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 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).

Enrolment of the first paediatric cohort into the Australian lupus registry and biobank: A single-centre experience.

INTRODUCTION: We aim to report on the feasibility of establishment of the first paediatric cohort as part of the longitudinal database of the Australian Lupus Registry and Biobank (ALRB) and to describe the enrolment data with a focus on clinical characteristics, serological data, treatment strategies and patient/parent-reported outcome measures. METHODS: All patients under the age of 18 years with a diagnosis of systemic lupus erythematosus (SLE) attending the paediatric rheumatology service of a single, tertiary hospital were identified. Patients were enrolled in the ALRB if they met ≥4/11 of the American College of Rheumatology (ACR) 1997 SLE classification criteria or the Systemic Lupus International Collaborating Clinics (SLICC) 2012 classification criteria. Enrolment data including demographics, clinical characteristics, serological profiles, disease activity and damage assessments were recorded. Peds-QL Rheumatology and General Modules were used to assess patient and parent-reported outcomes. RESULTS: Twenty-seven patients were eligible for inclusion, with 26 patients (96%) consenting for enrolment. Twenty-five patients (92%) consented for biobanking. Twenty patients (77%) were female. The median age at enrolment was 16 years (interquartile range (IQR) 13.7, 17.4). The median disease duration from diagnosis was 3.2 years (IQR 1.4, 5.3). Sixteen patients (62%) had synovitis, 16 (62%) had cutaneous involvement, 4 (15%) had serositis, 17 (65%) had haematological involvement and 7 (27%) had renal involvement at enrolment. Nineteen patients (73%) were prescribed at least two disease-modifying anti-rheumatic medications (DMARDs). Hydroxychloroquine (n = 22, 85%) and mycophenolate mofetil (n = 9, 35%) were the most commonly prescribed DMARDs. The median SLEDAI-2K score was 2 (IQR 2, 4). Six patients (23%) had active disease (SLEDAI-2K ≥6) at enrolment. Three patients (11.5%) had reported damage using the SLICC/ACR Damage Index. Twenty-three children (88%) and eighteen parents (69%) completed the Paediatric Quality of Life Inventory. Quality of life scores reported across domains of physical, emotional, social and school functioning at enrolment were comparable to previously studied paediatric cohorts with SLE and other chronic diseases. CONCLUSION: We have established our centre as the first paediatric participating site of the ALRB, providing contemporary data on the clinical characteristics, serological profile and health-related quality of life outcomes of Australian children with SLE. Paediatric involvement with this national registry will provide a unique perspective for future clinical and scientific research. Collection of Australian-specific paediatric longitudinal data will also enable a broader understanding of SLE within a multicultural Australian population.

Biomarkers of asthma relapse and lung function decline in adults with spontaneous asthma remission: A population-based cohort study.

BACKGROUND: The extent to which biomarkers of asthma activity persist in spontaneous asthma remission and whether such markers are associated with future respiratory outcomes remained unclear. We investigated the association between sub-clinical inflammation in adults with spontaneous asthma remission and future asthma relapse and lung function decline. METHODS: The Tasmanian Longitudinal Health Study is a population-based cohort (n = 8583). Biomarkers of systemic inflammation were measured on participants at age 45, and latent profile analysis was used to identify cytokine profiles. Bronchial hyperresponsiveness (BHR) and nitric oxide products in exhaled breath condensate (EBC NOx) were measured at age 50. Participants with spontaneous asthma remission at ages 45 (n = 466) and 50 (n = 318) were re-evaluated at age 53, and associations between baseline inflammatory biomarkers and subsequent asthma relapse and lung function decline were assessed. RESULTS: We identified three cytokine profiles in adults with spontaneous asthma remission: average (34%), Th2-high (42%) and Th2-low (24%). Compared to the average profile, a Th2-high profile was associated with accelerated decline in post-BD FEV1 /FVC (MD -0.18% predicted per-year; 95% CI -0.33, -0.02), while a Th2-low profile was associated with accelerated decline in both post-BD FEV1 (-0.41%; -0.75, -0.06) and post-BD FVC (-0.31%; -0.62, 0.01). BHR and high TNF-α during spontaneous remission were associated with an increased risk of asthma relapse. In contrast, we found no evidence of association between EBC NOx and either asthma relapse or lung function decline. CONCLUSION: BHR and serum inflammatory cytokines have prognostic value in adults with spontaneous asthma remission. At-risk individuals with BHR, Th2-high or Th2-low cytokine profiles may benefit from closer monitoring and on-going follow-up.

Comparisons between US norm-based two-component and Japanese norm-based three-component SF-36 summary scores in systemic lupus erythematosus patients.

OBJECTIVES: We compared the US norm-based two-component vs. Japanese norm-based three-component summary scores of the Medical Outcomes Study Short Form-36 (SF-36) in patients with systemic lupus erythematosus (SLE). METHODS: One hundred fourteen Japanese SLE patients were studied. SF-36 physical component summary (PCS) and mental component summary (MCS) scores were computed by the US norm-based two-component (US2) and Japanese norm-based three-component (JP3) models, respectively, and compared. Their association with demographics and disease characteristics was also analysed. RESULTS: The US2-PCS scores were significantly higher than the JP3-PCS scores (p < .001); however, the US2-MCS and JP3-MCS scores were not significantly different (p = .16). Bland-Altman analyses demonstrated that the US2-PCS scores were generally higher than the JP3-PCS scores, and their difference was larger in the subjects with lower PCS scores. However, the multiple linear regression analyses for the PCS and MCS scores computed by the different models demonstrated mostly equivalent standardized regression coefficients with the variables. CONCLUSIONS: Although the agreement between the US norm-based two-component and Japanese norm-based three-component models of the SF-36 was insufficient, their scores demonstrated similar associations with other variables. The application of the US original version could be acceptable in certain studies depending on the research question.

Measurement of specific organ domains in lupus randomized controlled trials: a scoping review.

OBJECTIVE: Randomized controlled trials (RCTs) in SLE (lupus) typically adopt composite responder definitions as primary efficacy endpoints; however, outcomes within individual organ domains are also important to understand. The aim of this scoping review was to evaluate how organ-specific disease activity and therapeutic responses have been measured and reported in lupus RCTs. METHODS: We searched MEDLINE, EMBASE, Cochrane registry and clinicaltrials.gov. Eligible studies were RCTs investigating efficacy of an immune-directed drug therapy in active SLE, published January 2000-March 2021, excluding studies limited to lupus nephritis. Data were extracted independently in duplicate into a template and summarized descriptively. RESULTS: Thirty-four RCTs were included, of which 32 (94%) reported activity and/or responses in at least one organ domain. Study populations had a high, although variable, frequency of baseline musculoskeletal and mucocutaneous activity and low, but also variable, representation of other domains. Definitions of organ-specific responses were inconsistent, even within individual instruments. Response in most organ domains were evaluated using BILAG and SLEDAI components but meaningful comparison between treatment arms was limited by small subgroups analysed in a post hoc fashion. Specific mucocutaneous and arthritis instruments were also used, including within pre-specified organ-specific endpoints, which discriminated between treatment arms in some studies. CONCLUSION: Mucocutaneous and musculoskeletal manifestations predominate in SLE RCTs. Organ-specific outcome measures are commonly reported, but definitions of involvement and response are inconsistent. Research into the development of new outcome measures for key organ domains, and validation and comparison of response definitions using existing instruments, is needed.

Fibromyalgia, mood disorders, cognitive test results, cognitive symptoms and quality of life in systemic lupus erythematosus.

OBJECTIVES: Cognitive dysfunction, and comorbidities such as mood disorder and fibromyalgia, are common in SLE. This study aims to explore the associations between fibromyalgia, mood disorders, cognitive symptoms and cognitive dysfunction in SLE patients, and their impact on quality of life. METHODS: We tested cognition in SLE patients and healthy controls, and evaluated cognitive symptoms, mood disorder, fibromyalgia, fatigue and quality of life using patient-reported outcome measures. We examined associations of these comorbidities with both patient-reported cognitive symptoms and cognitive test performance. RESULTS: High fibromyalgia symptom score and history of depression or anxiety were associated with cognitive dysfunction. There were no significant associations between current depression, anxiety symptoms or fatigue score and objective cognitive dysfunction. In contrast, mood disorder symptoms, history of mood disorder, fibromyalgia symptoms and fatigue all had significant associations with patient-reported cognitive symptoms. There were no significant associations between patient-reported cognitive symptoms and objective cognitive dysfunction. Objective cognitive dysfunction, patient-reported cognitive symptoms, history of mood disorder and fibromyalgia symptoms all had significant associations with poorer quality of life; fibromyalgia had the biggest impact. CONCLUSIONS: Cognitive symptoms are common in SLE, but there were no associations between cognitive symptoms and objective cognitive dysfunction. Depression, anxiety and fibromyalgia were more consistently associated with patient-reported cognitive symptoms than with objective cognitive dysfunction. These factors all have a significant impact on quality of life. Understanding the discrepancy between patient-reported cognitive symptoms and cognitive test performance is essential to advance care in this area of unmet need.

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.

Associations between physicians' global assessment of disease activity and patient-reported outcomes in patients with systemic lupus erythematosus: A longitudinal study.

OBJECTIVE: To determine longitudinal associations between Physician Global Assessment (PGA) and patient-reported outcomes (PROs) in patients with systemic lupus erythematosus (SLE). METHODS: Patients attending a rheumatology clinic between 2013 and 2017 completed specific (SLEQOL) and generic (SF36) health-related quality of life (HRQoL) surveys and rated their global rating of change (GRC) at each visit. PGA, SLEDAI-2K and SLE Flare Index (SFI) were also captured on all visits. Generalised estimating equations (GEE) methods were used to examine longitudinal associations of PGA with PROs and clinical indicators. RESULTS: 337 patients were followed for a median [IQR] of 3.2 [1.6, 3.4] years (2,059 visits). High PGA (>1) was strongly associated with high SLEDAI-2K scores, the presence of flares and poor PROs. Odd ratios (OR) [95% CI] of PGA > 1 in patients with SLEDAI-2K >4 & <10 and SLEDAI-2K ≥10, compared to SLEDAI-2K ≤ 4, were 3.46 [2.36, 5.08], p < 0.001 and 6.39 [4.30, 9.49], p < 0.001, respectively. OR [95% CI] of PGA > 1 in patients with mild-to-moderate or severe flares were 2.09 [1.62, 2.71], p < 0.001 and 4.42 [3.21, 6.07], p < 0.001, respectively. Mental components of both SLEQOL (mood, self-image) and SF36 (MCS) surveys demonstrated significant associations with high PGA. After adjusting for SLEDAI-2K, one-point increase in PGA was associated with reductions in SLEQOL total score and SF36-MCS by 2.33 (regression coefficient (RC) [95% CI] = -2.33 [-3.77, -0.88], p = 0.002), and 4.16 (RC [95% CI] = -4.16 [-5.19, -3.13], p < 0.001) points, respectively. Associations of some physical components (SLEQOL-symptoms, and SF36-PCS) with PGA attenuated when adjusted for SLEDAI-2K. Patients who rated low scores of GRC, which indicate health deterioration, were twice as likely to have PGA > 1 (OR [95%CI] 1.99 [1.25, 3.16], p = 0.004). CONCLUSION: High PGA was strongly associated with poor mental health, high disease activity and flares. This study confirms the value of PGA as an efficient assessment tool for SLE.

Outcomes of patients admitted to hospital medical units with back pain.

BACKGROUND: Hospital admissions for patients with back pain are increasing. Despite their significant contribution to the healthcare burden, they remain largely unstudied. AIM: To investigate the management and clinical outcomes of patients with acute back pain admitted to hospital under general medicine units when compared to a rheumatology unit. METHODS: A 36-month retrospective, observational study on patients presenting to the emergency department with back pain who were subsequently admitted to one of three general medicine units (GM) or a rheumatology unit (RU). Differences in patient demographics, management and clinical outcomes were assessed using Chi-squared tests for categorical variables and Kruskall-Wallis tests for continuous variables. Multivariate associations of two primary outcomes, length of stay (LOS) and complications were examined using generalised estimating equations. RESULTS: Data from 712 admissions from 594 patients across the four inpatient units were used for this study. Common discharge diagnoses were musculoskeletal/non-specific back pain (41%), disc-related illness (22%), vertebral fracture (14%) and sciatica (14%). Non-English speaking background (NESB), age ≥ 80 years, disc-related disease, vertebral fracture and sciatica were statistically significantly associated with both increased LOS and complications. The presence of comorbidities was associated with more complications. GM admission was associated with a longer LOS and more complications than RU admission. CONCLUSION: Multiple factors associated with an increased LOS and complications were identified, including older patients and patients of NESB. Given the observed variations in back pain management between general and specialty units, strategies to standardise care should be considered.

The Dose-Response Association between Nitrogen Dioxide Exposure and Serum Interleukin-6 Concentrations.

Systemic inflammation is an integral part of chronic obstructive pulmonary disease (COPD), and air pollution is associated with cardiorespiratory mortality, yet the interrelationships are not fully defined. We examined associations between nitrogen dioxide (NO2) exposure (as a marker of traffic-related air pollution) and pro-inflammatory cytokines, and investigated effect modification and mediation by post-bronchodilator airflow obstruction (post-BD-AO) and cardiovascular risk. Data from middle-aged participants in the Tasmanian Longitudinal Health Study (TAHS, n = 1389) were analyzed by multivariable logistic regression, using serum interleukin (IL)-6, IL-8 and tumor necrosis factor-α (TNF-α) as the outcome. Mean annual NO2 exposure was estimated at residential addresses using a validated satellite-based land-use regression model. Post-BD-AO was defined by post-BD forced expiratory ratio (FEV1/FVC) < lower limit of normal, and cardiovascular risk by a history of either cerebrovascular or ischaemic heart disease. We found a positive association with increasing serum IL-6 concentration (geometric mean 1.20 (95% CI: 1.1 to 1.3, p = 0.001) per quartile increase in NO2). This was predominantly a direct relationship, with little evidence for either effect modification or mediation via post-BD-AO, or for the small subgroup who reported cardiovascular events. However, there was some evidence consistent with serum IL-6 being on the causal pathway between NO2 and cardiovascular risk. These findings raise the possibility that the interplay between air pollution and systemic inflammation may differ between post-BD airflow obstruction and cardiovascular diseases.

Predictors of Organ Damage in Systemic Lupus Erythematosus in the Asia Pacific Region: A Systematic Review.

OBJECTIVE: Irreversible organ damage is common in patients with systemic lupus erythematosus (SLE). Despite evidence of increased prevalence and severity of SLE in Asia Pacific, organ damage is less well studied in this region. This systematic review aims to identify predictors of organ damage in SLE in the Asia Pacific region. METHODS: We searched Medline, PubMed, Embase, and Web of Science for observational studies on organ damage in adult patients with SLE in Asia Pacific from August 31, to September 5, 2022. Study selection and data extraction were completed by two independent reviewers using Covidence systematic review software. Risk of bias was assessed using the Newcastle-Ottawa Scale and Joanna Briggs Institute tool. Significant results from univariable and multivariable analyses were synthesized from included studies. RESULTS: Thirty-eight eligible studies were selected from 1999 to 2022; 22 (58%) of these reported organ damage at study enrollment and 19 (50%) reported damage accrual, as measured by the Systemic Lupus International Collaborating Clinic/American College of Rheumatology Damage Index. Factors predictive of organ damage included older age, glucocorticoid use, longer disease duration, and disease activity. Lupus nephritis was a risk factor for renal and overall damage accrual. Hydroxychloroquine was protective against overall organ damage. CONCLUSION: Predictors of organ damage in SLE in Asia Pacific are similar to other regions. Although glucocorticoid use is a modifiable risk factor for organ damage, the impact of immunosuppressives and biologic therapies needs further investigation. Effective strategies in early disease are needed to minimize initial organ damage as it predicts subsequent damage accrual.

Autoimmune rheumatic disease in Australian Aboriginal and Torres Strait Islander Peoples: What do we know?

Autoimmune rheumatic disease (AIRD) is a collective term, which comprises a group of multisystem inflammatory autoimmune diseases, including connective tissue disease, chronic inflammatory arthritis, sarcoidosis and systemic vasculitis. Some AIRD are prevalent in the general population, and all can cause significant morbidity and reduced quality of life, with some increasing the risk of premature mortality, such as systemic lupus erythematosus (SLE), a connective tissue disease that is more prevalent and severe in Australian Aboriginal and Torres Strait Islander Peoples with high mortality rates. To ensure that management of AIRD can be optimised for all Australians, it is important that we understand the prevalence and potential phenotypic variations of AIRD across the Australian population. However, to date there have been few described cases of AIRD other than SLE in Aboriginal and Torres Strait Islander Peoples. In this review, we summarise what is known about AIRD other than SLE in Aboriginal and Torres Strait Islander Peoples, particularly with regards to prevalence, phenotype and disease outcomes, and highlight the current gaps in knowledge.

Systemic lupus erythematosus in Aboriginal and Torres Strait Islander peoples in Australia: addressing disparities and barriers to optimising patient care.

The first inhabitants of Australia and the traditional owners of Australian lands are the Aboriginal and Torres Strait Islander peoples. Aboriginal and Torres Strait Islander peoples are two to four times more likely to have systemic lupus erythematosus (SLE) than the general Australian population. Phenotypically, SLE appears distinctive in Aboriginal and Torres Strait Islander peoples and its severity is substantially increased, with mortality rates up to six times higher than in the general Australian population with SLE. In particular, Aboriginal and Torres Strait Islander peoples with SLE have increased prevalence of lupus nephritis and increased rates of progression to end-stage kidney disease. The reasons for the increased prevalence and severity of SLE in this population are unclear, but socioeconomic, environmental, and biological factors are all likely to be implicated, although there are no published studies investigating these factors in Aboriginal and Torres Strait Islander peoples with SLE specifically, indicating an important knowledge gap. In this Review, we summarise the data on the incidence, prevalence, and clinical and biological findings relating to SLE in Aboriginal and Torres Strait Islander peoples and explore potential factors contributing to its increased prevalence and severity in this population. Importantly, we identify health disparities and deficiencies in health-care provision that limit optimal care and outcomes for many Aboriginal and Torres Strait Islander peoples with SLE and highlight potentially addressable goals to improve outcomes.

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.

Smith-specific regulatory T cells halt the progression of lupus nephritis.

Antigen-specific regulatory T cells (Tregs) suppress pathogenic autoreactivity and are potential therapeutic candidates for autoimmune diseases such as systemic lupus erythematosus (SLE). Lupus nephritis is associated with autoreactivity to the Smith (Sm) autoantigen and the human leucocyte antigen (HLA)-DR15 haplotype; hence, we investigated the potential of Sm-specific Tregs (Sm-Tregs) to suppress disease. Here we identify a HLA-DR15 restricted immunodominant Sm T cell epitope using biophysical affinity binding assays, then identify high-affinity Sm-specific T cell receptors (TCRs) using high-throughput single-cell sequencing. Using lentiviral vectors, we transduce our lead Sm-specific TCR into Tregs derived from patients with SLE who are anti-Sm and HLA-DR15 positive. Compared with polyclonal mock-transduced Tregs, Sm-Tregs potently suppress Sm-specific pro-inflammatory responses in vitro and suppress disease progression in a humanized mouse model of lupus nephritis. These results show that Sm-Tregs are a promising therapy for SLE.

Characterisation and outcomes of different subsets of low disease activity states in patients with systemic lupus erythematosus.

OBJECTIVES: The lupus low disease activity state (LLDAS) allows for certain clinical and/or serological activity of SLE, provided overall disease activity does not exceed predefined cut-offs. This study aimed to evaluate the outcomes of patients who achieved LLDAS with clinical activity, serological activity only or neither clinical nor serological activity. METHODS: Patients with SLE enrolled in a prospective multinational cohort from March 2013 to December 2020 who were in LLDAS at least once were included. Visits that fulfilled both LLDAS and Definition of Remission in SLE (DORIS) criteria were excluded. RESULTS: 2099 patients were included, with median follow-up of 3.5 (IQR 1.3-5.8) years. At 6150 visits, patients were in LLDAS but not DORIS criteria; of these 1280 (20.8%) had some clinical activity, 3102 (50.4%) visits had serological activity only and 1768 (28.8%) visits had neither clinical nor serological activity. Multivariable regression analysis showed that compared with non-LLDAS, all three subsets of LLDAS had a protective association with flares in the ensuing 6 months and damage accrual in the ensuing 36 months. LLDAS with no clinical or serological activity had a significantly stronger protective association with severe flares in the ensuing 6 months compared with LLDAS with clinical activity (HR 0.47, 95% CI (0.27 to 0.82), p=0.007). CONCLUSIONS: LLDAS without any clinical activity accounted for almost 80% of LLDAS visits. This study confirms that all subsets of LLDAS are associated with reduced flare and damage accrual. However, LLDAS without any clinical or serological activity has the strongest protective association with severe flares.

Association of sustained lupus low disease activity state with improved outcomes in systemic lupus erythematosus: a multinational prospective cohort study.

BACKGROUND: Validation of protective associations of the lupus low disease activity state (LLDAS) against flare, irreversible damage, health-related quality of life, and mortality has enabled the adoption of treat-to-target strategies in patients with systemic lupus erythematosus (SLE). Previous validation studies were of short duration, limiting the ability to detect longer term signals in flare rate and irreversible damage. In addition, previous studies have focused on percent time at target, rather than actual periods of time that are more useful in clinical practice and trials. We assessed long-term protective associations of LLDAS and remission, and specifically examined protective thresholds of sustained LLDAS and remission. METHODS: Patients aged 18 years or older with SLE were followed up from May 1, 2013, to Dec 31, 2020 in a prospective, multinational, longitudinal cohort study. Patients were recruited from 25 centres in 12 countries. Multi-failure time-to-event analyses were used to assess the effect of sustained LLDAS on irreversible damage accrual (primary outcome; measured with the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index) and flare (key secondary outcome; measured with the SELENA Flare Index), with dose exposure and threshold effects studied. Sustained LLDAS or remission were defined as two or more consecutive visits over at least 3 months in the respective state. This study is registered with ClinicalTrials.gov, NCT03138941. FINDINGS: 3449 patients were followed up for a median of 2·8 years (IQR 1·1-5·6), totalling 37 662 visits. 3180 (92·2%) patients were women, and 3031 (87·9%) were of Asian ethnicity. 2506 (72·7%) patients had sustained LLDAS at least once. Any duration of sustained LLDAS or remission longer than 3 months was associated with reduced damage accrual (LLDAS: hazard ratio 0·60 [95% CI 0·51-0·71], p<0·0001; remission: 0·66 [0·57-0·76], p<0·0001) and flare (LLDAS: 0·56 [0·51-0·63], p<0·0001; remission: 0·66 [0·60-0·73], p<0·0001), and increasing durations of sustained LLDAS corresponded to increased protective associations. Sustained DORIS remission or steroid-free remission were less attainable than LLDAS. INTERPRETATION: We observed significant protective associations of LLDAS and remission against damage accrual and flare, establish a threshold of 3 months sustained LLDAS or remission as protective, and demonstrate deepening protection with longer durations of sustained LLDAS or remission. FUNDING: The Asia Pacific Lupus Collaboration receives project support grants from AstraZeneca, Bristol Myers Squibb, EMD Sereno, GSK, Janssen, Eli Lilly, and UCB.