Efficacy and safety of treat-to-target strategy studies in rheumatic diseases: A systematic review and meta-analysis.

BACKGROUND: The concept of treat-to-target (T2T), a treatment strategy in which treatment is directed to reach and maintain a defined goal such as remission or low disease activity (LDA), has been explored for several diseases including rheumatic diseases such as rheumatoid arthritis (RA). However, a comprehensive review of T2T in all rheumatic diseases has not recently been undertaken. OBJECTIVE: To perform a systematic review and meta-analysis of the efficacy and safety of a T2T strategy in the management of adult patients with inflammatory rheumatic diseases. METHODS: PUBMED, EMBASE and CINAHL were searched from January 1990 to December 2023 using key words related to a T2T strategy and rheumatic diseases; T2T strategy clinical trials or observational studies were included. Clinical, physical function and radiologic outcomes, cost-effectiveness, and adverse events (AEs) of the T2T strategies were investigated and a random-effect meta-analysis was conducted for the most commonly used outcomes in RA studies. RESULTS: The search identified 7896 studies, of which 66 fit inclusion criteria, including 50 in RA, 3 in psoriatic arthritis (PsA), 1 in spondyloarthritis (SpA) and 12 in gout. For the studies comparing a T2T strategy with usual care (UC) in RA, 83.3% (20/24) showed a T2T strategy could achieve significantly better clinical outcomes, and the meta-analysis showed that patients treated with a T2T strategy were more likely to be in remission (pooled RR: 1.68 (1.47-1.92), p<0.001] and achieve DAS-28 response (pooled standardised mean difference (SMD): 0.47 (0.26-0.69), P<0.001] at 1 year than patients treated with UC. Sensitivity analyses showed that a T2T strategy with a predefined treatment protocol had better clinical efficacy than that without protocol. In terms of improving physical function and health-related quality of life (HRQoL), 11/19 (57.9%) studies found a T2T strategy was significantly more likely to achieve these than UC, with the meta-analysis for the mean change of HAQ score supporting this conclusion (pooled SMD: 1.48 (0.46-2.51), p=0.004). Five out of 9 studies (55.6%) demonstrated greater benefit regarding radiographic progression from a T2T strategy. In terms of cost-effectiveness and AEs, 2/2 studies found a T2T strategy was more cost-effective than UC and 8/8 studies showed no tendency for AEs to occur more often with a T2T strategy. For the studies in PsA and SpA, a T2T strategy was also demonstrated to be more effective than UC in clinical and functional benefits, but not in radiologic outcomes. All gout studies showed that sUA level could be controlled more effectively with a T2T strategy, and 2 studies revealed that the T2T strategy could inhibit erosion development or crystal deposition. CONCLUSIONS: For patients with active RA, a T2T strategy has been shown in mulitple studies to increase the likelihood of achieving clinical response and improving HRQoL without increasing economic costs and AEs. Limited studies have shown clinical and functional benefits from T2T strategies in active PsA and SpA. A T2T strategy has also been found to improve clinical and radiologic outcomes in gout. T2T trials in other rheumatic diseases are lacking.

Comparison of Attainment and Protective Effects of Lupus Low Disease Activity State In Patients With Newly Diagnosed Versus Established Systemic Lupus Erythematosus.

OBJECTIVE: To assess whether Lupus Low Disease Activity State (LLDAS) attainment is associated with favorable outcomes in patients with recent onset systemic lupus erythematosus (SLE). METHODS: Data from a 13-country longitudinal SLE cohort were collected prospectively between 2013 and 2020. An inception cohort was defined based on disease duration < 1 year at enrollment. Patient characteristics between inception and noninception cohorts were compared. Survival analyses were performed to examine the association between LLDAS attainment and damage accrual and flare. RESULTS: Of the total 4106 patients, 680 (16.6%) were recruited within 1 year of SLE diagnosis (inception cohort). Compared to the noninception cohort, inception cohort patients were significantly younger, had higher disease activity, and used more glucocorticoids, but had less organ damage at enrollment. Significantly fewer inception cohort patients were in LLDAS at enrollment than the noninception cohort (29.6% vs 52.3%, P < 0.001), but three-quarters of both groups achieved LLDAS at least once during follow-up. Limiting analysis only to patients not in LLDAS at enrollment, inception cohort patients were 60% more likely to attain LLDAS (hazard ratio 1.37, 95% CI 1.16-1.61, P < 0.001) than noninception cohort patients and attained LLDAS significantly faster. LLDAS attainment was significantly protective against flare in both the inception and noninception cohorts. A total of 88 (13.6%) inception cohort patients accrued organ damage during a median 2.2 years of follow-up. CONCLUSION: LLDAS attainment is protective from flare in recent onset SLE. Significant protection from damage accrual was not observed because of low rates of damage accrual in the first years after SLE diagnosis. (ClinicalTrials.gov: NCT03138941).

Risk of flare and damage accrual after tapering glucocorticoids in modified serologically active clinically quiescent patients with systemic lupus erythematosus: a multinational observational cohort study.

OBJECTIVES: To assess the risk of flare and damage accrual after tapering glucocorticoids (GCs) in modified serologically active clinically quiescent (mSACQ) patients with systemic lupus erythematosus (SLE). METHODS: Data from a 12-country longitudinal SLE cohort, collected prospectively between 2013 and 2020, were analysed. SLE patients with mSACQ defined as the state with serological activity (increased anti-dsDNA and/or hypocomplementemia) but without clinical activity, treated with ≤7.5 mg/day of prednisolone-equivalent GCs and not-considering duration, were studied. The risk of subsequent flare or damage accrual per 1 mg decrease of prednisolone was assessed using Cox proportional hazard models while adjusting for confounders. Observation periods were 2 years and censored if each event occurred. RESULTS: Data from 1850 mSACQ patients were analysed: 742, 271 and 180 patients experienced overall flare, severe flare and damage accrual, respectively. Tapering GCs by 1 mg/day of prednisolone was not associated with increased risk of overall or severe flare: adjusted HRs 1.02 (95% CI, 0.99 to 1.05) and 0.98 (95% CI, 0.96 to 1.004), respectively. Antimalarial use was associated with decreased flare risk. Tapering GCs was associated with decreased risk of damage accrual (adjusted HR 0.96, 95% CI, 0.93 to 0.99) in the patients whose initial prednisolone dosages were >5 mg/day. CONCLUSIONS: In mSACQ patients, tapering GCs was not associated with increased flare risk. Antimalarial use was associated with decreased flare risk. Tapering GCs protected mSACQ patients treated with >5 mg/day of prednisolone against damage accrual. These findings suggest that cautious GC tapering is feasible and can reduce GC use in mSACQ patients.

SMART-SLE: serology monitoring and repeat testing in systemic lupus erythematosus-an analysis of anti-double-stranded DNA monitoring.

OBJECTIVE: Disease activity monitoring in SLE includes serial measurement of anti-double stranded-DNA (dsDNA) antibodies, but in patients who are persistently anti-dsDNA positive, the utility of repeated measurement is unclear. We investigated the usefulness of serial anti-dsDNA testing in predicting flare in SLE patients who are persistently anti-dsDNA positive. METHODS: Data were analysed from patients in a multinational longitudinal cohort with known anti-dsDNA results from 2013 to 2021. Patients were categorized based on their anti-dsDNA results as persistently negative, fluctuating or persistently positive. Cox regression models were used to examine longitudinal associations of anti-dsDNA results with flare. RESULTS: Data from 37 582 visits of 3484 patients were analysed. Of the patients 1029 (29.5%) had persistently positive anti-dsDNA and 1195 (34.3%) had fluctuating results. Anti-dsDNA expressed as a ratio to the normal cut-off was associated with the risk of subsequent flare, including in the persistently positive cohort (adjusted hazard ratio [HR] 1.56; 95% CI: 1.30, 1.87; P < 0.001) and fluctuating cohort (adjusted HR 1.46; 95% CI: 1.28, 1.66), both for a ratio >3. Both increases and decreases in anti-dsDNA more than 2-fold compared with the previous visit were associated with increased risk of flare in the fluctuating cohort (adjusted HR 1.33; 95% CI: 1.08, 1.65; P = 0.008) and the persistently positive cohort (adjusted HR 1.36; 95% CI: 1.08, 1.71; P = 0.009). CONCLUSION: Absolute value and change in anti-dsDNA titres predict flares, including in persistently anti-dsDNA positive patients. This indicates that repeat monitoring of dsDNA has value in routine testing.

Comparison of the Effectiveness and Safety of Mycophenolate Mofetil and Cyclophosphamide in Lupus Nephritis: Evidence from a Real-World Study.

INTRODUCTION: Both mycophenolate mofetil (MMF) and intravenous cyclophosphamide (CYC) have been recommended in the induction therapy of lupus nephritis (LN) for years; nevertheless, their effectiveness and safety in a real-world setting are extremely lacking. Therefore, we decided to conduct this real-world study. METHODS: A total of 195 Chinese patients with LN who were initially treated with MMF (n = 98), or intravenous CYC (n = 97) as induction therapy were enrolled. All of the patients were followed up to 12 months. Complete renal remission (CRR) was defined as 24-h urinary protein (24 h-UTP) < 0.5 g, and partial renal remission (PRR) was defined as ≥ 50% reduction in 24 h-UTP to the subnephrotic level, however > 0.5 g, both with a change of serum creatinine (SCr) within 10% from baseline. The proportions of CRR, PRR, and total renal remission (TRR), as well as adverse events, were compared by Chi-square test and Kaplan-Meier analysis (log-rank test). Inverse probability of treatment weighting (IPTW) was used for propensity score matching and multivariable logistic regression analyses were employed. RESULTS: The cumulative proportion of TRR in 6 months (79.4 vs. 63.8%, p = 0.026) and CRR in 12 months (72.8 vs. 57.6%, p = 0.049) in MMF group were significantly higher than CYC group, and the above conclusions were further confirmed by IPTW. The proportions of PRR, CRR, and TRR at other time points were equivalent between two groups. Further subgroup analysis in 111 patients with biopsy-proven III-V LN also showed a significantly higher proportion of TRR at 6 months in the MMF group than in the CYC group (78.3 vs. 56.9%, p = 0.026). In the Kaplan-Meier analysis and after IPTW, the MMF group showed better TRR and CRR responses than CYC group in 12 months. Multivariable logistic regression analyses revealed that MMF use was the only predictor of CRR (HR 2.12, 95% CI 1.90-4.09, p = 0.026), while low complement level was also a predictor, albeit risk was reduced (HR 0.38, 95% CI 0.17-0.86, p = 0.019). Moreover, compared to the CYC group, MMF group patients were more likely to have significantly lower SCr (µmol/l) [72.5 (62.5, 86.5) vs. 79.0 (71.1, 97.5), p = 0.001] and daily dose of prednisone (mg/day) (15.7 ± 5.2 vs. 18.6 ± 11.3, p = 0.022) at 6 months; lower 24 h-UTP (g) [0.1 (0.1, 0.3) vs. 0.2 (0.1, 0.9), p = 0.005] and daily dose of prednisone (mg/day) (9.6 ± 3.3 vs. 11.2 ± 5.5, p = 0.023) at 12 months. Infection was the most common adverse event. Pneumonia and gastrointestinal discomfort were more frequently observed in the CYC group. CONCLUSIONS: Real-world data are a key component of the evidence supporting the effectiveness of drugs and are of interest to all stakeholders. Our comparative study demonstrated the effectiveness of MMF in LN induction therapy was at least equivalent to intravenous CYC, with superior tolerance.

Assessment of peripapillary retinal nerve fiber layer thickness and vessel density in newly diagnosed SLE patients without ocular symptoms.

PURPOSE: This study aims to assess peripapillary retinal nerve fiber layer thickness (pRNFLT) and peripapillary vessel density (PVD) in patients with newly diagnosed active and inactive systemic lupus erythematosus (SLE) by optical coherence tomography (OCT) and OCT angiography (OCTA). METHODS: This is a cross-sectional study, in which 77 newly diagnosed SLE patients without ocular symptoms (including 36 active SLE patients and 41 inactive SLE patients) and 72 age- and gender-matched healthy subjects were recruited. All participants underwent OCT and OCTA to evaluate pRNFLT, PVD, and radial peripapillary capillary density (RPCD), respectively. Clinical data at the time of initial diagnosis of SLE, including erythrocyte, leukocyte, platelet, albumin-globulin ratio, erythrocyte sedimentation rate, C-reactive protein, serum complement 3, serum complement 4, anti-dsDNA antibody, and 24-h proteinuria, were collected. RESULTS: No difference was found in pRNFLT between active SLE patients, and healthy controls, average pRNFLT, superonasal RNFLT, and inferonasal pRNFLT were reduced in inactive SLE patients than in healthy controls (p≤0.008). Temporal PVD, inferotemporal PVD, and inferotemporal RPCD in active SLE patients were significantly lower than those in healthy controls (p≤0.043). There also was a trend towards lower temporal RPCD in active SLE than healthy controls (p=0.089). Average PVD, average RPCD, superonasal RPCD, inferonasal RPCD, and inferotemporal RPCD were decreased in inactive SLE patients than in healthy controls (p≤0.047). Additionally, inferotemporal RPCD in active SLE patients was positively associated with albumin-globulin ratio (p=0.041). Temporal RPCD was negatively correlated with anti-dsDNA antibody (p=0.012) and 24-h proteinuria (p=0.006). CONCLUSIONS: PRNFL and PVD damage existed in newly diagnosed SLE patients without ocular symptoms. Temporal and inferotemporal RPCD were associated with the laboratory indicators of impaired renal function in active SLE patients, respectively.

AKR1B10 regulates M2 macrophage polarization to promote the malignant phenotype of gastric cancer.

BACKGROUND: Immunotherapy has brought new hope to gastric cancer (GC) patients. Exploring the immune infiltration pattern in GC and the key molecules is critical for optimizing the efficacy of immunotherapy. Aldo-keto reductase family 1 member B10 (AKR1B10) is an inflammatory regulator and is closely related to the prognosis of patients with GC. However, the function of AKR1B10 in GC remains unclear. METHODS: In the present study, the CIBERSORT algorithm was used to analyze the immune infiltration pattern in 373 samples in the Cancer Genome Atlas (TCGA) database. Differentially expressed genes (DEGs) were seared by combing the TCGA database and the Gene Expression Omnibus (GEO) database, and the key molecule AKR1B10 was identified by weighted gene coexpression network analysis (WGCNA). The biological functions of AKR1B10 in stomach adenocarcinoma (STAD) were investigated in vitro. RESULTS: Macrophage polarization was the main immune infiltration pattern in GC, and the state of macrophage polarization was closely related to the pathological grading of GC and the clinical stage of patients. AKR1B10, MUC5AC, TFF2, GKN1, and PGC were significantly down-regulated in GC tissues. Low AKR1B10 expression induced M2 macrophage polarization and promoted the malignant phenotype of GC. CONCLUSION: M2 macrophage polarization is the main immune infiltration pattern in GC. Low AKR1B10 expression induces M2 macrophage polarization and promotes the malignant transformation of GC.

Association of Modified Systemic Lupus Erythematosus Responder Index Attainment With Long-Term Clinical Outcomes: A Five-Year Prospective Study.

OBJECTIVE: In trials of systemic lupus erythematosus (SLE), the SLE Responder Index (SRI) is the most commonly used primary efficacy end point but has limited validation against long-term outcomes. We aimed to investigate associations of attainment of a modified version of the SRI (mSRI) with key clinical outcomes in SLE patients with up to 5 years of follow-up. METHODS: We used data from a large multicenter, longitudinal SLE cohort in which patients received standard of care. The first visit with active disease (defined as SLE Disease Activity Index 2000 [SLEDAI-2K] score ≥6) was designated as baseline, and mSRI attainment (defined as a reduction in SLEDAI-2K ≥4 points with no worsening in physician global assessment ≥0.3 points) was determined at annual intervals from baseline up to 5 years. Associations between mSRI attainment and outcomes including disease activity, glucocorticoid dose, flare, damage accrual, Lupus Low Disease Activity State (LLDAS), and remission were studied. RESULTS: We included 2,060 patients, with a median baseline SLEDAI-2K score of 8. An mSRI response was attained by 56% of patients at 1 year, with similar responder rates seen at subsequent annual time points. Compared to nonresponders, mSRI responders had significantly lower disease activity and prednisolone dose and higher proportions of LLDAS and remission attainment at each year, and less damage accrual at years 2 and 3. Furthermore, mSRI responder status at 1 year predicted clinical benefit at subsequent years across most outcomes, including damage accrual (odds ratio [OR] range 0.58-0.69, P < 0.05 for damage accrual ORs at all time points). CONCLUSION: In SLE patients with active disease receiving standard of care, mSRI attainment predicts favorable outcomes over long-term follow-up, supporting the clinical meaningfulness of SRI attainment as an SLE trial end point.

Impact of low disease activity, remission, and complete remission on flares following tapering of corticosteroids and immunosuppressive therapy in patients with systemic lupus erythematous: a multinational cohort study.

BACKGROUND: Targets of treatment for systemic lupus erythematosus (SLE) include the Lupus Low Disease Activity State (LLDAS), remission, and complete remission. Whether treatment can be tapered after attaining these targets and whether tapering is safer in patients in complete remission compared with LLDAS are unknown. We aimed to assess the odds of disease flares after treatment tapering in stable disease, versus continuing the same therapy. We also aimed to examine whether tapering in complete remission resulted in fewer flares or longer time to flare compared with tapering in LLDAS or remission. METHODS: This multinational cohort study was conducted at 25 sites across 13 Asia-Pacific countries. We included adult patients aged 18 years or older with stable SLE who were receiving routine clinical care, had two or more visits and had attained stable disease at one or more visits. We categorised stable disease into: LLDAS (Systemic Lupus Erythematosus Disease Activity Index 2000 [SLEDAI-2K] score ≤4, Physician Global Assessment [PGA] ≤1, and prednisolone ≤7·5 mg/day); Definitions of Remission in SLE (DORIS) remission (clinical SLEDAI-2K score 0, PGA <0·5, and prednisolone ≤5 mg/day); or complete remission on therapy (SLEDAI-2K score 0, PGA <0·5, and prednisolone ≤5 mg/day). Stable disease categories were mutually exclusive. Tapering was defined as any decrease in dose of corticosteroids or immunosuppressive therapy (mycophenolate mofetil, calcineurin inhibitors, azathioprine, leflunomide, or methotrexate). Using multivariable generalised estimating equations, we compared flares (SELENA-SLEDAI Flare Index) at the subsequent visit after drug tapering. We used generalised estimating equations and Cox proportional hazard models to compare tapering attempts that had begun in LLDAS, remission, and complete remission. FINDINGS: Between May 1, 2013, and Dec 31, 2020, 4106 patients were recruited to the cohort, 3002 (73·1%) of whom were included in our analysis. 2769 (92·2%) participants were female, 233 (7·8%) were male, and 2636 (88·1%) of 2993 with ethnicity data available were Asian. The median age was 39·5 years (IQR 29·0-50·0). There were 14 808 patient visits for patients in LLDAS, or remission or complete remission, of which 13 140 (88·7%) entered the final multivariable model after excluding missing data. Among the 9863 visits at which patients continued the same therapy, 1121 (11·4%) flared at the next visit, of which 221 (19·7%) were severe flares. Of the 3277 visits at which a patient received a tapering of therapy, 557 (17·0%) flared at the next visit, of which 120 (21·5%) were severe flares. Tapering was associated with higher odds of flare compared with continuing the same therapy (odds ratio [OR] 1·24 [95% CI 1·10-1·39]; p=0·0005). Of 2095 continuous tapering attempts, 860 (41·1%) were initiated in LLDAS, 596 (28·4%) in remission, and 639 (30·5%) in complete remission. Tapering initiated in LLDAS (OR 1·37 [95% CI 1·03-1·81]; p=0·029) or remission (1·45 [1·08-1·94]; p=0·013) had higher odds of flare in 1 year compared with complete remission. Tapering in LLDAS (hazard ratio 1·24 [95% CI 1·04-1·48]; p=0·016) or remission (1·30 [1·08-1·56]; p=0·0054) had a significantly shorter time to first flare than tapering initiated in complete remission. Attaining sustained LLDAS, remission, or complete remission for at least 6 months just before the time of taper was associated with lower odds of flare at next visit, flares in 1 year, and longer time to flare. INTERPRETATION: Tapering of corticosteroids or immunosuppressive therapy in patients with stable SLE was associated with excess flares. Our findings suggest that drug tapering should be carefully considered, weighing the risks and benefits, and is best exercised in complete (clinical and serological) remission and after maintaining stable disease for at least 6 months. FUNDING: AstraZeneca, BMS, Eli Lily, Janssen, Merck Serono, GSK, and UCB.

Low-dose glucocorticoids withdrawn in systemic lupus erythematosus: a desirable and attainable goal.

OBJECTIVES: To assess the risk of flare in systemic lupus erythematosus (SLE) patients after low-dose glucocorticoid (GC) discontinuation and to evaluate the risk factors of flare. METHODS: SLE patients who ever discontinued GCs were identified from the Peking University First Hospital SLE cohort. The disease flare profile after GC discontinuation was analysed. The flare rate was analysed using Kaplan-Meier analysis. Cox regression was used to determine the effects of variables on SLE flare. A prognostic nomogram using Cox proportional hazards regression modelling was developed. RESULTS: A total of 132 SLE patients were eligible for the final analysis. They were followed up for a median of 21.8 months (interquartile range 9.01-36.7). The cumulative probability of flare after GC discontinuation was 8.3% at 6 months, 16.8% at 1 years and 27.5% at 2 years. In multivariate Cox analysis, hypocomplementemia and serologically active clinically quiescent (SACQ) were independent risk factors of flare [hazard ratio (HR0 2.53 (95% CI 1.32, 4.88); HR 3.17 (95% CI 1.44, 6.97), respectively]. Age ≥40 years at GC withdrawal and hydroxychloroquine (HCQ) usage were independent protective factors of flare [HR 0.53 (95% CI 0.29, 0.99); HR 0.32 (95% CI 0.17, 0.62), respectively]. The protective effect of HCQ was dosage related. From the perspective of different tapering strategies embodied as the duration from prednisone 5 mg/day to complete discontinuation, a slower tapering strategy (12-24 months) significantly reduced the risk of flare compared with a faster tapering strategy (<3 months) [HR 0.30 (95% CI 0.11, 0.82), P = 0.019]. The prognostic nomogram including the aforementioned factors effectively predicted the 1 and 2 year probability of being flare-free. CONCLUSION: Low-dose GC is feasibly discontinued in real-life settings. SACQ and younger age are potential risk factors of SLE flare, while HCQ use and slow GC tapering to withdrawal can reduce relapse. The visualized model we developed may help to predict the risk of flare among SLE patients who discontinued GC.

'Not at target': prevalence and consequences of inadequate disease control in systemic lupus erythematosus-a multinational observational cohort study.

BACKGROUND: The unmet need in systemic lupus erythematosus (SLE) with the current standard of care is widely recognised, but few studies have quantified this. The recent definition of treat-to-target endpoints and other thresholds of uncontrolled disease activity provide an opportunity to formally define unmet need in SLE. In this study, we enumerated the prevalence of these states and examined their association with adverse outcomes. METHODS: Data were collected prospectively in a 13-country longitudinal SLE cohort between 2013 and 2019. Unmet need was defined as never attaining lupus low disease activity state (LLDAS), a time-adjusted mean SLEDAI-2K (AMS) > 4, or ever experiencing high disease activity status (HDAS; SLEDAI-2K ≥10). Health-related quality of life (HRQoL) was assessed using SF36 (v2) and damage accrual using the SLICC-ACR SLE Damage Index (SDI). RESULTS: A total of 3384 SLE patients were followed over 30,313 visits (median [IQR] follow-up 2.4 [0.4, 4.3] years). Eight hundred thirteen patients (24%) never achieved LLDAS. Median AMS was 3.0 [1.4, 4.9]; 34% of patients had AMS > 4. Twenty-five per cent of patients had episodes of HDAS. Each of LLDAS-never, AMS>4, and HDAS-ever was strongly associated with damage accrual, higher glucocorticoid use, and worse HRQoL. Mortality was significantly increased in LLDAS-never (adjusted HR [95% CI] = 4.98 [2.07, 12.0], p<0.001) and HDAS-ever (adjusted hazard ratio (HR) [95% CI] = 5.45 [2.75, 10.8], p<0.001) patients. CONCLUSION: Failure to achieve LLDAS, high average disease activity, and episodes of HDAS were prevalent in SLE and were significantly associated with poor outcomes including organ damage, glucocorticoid exposure, poor quality of life, and mortality.

Flare rates and factors determining flare occurrence in patients with systemic lupus erythematosus who achieved low disease activity or remission: results from a prospective cohort study.

OBJECTIVE: To investigate the frequency and determinants of flare in Chinese patients with lupus, focusing on the effect of glucocorticoid (GC) tapering on flare in patients who achieved low disease activity or remission. METHODS: We collected baseline and follow-up data from all consecutive patients in a prospective lupus cohort between January 2017 and December 2020. We defined low disease activity using the lupus low disease activity status (LLDAS), applied the DORIS (Definitions of Remission in SLE) for remission criteria and then assessed flare using the SELENA-SLEDAI Flare Index. RESULTS: Among a total of 185 patients enrolled, 139 exhibited low disease activity or remission with a median follow-up of 29.8 (21.2-35.2) months. The flare rates after achievement of LLDAS, clinical remission and complete remission on treatment were 0.23, 0.12 and 0.1 per patient-year, respectively. In contrast, the flare rate of patients who never achieved remission or LLDAS was 0.49 per patient-year. In patients with LLDAS or remission achievement, multivariate Cox regression analysis showed that lower C3 level at the time of first achieving LLDAS or clinical remission was an independent predictive factor for subsequent flares. Kaplan-Meier curves showed a significantly lower flare-free survival during the subsequent follow-up in patients with GC withdrawal compared with those maintained on a low dose of prednisone (≤7.5 mg/day) (HR=6.94, 95% CI 1.86 to 25.86, p=0.004). However, no significant differences in flare were observed in patients maintained on different low doses of prednisone (>5 mg/day and ≤7.5 mg/day vs >2.5 mg/day and ≤5 mg/day vs >0 mg/day and ≤2.5 mg/day) (p=0.200). CONCLUSIONS: Target achievement significantly lowered the rate of subsequent flare, from the perspective of both stricter targets and longer period in targets. C3 level was a strong predictor of flare in patients who have achieved treatment targets. Although GC tapering to minimal doses was feasible, its withdrawal may accelerate the risk of recurrence.

Determinants and protective associations of the lupus low disease activity state in a prospective Chinese cohort.

OBJECTIVE: To investigate the frequency and determinants of achieving the lupus low disease activity state (LLDAS), and the effect of LLDAS attainment on disease flare and damage accrual in a prospective, single-center cohort of Chinese lupus patients. METHODS: Baseline and follow-up data from consecutive patients at the Peking University First Hospital were collected from January 2017 to June 2020. RESULTS: A total of 185 patients were enrolled, with median (range) disease duration at enrolment of 2.3 (0.8-7.7) years, and median follow-up of 2.2 (1.0-2.9) years. By the end of the study, 139 (75.1%) patients had achieved LLDAS at least once; 82 (44.3%) patients achieved LLDAS for ≥ 50% of observations. Multivariable logistic regression analysis showed that 24-h urinary total protein (UTP; per g) (OR = 0.447, 95%CI [0.207-0.968], p = 0.041), serum creatinine (Scr; per 10 µmol/L) (OR = 0.72, 95%CI [0.52-0.99], p = 0.040), and C3 level (per 100 mg/L) (OR = 1.60, 95%CI [1.18-2.17], p = 0.003) at recruitment had independent negative associations with achieving LLDAS for ≥ 50% of observations. Kaplan-Meier analyses showed a significant reduction in flare rate with increased proportion of time in LLDAS. Attainment of LLDAS in at least 50% of observations was an independent protective factor for damage accrual (OR = 0.19, 95%CI [0.04-0.99], p = 0.049). CONCLUSIONS: In this prospective Chinese cohort, LLDAS was an attainable goal in clinical practice. Nephritis-related markers (UTP and Scr) and C3 level at recruitment negatively influenced achievement of LLDAS. LLDAS achievement was significantly protective from flare and damage accrual. KEY POINTS: • Low disease activity status (LLDAS) is an achievable target during SLE treatment in China. Urine protein, serum creatinine, and C3 level at recruitment independently affect LLDAS achievement in this group of Chinese lupus patients. • As a treatment target, LLDAS achievement has a highly protective effect for preventing flare and damage accrual, especially in case of achieving LLDAS for ≥ 50% of observations. • The present results further highlight the practical significance of treat-to-target principle in SLE management (T2T/SLE) and the needs for promoting the application of T2T/SLE in clinical practice as well as exploring the concrete implement strategy.

Patterns of Medication Use in Systemic Lupus Erythematosus: A Multicenter Cohort Study.

OBJECTIVE: Evidence for the utility of medications in settings lacking randomized trial data can come from studies of treatment persistence. The present study was undertaken to examine patterns of medication use in systemic lupus erythematosus (SLE) using data from a large multicenter longitudinal cohort. METHODS: Prospectively collected data from the Asia Pacific Lupus Collaboration cohort including disease activity (SLE Disease Activity Index 2000 [SLEDAI-2K]) and medication details, captured at every visit from 2013-2018, were used. Medications were categorized as glucocorticoids (GCs), antimalarials (AM), and immunosuppressants (IS). Cox regression analyses were performed to determine the time-to-discontinuation of medications, stratified by SLE disease activity. RESULTS: Data from 19,804 visits of 2,860 patients were analyzed. Eight medication categories were observed: no treatment; GC, AM, or IS only; GC plus AM; GC plus IS; AM plus IS; and GC plus AM plus IS (triple therapy). Triple therapy was the most frequent pattern (31.4% of visits); single agents were used in 21% of visits, and biologics in only 3%. Time-to-discontinuation analysis indicated that medication persistence varied widely, with the highest treatment persistence for AM and lowest for IS. Patients with a time-adjusted mean SLEDAI-2K score of ≥10 had lower discontinuation of GCs and higher discontinuation of IS. CONCLUSION: Most patients received combination treatment. GC persistence was high, while IS persistence was low. Patients with high disease activity received more medication combinations but had reduced IS persistence, consistent with limited utility. These data confirm unmet need for improved SLE treatments.

Lupus low disease activity state and remission and risk of mortality in patients with systemic lupus erythematosus: a prospective, multinational, longitudinal cohort study.

BACKGROUND: Treat-to-target goals for patients with systemic lupus erythematosus (SLE) have been validated to protect against organ damage and to improve quality of life. We aimed to investigate the association between lupus low disease activity state (LLDAS) and remission and risk of mortality in patients with SLE. We hypothesised that LLDAS has a protective association with mortality risk. METHODS: In this prospective, multinational, longitudinal cohort study, we used data from patients with SLE in the Asia Pacific Lupus Collaboration cohort collected between May 1, 2013, and Dec 31, 2020. Eligible patients were adults (aged ≥18 years) who met either the 1997 American College of Rheumatology modified classification criteria for SLE or the 2012 Systemic Lupus International Collaborating Clinics classification criteria. The primary outcome was all-cause mortality, and LLDAS, remission, and variations of remission with lower glucocorticoid thresholds were the primary exposure variables. Survival analyses were used to examine longitudinal associations between these endpoints and risk of mortality. This study is registered with ClinicalTrials.gov, NCT03138941. FINDINGS: Among a total of 4106 patients in the cohort, 3811 (92·8%) patients were included in the final analysis (median follow-up 2·8 years [IQR 1·0-5·3]; 3509 [92·1%] women and 302 [7·9%] men), of whom 80 died during the observation period (crude mortality rate 6·4 deaths per 1000 person-years). LLDAS was attained at least once in 43 (53·8%) of 80 participants who died and in 3035 (81·3%) of 3731 participants who were alive at the end of the study (p<0·0001); 22 (27·5%) participants who died versus 1966 (52·7%) who were alive at the end of the study attained LLDAS for at least 50% of observed time (p<0·0001). Remission was attained by 32 (40·0%) of 80 who died and in 2403 (64·4%) of 3731 participants who were alive at the end of the study (p<0·0001); 14 (17·5%) participants who died versus 1389 (37·2%) who were alive at the end of the study attained remission for at least 50% of observed time (p<0·0001). LLDAS for at least 50% of observed time (adjusted hazard ratio 0·51 [95% CI 0·31-0·85]; p=0·010) and remission for at least 50% of observed time (0·52 [0·29-0·93]; p=0·027) were associated with reduced risk of mortality. Modifying the remission glucocorticoid threshold (<5·0 mg/day prednisolone) was more protective against mortality than current remission definitions (0·31 [0·12-0·77]; p=0·012), and glucocorticoid-free remission was the most protective (0·13 [0·02-0·96]; p=0·046). INTERPRETATION: LLDAS significantly reduced the risk of mortality in patients with SLE. Remission did not further reduce the risk of mortality compared with LLDAS, unless lower glucocorticoid thresholds were used. FUNDING: The Asia-Pacific Lupus Collaboration received funding from Janssen, Bristol Myers Squibb, Eli Lilly, and UCB for this study.

Associations of improvement in laboratory tests with clinical outcomes in patients with active systemic lupus erythematosus: a multinational longitudinal cohort study.

BACKGROUND: The selection and categorisation of laboratory tests in disease activity measures used within systemic lupus erythematosus (SLE) trial endpoints lack strong evidence. We aimed to determine whether longitudinal improvements in routinely measured laboratory tests are associated with measures of clinical improvement in patients with baseline active SLE. METHODS: We included patients from a multicentre longitudinal cohort (recruited between May 1, 2013, and Dec 31, 2019) with active SLE (SLEDAI-2K ≥6) coinciding with an abnormality in at least one of 13 routine laboratory tests, at a visit designated as baseline. At 12 months, we analysed associations between thresholds of improvement in individual laboratory test results, measured as continuous variables, and five clinical outcomes using logistic regression. Primary outcomes were damage accrual and lupus low disease activity state (LLDAS), and secondary outcomes were modified SLE responder index (mSRI), physician global assessment (PGA) improvement of at least 0·3, and flare. FINDINGS: We included 1525 patients (1415 [93%] women and 110 [7%] men, 1328 [87%] Asian ethnicity) in separate subsets for each laboratory test. The strongest associations with LLDAS and damage protection were seen with improvements in proteinuria (complete response: adjusted odds ratio [OR] 62·48, 95% CI 18·79-208·31 for LLDAS, OR 0·22, 95% CI 0·10-0·49 for damage accrual), albumin (complete response: adjusted OR 6·46, 95% CI 2·20-18·98 for LLDAS, OR 0·42, 95% CI 0·20-1·22 for damage accrual), haemoglobin (complete response: adjusted OR 1·97, 95% CI 1·09-3·53 for LLDAS, OR 0·33, 95% CI 0·15-0·71 for damage accrual), erythrocyte sedimentation rate (complete response: adjusted OR 1·71, 95% CI 1·10-2·67 for LLDAS, OR 0·53, 95% CI 0·30-0·94 for damage accrual), and platelets (complete response: adjusted OR 4·82, 95% CI 1·54-15·07 for LLDAS, OR 0·49, 95% CI 0·20-1·19 for damage accrual). Improvement in serological tests were mainly associated with PGA and mSRI. White cell and lymphocyte count improvements were least predictive. INTERPRETATION: Improvements in several routine laboratory tests correspond with clinical outcomes in SLE over 12 months. Tests with the strongest associations were discrepant with laboratory tests included in current trial endpoints, and associations were observed across a range of improvement thresholds including incomplete resolution. These findings suggest the need to revise the use of laboratory test results in SLE trial endpoints. FUNDING: Abbvie.

Construction and application of color fundus image segmentation algorithm based on Multi-Scale local combined global enhancement.

OBJECTIVE: Aiming at the problem of low accuracy in extracting small blood vessels from existing retinal blood vessel images, a retinal blood vessel segmentation method based on a combination of a multi-scale linear detector and local and global enhancement is proposed. METHODS: The multi-scale line detector is studied, and it is divided into two parts: small scale and large scale. The small scale is used to detect the locally enhanced image and the large scale is used to detect the globally enhanced image. Fusion the response functions at different scales to get the final retinal vascular structure. RESULTS: Experiments on two databases STARE and DRIVE, show that the average vascular accuracy rates obtained by the algorithm reach 96.62% and 96.45%, and the average true positive rates reach 75.52% and 83.07%, respectively. CONCLUSION: The segmentation accuracy is high, and better blood vessel segmentation results can be obtained.

[Effects of corn stover mulch quantity on mid-infrared spectroscopy of soil organic carbon in a no-tillage agricultural ecosystem]. / çŽ‰ç±³ç§¸ç§†è¦†ç›–è¿˜ç”°é‡å¯¹å è€•åœŸå£¤æœ‰æœºç¢³ä¸­çº¢å¤–å ‰è°±ç‰¹å¾çš„å½±å“.

We examined carbon chemical composition and stability along soil depth (topsoil 0-5 cm, mid-soil 20-40 cm, and deep soil 60-100 cm) in a no-tillage (NT) agricultural system with various amount of corn stover as mulch for 8 years, including 0 (NT0), 33% (NT33), 67% (NT67) and 100% (NT100), in Northeast China, using mid-infrared spectroscopy. The results showed that, relative to NT0, the treatments of NT33 and NT100 increased polysaccharide content of the top layer and mid-layer soils, the former decreased topsoil carbon component diversity, while the latter maintained soil carbon stability of three soil layers. NT67 increased carbon stability at the deep layer soil. Our results demonstrated that if corn stover resources were sufficient, NT with 100% corn stover mulch could both be beneficial to carbon availability at 0-40 cm soil layer and stability of the whole soil profile. The nonlinear relationship between the amount of corn stover mulch and the mid-infrared spectral characteristics of the soil called for further research on the microbial-control mechanism over soil carbon cycling under different amounts of corn stover mulch.

Treatments and outcomes in Chinese patients with serologically active clinically quiescent systemic lupus erythematosus: a retrospective observational study.

OBJECTIVE: To clarify the frequency and outcome of patients with systemic lupus erythematosus (SLE) who achieved the clinical state as serologically active clinically quiescent (SACQ) and to identify factors associated with the flare of disease. METHODS: Clinical data of patients diagnosed as SLE and followed in Peking University First Hospital from 2009 to 2015 were retrospectively reviewed. Six hundred eighty-two patients who were followed up for more than 6 months were analyzed. SACQ was defined as an at least a 6-month period with persistent serologic activity and without clinical activity and daily dose of prednisone or equivalent were less than 7.5 mg. Serologically quiescent clinically quiescent (SQCQ) patients served as control groups. Data including demographics, initial symptoms, duration to SACQ, treatments before and after SACQ, and characteristics of the patients suffered from flare were analyzed. RESULTS: Among the 682 patients, 170 patients were SACQ (24.9%) and 187 patients were SQCQ. SQCQ patients (38.61 ± 15.08 years old) were older at baseline than SACQ patients (38.61 ± 15.08 years vs. 32.09 ± 14.35 years, p < 0.001). Of 170 SACQ patients, 32.9% experienced flare that was significantly higher than 15.5% of SQCQ patients (29/187). Corticosteroids (OR 1.323, 95% CI 1.129 to 1.550; p = 0.001) was an independent risk factor for flare, while antimalarials (OR 0.045, 95% CI 0.004 to 0.474; p = 0.010) and immunosuppressants (OR 0.332, 95% CI 0.156 to 0.706; p = 0.004) were protective factors in SACQ patients; however, only antimalarials was protective factors in SQCQ patients (OR 0.028, 95% CI 0.001 to 0.743; p = 0.033). CONCLUSION: About one third of SLE patients with SACQ experience flare, significantly more frequent than that of patients with SQCQ. Thus, approach to prevent flare in SACQ patient is required. Maintenance therapy of hydroxychloroquine and immunosuppressant agents may be protective and beneficial treatment strategy in these patients.