The retrospective, multicenter cohort study was conducted across 5 centers in Jiangxi Province, China, from April 2023 to December 2024. Inclusion criteria were: (1) age between 18 and 65 years; (2) biopsy-proven primary IgAN; (3) patients treated with 160 mg telitacicept weekly; (4) proteinuria excretion ≥ 0.75 g/day after receiving stable and optimized renin-angiotensin-aldosterone system inhibitor therapy for ≥ 1 months; (5) estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73m² (calculated via the Chronic Kidney Disease Epidemiology Collaboration creatinine equation (20)). Exclusion criteria were: (1) secondary IgAN, including but not limited to Henoch-Schönlein purpura, systemic lupus erythematosus, viral hepatitis, rheumatoid arthritis and psoriasis; (2) lack of follow-up data. This study received approval from the Ethics Committee of the Second Affiliated Hospital of Nanchang University (Approval No. IIT-O-2025-270).

Participants were categorized into two groups based on their treatment regimens: the telitacicept group and the telitacicept + glucocorticoid/mycophenolate mofetil (GM) group. All patients received subcutaneous telitacicept at 160 mg weekly for 6 months, followed by a reduced frequency of 160 mg every other week for an additional 3 months. Hepatitis B carriers concurrently received ongoing antiviral prophylaxis. Patients in the telitacicept + GM group additionally received low-dose prednisone (0.4-0.6 mg/kg/day for 1 month, tapered by 20% every 2 weeks) or MMF (1.0-1.5 g/day during follow-up). Prophylaxis against Pneumocystis jirovecii pneumonia, as well as gastroprotection and bone protection, were also provided concomitantly in the telitacicept + GM group.

The primary outcomes were the changes in 24-hour proteinuria and eGFR. The secondary outcomes included remission rate, urinary red blood cells (RBC) count, serum albumin, lymphocyte subset cells and immunoglobulin levels. Complete remission (CR) was defined as 24-hour proteinuria ≤ 0.3 g/d, serum albumin (Alb) > 35 g/L, and stable renal function, characterized by a decrease in eGFR of ≤ 30%. Partial remission (PR) was defined as a reduction in proteinuria exceeding 50% from baseline and stable renal function, while not fulfilling the criteria for CR. The overall remission (OR) rate was calculated as the sum of CR and PR.

Statistical analyses were conducted using SPSS version 25.0 (IBM, Armonk, NY, USA), GraphPad Prism version 10.6, and R version 4.5.1 software. Data are expressed as mean ± standard deviation for normally distributed continuous variables, while non-normally distributed continuous variables are summarized as median (interquartile range). Data from patients lost to follow-up were censored at their last visit, and multiple imputation was applied for covariates with missing values. Comparison between the two groups for these variables were performed using independent-samples t-test and the Mann-Whitney U-test, respectively. For the longitudinal assessment of proteinuria, eGFR, urinary RBC count, and serum albumin during follow-up periods (at 1, 2, 3, 4, 5, 6, and 9 months), these variables were log-transformed and analyzed using analysis of covariance with baseline adjustment to control for regression to the mean. A linear mixed effects model was used to calculate the eGFR slope for both groups over the entire intervention period. Categorical variables are presented as numbers (percentages) and were compared using the chi-squared test or Fisher’s exact test, as appropriate. Kaplan-Meier curves were constructed to estimate the cumulative incidence of CR and OR in each group. Subsequently, multivariable Cox proportional hazards models were employed with an entry criterion of P < 0.1 in univariate analysis or based on clinical relevance. Furthermore, subgroup analyses were conducted, and the results are presented in a forest plot. P values less than 0.05 were considered statistically significant.

A total of 256 patients with IgAN were included: 125 received telitacicept and 131 received telitacicept + GM (Figure 1). The mean age of the patients was 39.5 ± 11.6 years, and 100 (39.1%) of the patients were male. Baseline characteristics were well matched between the two groups, with no statistically significant differences observed in age, sex, 24-hour proteinuria, urinary RBC count, eGFR, serum albumin, and pathological features (Table 1).

The level of 24-hour proteinuria at 9 months decreased from 1.64 g/day (IQR 1.08-2.86) to 0.22 g/day (IQR 0.16-0.31) in the telitacicept + GM group, and from 1.51 g/day (IQR 0.96-2.04) to 0.28 g/day (IQR 0.23–0.92) in the telitacicept group (Figure 2a). A significant difference in proteinuria between the groups emerged after 2 months of follow-up (Figure 2a). At 9 months, the change in proteinuria in the telitacicept + GM group was reduced to -1.32 g/day (IQR -0.85 to -2.12), a greater reduction than in the telitacicept group -0.94 g/day [(IQR -0.64 to -1.38), P < 0.001, Figure 2b]. In the telitacicept + GM group, a slight improvement in eGFR was observed at 9 months compared to baseline [67.6 ml/min/1.73 m² (IQR 43.9-89.4) versus 66.9 ml/min/1.73 m² (IQR 41.5-88.9), Figure 2c]. Conversely, the telitacicept group exhibited a decline in eGFR over the 9-month period [54.7 ml/min/1.73 m² (IQR 38.6-81.5) versus 57.2 ml/min/1.73 m² (IQR 38.3-80.8), Figure 2c]. This finding is supported by the eGFR slope of 2.74 ml/min/1.73 m²/year in the telitacicept + GM group, compared to -0.56 ml/min/1.73 m²/year in the telitacicept group (P = 0.014, Figure 2d).

Although the two groups showed comparable reductions in urinary RBC count over 9 months (Figure 2e), the magnitude of reduction was significantly greater in the telitacicept + GM group at the study endpoint, with a median change of -35.5/µL (IQR -88.0 to -6.0) compared to -9.0/µL (IQR -38.0 to 0.0) in the telitacicept group (P = 0.009; Figure 2f). Within 9 months of treatment, the changes in serum albumin levels were similar between the two groups (Figures 2g, h).

At 9 months, the CR and OR rates were 54.2% and 78.6% in the telitacicept + GM group, compared to 40.8% and 70.4% in the telitacicept group, respectively. Kaplan-Meier analysis confirmed that the telitacicept + GM group had significantly higher CR (log-rank test, χ² = 7.829, P = 0.005) and OR (log-rank test, χ² = 5.984, P = 0.014) rates over time (Figures 3A, B). We employed multivariable Cox proportional hazards models to evaluate the impact of treatment on 9-month CR and OR, with adjustments for various covariates across models (Table 2). In the crude model, the telitacicept + GM group was associated with a significantly increased likelihood of achieving both CR [HR 1.58 (95% CI 1.10-2.26), P = 0.013] and OR [HR 1.36 (95% CI 1.02-1.81), P = 0.035] rates at the 9-month follow-up compared to the telitacicept group. After sequential adjustment for age, sex, BMI, hypertension, proteinuria, urinary RBC count, eGFR, and Oxford classification scores, the fully adjusted model confirmed that the telitacicept + GM regimen was independently associated with higher CR [adjusted HR 2.18 (95% CI 1.46-3.22), P < 0.001] and OR [adjusted HR 1.46 (95% CI 1.08-2.00), P = 0.013] rates at the 9-month follow-up. A sensitivity analysis based on the complete-case dataset (excluding cases with missing pathology data) is presented in the Supplementary Table S1.

Among the 256 participants, 136 were monitored for lymphocyte subsets and immunoglobulin levels at the 3-months point, with 69 in the telitacicept + GM group and 66 in the telitacicept group. At 3 months, there was a notable decrease in IgA, IgG, and IgM levels compared to the baseline (Supplementary Figures S1a–c). The median reduction in CD19+ B cells was 96.0 cells/µL (35.3%) in the telitacicept + GM group and 54.5 cells/µL (19.1%) in the telitacicept group at 3 months, with both reductions being statistically significant from baseline (Supplementary Figure S1d). In contrast, CD4+ T cells decreased significantly only in the telitacicept+GM group at 3 months (Supplementary Figure S1f). Serum complement C3 levels remained stable in both groups (Supplementary Figure S1g).

Subgroup analysis revealed consistent benefits of the telitacicept + GM regimen across all predefined subgroups, with no significant interaction effects detected (all P for interaction ≥ 0.05), indicating that the treatment effects of telitacicept + GM were consistent regardless of baseline characteristics such as age, sex, eGFR, or proteinuria (Figures 4A, B).

The telitacicept + GM group was further stratified into two subgroups: telitacicept + glucocorticoids (n = 46) and telitacicept + MMF (n = 69) (Figure 1), which were well-balanced at baseline (Supplementary Table S2). With the exception of between-group differences in the reduction of hematuria levels at 2–4 months, no significant differences were observed between the two subgroups in terms of proteinuria, eGFR, or serum albumin levels (Supplementary Figure S2). Consistent with these findings, Kaplan-Meier analysis revealed no significant between-subgroup differences in either CR or OR rate (Supplementary Figure S3).

The telitacicept + GM group experienced a greater overall rate of non-serious side effects, such as obesity, osteoporosis, gastritis, and fatigue, compared to the telitacicept group (28.2% versus 11.2%, Supplementary Table S3), but neither treatment group reported any serious adverse events.