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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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: This study aimed to depict the clinical features, including myositis specific or associated antibody (MSA/MAA) profile of systemic lupus erythematosus (SLE) patients with muscle involvement in a Chinese cohort., Methods: We retrospectively studied a cohort of 1696 SLE inpatients and screened for concurrent myositis features from January 2013 to June 2021. Propensity score matching was applied to enroll controls without myositis features from our cohort. Demographic, clinical and laboratory variables were collected. MSA/MAA panels containing 16 autoantibodies (TIF1-γ, MDA5, NXP2, Mi-2α/β, SAE1, Jo-1, PL-7, PL-12, EJ, OJ, SRP, HMGCR, cN-1A, PM-Scl75/100, Ku and Ro52) were tested by line-blotting assay. Binary logistic regression and K-means clustering were applied., Results: Forty-one of 1696 (2.42%) SLE patients in our SLE inpatient cohort showed features of myositis. Binary logistic regression revealed that new-onset SLE (odds ratio [OR] = 4.77, 95% CI = 1.10-20.57), interstitial lung disease (ILD) (OR = 10.07, 95% CI = 1.65-61.51), positive anti-U1RNP antibody (OR = 4.38, 95% CI = 1.08-17.75), and Raynaud's phenomenon (OR = 7.94, 95% CI = 1.41-44.69) were associated with muscle involvement. Except for anti-Ro52 (50%), anti-Ku antibody (38.2%) was the next frequently detected MSA/MAA in the panel, followed by anti-NXP2 antibody (11.8%). It was noteworthy that multiple MSA/MAAs (≥2, excluding anti-Ro52) coexisted in 9 patients. Patients with myositis features were clustered into 2 subgroups. Cluster 1 was characterized by anti-Ku or anti-Ro52 with high SLE Disease Activity Index, whereas cluster 2 presented with anti-U1RNP, Raynaud's phenomenon and pulmonary arterial hypertension resembling mixed connective tissue disease., Conclusion: In our Chinese SLE inpatient cohort, muscle involvement was infrequent. Nevertheless, distinct features in these SLE patients deserve further study., (© 2022 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Objective: Sodium-glucose cotransporter-2 inhibitors have been identified profound renal/cardiac protective effects in different diseases. Here, we assessed the safety and efficacy of dapagliflozin among adult patients with systemic lupus erythematosus (SLE)., Methods: We conducted a single-arm, open-label, investigator-initiated phase I/II trial of dapagliflozin in Chinese patients with SLE with/without lupus nephritis (LN). Patients received oral dapagliflozin at a daily dose of 10 mg added to the standard of care for 6 months. The primary end point was the safety profile. The secondary efficacy end points were composite assessments of disease activity., Results: A total of 38 eligible patients were enrolled. Overall, 19 (50%) adverse events (AEs) were recorded, including 8 (21%) AEs leading to drug discontinuation, of which 4 (10.5%) were attributed to dapagliflozin. Two serious AEs (one of major lupus flare and one of fungal pneumonia) were recorded. Lower urinary tract infection was observed in one (2.63%) patient. The secondary end points revealed no improvement of SLE Disease Activity Index scores or proteinuria (among 17 patients with LN); the cumulative lupus flare rate was 18%, and a reduction of ~30% in the prednisone dose was captured. Net changes in body mass index (-0.50 kg/m 2 ), systolic blood pressure (-3.94 mm Hg) and haemoglobin levels (+8.26 g/L) were detected. The overall estimated glomerular filtration rate (eGFR) was stable, and there was an improvement in the eGFR slope among patients with LN with a baseline eGFR <90 mL/min/1.73 m 2 ., Conclusion: Dapagliflozin had an acceptable safety profile in adult patients with SLE. Its possible renal/cardiac protective effects and long-term safety issues in patients with SLE, patients with LN in particular, call for further exploration., Trial Registration Number: ChiCTR1800015030., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Objectives: Low disease activity status and remission are crucial treat-to-target (T2T) endpoints in systemic lupus erythematosus (SLE). To evaluate the efficacy of metformin add-on in attaining T2T among Chinese patients with mild-to-moderate lupus, a post-hoc analysis combining our previous two randomised trials was carried out., Methods: Data from the open-labeled proof-of-concept trial (ChiCTR-TRC-12002419) and placebo-controlled trial (NCT02741960) were integrated together. Disease flares were compared between patients attaining T2T or not at baseline. The efficacy of metformin versus placebo/nil add-on to standard therapy in SLE patients who did not meet the T2T criteria at baseline was evaluated in terms of attaining T2T at 12-month follow-up., Results: Of 253 SLE patients, 43.8% (n=89) attained T2T at baseline. During the 12 months, 15 patients flared in the T2T group, which was significantly lower than that in the non-T2T group (16.9% vs. 36.0%, p=0.001). For 164 patients who did not meet the T2T criteria at entry, 59.0% and 43.6% of the 78 patients taking metformin in this population attained the lupus low disease activity status (LLDAS) and remission endpoints at last visit, respectively, as compared to 37.2% and 24.4% of the 86 patients in the placebo/nil group (LLDAS p=0.008; remission p=0.013). Over time, metformin helped patients achieving T2T earlier and maintain longer T2T duration over placebo/nil (LLDAS duration: 44.9% vs. 26.4%, p=0.002; remission duration:19.1% vs. 10.7%, p=0.014)., Conclusions: This post-hoc analysis suggested that metformin might be an adjuvant therapy in achieving treat-to-target in SLE patients.

Objective: To evaluate the risk of major infections and the relationship between major infections and mortality in patients with newly diagnosed SLE., Methods: A newly diagnosed (<3 months) hospitalised Systemic Lupus Inception Cohort (hSLIC) in our centre during 1 January 2013 and 1 November 2020 was established. All patients were followed up for at least 1 year or until death. Patient baseline characteristics were collected. Major infection events were recorded during follow-up, which were defined as microbiological/clinical-based diagnosis treated with intravenous antimicrobials. The cohort was further divided into a training set and a testing set. Independent predictors of major infections were identified using multivariable logistic regression analysis. Kaplan-Meier survival analyses were conducted., Results: Among the 494 patients enrolled in the hSLIC cohort, there were 69 documented episodes of major infections during the first year of follow-up in 67 (14%) patients. The major infection events predominantly occurred within the first 4 months since enrolment (94%, 65/69) and were associated with all-cause mortality. After adjustments for glucocorticoid and immunosuppressant exposure, a prediction model based on SLE Disease Activity Index >10, peripheral lymphocyte count <0.8×10 9 /L and serum creatinine >104 µmol/L was established to identify patients at low risk (3%-5%) or high risk (37%-39%) of major infections within the first 4 months., Conclusions: Newly onset active SLE is susceptible to major infections, which is probably due to underlying profound immune disturbance. Identifying high-risk patients using an appropriate prediction tool might lead to better tailored management and better outcome., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Recurrent disease flare is one of the key problems in lupus patients. A Chinese Flare-Prevention Lupus Initiative Cohort (FLIC) was established. Risk factors of disease flare were evaluated accordingly., Methods: Patients with low-grade disease activity (the Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) =≤6, daily prednisone ≤20 mg, no British Isles Lupus Assessment Group A or no more than one B organ domain score) from January 2014 to August 2020 were included in the FLIC. Disease flares were defined by the modified SELENA--SLEDAI Flare Index. Low disease activity status (LDAS) and remission were also assessed. The cumulative flare rate was estimated by an event per 100 person-years analysis. Cox proportional hazards models were performed to identify risk factors of subsequent disease flares after adjusting clinical confounders. Survival was assessed with the Kaplan-Meier method., Results: 448 eligible patients with low-grade disease activity were included in FLIC. During a mean follow-up of 30.4 months, 170 patients flared. The cumulative lupus flare rate was 22.2 events per 100 patient-years. Compared with patients without flare, those with lupus flares were taking more prednisone, had higher disease activity index and with less patients attained LDAS/remission at baseline. They also had higher rates of antiphospholipid antibodies (aPLs) and antiribosomal P antibody. Cox regression analysis confirmed that attainment of either LDAS or remission at baseline were independent protective factors against subsequent disease flare (LDAS but not in remission: HR 0.58, 95% CI 0.38~0.88; remission: HR 0.46, 95% CI 0.30~0.69), while aPL was a risk factor of lupus flares (HR 1.95, 95% CI 1.36~2.78). Kaplan-Meier curves indicated that attaining LDAS or remission and absence of aPL at baseline had the least flare risk., Conclusions: In our real-world cohort study, not attaining LDAS or remission at baseline and aPL positivity was associated with higher risk of disease flares in patients with low-grade SLE., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: SLE is a chronic inflammatory systemic autoimmune disease with relapsing-remitting pattern. B-lymphocyte stimulator was involved in the pathogenesis of SLE. The humanised monoclonal antibody belimumab with 10 mg/kg was effective for active patients. However, the efficacy of low-dose belimumab for prevention of disease flares in patients with SLE with low disease activity is to be explored., Methods and Analysis: This is a multicentre, randomised, double-blind, placebo-controlled clinical trial. Patients who have Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) scores no higher than 6; with no A score or no more than one B score on the British Isles Lupus Assessment Group (BILAG) scale; and who are treated with prednisone (≤20 mg per day) at screening will be enrolled. 334 adults will be randomly assigned in a 1:1 ratio to receive intravenous 120 mg belimumab or placebo (saline) arm on weeks 0, 2, and 4, and then every 4 weeks until 48 weeks, with standard of care. The primary outcome measure is a composite index of severe or mild-to-moderate disease flares (SELENA-SLEDAI Flare Index) within 52 weeks. Secondary outcomes include the percentage of severe flare, the percentage of mild-to-moderate flare, time to first disease flare, changes in prednisone dose, SELENA-SLEDAI, as well as BILAG score, the percentage of patients achieving prednisone free and safety analysis., Ethics and Dissemination: The protocol has been approved by the Ethics Committee of the Renji Hospital, Huashan Hospital and the Sixth People's Hospital. The trial has been registered and the detailed information is available at https://clinicaltrialsgov/ct2/show/NCT04515719. The results of this clinical trial will be submitted for publication in peer-reviewed journals and key findings will also be presented at national and international conferences., Trial Registration Number: NCT04515719., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To confirm that metformin prevents flares in patients with SLE with low disease activity, we performed a post hoc analysis combining our previous two randomised trials., Methods: Post hoc analyses were performed on data from the open-labelled proof-of-concept trial (n=113, ChiCTR-TRC-12002419) and placebo-controlled 'Met Lupus' trial (n=140, NCT02741960) comparing the efficacy of metformin versus placebo/nil add-on to standard therapy in patients with SLE with low disease activity (SELENA-SLEDAI ≤4). The primary endpoint was defined by the SELENA-SLEDAI Flare Index at 12-month follow-up. A subgroup analysis was performed., Results: Overall, 201 eligible patients were included, with 99 allocated to metformin group and 102 allocated to the placebo/nil group. By 12 months of follow-up, 21 patients (21.2%) flared in the metformin group, as compared with 36 (35.3%) in the placebo/nil group (p=0.027, risk ratio=0.68, 95% CI 0.46 to 0.96). Subgroup analysis showed that patients with negative anti-dsDNA antibody and normal complement at baseline, and a disease duration <5 years with concomitant use of hydroxychloroquine had a better response to metformin., Conclusion: Post hoc pooled analyses suggested that metformin reduced subsequent disease flares in patients with SLE with low disease activity, especially for serologically quiescent patients., Competing Interests: Competing interests: SY reports personal grants from Shanghai Shenkang Promoting Project (16CR1013A); LL reports grants from the National Key Research and Development Program of China (2017YFC0909002); LM reports a grant from the National Institutes of Health (R01 AI128901)., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Systemic lupus erythematosus (SLE) gastrointestinal (GI) complication is characterized by multi-segment and multi-compartment involvement. The aim of this study is to develop a computed tomography (CT) image-based system for disease evaluation. SLE patients with GI involvement from two independent cohorts were retrospectively included. Baseline abdominal CT scan with intravenous and oral contrast was obtained from each individual. A CT scoring system incorporating the extent of GI tract involvement and intestinal wall thickness, along with extra-GI compartment involvement, was developed and validated. The outcome measurement was the time to GI functional recovery, defined as the time to tolerable per os (PO) intake ≥50% of ideal calories (PO50). A total of 54 and 37 patients with SLE GI involvement were enrolled in the derivation and validation cohorts, respectively. The CT scores for SLE GI involvement were positively correlated with patients' time to PO50 (r = 0.57, p < 0.0001, derivation cohort; r = 0.42, p = 0.0093, validation cohort). Patients with a CT score ≤ 3 had a shorter time to PO50 (median time of 0 day) in pooled cohort, whereas those with a CT score > 3 incurred a significantly prolonged recovery with a median time to PO50 of 13 days (p < 0.0001). The CT-based scoring system may facilitate more accurate assessment and individualized management of SLE patients with GI involvement.

Thrombotic microangiopathy (TMA) includes a series of life-threatening disorders. Systemic lupus erythematosus (SLE) is one of the most common acquired causes. To identify predictors of prognosis in patients with TMA secondary to SLE, we conducted a single-center historical study. From January 2013 to June 2016, of 2182 SLE hospitalized patients in the Ren Ji Hospital, a total of 21 consecutive patients with TMA secondary to SLE were identified. The 90-day short-term mortality was 33.3%. The kidney involvement (66.7%) was associated with poor prognosis, while the administration of rituximab (n = 13) was an independent protective factor according to logistic regression analysis. Compared to conventional treatment, i.e., plasma exchange, high-dose glucocorticoids, and intravenous immunoglobulin, the overall survival is significantly higher among patients receiving rituximab add-on (92.2 vs 33.3%, p = 0.0173); however, five out of seven patients with renal involvement in the rituximab group were eventually hemodialysis dependent. Our data indicated that add-on rituximab in the background of conventional therapy may improve the overall but not the renal survival in SLE-TMA patients.

To compare the performance of different commercial anti-dsDNA autoantibody assays, including multiplex-based immunoassay (Bio-Plex), Farr radioimmunoassay (Farr), ELISA, chemiluminescent immunoassay (CLIA), and Crithidia Luciliae indirect immunofluorescence test (CLIFT) in Chinese patients with systemic lupus erythematosus (SLE). SLE patients (n = 119) as well as healthy controls (n = 200) and disease controls (n = 100) were recruited, and serum anti-dsDNA autoantibodies were detected by Bio-Plex, Farr, two ELISA assays (Medical & Biological Laboratories-ELISA, EUROIMMU-ELISA), CLIA, and a standard CLIFT. The correlation of anti-dsDNA autoantibody levels to SLE disease activity was calculated, and the specificity and sensitivity of these methods were measured by receiver-operator characteristic (ROC) curve analysis. In ROC curve analysis, Bio-Plex showed the largest area under the curve (AUC) over other assays. Cutoff adjustment according to ROC enhanced the performance of all quantitative assays. Overall, Bio-Plex and CLIFT have higher specificity (>90.00%). ELISA and CLIA results are correlated with disease activity, and Bio-Plex results have the strongest correlation with SLEDAI score and active renal involvement. Bio-Plex assay has better overall performance in anti-dsDNA detection over Farr, ELISA, and CLIA methods in Chinese SLE patients.