Association of systemic lupus erythematosus standard of care immunosuppressants with glucocorticoid use and disease outcomes: a multicentre cohort study.

BACKGROUND: This study examines the association of standard-of-care systemic lupus erythematosus (SLE) medications with key outcomes such as low disease activity attainment, flares, damage accrual, and steroid-sparing, for which there is current paucity of data. METHODS: The Asia Pacific Lupus Collaboration (APLC) prospectively collects data across numerous sites regarding demographic and disease characteristics, medication use, and lupus outcomes. Using propensity score methods and panel logistic regression models, we determined the association between lupus medications and outcomes. RESULTS: Among 1707 patients followed over 12,689 visits for a median of 2.19 years, 1332 (78.03%) patients achieved the Lupus Low Disease Activity State (LLDAS), 976 (57.18%) experienced flares, and on most visits patients were taking an anti-malarial (69.86%) or immunosuppressive drug (76.37%). Prednisolone, hydroxychloroquine and azathioprine were utilised with similar frequency across all organ domains; methotrexate for musculoskeletal activity. There were differences in medication utilisation between countries, with hydroxychloroquine less frequently, and calcineurin inhibitors more frequently, used in Japan. More patients taking leflunomide, methotrexate, chloroquine/hydroxychloroquine, azathioprine, and mycophenolate mofetil/mycophenolic acid were taking ≤ 7.5 mg/day of prednisolone (compared to > 7.5 mg/day) suggesting a steroid-sparing effect. Patients taking tacrolimus were more likely (Odds Ratio [95% Confidence Interval] 13.58 [2.23-82.78], p = 0.005) to attain LLDAS. Patients taking azathioprine (OR 0.67 [0.53-0.86], p = 0.001) and methotrexate (OR 0.68 [0.47-0.98], p = 0.038) were less likely to attain LLDAS. Patients taking mycophenolate mofetil were less likely to experience a flare (OR 0.79 [0.64-0.97], p = 0.025). None of the drugs was associated with a reduction in damage accrual. CONCLUSIONS: This study suggests a steroid-sparing benefit for most commonly used standard of care immunosuppressants used in SLE treatment, some of which were associated with an increased likelihood of attaining LLDAS, or reduced incidence of flares. It also highlights the unmet need for effective treatments in lupus.

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.

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.

Montreal cognitive assessment as a screening instrument for cognitive impairment in systemic lupus erythematosus patients without overt neuropsychiatric manifestations.

OBJECTIVES: The Montreal Cognitive Assessment (MoCA) is an increasingly used screening tool for cognitive impairment. The aim of this study was to examine how MoCA performed in identifying cognitive impairment (CI) domains in SLE patients compared with formal standardized neuropsychological testing (NPT). Factors related to SLE disease, immunologic and psychological state associated with CI were also explored. METHODS: This cross-sectional study recruited 50 SLE patients without overt neuropsychiatric manifestations from April 2017 to May 2018. The patients were evaluated with MoCA, formal NPT and the Depression, Anxiety, and Stress Scales (DASS) 42-item self-report questionnaire. Values of sensitivity and specificity were computed for different cut-offs of MoCA within each cognitive domain of NPT and descriptive analysis was used to identify the factors affecting cognitive function. RESULTS: The median score for MoCA was 27.5 (range 22-30). Using a MoCA cutoff of <26, 18 (36%) were identified to have CI using NPT compared to 8 (16%) using MoCA. The most frequently affected cognitive domain was executive functioning with 15 affected patients. Sensitivities and specificities of the MoCA range from 50% to 100% and 5.7% to 16.7%, respectively, across cognitive domains. A lower MoCA cutoff of <25 improve sensitivity of identifying impairment in executive functioning from 60% to 80%. In univariate analysis, DASS scores, disease activity, presence of antiphospholipid antibodies, presence of concurrent autoimmune disease, current, and cumulative corticosteroid therapy did not predict cognitive performance. CONCLUSION: MoCA may be a useful screening tool to identify the most frequently affected cognitive domain which is executive functioning using a lower cutoff of <25 in SLE patients without overt neuropsychiatric manifestations.

'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.

Colorimetric and fluorescent TRAP assays for visualising and quantifying fish osteoclast activity.

Histochemical detection of tartrate-resistant acid phosphatase (TRAP) activity is a fundamental technique for visualizing osteoclastic bone resorption and assessing osteoclast activity status in tissues. This approach has mostly employed colorimetric detection, which has limited quantification of activity in situ and co-labelling with other skeletal markers. Here we report simple colorimetric and fluorescent TRAP assays in zebrafish and medaka, two important model organisms for investigating the pathogenesis of bone disorders. We show fluorescent TRAP staining, utilising the ELF97 substrate, is a rapid, robust and stable system to visualise and quantify osteoclast activity in zebrafish, and is compatible with other fluorescence stains, transgenic lines and antibody approaches. Using this approach, we show that TRAP activity is predominantly found around the base of the zebrafish pharyngeal teeth, where osteoclast activity state appears to be heterogeneous.

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.

Independent associations of lymphopenia and neutropenia in patients with systemic lupus erythematosus: a longitudinal, multinational study.

OBJECTIVE: The prevalence and associations of leucopenia in SLE remain incompletely understood. We evaluated associations of disease activity and medication use with leucopenia (lymphopenia and neutropenia) in a multinational, prospectively followed SLE cohort. METHODS: Data from the Asia Pacific Lupus Collaboration cohort, in which disease activity and medications were prospectively captured from 2013 to 2018, were used. Predictors of lymphopenia (lymphocyte count <0.8 × 109/l) and neutropenia (neutrophil count <1.5 × 109/l) were examined using multiple failure, time-dependent survival analyses. RESULTS: Data from 2330 patients and 18 287 visits were analysed. One thousand and eighteen patients (43.7%) had at least one episode of leucopenia; 867 patients (37.2%) had lymphopenia, observed in 3065 (16.8%) visits, and 292 (12.5%) patients had neutropenia, in 622 (3.4%) visits. After multivariable analyses, lymphopenia was associated with overall disease activity, ESR, serology, prednisolone, AZA, MTX, tacrolimus, CYC and rituximab use. MTX and ciclosporin were negatively associated with neutropenia. Lupus low disease activity state was negatively associated with both lymphopenia and neutropenia. CONCLUSION: Both lymphopenia and neutropenia were common in SLE patients but were differentially associated with disease and treatment variables. Lymphopenia and neutropenia should be considered independently in studies in SLE.

Factors associated with damage accrual in patients with systemic lupus erythematosus with no clinical or serological disease activity: a multicentre cohort study.

BACKGROUND: Evaluating the contribution of glucocorticoid use to organ damage in systemic lupus erythematosus is confounded by glucocorticoid use in active disease. We sought to determine the independence of the contribution of glucocorticoid use to damage accrual from associations with disease activity by analysing patients without measurable disease activity. METHODS: Patients (age >18 years) who met the criteria for systemic lupus erythematosus were recruited from 13 centres in Australia, Indonesia, Japan, Malaysia, the Philippines, Singapore, Taiwan, and Thailand, and followed longitudinally. Disease activity (Systemic Lupus Erythematosus Disease Activity Index 2000 [SLEDAI-2K] and Physician Global Assessment [PGA] scores) and treatment details were recorded at each visit (at least once every 6 months), and organ damage measured annually according to the Systemic Lupus International Collaborating Clinics Damage Index (SDI). Glucocorticoid use during the study period was recorded as any exposure to prednisolone, cumulative prednisolone exposure, and time-adjusted mean daily prednisolone dose. Multivariate survival analyses were used to examine time-dependent associations of glucocorticoid use with damage accrual (defined as an increase of ≥1 on SDI). A SLEDAI-2K score of 0 was taken to indicate the absence of clinical and serological disease activity; a subset of patients without disease activity during the study were defined by a time-adjusted mean SLEDAI-2K (AMS) score of 0. FINDINGS: Between May 1, 2013, and Dec 31, 2016, 1707 patients were recruited. Over a median observation period of 2·2 years (IQR 1·5-3·0), damage accrual events were observed in 255 (14·9%) patients. 1405 (82·3%) of patients were exposed to prednisolone, with a median time-adjusted mean prednisolone dose of 5·0 mg/day (IQR 1·9-8·8). As SLEDAI-2K and PGA scores were highly correlated, two multivariable models were set, each including one of these two variables. In the model including AMS score, baseline SDI damage (SDI >0) was independently associated with damage accrual (HR 1·32 [95% CI 1·01-1·73], p=0·0427). In the other model, time-adjusted mean PGA score was independently associated with damage accrual (1·05 [1·02-1·08], p=0·0012). In both models, factors independently associated with damage accrual included time-adjusted mean prednisolone dose, age at enrolment, and ethnicity (Asian vs non-Asians). 157 (9·2%) patients had an AMS score of 0 (no disease activity), among whom 103 (65·6%) had glucocorticoid exposure and the median time-adjusted mean prednisolone dose was 2·0 mg/day (IQR 0·0-5·0). Accrual of irreversible organ damage occurred in 21 (13·4%) of these patients and was independently associated with time-adjusted mean prednisolone dose (HR 1·14 [95% CI 1·03-1·26], p=0·0117), time-adjusted mean PGA score (1·13 [1·03-1·23], p=0·0144), and age at enrolment (1·04 [1·01-1·07], p=0·0061), but not baseline SDI damage (0·94 [0·43-2·06], p=0·8675). INTERPRETATION: Glucocorticoid use contributes to damage accrual in systemic lupus erythematosus independently of the presence of clinical or serological disease activity. FUNDING: UCB Pharma, GlaxoSmithKline, Janssen, Bristol-Myers Squibb, and AstraZeneca (to the Asia-Pacific Lupus Collaboration).

Development of the Asia Pacific Lupus Collaboration cohort.

AIM: The aim of this manuscript is to describe the development of the Asia Pacific Lupus Collaboration (APLC) cohort. METHOD: The APLC cohort is an ongoing, prospective longitudinal cohort. Adult patients who meet either the American College of Rheumatology (ACR) Modified Classification Criteria for systemic lupus erythematosus (SLE), or the Systemic Lupus International Collaborating Clinics (SLICC) Classification Criteria, and provide informed consent are recruited into the cohort. Patients are routinely followed up at 3- to 6-monthly intervals. Information on demographics, clinical manifestations, treatment, pathology results, outcomes, and patient-reported quality of life (Short-form 36 version 2) are collected using a standardized case report form. Each site is responsible for obtaining local ethics and governance approval, patient recruitment, data collection, and data transfer into a centralized APLC database. RESULTS: The latest APLC cohort comprises 2160 patients with >12 000 visits from Australia, China, Hong Kong, Indonesia, Japan, Malaysia, Philippines, Singapore, Taiwan and Thailand. The APLC has proposed the Lupus Low Disease Activity State (LLDAS) as a treat-to-target (T2T) endpoint, and reported several retrospective and cross-sectional analyses consistent with the validity of LLDAS. Longitudinal validation of LLDAS as a T2T endpoint is currently underway. CONCLUSION: The APLC cohort is one of the largest contemporary SLE patient cohorts in the world. It is the only cohort with substantial representation of Asian patients. This cohort represents a unique resource for future clinical research including evaluation of other endpoints and quality of care.

Evaluation of remission definitions for systemic lupus erythematosus: a prospective cohort study.

BACKGROUND: Validated outcome measures are needed from which to derive treatment strategies for systemic lupus erythematosus (SLE). However, no definition of remission for SLE has been widely adopted. The Definitions of Remission in Systemic Lupus Erythematosus (DORIS) group has proposed a framework with multiple potential definitions of remission. In this study, we aimed to assess the attainability and effect on disease outcomes of the DORIS definitions of remission, compared with the lupus low disease activity state (LLDAS), in patients with SLE. METHODS: In this prospective cohort study, we enrolled patients with SLE from 13 international centres that are part of the Asia Pacific Lupus Collaboration. Eligible patients were older than 18 years and fulfilled one of two classification criteria for SLE (1997 American College of Rheumatology criteria or the 2012 Systemic Lupus International Collaborating Clinics criteria). Visits were according to clinical need, with a minimum frequency of one visit per 6 months. We assessed attainment of remission on the basis of the eight DORIS definitions of remission, which varied in terms of serological activity, glucocorticoid use, and use of immunosuppresive agents; attainment of LLDAS; and disease flares at each visit. Irreversible organ damage accrual was recorded annually. Our primary aim was to assess exposure of patients to each of the remission definitions or LLDAS, and the respective association of these states with accrual of irreversible organ damage as the primary outcome measure. Occurrence of disease flares was the key secondary outcome. We used time-dependent Cox proportional hazards models and generalised linear models to assess DORIS definitions of remission and LLDAS in terms of their association with damage accrual and disease flares. FINDINGS: Between May 1, 2013, and Dec 31, 2016, 1707 patients with SLE were recruited and followed for a mean of 2·2 years (SD 0·9), totalling 12 689 visits. Remission, depending on DORIS definition, was achieved in 581 (4·6%) to 4546 (35·8%) of 12 689 visits. Spending 50% or more of observed time in any remission state was associated with a significant reduction in damage accrual, except for the two most stringent remission definitions, for which the frequency of attainment was lowest. Remission definitions disallowing serological activity were associated with the greatest reductions in disease flares. LLDAS was more attainable than any remission definition and was associated with a similar magnitude of protection from damage accrual and disease flares. Sustained remission and LLDAS were associated with a wider spread of effect sizes for reduction in risk of damage. By analysing patients who met the definition for LLDAS but not remission, we found that LLDAS was significantly associated with reduction in damage accrual, independent of all definitions of remission, except the least stringent. INTERPRETATION: Attainment of remission was associated with significant reductions in damage accrual and disease flares. LLDAS was more achievable than remission based on the DORIS criteria, but was similarly protective. Remission definitions with less stringency might be insufficiently distinct from LLDAS to substantially affect outcome measures, and further studies are needed to distinguish the protective effects of the various remission definitions. FUNDING: UCB, GlaxoSmithKline, Janssen, Bristol-Myers Squibb, and AstraZeneca.

Lupus low disease activity state as a treatment endpoint for systemic lupus erythematosus: a prospective validation study.

BACKGROUND: Treat-to-target strategies have improved outcomes in single-organ diseases with simple clinical or laboratory endpoints. A lack of validated endpoints has prevented adoption of treat to target for complex multiorgan conditions, such as systemic lupus erythematosus (SLE). We report the first prospective study undertaken to specifically validate a treat-to-target endpoint for SLE. METHODS: In this prospective cohort study, patients aged 18 years or older with SLE were recruited from 13 centres in eight countries and followed prospectively. Patients with at least two visits over the study period no more than 6 months apart were included in the longitudinal analysis. Patients with no visits in the final year of the study were censored from their last visit. Attainment of the lupus low disease activity state (LLDAS) was assessed at each visit. The primary outcome measure was accrual of irreversible end-organ damage, defined as at least a 1-point increase in the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. We used time-dependent hazard regression models and generalised linear models to measure the association between LLDAS (attainment at any timepoint, cumulative time in LLDAS, and sustained LLDAS) with accrual of irreversible end-organ damage or flare (key secondary outcome). This study is registered with ClinicalTrials.gov, NCT03138941. FINDINGS: Between May 1, 2013, and Dec 31, 2016, 1707 patients were recruited and followed for a mean of 2·2 years (SD 0·9), totalling 12 689 visits. Attainment of LLDAS at any timepoint was associated with reduction in damage accrual (hazard ratio 0·59, 0·45-0·76; p<0·0001) and subsequent flare (0·65, 95% CI 0·56-0·75; p<0·0001). Cumulative time in LLDAS was associated with improved outcomes: compared with patients with less than 50% of observed time in LLDAS, those with at least 50% of observed time in LLDAS had reduced risk of damage accrual (0·54, 0·42-0·70; p<0·0001) and flare (0·41, 0·35-0·48; p<0·0001). Similarly, increased durations of sustained LLDAS were associated with incremental reductions in the risk of damage accrual. The association of LLDAS with reduced damage accrual was observed regardless of pre-existing damage or disease activity at study entry. INTERPRETATION: LLDAS attainment is associated with significant protection against flare and damage accrual in SLE. These findings validate LLDAS as an endpoint for clinical studies in SLE. FUNDING: The Asia Pacific Lupus Collaboration received project support grants from UCB Pharma, GlaxoSmithKline, Janssen, Bristol-Myers Squibb, and AstraZeneca.

Association of the lupus low disease activity state (LLDAS) with health-related quality of life in a multinational prospective study.

BACKGROUND: Systemic lupus erythematosus (SLE) is associated with significant impairment of health-related quality of life (HR-QoL). Recently, meeting a definition of a lupus low disease activity state (LLDAS), analogous to low disease activity in rheumatoid arthritis, was preliminarily validated as associated with protection from damage accrual. The LLDAS definition has not been previously evaluated for association with patient-reported outcomes. The objective of this study was to determine whether LLDAS is associated with better HR-QoL, and examine predictors of HR-QoL, in a large multiethnic, multinational cohort of patients with SLE. METHODS: HR-QoL was measured using the Medical Outcomes Study 36-item short form health survey (SF-36v2) in a prospective study of 1422 patients. Disease status was measured using the SLE disease activity index (SLEDAI-2 K), physician global assessment (PGA) and LLDAS. RESULTS: Significant differences in SF-36 domain scores were found between patients stratified by ethnic group, education level and damage score, and with the presence of active musculoskeletal or cutaneous manifestations. In multiple linear regression analysis, Asian ethnicity (p < 0.001), a higher level of education (p < 0.001), younger age (p < 0.001) and shorter disease duration (p < 0.01) remained significantly associated with better physical component scores (PCS). Musculoskeletal disease activity (p < 0.001) was negatively associated with PCS, and cutaneous activity (p = 0.04) was negatively associated with mental component scores (MCS). Patients in LLDAS had better PCS (p < 0.001) and MCS (p < 0.001) scores and significantly better scores in multiple individual SF-36 domain scores. Disease damage was associated with worse PCS (p < 0.001), but not MCS scores. CONCLUSIONS: Ethnicity, education, disease damage and specific organ involvement impacts HR-QoL in SLE. Attainment of LLDAS is associated with better HR-QoL.