OBJECTIVES:Cardiac involvement in idiopathic inflammatory myopathies (IIM) is rare but potentially severe. Anti-mitochondrial M2 antibody (AMA-M2) has been implicated in cardiac involvement, but the association remains underexplored. This study aims to evaluate the clinical, pathological and prognostic features of AMA-M2 IIM. METHODS:This historic prospective cohort included IIM patients hospitalized at Peking Union Medical College Hospital between 2008 and 2020. Outcomes were prospectively collected through the Prospective Registry Of MyositIS (PROMIS) registry. Cox regression models were employed to identify risk factors of cardiac involvement and mortality. RESULTS:Among 987 IIM patients, 55 (6%) were AMA-M2 positive. These patients exhibited higher rates of PM (56% vs 23.5%, P < 0.001), and elevated baseline gamma-glutamyl transferase (78.0 vs 35.0, P < 0.001) and alkaline phosphatase (85.0 vs 64.0, P < 0.001). Throughout disease courses, AMA-M2-positive patients had significantly higher rates of cardiac involvement (60% vs 12.9%, P < 0.001), including arrhythmias (56%), heart failure (44%) and pulmonary hypertension (31%). Some of the muscle biopsies showed features consistent with immune-mediated necrotizing myopathy, cardiac biopsies demonstrating structural degeneration with minimal inflammation and liver biopsies confirming early-stage primary biliary cholangitis (PBC). Multivariate Cox analysis identified AMA-M2 positivity as an independent risk factor for cardiac involvement (hazard ratio 3.156, P < 0.001). Despite frequent cardiac manifestations, long-term survival did not differ between AMA-M2-positive and -negative patients (mean survival: 103.9 months vs 98.0 months, P = 0.86). CONCLUSION:AMA-M2 positivity defines an IIM subgroup with significant cardiac involvement and an immune-mediated inflammatory muscle histology, but not necessarily worse long-term survival. These findings highlight the need for early recognition and tailored management of AMA-M2 IIM.

Background Systemic lupus erythematosus (SLE) is a clinically heterogeneous autoimmune disease with multifactorial pathogenesis. Although polygenic risk scores (PRSs) have been developed to enable early prediction, their accuracy remains limited. To address this limitation, we constructed a meta-polygenic risk score (metaPRS) integrating genetic markers associated with multiple SLE-associated traits. Methods 14 SLE-associated traits were identified through literature review, and trait-level PRSs were constructed based on the largest available East Asian genome-wide association studies datasets using SNP genotyping data of 2388 patients and 1132 controls from our own cohort. Significant trait-PRSs were integrated into a metaPRS using elastic net regression, which was further evaluated for disease prediction, risk stratification and clinical manifestation correlation, with internal validation via bootstrapping. Results Five trait-level PRSs were significantly associated with SLE in East Asian population: SLE development, smoking initiation, serum selenium levels, endometriosis and Graves' disease. The metaPRS merged from these five traits exhibited robust predictive performance (OR=2.12, area under the receiver operating characteristic curve (AUC)=0.69) and risk stratification (high risk vs low risk: OR=4.93, p<2e-16). Compared with the conventional PRS based solely on SLE risk genetic variants, the metaPRS achieved a 4.43% increase in OR and exhibited a statistically significant improvement in diagnostic discrimination, as measured by the AUC (p=0.046). Furthermore, metaPRS was associated with positivity for multiple autoantibodies and demonstrated better performance in childhood-onset SLE compared with adult-onset cases. Decomposition of the metaPRS revealed that both PRSSLE and PRSriskfactor contributed to SLE susceptibility, while clinical manifestations were exclusively driven by PRSSLE. Conclusions We developed the first metaPRS of SLE by integrating genetic characteristics from multiple SLE-related risk factors, offering a new perspective for risk stratification and early diagnosis.

Background Rhino-orbito-cerebral mucormycosis, caused by pathogens such as Rhizopus delemar, is a life-threatening opportunistic infection primarily affecting immunosuppressed individuals. Anti-melanoma differentiation-associated protein 5-positive dermatomyositis (MDA5(+) DM) is a distinct subtype of DM associated with interstitial lung disease (ILD) and high mortality. Fungal co-infections in anti-MDA5(+) DM, particularly mucormycosis, are rarely reported. Case presentation We report a case of rhino-orbito-cerebral mucormycosis caused by Rhizopus delemar in a patient with anti-MDA5(+) DM. The patient was receiving high-dose glucocorticoids and immunosuppressive therapy for rapidly progressive ILD, and later she developed progressive neurological symptoms, palatal ulceration with black eschar, and periorbital swelling. Metagenomic next-generation sequencing (mNGS) of blood subsequently identified Rhizopus delemar, and the diagnosis was further supported by cerebrospinal fluid mNGS. Antifungal therapy was adjusted promptly after pathogen identification. Despite aggressive treatment, the infection progressed rapidly with central nervous system involvement. Conclusions This case highlights the heightened susceptibility to invasive mucormycosis in patients with anti-MDA5(+) DM, likely exacerbated by immunosuppressive therapy. Early diagnosis using mNGS and prompt initiation of targeted antifungal therapy are critical in managing such co-infections. Clinicians should maintain a high index of suspicion for invasive fungal infections in immunosuppressed anti-MDA5(+) DM patients presenting with non-specific neurological or sinus symptoms.

OBJECTIVES: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. METHODS:This study analysed 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: (i) intensifying glucocorticoids (GC) only; (ii) intensifying immunosuppressants (IM) only; (iii) intensifying both GC and IM. The primary outcome was recurrent relapses. A decision tree model was developed to predict recurrent relapses. RESULTS: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 fewer relapses compared with those who intensified IM alone, while those who only intensified GC had a tendency to experience fewer 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. CONCLUSION: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.

BACKGROUND: Children with juvenile dermatomyositis (JDM) experience significant mental health burdens, including anxiety and depression. Inflammatory activation can alter tryptophan metabolism, particularly through IDO-driven kynurenine pathway induction, which has been implicated in diseases such as mood disorders and SLE. We therefore investigated skewed tryptophan metabolism and its association with disease activity and mental health symptoms in JDM. METHODS: Serum samples from JDM, juvenile idiopathic arthritis (JIA), and healthy controls (HC) were analysed for tryptophan metabolites by ELISA. Interferon-regulated genes were measured using qPCR. Ability of serum to induce indoleamine 2,3-dioxygenase (IDO) was assessed by flow cytometry in presence or absence of interferon antagonists. Cluster analysis was used to identify subgroups. RESULTS: In JDM patients, serum tryptophan and serotonin levels were lower, while kynurenine/tryptophan ratios, kynurenic acid, and quinolinic acid levels were higher compared to healthy controls. Metabolites from the kynurenine pathway were correlated with muscle inflammation (CRP, ESR, aldolase and CK), mental health outcomes (PSC-17 and PHQ-9 scores) and disease progression (PGA scores). Further, IDO1 mRNA levels correlated inversely with serotonin levels and positively with type I interferon signature marker MX2 in PBMCs. Serum from JDM patients induced IDO protein expression in monocytes through an IFN-dependent mechanism, which was significantly inhibited by both baricitinib and anifrolumab. Four clinical subgroups were identified. CONCLUSIONS: Our study reveals a novel role of IFN in JDM pathogenesis, specifically in the upregulation of IDO and subsequent skewing of tryptophan metabolism towards kynurenine pathway, which may correspond to poor mental well-being and disease progression. Targeting this pathway may offer therapeutic potential for both disease activity and psychological outcomes for JDM children.

Background Systemic lupus erythematosus (SLE) predominantly affects women of childbearing age and is often associated with adverse pregnancy outcomes (APOs). Antiphospholipid antibodies (aPLs) are known risk factors for APOs in the general population, and the prevalence of aPLs is higher in patients with SLE than healthy women. Objective This study aimed to investigate the impacts of aPLs and different aPLs profiles on pregnancy outcomes in patients with SLE. Study design This study analysed data from a single-centre SLE cohort in China. aPLs profiles, including anticardiolipin antibodies (aCL) IgG/IgM, anti-β2 glycoprotein I (anti-β2GPI) antibodies IgG/IgM and lupus anticoagulant (LA), were measured. APOs were defined as prefetal death, fetal death, pre-eclampsia with severe features occurring before 34 weeks of gestation and placental insufficiency with severe features occurring before 34 weeks of gestation. Results The study comprised 441 singleton pregnancies occurring in 410 patients with SLE and 78 (17.9%) were positive for aPLs. Seventy-one (16.1%) patients developed APOs and 391 (88.7%) patients succeeded in giving a live birth. Patients with positive aPLs experienced APOs more frequently (29.5% vs 13.2%), with an OR of 2.56 (95% CI 1.38 to 4.65, p=0.002). aPLs were also associated with higher risks of fetal death (OR 3.87, 95% CI 1.17 to 12.19, p=0.021) and failure of live birth (OR 2.54, 95% CI 1.22 to 5.15, p=0.011). Analysis on the aPLs profiles revealed that aCL IgG (OR 3.02, 95% CI 1.44 to 6.15, p=0.003), anti-β2GPI IgG antibodies (OR 2.60, 95% CI 1.13 to 5.72, p=0.020) and LA (OR 2.85, 95% CI 1.44 to 5.56, p=0.002) increased the risks of APOs significantly, but aCL IgM and anti-β2GPI IgM antibodies did not. Further analysis demonstrated that LA plus IgG isotypes of aCL and/or anti-β2GPI antibodies was the highest-risk profile, increasing the incidences of APOs with an OR of 3.98 (95% CI 1.66 to 9.35, p=0.002), while the other combinations of aPLs positivity did not (OR 1.82, 95% CI 0.81 to 3.81, p=0.128). Conclusion This study demonstrated the adverse effects of aPLs in patients with SLE regarding the pregnancy outcomes, and different aPLs profiles displayed distinct impacts. This highlights the importance of risk stratification when managing pregnancy among patients with SLE, putting more focus on those with positive aPLs, especially those positive for LA plus IgG isotypes of aCL and/or anti-β2GPI antibodies.

BACKGROUND AND AIM:Ursodeoxycholic acid (UDCA) is first-line therapy for primary biliary cholangitis (PBC), evidence for dose reduction after biochemical remission remains limited. This study aimed to evaluate the feasibility and safety of UDCA reduction in PBC. METHODS:In this open-label randomized controlled clinical trial, PBC patients who reached complete biochemical response (Paris-II criteria) after ≥ 6 months of standard 13-15 mg/kg/day UDCA therapy were prospectively enrolled. Eligible patients were assigned in a 1:1:1 ratio to receive either (1) continued 13-15 mg/kg/day, (2) 10 mg/kg/day, or (3) 5-mg/kg/day UDCA. The primary endpoint was biochemical relapse rate within 12 months. Secondary endpoints included changes in liver biochemistry, changes in patient-reported symptoms, and changes in GLOBE and UK-PBC scores, as well as adverse events. RESULTS:From January 2020 to March 2024, 96 patients who complied with the protocol after randomization were analyzed. Within the 12-month follow-up period, the relapse rates in the three groups were 0%, 2.9%, and 19.4%, respectively (overall p = 0.008). Secondary outcomes showed no significant intergroup differences. In patients with a disease relapse, prompt retreatment with a standard dose of UDCA could help liver function recover. No severe adverse events were observed. CONCLUSIONS:The relapse rate in the 5-mg/kg/day group was significantly higher than that in the standard-dose group, necessitating close clinical monitoring, and no significant difference in relapse was observed between the 10 mg/kg/day and standard-dose group, suggesting it may be a potential dose-reduction strategy, though further studies are needed for confirmation.

Background:Patients with rheumatic diseases are at high risk for latent tuberculosis infection (LTBI) reactivation. We aimed to evaluate whether a modified 3-month regimen (3HP-PUMCH) was non-inferior to the standard 9-month isoniazid regimen (9H) for tuberculosis preventive treatment in this vulnerable population. Methods:We conducted a multicenter, open-label, randomized, non-inferiority trial at nine tertiary general hospitals in China. Eligible participants were adults (18-70 years) with high-risk rheumatic diseases and LTBI undergoing immunosuppressive therapy. Patients were randomized (1:1) to receive either the 3HP-PUMCH regimen (twice-weekly rifapentine 450 mg plus daily isoniazid 300 mg) or the 9H regimen (daily isoniazid 300 mg). The primary endpoint was the occurrence of tuberculosis, with a non-inferiority margin of 1.4 percentage points. Analysis used the modified intention-to-treat population. The trial was registered with Chinese Clinical Trial Registry ChiCTR1800018242. Findings:Between 19 September 2018 and 18 August 2021, 536 patients with rheumatic diseases were enrolled. The cumulative rate of tuberculosis was 0.00% (0 of 249, 95% CI 0.00-1.47) in the 3HP-PUMCH group, compared with 1.15% (3 of 260, 95% CI 0.24-3.34) in the 9H group, with a rate difference of -1.15 percentage points (95% CI -2.4 to 0.14). Drug discontinuation rates due to serious adverse events or tuberculosis occurrence were 2.8% (7 of 249) in the 3HP-PUMCH group and 1.9% (5 of 260) in the 9H group (p = 0.509). Adverse drug reactions occurred in 24 (9.6%) of 249 patients versus 39 (15.0%) of 260 (p = 0.066), with hepatotoxicity in 11 (4.4%) of 249 versus 27 (10.4%) of 260 (p = 0.010). 223 (89.6%) of 249 patients completed treatment in the 3HP-PUMCH and 237 (91.2%) of 260 in the 9H group (p = 0.54). Interpretation:The short-course 3HP-PUMCH regimen was non-inferior to the 9H regimen in preventing tuberculosis and demonstrated a favorable safety profile, with high treatment completion in LTBI patients with rheumatic diseases. This regimen might be more suitable for patients with underlying diseases and those on concomitant medications. Funding:National Natural Science Foundation of China.

Background: Patients with systemic autoimmune diseases (sAIDs) are susceptible to active tuberculosis (ATB), especially in high-burden countries and regions. However, a comprehensive overview of the ATB burden across the full spectrum of sAIDs remains lacking. Methods: In this nationwide retrospective cohort study, we linked individual-level data from the Chinese Rheumatism Data Center (CRDC), the Infectious Disease Reporting System (IDRS), and the Tuberculosis Information Management System (TBIMS). Patients of all ages registered in CRDC between 2016 and 2023, with a confirmed diagnosis of 1 of 10 sAIDs, including rheumatoid arthritis, systemic lupus erythematosus, spondyloarthritis, primary Sjögren's disease, idiopathic inflammatory myopathies, undifferentiated connective tissue disease, systemic sclerosis, Behçet's disease (BD), Takayasu arteritis (TAK), and ANCA-associated vasculitis (AAV), were included. We estimated incidence rates, point prevalence, cumulative incidence, and age- and gender-adjusted standardized incidence ratios (SIRs) for ATB, and examined associations between SIRs and region-level socioeconomic indicators using Cox proportional hazards models. Findings: Among 255,103 eligible patients, 2,775 incident ATB cases were confirmed across all 10 sAIDs. The overall ATB incidence rate in 2023 was 157.79 per 100,000 person-years. Point prevalence of ATB among patients with sAIDs rose from 393.83 per 100,000 people in 2016 to 904.65 per 100,000 people in 2023. Cumulative incidence exceeded 1% within 10 years of sAID diagnosis. Patients with TAK (7.60, 95% CI 4.92-11.22), AAV (6.96, 4.90-9.59), BD (6.30, 4.25-9.00) carried the highest relative risks of ATB, and male and female patients exhibited comparable ATB susceptibility compared with general population. At the area level, higher urbanization was associated with increased ATB risk in patients with sAIDs, whereas higher educational attainment was protective. Interpretations: Patients with sAIDs constitute a distinctly high-risk population for ATB, with a burden substantially exceeding that of the general population and marked heterogeneity across diseases and socioeconomic context. These findings support the systematic integration of targeted TB screening and preventive strategies into routine rheumatology care, particularly in TB-endemic settings.

Abstract Neuropsychiatric systemic lupus erythematosus (NPSLE) is a potentially severe complication of systemic lupus erythematosus (SLE), yet its pathogenesis remains largely elusive. By jointly probing the immune dynamics of subjects’ cerebrospinal fluid (CSF) and peripheral blood, we showed that both innate and adaptive immune responses jointly contribute to the pathogenesis of NPSLE. In particular, we found the remarkable enrichment of BAM-CCL3, a subtype of border-associated macrophages with strong recruitment capacity, implicating its potential role in central nervous system (CNS) inflammation. We also observed pronounced activation of memory B cells and CD4 + regulatory T cells in NPSLE CSF, along with the preferential blood-to-CSF migration and subsequent within-CSF clonal expansion of CD8 + effector memory T cells in NPSLE patients, suggesting a persistent CNS-localized adaptive immune dysregulation. Finally, we developed the single-cell CNS disease CSF–Blood Atlas (scCDCB), a comprehensive collection for CSF and peripheral blood of multiple CNS diseases, which is publicly available at ( https://sccdcb.gao-lab.org ) to serve as a reference for future research on CNS diseases.

Autoimmune diseases (AIDs) affect 5-10% of the global population, yet effective diagnosis and treatment remain challenging due to their complexity and heterogeneity. Autoantibodies serve as crucial biomarkers for disease classification and prognosis, making comprehensive autoantigen profiling essential for advancing our understanding of autoimmune pathogenesis. Phage ImmunoPrecipitation sequencing (PhIP-Seq) has emerged as a transformative high-throughput technology that combines phage display with next-generation sequencing to comprehensively profile antibody-antigen interactions. This review systematically examines PhIP-Seq's methodology, comparing it with conventional approaches including protein microarrays, immunoprecipitation-mass spectrometry, and traditional serological assays. We detail the experimental workflow encompassing library design, immunoprecipitation protocols, and computational analysis pipelines, while highlighting recent algorithmic advances including generalized Poisson models, Z-score methods, and machine learning approaches for hit determination. PhIP-Seq's applications in autoimmune diseases span autoantibody discovery; clinical model development for disease stratification; high-resolution epitope mapping enabling resolution at tens of amino acids; and longitudinal studies tracking disease progression. The technology's integration with other omics platforms and investigation of viral-autoimmune disease associations further demonstrates its versatility. While PhIP-Seq excels in linear epitope identification and high-throughput screening, limitations include inability to detect conformational epitopes, challenges with low-abundance antigens, and lack of post-translational modifications. This review discusses ongoing advancements in library design, methodological improvements, and data integration to address these issues and unlock PhIP-Seq's full potential in autoimmune research.

Patients with autoimmune diseases (AIDs) are at an increased risk of developing cancer; however, the immunometabolic programs that shape this comorbidity remain incompletely defined. We integrated targeted serum metabolomics with multiplex profiling of cytokines, chemokines, and immune checkpoint proteins in patients with five major AIDs-idiopathic inflammatory myopathies, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, and systemic sclerosis-with or without cancer. A total of 49 patients with AID and comorbid cancer (AID-CA), 47 patients with AID alone, and 15 healthy controls were enrolled. Compared with AID alone, AID-CA was associated with coordinated remodeling of amino acid and nucleotide metabolism, dominated by the alanine, aspartate, and glutamate pathways. Decreased L-glutamine and increased L-glutamic acid levels were consistently observed and remained significant after the false discovery rate correction. Immune profiling revealed modest but consistent differences, including higher levels of CXCL9 and Galectin-9 and lower levels of selected checkpoint molecules in AID-CA. The effects of major metabolites and immune mediators were directionally stable after adjusting for age, sex, treatment exposure, and autoimmune disease subtype. Integrative analyses revealed stronger associations between metabolites and immune mediators in AID-CA, centered on CXCL9 and Galectin-9, and linked to amino acid and pyrimidine metabolism. In ex vivo assays, perturbation of glutamine or arginine availability preferentially modulated the release of CXCL9 and Galectin-9 from peripheral blood mononuclear cells of patients with AID-CA. Together, these findings define an internally consistent immunometabolic pattern associated with cancer comorbidities in patients with AIDs. They nominated amino acid metabolism and CXCL9/Galectin-9-centered immune signaling as candidates for mechanistic investigation and biomarker development, while underscoring the need for validation in larger, longitudinal, and disease-specific cohorts.

OBJECTIVE:Although Takayasu arteritis (TAK) is not a prototypical autoantibody-mediated disease, accumulating evidence suggests that B cells are involved. This study aimed to investigate the pathway of B cell activation and its contributions to TAK pathogenesis. METHODS:Histologic analysis of paravascular lymph nodes and affected arteries was conducted to investigate B cell activation pathways in TAK. Bulk RNA-seq, single-cell RNA-seq (scRNA-seq), flow cytometry, and in vitro experiments were performed to characterize the composition, transcriptomic features, and functional profiles of B cells. The numeric and phenotypic alterations induced by tumor necrosis factor (TNF) and JAK inhibition were assessed both in vitro and in four patients with TAK. RESULTS:Histologic (n = 5), flow cytometric (n = 125), and bulk RNA-seq (n = 12) analyses indicated the presence of extrafollicular response and up-regulated age-associated B cell (ABC) production in TAK, along with cross-data set transcriptomic differences between B cells from patients with TAK and systemic lupus erythematosus (SLE). Cross-data set scRNA-seq analysis and in vitro experiments (n = 5) demonstrated that ABC differentiation in TAK was largely uncoupled from antibody-secreting cell (ASC) generation, unlike that in SLE. Functional experiments showed that ABCs exhibited proinflammatory properties, including proinflammatory cytokine production, and that CD11c+ B cells, which contain the ABC compartment, promoted Th17 cell differentiation (n = 6). In vitro, tofacitinib was more effective than adalimumab at reducing ABC proportions and attenuating their proinflammatory phenotype (n = 15), consistent with trends in the exploratory clinical follow-up (n = 4). CONCLUSION:ABCs promote inflammation through proinflammatory functions independent of ASC differentiation in TAK. JAK inhibition exerts distinct suppressive effects on ABCs compared with anti-TNF therapy.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron degeneration, while primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease with prominent immune dysregulation. Although immune-related alterations have been implicated in ALS and autoimmune diseases, the clinical coexistence of ALS and pSS remains poorly characterized. We aimed to describe the clinical features of patients with concomitant ALS and pSS and to explore peripheral blood transcriptomic patterns in independent ALS and pSS cohorts. We retrospectively identified patients with both ALS and pSS through systematic electronic health record screening and multidisciplinary clinical review. Clinical characteristics, disease chronology, treatment exposure, and outcomes were summarized. In parallel, we performed an exploratory transcriptomic analysis using publicly available peripheral blood datasets from independent ALS and pSS cohorts. Differentially expressed genes and overlapping inflammatory signatures were evaluated, with additional sensitivity assessment performed using an independent ALS cohort. Seven patients fulfilling diagnostic criteria for both ALS and pSS were identified. The temporal relationship between the two diseases was heterogeneous, with variable disease onset sequences and clinical trajectories. Immunomodulatory treatments were associated with transient improvement in systemic autoimmune manifestations in some patients, but no conclusions regarding modification of ALS progression could be established. Transcriptomic analyses identified overlapping upregulated genes between ALS and pSS cohorts, enriched in interferon- and NF-κB-related inflammatory signatures. However, these signatures represent commonly observed inflammatory responses across multiple disease contexts and should not be interpreted as evidence of ALS–pSS-specific biological convergence. Sensitivity assessment using an independent ALS cohort demonstrated partial reproducibility of selected non-specific inflammatory signatures across datasets. Taken together, these findings present two independent, exploratory observations: a rare clinical co-occurrence and a non-specific systemic inflammatory signature identified in unrelated public datasets, both requiring sensitivity assessment and serving as hypothesis-generating baselines for future studies.

OBJECTIVES:This study aimed to explore the risk factors for progression in immunoglobulin G4-related disease (IgG4-RD) under watchful waiting and the temporal distribution of progression events to inform clinical decision-making. METHODS:A total of 40 IgG4-RD patients managed with the watchful waiting strategy were identified and included. Patients were categorised into 'without internal organ involvement' (WOI, n=26) and 'with internal organ involvement' (WI, n=14) groups. Baseline characteristics and progression rates were compared. Risk factors for progression were further identified using logistic and Cox regression analyses in the WOI group. The distribution of time to disease progression was summarised. RESULTS:Progression occurred in 12/40 patients (5 in WOI vs. 7 in WI). Kaplan-Meier analysis showed a significantly higher stability probability in the WOI group (p=0.048). Paranasal sinus involvement, high response index (RI), elevated eosinophil percentage (Eos%), and high IgE levels were significant risk factors for progression in WOI group. Notably, all progression events occurred within the first year of follow-up, with the estimated hazard function peaking at 6 to 8 months and declining thereafter. CONCLUSIONS:IgG4-RD patients with internal organ involvement exhibit a higher rate of disease progression under watchful waiting. Paranasal sinus involvement, high RI, high Eos%, and high IgE levels were identified as potential risk factors for disease progression. Intensive surveillance is especially warranted during the early phase.