Long-term dynamic changes and influencing factors of corneal morphology after multiple intravitreal injections of anti-VEGF drugs.

To observe alterations in corneal morphology caused by repeated intravitreal injections of anti-vascular endothelial growth factor (VEGF). Prospective cohort study. Seventy-seven eyes were treated with intravitreal injection of anti-VEGF from June 2021 to March 2023. There were 25 eyes of neovascular age-related macular degeneration (nAMD), 24 eyes of diabetic macular edema (DME), and 28 eyes of retinal vein occlusion (RVO). Aflibercept was used in 37 eyes and Ranibizumab was used in 40 eyes. 3 + PRN was used. Corneal endothelium and corneal thickness were measured using a corneal endothelial microscope. The data related to central corneal thickness, corneal endothelial cell density (ECD), average cell size, coefficient of variation (CV), proportion of hexagonal cells (Hex%) was collected. A comparison was also made between baseline and the dynamic changes of all indexes 1 year following the last injection. It was observed that in comparison to baseline, ECD and Hex% decreased significantly after the 3rd injection of Aflibercept and Ranibizumab. However, ECD did not decrease further and remained at the same level as after the last injection. Hex% and average cell size increased to a certain extent in comparison to the last injection. All the changes were found to be statistically significant (P < .01). After 3 injections, ECD in DME group was markedly lower than that in nAMD and RVO group, but the CV in DME group was higher than that in nAMD as well as RVO groups, and all the differences were statistically significant (P < .05). Following intravitreal anti-VEGF therapy, DME is more likely than other disorders to result in a decrease in ECD. Repeated intravitreal injections of anti-VEGF drugs can reduce the Hex% and ECD to a certain extent. After the last injection, Hex% can progressively recover, and ECD can remain stable without further declining. After injections, ECD in DME group was found to be significantly lower than that in nAMD and RVO groups, but CV in DME group was significantly higher in comparison to the other 2 groups. In patients with macular edema, repeated intravitreal injections of anti-VEGF may have certain effects on corneal morphology. Patients with diabetes mellitus in particular should pay special attention to corneal safety following repeated intravitreal injections if they have significantly reduced ECD at baseline.

Anti-synthetase syndrome is associated with a higher risk of hospitalization among patients with idiopathic inflammatory myopathy and COVID-19.

Background: Data with fine granularity about COVID-19-related outcomes and risk factors were still limited in the idiopathic inflammatory myopathies (IIMs) population. This study aimed to investigate clinical factors associated with hospitalized and severe COVID-19 in patients with IIMs, particularly those gauged by myositis-specific antibodies. Methods: This retrospective cohort study was conducted in the Renji IIM cohort in Shanghai, China, under an upsurge of SARS-CoV-2 omicron variant infections from December 2022 to January 2023. Clinical data were collected and analyzed by multivariable logistic regression to determine risk factors. High-dimensional flow cytometry analysis was performed to outline the immunological features. Results: Among 463 infected patients in the eligible cohort (n=613), 65 (14.0%) were hospitalized, 19 (4.1%) suffered severe COVID-19, and 10 (2.2%) died. Older age (OR=1.59/decade, 95% CI 1.18 to 2.16, p=0.003), requiring family oxygen supplement (2.62, 1.11 to 6.19, 0.028), patients with anti-synthetase syndrome (ASyS) (2.88, 1.12 to 7.34, 0.027, vs. other dermatomyositis), higher IIM disease activity, and prednisone intake >10mg/day (5.59, 2.70 to 11.57, <0.001) were associated with a higher risk of hospitalization. Conversely, 3-dose inactivated vaccination reduced the risk of hospitalization (0.10, 0.02 to 0.40, 0.001, vs. incomplete vaccination). Janus kinase inhibitor (JAKi) pre-exposure significantly reduced the risk of severe COVID-19 in hospitalized patients (0.16, 0.04 to 0.74, 0.019, vs. csDMARDs). ASyS patients with severe COVID-19 had significantly reduced peripheral CD4+ T cells, lower CD4/CD8 ratio, and fewer naive B cells but more class-switched memory B cells compared with controls. Conclusion: ASyS and family oxygen supplement were first identified as risk factors for COVID-19-related hospitalization in patients with IIMs. JAKi pre-exposure might protect IIM patients against severe COVID-19 complications.

Serum levels of CXCL5 are decreased and correlate with circulating platelet counts in systemic lupus erythematosus.

OBJECTIVE: To identify disease-specific serum chemokine profiles and potential anti-inflammatory chemokines in three rheumatic diseases. METHODS: The discovery cohort included 18 patients with rheumatoid arthritis (RA), 20 patients with primary Sjögren's syndrome (pSS), 24 patients with systemic lupus erythematosus (SLE) and 28 healthy subjects. Findings from the discovery cohort were validated in two replication cohorts, consisting of 23 patients with SLE matched with 23 healthy subjects and 62 patients with SLE, 16 patients with ANCA-associated vasculitis (AAV), and 32 healthy controls, respectively. Serum levels of chemokines were determined using multiplex assay or ELISA. RESULTS: In the discovery cohort, serum levels of multiple chemokines were increased in one or more diseases in comparison to healthy subjects, including CCL2, CCL20, CXCL9, CXCL10, and CXCL11 in SLE, CCL2, CCL4, and CXCL11 in pSS, and CCL2, CCL4, and CXCL9 in RA. Notably, serum levels of CCL3 (p = .0003) and CXCL5 (p = .0003) were decreased in SLE. The SLE-specific decrease in CXCL5 serum levels was confirmed in the two replication cohorts, with p = .0034 and p = .0006, respectively. Moreover, a positive correlation between serum levels of CXCL5 and circulating platelet counts (R = .71, p = .00018) in SLE observed in the discovery cohort was confirmed in both replication cohorts (R = .52, p = .011 and R = .49, p = .00005, respectively). CONCLUSION: In the present study, we demonstrate that serum levels of CXCL5 are decreased in patients with SLE and positively correlated with circulating platelet count. These findings suggest that platelet-associated CXCL5 is presumably involved in the development of SLE.

Pyruvate Kinase M2 Nuclear Translocation Regulate Ferroptosis-Associated Acute Lung Injury in Cytokine Storm.

Cytokine storm (CS) is linked with macrophage dysfunction and acute lung injury (ALI), which can lead to patient mortality. Glycolysis is preferentially exploited by the pro-inflammatory macrophages, in which pyruvate kinase M2 (PKM2) is a critical enzyme. The mechanism underlying the link between CS and ALI involves cell death, with the recently discovered programmed cell death known as ferroptosis being involved. However, the relationship between the glycolysis and ferroptosis in the context of CS-related ALI remains unclear. CS-associated ALI induced by poly I:C (10 mg/kg, i.v) and LPS (5 mg/kg, i.p) (IC: LPS) exhibit significant ferroptosis. Ferrostatin-1 (ferroptosis inhibitor) treatment attenuated IC:LPS­induced mortality and lung injury. Moreover, Alveolar macrophage (AM) from IC:LPS model exhibited enhanced glycolysis and PKM2 translocation. The administration of ML-265(PKM2 monomer/dimer inhibitor) resulted in the formation of a highly active tetrameric PKM2, leading to improved survival and attenuation of ALI. Furthermore, ML-265 treatment decreased ferroptosis and restored the balance between anaerobic glycolysis and oxidative phosphorylation. Notably, in patients with lung infection, intracellular expression level of PKM2 were correlated with circulating inflammation. Enhanced ferroptosis and PKM2 nuclear translocation was noticed in CD14+ blood monocytes of lung infection patients with CS. In conclusion, PKM2 is a key regulatory node integrating metabolic reprograming with intra-nuclear function for the regulation of ferroptosis. Targeting PKM2 could be explored as a potential means in the future to prevent or alleviate hyper-inflammatory state or cytokines storm syndrome with aberrant ferroptotic cell death.

Severe gastrointestinal involvements in patients with adult dermatomyositis with anti-NXP2 antibody.

OBJECTIVE: Gastrointestinal (GI) involvements were scarcely reported in adult anti-nuclear matrix protein 2 (NXP2) dermatomyositis (NXP2+DM). In this study, we investigated the clinical, pathological and molecular features as well as treatment options of this rare yet life-threatening disease. METHODS: We retrospectively collected the data of the cohort of NXP2+ DM from 2012 to 2022 in our hospital. RNA sequencing was performed in intestinal samples of perforated patients compared with healthy controls data set. RESULTS: A total of 56 patients with adult NXP2+DM were collected including 10 cases with GI involvements. Abdominal pain and melena were the initial manifestations for GI involvements with a median 10-month time lag after the diagnosis of NXP2+DM when myositis largely subsided. Within weeks, GI perforation occurred in 8 of 10 patients, while five patients underwent eight surgical interventions subsequently. The short-term mortality was observed in four patients. NXP2+DM with GI involvements presented with more extramuscular systemic manifestations such as interstitial lung disease and subcutaneous calcinosis. The GI pathological features encompassed vasculitis/vasculopathy with high MxA expression, intestinal smooth muscle necrosis and serosal calcinosis. Gene expression profile validated the type-I interferon activation and revealed that epithelial mesenchymal transition and focal adhesion pathway may also contribute. Finally, vedolizumab, an anti-α4ß7-integrin monoclonal antibody, exhibited promising therapeutic signals which should be further investigated. CONCLUSIONS: GI involvement is a unique complication in patients with adult NXP2+DM. Timely recognition and targeted therapy may turn out to be lifesaving.

PD-1/PD-L1 governed cross-talk of exhausted CD8+ T and memory B cells in systemic lupus erythematosus.

BACKGROUND: Indeterminate readout of the quantitative interferon-γ release test (QFT) for Mycobacterium tuberculosis screening is a specific laboratory finding for systemic lupus erythematosus (SLE), which may be due to T-cell exhaustion and abnormal programmed death receptor 1 (PD-1)/programmed death-ligand 1 (PD-L1) signalling. METHODS: We enrolled 104 patients with SLE and 225 with other rheumatic musculoskeletal diseases (RMDs) who presented to the outpatient clinic between 2020 and 2023. Twenty healthy donors served as the controls. The QFT was performed in all participants, and those with indeterminate results were compared among the groups. Immunophenotyping and functional assays were performed using blood mononuclear cells. Interferon (IFN)-γ was detected in vitro and ex vivo in patients with SLE with indeterminate or negative QFT results, before or after rituximab therapy. RESULTS: 104 patients with SLE had a significantly higher rate of indeterminate QFT results was significantly higher (17.31%) than that of 225 patients with RMD (3.56%). Patients with SLE with indeterminate QFT had more active disease (SLEDAI-2K, mean 10.94 vs 4.02, p<0.0001), including a higher incidence of active nephritis (55.56% vs 29.07%). Indeterminate QFT in SLE is mainly caused by an insufficient IFN-γ response in CD8+T cells with exhausted immunophenotypes. The abnormal interaction between exhausted PD-1 high CD8+ T cells and activated PD-L1 low memory B cells in SLE can be reversed with a PD-1 agonist or increased PD-L1 expression. Rituximab treatment indirectly reversed this IFN-γ response. CONCLUSION: The PD-1/PD-L1 signalling pathway, which governs the crosstalk between exhausted CD8+ T cells and activated memory B cells, is a mechanistic explanation for insufficient interferon-γ response in patients with SLE.

Discovery of novel oridonin sulfamide derivatives as potent NLRP3 inhibitors by a visible-light photocatalysis-enabled peripheral editing.

The progress of organicsyntheticmethod can promote late-stage lead compound modification and novel active compound discovery. Molecular editing technology in the field of organic synthesis, including peripheral and skeletal editing, facilitates rapid access to molecular diversity of a lead compound. Peripheral editing of CH bond activation is gradually used in lead optimization to afford novel active scaffolds and chemical space exploitation. To develop oridonin derivatives with high anti-inflammatory potency, novel oridonin sulfamides had been designed and synthesized by a scaffoldhopping strategy based on a visible-light photocatalysis peripheral editing. All novel compounds revealed measurable inhibition of IL-1ß and low cytotoxicity in THP-1 cells. The docking study indicated that the best active compound ZM640 was accommodated in thebinding site of NLRP3 with two hydrogen bond interaction. These preliminary results confirm that α, ß-unsaturated carbonyl of oridonin is not essential for NLRP3 inhibitory effect. This new oridonin scaffold has its potential to be further developed as a promising class of NLRP3 inhibitors.

Clinical phenotypes and prognoses of microscopic polyangiitis based on kidney biopsies.

BACKGROUND: To classify the different clinical phenotypes and compare the distinct prognoses of microscopic polyangiitis (MPA). METHODS: A retrospective analysis of 436 patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) from 2015 to 2022 was conducted in our center, of which 90 patients were diagnosed with MPA and underwent renal biopsy. RESULTS: Among the 90 MPA patients, 63% were female, and the median age at onset was 63 years (25th-75th percentile: 58-68). The median follow-up time was 26 months (25th-75th percentile: 10-53). We identified four subtypes: renal impairment type (cluster 1, 39%), pure type (cluster 2, 22%), systemic inflammation type (cluster 3, 26%), and rapid progress type (cluster 4, 13%). Cluster 1, characterized by renal dysfunction at onset (80%), demonstrated poor prognoses with only 26% achieved complete remission (CR), 11% dying, and 19% developing renal failure. In contrast, patients in cluster 2, exclusively female, most had only kidney involvement showed the best prognoses with 55% achieving CR and none experiencing death or renal failure within 10 years. Cluster 3 mostly consisted of males; high fever and C-reactive protein levels were the primary characteristics. These cases exhibited moderate prognoses with 53% achieving CR, 9% dying, and 4% developing renal failure. Finally, patients in cluster 4, which was characterized by rapidly progressive glomerulonephritis, had the worst prognoses, with none achieving CR, 8% dying, and 75% developing renal failure despite aggressive treatment. CONCLUSIONS: MPA is classified into four subtypes with distinct clinical manifestations and prognoses.

A tRF-5a fragment that regulates radiation resistance of colorectal cancer cells by targeting MKNK1.

Radiotherapy serves as a crucial strategy in the treatment of colorectal cancer (CRC). However, its efficacy is often hindered by the challenge of radiation resistance. Although the literature suggests that some tRNA-derived small RNAs (tsRNAs) are associated with various cancers, studies reporting the relationship of tsRNAs with cancer cell radiosensitivity have not been published yet. In our study, we utilized tsRNAs sequencing to predict differentially expressed tsRNAs in two CRC cells and their radioresistant cells, and 10 tsRNAs with significant differences in expression were validated by qPCR. The target genes of tRF-16-7X9PN5D were predicted and verified by the bioinformatics, dual-luciferase reporter gene assay and western blotting analyses. Wound healing, colony formation, transwell invasion and CCK-8 assays were performed to detect the effects of tRF-16-7X9PN5D on cell function and radiosensitivity. Western blotting evaluated the relationship between tRF-16-7X9PN5D and the MKNK-eIF4E axis. Our findings demonstrated that tRF-16-7X9PN5D expression was substantially downregulated in radioresistant CRC cells. Furthermore, tRF-16-7X9PN5D could promote CRC cells' ability to proliferate, migrate, invade and obtain radiation resistance by targeting MKNK1. Finally, tRF-16-7X9PN5D could regulate eIF4E phosphorylation via MKNK1. This investigation indicated that tRF-16-7X9PN5D has an essential regulatory role in the radiation resistance of CRC by directly targeting MKNK1, and may be a new pathway for regulating the CRC radiosensitivity.

A prognostic model for systemic lupus erythematosus-associated pulmonary arterial hypertension: CSTAR-PAH cohort study.

BACKGROUND: Pulmonary arterial hypertension is a major cause of death in systemic lupus erythematosus, but there are no tools specialized for predicting survival in systemic lupus erythematosus-associated pulmonary arterial hypertension. RESEARCH QUESTION: To develop a practical model for predicting long-term prognosis in patients with systemic lupus erythematosus-associated pulmonary arterial hypertension. METHODS: A prognostic model was developed from a multicenter, longitudinal national cohort of consecutively evaluated patients with systemic lupus erythematosus-associated pulmonary arterial hypertension. The study was conducted between November 2006 and February 2020. All-cause death was defined as the endpoint. Cox regression and least absolute shrinkage and selection operators were used to fit the model. Internal validation of the model was assessed by discrimination and calibration using bootstrapping. RESULTS: Of 310 patients included in the study, 81 (26.1%) died within a median follow-up of 5.94 years (interquartile range 4.67-7.46). The final prognostic model included eight variables: modified World Health Organization functional class, 6-min walking distance, pulmonary vascular resistance, estimated glomerular filtration rate, thrombocytopenia, mild interstitial lung disease, N-terminal pro-brain natriuretic peptide/brain natriuretic peptide level, and direct bilirubin level. A 5-year death probability predictive algorithm was established and validated using the C-index (0.77) and a satisfactory calibration curve. Risk stratification was performed based on the predicted probability to improve clinical decision-making. CONCLUSIONS: This new risk stratification model for systemic lupus erythematosus-associated pulmonary arterial hypertension may provide individualized prognostic probability using readily obtained clinical risk factors. External validation is required to demonstrate the accuracy of this model's predictions in diverse patient populations.

The effective threshold dose of etanercept in patients with methotrexate-resistant rheumatoid arthritis.

INTRODUCTION: The therapy of rheumatoid arthritis (RA) was advanced by biological agents, yet costly. This study aims to identify the effective threshold dose of etanercept (ENT) and cost-effectiveness in methotrexate (MTX)-resistant RA in real world. METHODS: Eligible patients had an inadequate response (DAS28-ESR > 3.2) to initial MTX monotherapy, and subsequently received etanercept. The effective cut-off value of cumulative dose was identified to maintain remission response (DAS28-ESR < 2.6) at month 24 by using restricted cubic splines. Remission rate, low disease activity (LDA) rate, glucocorticoid exposure, safety, and cost-effectiveness were compared between the saturated and non-saturated dose groups divided by the cut-off dose. RESULTS: Seventy-eight (14.2%) of 549 enrolled patients were eligible, and 72 patients completed follow-up. The 2-year cumulative cut-off dose that maintained remission response at 24 months was 1975 mg. And the recommended threshold dosing strategy of etanercept was twice weekly (BIW) for the first 6 months, every week (QW) for the next 6 months, and every 2 weeks (Q2W) and every month (QM) for the second year. Greater net changes in DAS28-ESR score were observed in the ENT saturated dose group than in the non-saturated dose group (average change 0.569, 95%CI 0.236-0.901, p = 0.001). The proportion of patients achieving remission (27.8% vs 72.2%, p < 0.001) and LDA (58.3% vs 83.3%, p = 0.020) in the non-saturated group was both significantly lower than that in the saturated group at 24 months. The incremental cost-effectiveness ratio of the saturated group referred to the non-saturated group was 5791.2 $/QALY. CONCLUSIONS: In refractory RA patients, the effective cumulative cut-off dose of etanercept for sustained remission at 24 months was calculated as 1975 mg, and receiving saturated dose was more effective and cost-effective than with non-saturated dose. Key Points • The effective cumulative cut-off dose of etanercept for sustained remission at 24 months in RA patients is calculated as 1975 mg. • Receiving saturated dose of etanercept is more effective and cost-effective than with non-saturated dose in refractory RA patients.

Ag-containing metal organic framework reacted with AsH3: Mechanism and application for inorganic arsenic detection by hydride generation-smartphone RGB readout colorimetric system.

The reaction mechanism of Ag-containing metal organic framework (Ag-BTC) and hydrogen arsenide (AsH3) was discussed in detail in this work. Silver ions in Ag-BTC were reacted with AsH3, and silver nanoparticles were generated on the surface of Ag-BTC, causing its color changed. This property was further applied to a hydride generation-colorimetric analytical system. As(III) was converted to AsH3via hydride generation and then reacted with the Ag-BTC (immobilized on test paper), leading to the test paper changed from white to black. Visual colorimetric and smartphone RGB readout mode were used for this analytical system. The results could be readout by naked-eye in visual colorimetric mode and a smartphone in RGB readout mode. Under the optimized conditions, As(III) concentration as low as 10 µg/L and 50 µg/L could be readout by smartphone and naked-eye, respectively. This method was further successful applied to As(III) determination in real samples (drinking water samples and scented tea samples), with recoveries of 91-113%.

Effect of repeated intravitreal anti-vascular endothelial growth factor drugs on corneal nerves.

To investigate the potential effect of repeated intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) drugs on corneal nerves. A total of 64 patients were treated with intravitreal injection of anti-VEGF drugs. There were 19 cases of neovascular age-related macular degeneration (AMD), 20 cases of diabetic macular edema (DME) and 25 cases of retinal vein occlusion (RVO). Twenty-nine cases were treated with aflibercept (2 mg/0.05 mL) whereas 35 cases were managed with ranibizumab (0.5 mg/0.05 mL). A corneal confocal microscope was used to collect images of corneal subbasal nerve plexus, and Image J was used for image analysis. The changes in corneal nerve were compared between 1 month after each injection and before injection. There were no significant differences in the density and length of corneal nerve at specific time after the surgery in comparison with baseline in patients who were given 3 intravitreal injections. There was no significant correlation between the numbers of injections and the changes of the corneal nerves. After 3rd injection, the nerve length of the DME group was markedly lower than that of AMD and RVO groups, the difference was statistically significant (P < .05). The nerve density of the DME group was not significantly different from that of AMD and RVO groups, whereas the nerve length and nerve density of the AMD and RVO groups were not statistically significant between each other also. The corneal nerve length after the 2nd and 3rd injections of Aflibercept were lower than that before surgery, the difference was statistically significant. There were no significant differences in nerve density and nerve length at each time point after Ranibizumab injection. The length and density of the corneal nerve after multiple injections in contralateral eye displayed no significant changes compared with the baseline. Repeated intravitreal anti-VEGF drug can reduce the length of corneal nerves. For patients who need repeated intravitreal injections of anti-VEGF drugs, especially in DM, attention should be paid on the changes affecting the corneal nerves. It is also needed to strengthen the local anti-inflammatory therapy to avoid infection and to use artificial tears to protect the microenvironment of the ocular surface after the surgery.

Genomic profiling of ovarian clear cell carcinoma in Chinese patients reveals potential prognostic biomarkers for survival.

INTRODUCTION: Ovarian clear cell carcinoma (OCCC) has distinct clinical and molecular features and heterogeneous prognosis. Insights into the somatic genomic abnormalities of OCCC provide the basis for deeper understanding and potential therapeutic avenues. Herein, we performed extensive genomic profiling in Chinese patients to illustrate the mutation landscape and genetic prognostic biomarkers of OCCC. PATIENTS AND METHODS: We used targeted DNA sequencing on 61 OCCC cases with a panel of 520 cancer-related genes. Correlations between clinicopathological features and survival were evaluated. Nomogram-based models were constructed to predict progress-free survival (PFS). RESULTS: We detected 763 somatic mutations spanning 286 genes. The most frequent genetic alterations, ARID1A (49%) and PIK3CA (48%), were concurrently mutated. Comprehensive copy number alterations (CNAs) were identified in chromosomes 20q13.2 and 8q. Most (73.7%) patients harboured potentially targetable driver mutations. The mean and median tumour mutational burden were 7.0 and 3.0 mutations/Mb, respectively. Microsatellite instability (high) was identified in 8.2% of patients. Mutation of the base-excision repair pathway was significantly higher in patients of stage II/III/IV. ATM mutation was associated with platinum sensitivity (p < .05). Survival analysis identified chr8q CNAs in all patients, PIK3CA mutations in stage I patients and SWI/SNF complex (ARID1A and SMARCA4) mutations in stage II/III/IV patients as potential prognosticators (p < .05). Integration of genetic alterations (SWI/SNF complex mutations, ATM mutations and chr8q CNAs) improved the performance of a nomogram based on tumour stage and residual disease (concordance index 0.75 vs. 0.70, p < .05). CONCLUSIONS: We described somatic genomic alterations in Chinese OCCC patients and observed different genomic alterations between stage I and stage II/III/IV tumours. Genetic factors may supplement clinical factors in nomogram modelling for PFS prediction.Key MessagesWe performed extensive genomic profiling in a well-annotated cohort of 61 Chinese ovarian clear cell carcinoma (OCCC) patients.PIK3CA mutations were associated with worse overall survival (OS) in stage I OCCC, and SWI/SNF gene mutations were associated with improved OS in stage II/III/IV disease.We propose an easy-to-use nomogram using clinical factors (tumour stage and residual disease) and genetic alterations (SWI/SNF complex mutations, ATM mutations and chr8q CNAs) to predict the progress-free survival (PFS) of OCCC.

Four trajectories of 24-hour urine protein levels in real-world lupus nephritis cohorts.

OBJECTIVES: A 24-hour urine protein (24hUP) is a key measurement in the management of lupus nephritis (LN); however, trajectories of 24hUP in LN is poorly defined. METHODS: Two LN cohorts that underwent renal biopsies at Renji Hospital were included. Patients received standard of care in a real-world setting and 24hUP data were collected over time. Trajectory patterns of 24hUP were determined using the latent class mixed modelling (LCMM). Baseline characters were compared among trajectories and multinomial logistic regression was used to determine independent risk factors. Optimal combinations of variables were identified for model construction and user-friendly nomograms were developed. RESULTS: The derivation cohort composed of 194 patients with LN with 1479 study visits and a median follow-up of 17.5 (12.2-21.7) months. Four trajectories of 24hUP were identified, that is, Rapid Responders, Good Responders, Suboptimal Responders and Non-Responders, with the KDIGO renal complete remission rates (time to complete remission, months) of 84.2% (4.19), 79.6% (7.94), 40.4% (not applicable) and 9.8% (not applicable), respectively (p<0.001). The 'Rapid Responders' distinguish itself from other trajectories and a nomogram, composed of age, systemic lupus erythematosus duration, albumin and 24hUP yielded C-indices >0.85. Another nomogram to predict 'Good Responders' yielded C-indices of 0.73~0.78, which composed of gender, new-onset LN, glomerulosclerosis and partial remission within 6 months. When applied to the validation cohort with 117 patients and 500 study visits, nomograms effectively sorted out 'Rapid Responders' and 'Good Responders'. CONCLUSION: Four trajectories of LN shed some light to guide the management of LN and further clinical trials design.