (P < 0.05). Histopathological analysis revealed extensive lymphocytic infiltration, marked periductal fibrosis, and substantial loss of acinar structures. The immune infiltrate was dominated by CD4+ T cells, particularly the Th17 subset, with corresponding upregulation of IL-17A both at transcriptional and protein levels. Crucially, we established a mouse model of anti-PD-1-induced sialadenitis and demonstrated that therapeutic blockade of IL-17A restores salivary function. This study establishes ICI-associated sialadenitis as a distinct pathological entity characterized by CD4+T cell-driven inflammation mediated through the Th17/IL-17 axis, which differs from Sjögren syndrome, predominantly involving B cells and from IgG4 related sialadenitis. By demonstrating therapeutic efficacy in a preclinical model, our findings provide the first preclinical validation of the IL-17 axis as an actionable therapeutic target for this condition.
Antimitochondrial antibodies (AMA), the hallmark of primary biliary cholangitis (PBC), have been inconsistently reported and poorly characterized in systemic sclerosis (SSc). Although recently linked to subclinical dysmotility in a cohort enriched for gastrointestinal (GI) involvement, data on the prevalence and clinical relevance of AMA in real-life SSc cohorts remain limited. A retrospective cross-sectional study was conducted on consecutive SSc patients followed at a referral center for the disease. Patients were tested for serum AMA according to reference standards, including HEp-2 immunofluorescent screening and ELISA confirmation (anti-E2 pyruvate dehydrogenase). Patients’ features were compared between AMA-positive and -negative cases. Among 165 SSc patients (20% diffuse cutaneous disease, 33% interstitial lung disease, 7.3% pulmonary arterial hypertension; 51% positive for anticentromere antibodies, 29% anti-topoisomerase I, 12% anti-RNA polymerase III), 37 (22%) were AMA-positive. While strongly associated with PBC, AMA were not linked to significant differences in cutaneous, vascular, pulmonary, or myocardial involvement. However, AMA were associated with GI vascular involvement (OR 13.3, 95% CI 2.53–95.0; p = 0.002), including gastric antral vascular ectasia (OR 7.99, 95% CI 1.05–72.5; p = 0.045), independently from PBC or symptoms of SSc-GI involvement. These complications are clinically relevant, as they may lead to GI bleeding and refractory iron-deficiency anemia. In our cohort of SSc patients systematically screened for autoantibodies, we found a high prevalence of AMA and identified a novel putative association with GI vascular involvement, which warrants confirmation in independent studies.
A newsletter analisa o estudo ESTIVAL, que avaliou a estimulação do nervo vago na osteoartrite erosiva, demonstrando melhora funcional e analgésica em pacientes com sinovite exuberante, apesar de um desfecho primário global negativo. Discute também como a ativação do sistema complemento (especialmente C3dg) prediz a progressão radiográfica na espondiloartrite axial independentemente do controle da PCR. Por fim, destaca atualizações sobre o FRAX 2.0 e o manejo da doença relacionada à IgG4.
A newsletter discute o impacto do belimumabe no lúpus inicial, demonstrando redução na progressão da doença e maior sucesso no desmame de corticoides. Apresenta também dados da coorte brasileira APS-Rio sobre SAF primária, destacando que metade das re-tromboses ocorre mesmo em faixa terapêutica de INR, além de abordar atualizações em Artrite Psoriásica, FRAX 2.0 e Doença relacionada à IgG4.
A newsletter detalha as atualizações do ACR 2025, evidenciando que a resistência insulínica é o fator causal da hiperuricemia na gota e reforçando a segurança de diversos imunobiológicos durante a gestação e lactação. Além disso, aborda a eficácia de imunossupressores em manifestações não-critério da síndrome antifosfolípide e novas perspectivas sobre o metabolismo do ferro nas espondiloartrites.
Rare eosinophilic disorders are challenging to manage due to their heterogeneity and lack of targeted therapies. Benralizumab, an anti-IL-5 receptor monoclonal antibody approved for the treatment of severe eosinophilic asthma and eosinophilic granulomatosis with polyangiitis (EGPA), has not been systematically studied in other eosinophilic conditions. To assess the efficacy and safety of benralizumab in adults with rare, non-asthmatic eosinophilic disorders over 52 weeks. In this single-center, prospective, open-label study, 17 adults with diverse eosinophilic diseases received benralizumab 30 mg every 4 weeks for 24 weeks; responders continued up to 52 weeks. The primary endpoint was ≥50% reduction in peripheral eosinophil counts or tissue infiltration. Secondary outcomes included symptom improvement, reduced exacerbations, corticosteroid withdrawal, and safety. Of the 19 enrolled patients, 17 initiated treatment. Sixteen achieved clinical resolution, and all showed complete peripheral eosinophil depletion. Corticosteroids were discontinued in all completers. One patient had a partial response, and one discontinued due to mild, unrelated liver enzyme elevation. No serious adverse events occurred. Relapses were observed after treatment cessation. Efficacy was demonstrated across heterogeneous conditions, including eosinophilic leukemia, folliculitis, vaginitis, and IgG4-related disease. Benralizumab is safe, well-tolerated, and effective in diverse rare eosinophilic disorders, enabling corticosteroid discontinuation and symptom control. These findings support its broader therapeutic potential and warrant further investigation.
To analyze the clinical and volumetric responses to different corticosteroid administration methods for IgG4-related ophthalmic disease (IgG4-ROD). The medical records of patients with bilateral lacrimal gland (LG) enlargement diagnosed with IgG4-ROD through unilateral LG biopsy between January 2011 and January 2022 were retrospectively reviewed. Clinical signs and the non-biopsied LG volume across three administration routes were compared: oral prednisolone (Pd), intravenous (IV) methylprednisolone (methylPd), and local triamcinolone (TA) injection. Radiological relapse was defined as the first instance of failure to satisfy the radiological response criteria, i.e., a post-treatment volume of <1.0 cm3 or a post-treatment to pre-treatment volume ratio of <35%. Among the 28 patients, eight, ten, and ten received oral Pd, IV methylPd, and local TA injection, respectively. No significant differences were observed between the groups in terms of the baseline characteristics. Ophthalmic adverse effects were not observed in any patient. Kaplan-Meier survival analysis revealed that the 2-year radiological relapse-free survival in the IV methylPd group (80.0%) was higher than that in the oral Pd group (37.5%, p = 0.036) but comparable with that in the local TA group (100.0%, p = 0.886). The median post-treatment to pre-treatment volume ratio in the IV methylPd group (35.4%) was significantly lower than that in the oral Pd group (75.0%, p = 0.042) but comparable with that in the local TA injection group (38.5%, p = 0.321) one year after treatment. Compared with oral Pd, IV methylPd yielded better and more sustained radiological responses in patients with LG-involving IgG4-ROD. Local TA injection was also an effective alternative treatment option.
Immunoglobulin G4-related disease (IgG4-RD) is a rare, multisystemic fibro-inflammatory condition affecting various organs, including kidneys, lungs, nasal cavity, pancreas, salivary glands, and orbit. Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAVs) is a multi-systemic inflammatory vascular disease encompassing eosinophilic granulomatosis with polyangiitis (EGPA), microscopic polyangiitis (MPA), and granulomatosis with polyangiitis (GPA). It often overlaps with the organs or tissues affected by IgG4-RD. Clinically, some individuals with IgG4-RD are ANCA-positive, while some with AAV exhibit elevated IgG4 levels or IgG4-positive plasma cell infiltration, making these conditions difficult to distinguish. Reports have documented cases of overlap syndromes involving IgG4-RD and AAV, highlighting shared pathogenic mechanisms that may include macrophages, B cells, CD4+T cells, and inflammatory cytokines. However, the pathophysiological mechanism underlying these overlap syndromes remains unclear. This review examines potential pathophysiological links between IgG4-RD and AAVs (GPA/MPA) overlap syndromes.
VEXAS syndrome is a rare, adult-onset autoinflammatory disorder caused by somatic mutations in the UBA1 gene. Patients may present with symptoms similar to IgG4-related disease (IgG4-RD) or systemic vasculitis. We report the case of a 70-year-old man who presented with periorbital swelling, fever, and elevated serum IgG4. However, a biopsy of the lacrimal gland did not show histological evidence of IgG4-RD. Consecutively, the patient developed progressive pulmonary infiltrations, bicytopenia and leukocytoclastic vasculitis. Chest-CT showed organizing pneumonia, which was histologically proven by transbronchial lung cryobiopsy (TBLC), again excluding IgG4-RD. PET/CT revealed hypermetabolic bone marrow and bone marrow aspiration biopsy showed vacuolization of granulocytic precursor cells. Finally, genetic testing for UBA1 mutation confirmed the diagnosis of VEXAS syndrome. Treatment with ruxolitinib in addition to steroids, led to temporary stabilization but long-term prognosis was unfavorable. This case highlights the importance of considering VEXAS syndrome a relevant differential diagnosis of vasculitis and IgG4-RD in men. Furthermore, we present valuable insights into the pathophysiology of VEXAS through transmission electron microscopy (TEM) of TBLC samples.
IgG4-related disease (IgG4-RD) is a chronic immune-mediated disease characterised by mass-forming lesions. The smouldering tempo and often asymptomatic nature of IgG4-RD pose challenges in the monitoring of disease activity. The goal of this study is to identify novel biomarkers capable of distinguishing active disease from remission. Ninety-two inflammation-associated proteins were measured across 67 patients with IgG4-RD, 49 healthy donors (HDs), and 21 patients with sarcoidosis. Statistical analyses were adjusted for age, sex, race, and false discovery rate. Biomarkers that distinguished IgG4-RD were studied by unsupervised hierarchical clustering, receiver operator characteristic curves, and statistical analyses. Quantitative enzyme-linked immunosorbent assay (ELISA) was used to validate findings in a cohort of 80 patients with IgG4-RD, including 28 patients with paired longitudinal samples, and 80 age, sex, and race-matched HDs. Twelve inflammation-associated proteins distinguished IgG4-RD. Although most markers correlated with one another, CCL19, CCL2, and CCL13 were the most distinguishing of IgG4-RD. Among these, only CCL19 decreased during treatment-induced remission relative to active IgG4-RD. CCL19 correlated with clinical and laboratory parameters of disease activity and severity. Quantitative ELISA validated the systemic elevation of CCL19 in patients with IgG4-RD. CCL19 performed similarly to IgG4 in dynamically declining in response to treatment and increasing with subsequent relapse. Importantly, CCL19 and IgG4 supplemented one another in distinguishing active disease from remission. CCL19 is a novel and promising biomarker for the longitudinal monitoring of disease activity in patients with IgG4-RD and may provide supplemental value to IgG4 in identifying relapsing disease.
IgG4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory disorder of unknown aetiology, potentially linked to genetic factors. This study conducted the first genome-wide association study on IgG4-RD in the Chinese Han population to identify genetic susceptibility loci. The study analysed data from 1161 patients with IgG4-RD and 10,539 controls across 2 independent cohorts, with 1115 patients and 10,154 controls passing quality control criteria. Using the Han-MHC reference dataset of the Chinese Han population, IgG4-RD genotyping data were imputed for the human leukocyte antigen (HLA) locus. Additionally, the study assessed the association between genetic variants and clinical characteristics, including disease activity, subtype classification, and relapse. We identified 22 single nucleotide polymorphisms (SNPs) that surpassed genome-wide significance thresholds (P < 5E-08) and replicated consistently across both cohorts, defining 16 distinct genetic susceptibility loci. The strongest signal mapped to chromosome 6 in the extended major histocompatibility complex region. Notably, chromosome 1 harboured significant loci involving immune-related genes such as the FC-γ receptor gene family. Fine mapping identified 6 independent HLA alleles, 2 amino acid mutations, and SNP rs3888777 as independent significant signals. Genetic variants were significantly associated with clinical manifestations such as serum immunoglobulin G4 levels, extent and pattern of organ involvement, clinical subtypes, and relapse risk. Furthermore, meta-analysis integrating Japanese cohort data confirmed known loci and revealed novel susceptibility variants. This study identified multiple susceptibility loci for IgG4-RD, uncovering novel genetic variants closely linked to clinical features and disease prognosis. These findings provide valuable genomic insights, advancing the understanding of IgG4-RD pathogenesis.
Retroperitoneal fibrosis is a rare immune-mediated disease characterised by a periaortoiliac fibro-inflammatory tissue that often encases neighbouring structures (eg, ureters). Idiopathic retroperitoneal fibrosis can be isolated or part of IgG4-related disease, whereas secondary forms recognise different aetiologies, such as histiocytosis, malignancies, and infections. Idiopathic retroperitoneal fibrosis has a multifactorial origin, with genetic, environmental, and lifestyle factors being main contributors. The immunopathogenesis of the disease involves B-lymphocyte and T-lymphocyte crosstalk, macrophage and fibrocyte chemotaxis, and recruitment of eosinophils and mast cells. Idiopathic retroperitoneal fibrosis can cause severe complications, such as acute or chronic kidney injury, caval occlusion, and deep vein thrombosis. Although interventional or surgical procedures can be necessary to manage these complications, medical therapy remains the cornerstone of treatment. Glucocorticoids are effective, and B-cell-targeting therapies are increasingly used. However, relapses are frequent after treatment discontinuation. In this Seminar, we provide a contemporary overview of retroperitoneal fibrosis focusing on pathophysiology, differential diagnosis, and management.
The objective of this study was to describe the IgG4-related disease (IgG4-RD) allergen profile and its clinical associations. One hundred patients with IgG4-RD and 40 healthy controls (HCs) were enrolled. We measured allergen-specific IgE (AsIgE) in all participants and AsIgG4 in 20 patients with higher serum IgG4 and AsIgE levels. We described the AsIgE positivity rate and allergen profiles, compared clinical parameters, and further analysed antibody correlations (AsIgE and AsIgG4) in IgG4-RD. The AsIgE-positive rate in IgG4-RD patients (59%) was significantly higher than that in HCs (15%) (P < 0.001). The four most frequently detected allergens in IgG4-RD patients were house dust mites (47%), cockroach (26%), moulds (14%) and grasses (14%). Patients with positive AsIgE tended to coexist with high levels of total IgE (T-IgE) (P < 0.0001) and TNF-α (P < 0.05). Additionally, the number of detected allergens for each patient was positively correlated with serum IgG4 (P < 0.0001), T-IgE (P < 0.0001), etc., but exhibited a significant inverse correlation with complement 3 (C3) (P < 0.0001), C4 (P < 0.001), etc. Notably, cockroach-sIgE positivity showed an association with ureter (P < 0.05)/sinus (P < 0.05) involvement, while mulberry- and moulds-sIgE positivity was linked to renal (P < 0.01) and orbital (P < 0.05)/lacrimal (P < 0.01) involvement separately. Moreover, no significant AsIgE-AsIgG4 correlation was found. Our study characterized the allergen profile in IgG4-RD patients, and reported its association with enhanced inflammation and distinct organ involvement. Non-overlapping IgE and IgG4 reactivity against allergens suggested potentially distinct cellular origins and/or induction pathways for them in IgG4-RD.
IgG4-related disease (IgG4-RD) is a rare fibro-inflammatory disorder characterized by progressive fibrosis involving multiple organs and tissues. Clinical manifestations are highly variable, reflecting the organs affected. Oral glucocorticoids (GC) are established as first-line therapy; however, relapse occurs in 15–60% of patients. To reduce relapse risk and GC-related adverse effects, GC-sparing strategies using disease-modifying antirheumatic drugs (DMARDs) may be considered. This study aims to evaluate the efficacy and safety of azathioprine in the management of IgG4-RD and provides an overview of the current literature. This retrospective case series assesses disease activity under azathioprine therapy in patients with IgG4-RD treated at the Medical University of Graz between 2006 and 2024. Patients with a confirmed IgG4-RD diagnosis according to the 2019 ACR/EULAR criteria who received azathioprine following initial GC therapy were included. Ten male patients (mean age at disease onset: 59.4 years) with a mean follow-up of 75.2 months were analyzed. All patients fulfilled the 2019 ACR/EULAR classification criteria. Indications for initiating azathioprine included disease relapse on GC (n = 3), GC-related adverse effects (n = 3), and the intention to reduce GC exposure (n = 7). During azathioprine therapy, three patients (30%) experienced a total of five relapses. Seven patients receiving azathioprine remained in remission throughout the observation period. Adverse events included infections (n = 2), hematologic abnormalities (n = 4), and elevated liver enzymes (n = 1). At last follow-up, five patients (50%) remained on azathioprine, two (20%) had switched to rituximab, one of whom was in remission and off therapy, and three patients (30%) were no longer receiving immunosuppressive treatment (two due to hematologic abnormalities, one by patient request), with no further therapy initiated. Azathioprine represents an appropriate maintenance therapy for IgG4-RD. In cases with relapse under azathioprine, alternative DMARDs, such as
IgG4-related disease is a rare autoimmune disorder characterised by tissue infiltration of IgG4-positive plasma cells, storiform fibrosis, elevated serum IgG4 concentrations, and increased risk of tumour complications. Previous genetic studies have implicated FCGR2B and HLA loci in susceptibility to IgG4-related disease; however, most relied on microarray-based genotyping and imputation, which have limited resolution in highly polymorphic and structurally complex regions. This study aimed to investigate genetic susceptibility to IgG4-related disease using comprehensive genomic variant analysis, including low-frequency and structural variants not readily captured by microarrays. We conducted a genome-wide association study using whole-genome sequencing data in a two-set, subtype-stratified case-control design in the Japanese population. Set 1 included samples (cases) from patients with IgG4-related disease from 50 hospitals across Japan participating in the Japanese IgG4-related disease Working Consortium (recruited between Oct 27, 2008, and March 3, 2016) and previously sequenced Japanese population control samples. Set 2 included samples (cases) from patients with IgG4-related disease from eight hospitals of the Consortium (recruited between Aug 12, 2021, and Dec 20, 2023) and previously sequenced healthy individuals residing in the Tokyo metropolitan area (controls). No specific inclusion or exclusion criteria were applied to either cases and controls. We used whole-genome sequencing at depths of 15× or 30× using HiSeqX and NovaSeq platforms (Illumina; San Diego, CA, USA) to enable the inclusion of previously uncaptured single nucleotide polymorphisms and direct analysis of HLA amino acid residues. We investigated complement component 4 copy number variations using short-read sequencing data and established read-depth-based typing methods. People with lived experience of IgG4-related disease were not involved in the study. This whole-genome sequencing study comprised of 2 sets. Set 1 included 646 patient samples (172 [26·6%] were female,
IgG4-RD is a rare but increasingly recognized systemic condition characterized by complex clinical manifestations and multi-organ involvement, often leading to misdiagnosis or delayed diagnosis. This study aims to elucidate the clinical features of IgG4-RD and evaluate the diagnostic and therapeutic utility of key laboratory indicators. We conducted a retrospective analysis of IgG4-RD patients, comparing laboratory profiles across different organ involvement patterns. The diagnostic and therapeutic value of serum IgG4 levels in IgG4-RD was evaluated, with comparative analyses of serum IgG4 levels extended to non-IgG4-RD patients. Distinct patterns of laboratory markers were observed across affected organs, with elevated IgG and ESR levels consistently noted. The optimal diagnostic cutoff for serum IgG4 in IgG4-RD was 1.94 g/L, while a cutoff of 9.05 g/L effectively identified multi-organ involvement. Following 6 months of standardized treatment, serum IgG4 levels in IgG4-RD patients decreased significantly. Notably, ANCA-associated vasculitis patients exhibited markedly elevated serum IgG4 levels, which remained unchanged post-treatment. The integration of serum IgG4 with other laboratory markers enhances diagnostic precision for IgG4-RD. Elevated serum IgG4 levels are associated with multi-organ involvement, underscoring their utility in assessing disease extent. Serum IgG4 is indispensable for monitoring therapeutic response. Given the overlapping clinical features between ANCA-associated vasculitis and IgG4-RD, accurate differentiation is essential for optimal clinical management. Key Points • IgG4-RD predominantly affects middle-aged and elderly males, yet its occurrence in younger individuals and less commonly involved organs (e.g., brain and heart) warrants attention. • Affected organs demonstrate distinct laboratory marker profiles, providing valuable insights for clinical diagnosis and therapeutic strategies. • Serum IgG4 levels are instrumental in diagnosing, assessing disease progression, and monitoring treatment response, though their interpretation should be integrated with other clinical indicators. • In ANCA-associated vasculitis, serum IgG4
There is a high prevalence of allergic conditions in patients with IgG4-related disease (IgG4-RD), paralleled by shared dysregulation in immune responses. The aim of this study was to explore the clinical features and outcomes of IgG4-RD patients with allergy history. 215 IgG4-RD patients were retrospectively enrolled and clinical features were compared between IgG4-RD patients with and without allergy history. Subsequently, 148 patients who had been followed up for ≥ 1 year were further selected to evaluate the outcomes and risk factors of relapse by conventional COX and Bayesian Cox proportional hazards models. Among IgG4-RD patients, 81 (37.7%) had allergy history. IgG4-RD patients with allergy history were found to have lower proportion of males, younger age of disease onset, higher peripheral blood eosinophil, more proliferative subtype, less fibrotic subtype, higher incidence of lacrimal gland, parotid gland, submandibular gland involvement, sinusitis and lower incidence of retroperitoneal fibrosis, pancreas, biliary tree involvement. Allergy history was correlated with a shorter relapse-free survival time (HR 95% CI: 1.067-2.604, p = 0.02). More organs involved, higher IgG4-RD responder index (IgG4-RD RI), allergy history, lacrimal gland involvement, sinusitis, retroperitoneal fibrosis and Immunosuppressants (IMs) usage were associated with relapse. IgG4-RD patients with allergy history have distinctive phenotypes and prognosis. Therefore, differentiated treatment strategies and novel medications are required for them. Key Points • IgG4-RD patients with allergy history exhibit high prevalence of allergic conditions. • Conventional and Bayesian Cox regression models were used to analyze the risk factors of relapse. • Allergy history are correlated with distinctive phenotypes and shorter relapse-free survival time in IgG4-RD.
BACKGROUND: To investigate the feasibility and potential efficacy of “watchful waiting” strategy in IgG4-related disease (IgG4-RD) patients being asymptomatic or having low disease activity. METHODS: IgG4-RD patients presented in our station between October 2018 to October 2022, who met the criteria for “watchful waiting” modified from the 2015 International Consensus Guidance Statement were included. Deidentified clinical laboratory data were retrospectively collected and statistically analyzed between patients undergone watchful waiting (“WAIT” group) and received routine medical treatments (“TREAT” group). Subgroup analyses in “WAIT” group were also performed to compare the features between patients with and without receiving surgical resection of involved organs. RESULTS: A total of 49 patients meeting the “watchful waiting” criteria were included and followed for a median of 48 [IQR 24.00, 48.00] months. The median IgG4-RD responder index (RI) of them was 2; 71.4% of them were ‘Head and Neck-Limited’ clinical phenotype, and 63.3% were single organ involved. While 25 of the 49 patients chose “watchful waiting” strategy, others received treatment of glucocorticoids and steroid-sparing agents. The WAIT group showed a significantly higher cumulative recurrence rate (42.4%, 95%CI: 0.18–0.60) than the TREAT group (8.3%, 95%CI: 0-0.19), during the follow-up periods. Further analyses into the WAIT group revealed all relapse events of them were observed in patients undergone surgical resection of involved organs, who scored significantly higher based on the 2019 ACR/EULAR classification criteria for IgG4-RD. CONCLUSIONS: “Watchful waiting” strategy may not be the optimal immediate choice for patients with mild symptoms, low disease activity, and limited organ involvement, even after the surgical resection of involved organs.
Erdheim-Chester disease (ECD) and immunoglobulin G4-related disease (IgG4-RD) are both rare, multisystem disorders with overlapping clinical, radiologic, and histopathologic features. This overlap leads to delays or misdiagnoses. Early diagnosis with proper distinction is critical for treatment and a better prognosis. A review of the literature using PubMed and Google Scholar was conducted to identify distinguishing features between ECD and IgG4-RD. The focus was on clinical presentation, diagnostic imaging, histopathologic findings, immunohistochemistry, and genetic mutations. Relevant articles were screened, and data were synthesized to create a diagnostic framework. Both disorders can be characterized by retroperitoneal fibrosis, central nervous system involvement, and IgG4-positive plasma cell infiltration. ECD is characterized by long bone osteosclerosis, "hairy kidneys," a coated aorta, and diabetes insipidus, and is associated with BRAF V600E or MAPK pathway mutations. In contrast, IgG4-RD is characterized by autoimmune pancreatitis, sialadenitis, and increased serum IgG4, as well as storiform fibrosis and obliterative phlebitis on histology. Imaging is key: FDG-PET and MRI frequently show skeletal and cerebellar uptake in ECD, which is typically absent in IgG4-RD. Therapeutically, ECD often requires targeted therapies such as BRAF or MEK inhibitors, whereas IgG4-RD responds to corticosteroids or rituximab or inebilizumab. Treatment response emerged as a new diagnostic clue. This review provides a structured, multimodal approach to distinguish ECD from IgG4-RD, which improves diagnostic accuracy by integrating genetic testing, advanced imaging, neurological features, and treatment response. This allows clinicians to avoid misdiagnoses, implement targeted treatments, and improve patient outcomes.
Immunoglobulin G4-related disease (IgG4-RD) is a systemic fibroinflammatory condition that may affect any organ. Prostatic involvement is uncommon and under-recognised. The presentation often mimics benign prostatic hyperplasia or prostate carcinoma, causing diagnostic uncertainty. This systematic review synthesises evidence on IgG4-related prostatitis, focusing on clinical manifestations, diagnostic approaches, treatment, and outcomes. Following PRISMA 2020 guidelines, PubMed, Scopus, Web of Science, and Ovid were searched from inception to 12 February 2025. Eligible studies included English-language case reports, case series, and observational studies describing prostatic involvement in IgG4-RD. Data on demographics, clinical and laboratory findings, management, and outcomes were extracted and analysed descriptively. Fifty studies reporting 66 cases were included. Median age was 64 years (range 20-82). Serum IgG4 concentrations were elevated in most (median 832 mg/dL, range 5-4,500), while prostate-specific antigen (PSA) levels varied widely (0.01-180 ng/mL). Multiorgan involvement occurred in 57.8%, isolated disease in 6.2%. Lower urinary tract symptoms were most frequent (39.6%). Glucocorticoids, mainly prednisone, were the main therapy (69.2%), followed by surgery, chiefly transurethral resection of the prostate. Complete and partial responses occurred in 50.9% and 43.4%. Treatment type correlated with outcome (χ²=49.70; p<0.001). Malignancy (18.5%) was associated with higher mortality (p=0.028). IgG4-related prostatitis is a rare and likely under-recognised manifestation of IgG4-RD. Its overlap with benign and malignant prostatic disorders delays diagnosis. Serum IgG4 and PSA are unreliable markers of disease and monitoring. Glucocorticoids remain first-line therapy, with surgery in obstructive cases. Multicentre studies are needed to define prevalence, natural history, and optimal management.
IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory disorder characterised by tissue infiltration of IgG4+ plasma cells, yet the precise roles of B cells remain unclear. This study aimed to characterise the longitudinal immune dynamics in IgG4-RD during B-cell depletion therapy to identify pathogenic cell subsets and specific biomarkers associated with relapse. We performed a longitudinal multiomics analysis on 119 peripheral blood samples from patients with IgG4-RD undergoing rituximab treatment, spanning active, remission, and relapse phases. Integrated single-cell transcriptomics, B-cell receptor (BCR) sequencing, and serum proteomics were performed on matched blood and tissue samples from submandibular gland and lymph nodes, with Sjögren's syndrome and healthy individuals as controls. We identified a previously unrecognised, disease-specific IgG4+ plasma cell subset characterised by aberrant expression of the neuropeptide NMU and highly skewed IGHV1-69 usage. Circulating follicular helper T cells (CD4+Tfh) displayed signatures consistent with chronic antigen stimulation and type 2 immunity. Furthermore, markedly expanded double-negative T cells (dnT) highly expressed IL10, suggesting their involvement in immune regulation and isotype class switching. Longitudinal analysis following B-cell depletion emphasised the reconstitution dynamics of pathogenic plasma cells, furthermore highlighting the concurrent shifts in CD4+Tfh and dnT that mirrored disease remission and relapse, and underscored the amelioration of proinflammatory immune profiles. NMU-expressing IGHV1-69+ plasma cells represent a pathogenic effector population driving IgG4-RD recurrence. These findings establish a mechanistic framework for B-cell depletion and identify specific cellular and molecular biomarkers to improve disease monitoring and relapse prediction in clinical practice.
Immunoglobulin G4-related disease (IgG4-RD) is a chronic fibroinflammatory disorder with heterogeneous clinical behaviour. Although glucocorticoids remain the mainstay of treatment, relapse and fibrosis are common. This study investigated predictors of relapse and mortality, integrating disease subtype and cumulative drug exposure using the defined daily dose (DDD) framework. Eighty-five patients fulfilling the 2020 revised comprehensive diagnostic criteria for IgG4-RD were retrospectively analysed. Clinical features, laboratory data and cumulative DDD (cDDD) of corticosteroids and immunosuppressants were compared between proliferative or fibrotic subtypes. Multivariate Cox regression identified predictors of relapse and mortality, and forest plots were used for overall and subgroup analysis. Azathioprine cDDD and hydroxychloroquine cDDD showed a weak positive correlation with alanine aminotransferase (ALT) levels, which reflects hepatic involvement of IgG4-RD. Elevated ALT, higher serum IgG and greater steroid exposure (>1225 cDDD) independently predicted relapse, while anaemia (Hb <10.9 g/dl) predicted both relapse and mortality. Lower IgG levels (<1600 mg/dl), low steroid exposure (<1225 cDDD), or classified as non-responders were less likely to experience flare. Early hydroxychloroquine use and lower initial steroid exposure were linked to improved survival. The fibrotic subtype was associated with older age, renal impairment, and lower flare risk, but higher hydroxychloroquine dosage and anaemia increased risk of flare. Proliferative disease exhibited greater responsiveness to immunosuppressive therapy but has shorter median time to first relapse. Distinct proliferative and fibrotic phenotypes exhibit divergent risks and treatment responses. Quantitative cDDD assessment enables objective evaluation of therapeutic intensity and outcome prediction, supporting a stage-tailored, precision approach to IgG4-RD management.
Due to its progressive fibro-inflammatory nature and frequent delays in diagnosis, IgG4-related disease (IgG4-RD) carries a significant risk of permanent organ damage. An index to evaluate the damage in IgG4-RD has been developed recently. The aim of this follow-up study was to assess the prognosis of IgG4-RD, with a focus on damage progression. Data on IgG4-RD baseline characteristics, treatment, relapses, damage progression and deaths during follow-up were retrospectively extracted from electronic medical records of patients with IgG4-RD diagnosed and monitored at our rheumatology centre. Damage was assessed using the CIC IgG4-RD Damage Index (CIC IgG4-RD DI) at baseline, 12 months, 24 months and at the last follow-up visit. Risk factors for damage at the last visit and for death were evaluated by Cox proportional-hazards regression analysis. Of 59 patients diagnosed between January 2012 and December 2024, 55 were followed for a median (IQR) of 44.7 (20.4; 81.2) months (37/55 patients were followed for more than 24 months), while 4 were lost to follow-up. At diagnosis, 36 patients (65.5%) had already developed damage. At the 12-, 24-month visits and last follow-up visit of a subgroup followed-up for more than 24 months, 37/50 (74%), 29/37 (78.4%) and 32/37 (86.5%) patients had developed damage, respectively. A relapsing disease course was identified as a factor associated with damage at the last patient's visit (HR 5.3 (95%CI 1.1; 24,4), p=0.035). Eight patients (14.5%) died during follow-up, with 4 deaths related to IgG4-RD or its treatment. Damage at the last visit emerged as a risk factor for death (HR 1.5 (95%CI 1.0; 2.2), p=0.036). At diagnosis, damage was already present in nearly two-thirds of our patients. During follow-up, damage progressively accumulated and was associated with patient
IgG4-related disease (IgG4-RD) is a rare immune-mediated, fibroinflammatory disease with heterogenous presentations and no standardized treatment recommendations. This study investigates long-term efficacy and safety of current therapeutic strategies with a focus on rituximab. A retrospective analysis was conducted on 24 patients diagnosed with IgG4-RD at a German tertiary center (2010-2020) using the 2020 revised comprehensive diagnostic criteria. Patients were recruited from Rheumatology and Nephrology. Data included organ involvement, laboratory results, histology, treatments, relapses, therapy-related damage, and comorbidities. The cohort included 12 males and 12 females, median age at diagnosis 53 (95%CI 37.0; 61.0) years. Males had more affected organs (2.4 vs. 1.6; p = 0.036) and higher IgG4 levels (>5× upper limit: 33.3% vs. 16.7%; p = 0.036). Immunosuppressive therapy was initiated in 87.5% of patients, with glucocorticoids (GC) universally included. Rituximab was administered to 71.4%, mainly as a 4 x 375 mg/m² regimen (77.3%), with a median follow-up post first rituximab of 51.0 months (95%CI 27.0; 63.0). Adverse events were not more frequent with rituximab compared to other regimens. At last visit, 47.6% were off immunosuppressives and 38.1% remained on GC. Active organ involvement declined, though 16.7% showed organ damage progression. Relapses were frequent (81.0%), but less common upon rituximab initiation (26.7%). This representative IgG4-RD cohort demonstrates that long-term treatment with rituximab as maintenance therapy is generally effective and safe regardless of therapeutic regimen. Despite this glucocorticoid use remains high, highlighting the need for guidelines to standardize the use of glucocorticoids and DMARDs like rituximab in both induction and maintenance therapy.
18F-Fibroblast activation protein inhibitor ([18F]FAPI) positron emission tomography (PET)/CT is an emerging tool for detecting IgG4-related disease (IgG4-RD). However, standardised quantitative analysis and image scoring present ongoing challenges in patients with IgG4-RD. To establish organ-specific reference thresholds for IgG4-RD involvement on [18F]FAPI PET/CT images, and to develop a novel, clinically applicable scoring system to monitor disease activity in patients with IgG4-RD. This retrospective study recruited 85 patients with IgG4-RD and 10 healthy individuals, all of whom underwent [18F]FAPI PET/CT. Organ-specific uptake thresholds were defined as [18F]FAPI uptake greater than the maximal standardised uptake value +3 SD in the corresponding anatomical regions of healthy individuals. Moreover, we developed a novel method, [18F]FAPI PET/CT Activity Score of IgG4-RD (FPAS-IgG4), for scoring disease activity using a logistic regression model with receiver operating characteristics curve analysis. Among 85 patients with IgG4-RD, 64 lesions suspected of IgG4-RD involvement were biopsied and 58 (90.6%) of these lesions were positive for IgG4. [18F]FAPI PET/CT achieved a sensitivity, specificity and accuracy of 86.2%, 83.3% and 85.9%, respectively, for detecting IgG4-RD based on organ-specific uptake thresholds. The active disease group had a higher FPAS-IgG4 than the inactive disease group (5.2±3.0 vs 1.7±1.3, p<0.0001). FPAS-IgG4 >2 showed a sensitivity of 93.2% and a specificity of 73.1% in distinguishing between active and inactive disease. Multivariable logistic regression analysis demonstrated that FPAS-IgG4 was strongly associated with active IgG4-RD (p=0.001). [18F]FAPI PET/CT could be a valuable tool for monitoring the activity of IgG4-RD, aiding in disease stratification.
B cells drive B-cell malignancies and diverse autoimmune diseases through autoantibody production, antigen presentation, and cytokine dysregulation, and persistence of pathogenic B-cell or plasma-cell compartments. Across autoimmune diseases, the dominant pathogenic compartment varies, ranging from precursor-dependent states to tissue-compartment inflammation and long-lived plasma cell-weighted autoantibody production. This review synthesizes the biological rationale for B-cell-axis targeting across oncology and autoimmunity and proposes a pathobiological framework spanning precursor-dependent, compartment-dominant, and long-lived plasma cell-weighted archetypes. We outline the mechanisms, lineage coverage, depletion depth, durability, and tolerability of CD20-, CD19-, CD38-, and BCMA-directed antibodies, bispecific T-cell engagers, and chimeric antigen receptor (CAR) T cells, and map these modalities onto biologically defined autoimmune archetypes. We also compare dosing paradigms, pharmacokinetics/pharmacodynamics (PK/PD), exposure-response relationships, and safety trade-offs between oncology-style induction and chronic maintenance in autoimmunity, emphasizing biomarker-guided retreatment, infection-risk mitigation, and regimen adaptation for non-malignant disease. Clinically, therapies developed for lymphoma and myeloma have transformed B-cell cancer care and are now being repurposed for rheumatoid arthritis, multiple sclerosis, neuromyelitis optica spectrum disorder, IgG4-related disease, myasthenia gravis, systemic lupus erythematosus, and related disorders. We summarize pivotal translational inflection points, from rituximab extension beyond lymphoma to approvals of ocrelizumab, ofatumumab, ublituximab, and inebilizumab in neuroimmunology. We further review plasma cell-directed and T-cell-engaging strategies for deep immune resets in refractory disease, while clarifying implications for trial design, long-term safety, and implementation. Finally, we introduce a model-informed roadmap integrating population PK/PD, exposure-response, and quantitative systems pharmacology to optimize indication selection, patient enrichment, and dose/regimen design-supporting confident extrapolation rather than empiricism.