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ObjectiveOutcome measures used in SLE randomised controlled trials (RCTs) have impeded trial success and drug approval. In an ongoing global project to develop a novel outcome measure for SLE RCTs, a ‘core set’ of domains with which to determine treatment response was chosen via consensus. We investigated the impact of restricting disease activity assessment to this core set on responder classification in RCTs.MethodsUsing pooled baseline and week 52 data from two phase III SLE RCTs (Belimumab in Subjects with Systemic Lupus Erythematosus (BLISS)-52, NCT00424476; BLISS-76, NCT00410384), we divided items from the British Isles Lupus Assessment Group (BILAG) disease activity index into core and non-core sets. The core set included 30 of 86 BILAG items across five domains: mucocutaneous (rash, alopecia, mucosal ulcers), haematological (thrombocytopenia, haemolytic anaemia), arthritis, serositis and nephritis. We analysed baseline disease activity and treatment response at week 52.ResultsWe analysed 1526 patients. At baseline, the core set captured the majority of disease activity captured using the full BILAG (1426/1526 (93.5%) of patients). Cutaneous vasculitis, non-haemolytic anaemia, leucopenia, dyspnoea and fatigue were the most common non-core set manifestations present. At week 52, about 1278/1426 (89.5%) patients demonstrated concordant treatment responses measured with the core set only versus all BILAG items. Discordance was again driven by cutaneous vasculitis, non-haemolytic anaemia, leucopenia and fatigue.ConclusionsLimiting the classification of treatment response to a core set of domains has the potential to simplify SLE RCT endpoints without a significant negative impact on patient inclusion or responder classification.

BackgroundKnowledge of the role of IgA isotype autoantibodies in systemic lupus erythematosus (SLE) is lacking. We aimed to explore associations between serum IgA autoantibody profiles and SLE clinical phenotypes using an unbiased approach.Methods1613 serum IgA autoantibodies were quantified in 60 patients with SLE using the i-Ome protein array, customised to also detect antibodies against three interferons (IFNα1, IFNω and IFNγ). Using clustering analysis, patients were grouped according to IgA autoantibody profiles; associations between clusters and clinical features were assessed using multinomial logistic regression. Associations between individual autoantibodies and clinical features were assessed via differential abundance analysis and supervised learning.ResultsFive patient clusters were identified; patients in cluster 4, characterised by antitransforming acidic coiled-coil-containing protein 1 (anti-TACC1) and anti-cAMP-dependent protein kinase type I-alpha regulatory subunit (anti-PRKAR1A) IgA profiles, were significantly more likely to be of Asian ethnicity and have lupus nephritis than those in clusters 1 and 3. Patients in cluster 4 and those in cluster 3, characterised by antiangiomotin-like protein 2 (anti-AMOTL2) IgA profiles, were significantly more likely to use immunosuppression than those in cluster 2. Analysis of individual autoantibodies revealed a significant association between antisignal transducing adaptor molecule 2 (anti-STAM2) and haematological disease activity. Targeted analysis demonstrated associations between several autoantibodies to IFN-associated proteins and SLE phenotypes, including ethnicity, disease activity, immunosuppression and organ damage.ConclusionsClustering according to IgA autoantibody profiles suggests the presence of a subgroup of patients with SLE associated with Asian ethnicity, lupus nephritis and immunosuppression use. Additionally, a novel association between anti-STAM2 IgA and haematological disease was discovered. These findings demonstrate the pathophysiological relevance of IgA autoantibodies in SLE and suggest their potential as SLE biomarkers.

ObjectiveThis study describes baseline demographics, clinical characteristics and treatments of patients diagnosed with systemic lupus erythematosus (SLE) at the time of registration in the registries of the Lupus Federated Data Network (LupusNet).MethodsData were collected from five SLE registries in four global regions: APLC (Asia Pacific), FORWARD (North America), RELESSER (Europe), GLADEL 2.0 and Almenara (Latin America). LupusNet uses a federated data network approach and a privacy-by-design method, where only aggregated results are shared. Demographics, disease activity (based on Physician Global Assessment (PGA) and Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) scores), accumulated damage (Systemic Lupus International Collaborating Clinics Damage Index) and treatment use data were mapped and harmonised using the Observational Medical Outcomes Partnership Common Data Model V.5.4.ResultsA total of 10 370 patients were included in the analysis; of those, 3908 patients were in Asia Pacific, 3066 in North America, 1806 in Europe and 1590 in Latin America. The majority of patients were female (91%); the median (IQR) duration from SLE diagnosis to registry entry ranged from 5 (1–12) to 12 (6–19) years. Heterogeneity in disease activity was observed across registries based on mean (SD) SLEDAI-2K total (3.0 (4.1)−7.0 (7.4)) and PGA (0.4 (0.5)−1.2 (1.0)) scores. Across registries, SLE features most common were related to serologic activity (low complement and increased DNA binding (19%–47%)); other common clinical features included proteinuria and arthritis (4%–37%). Cataracts (4%–9%) were the most common characteristic related to accumulated damage. Glucocorticoids, antimalarials and immunosuppressants were the most commonly used treatments, with variations in their proportions observed across registries.ConclusionsThese findings demonstrate significant heterogeneity in clinical characteristics and treatment patterns across the registries in LupusNet. By recognising regional differences, findings from LupusNet may help guide treatment approaches in SLE and optimise patient outcomes.

Background The utility of generic health-related quality of life (HRQoL) questionnaires in patients with systemic lupus erythematosus (SLE) is uncertain. We compared the performance of generic (SF36) and specific (SLEQOL) HRQoL surveys by examining their associations with the Global Rating of Change (GRC) and SLE clinical indicators. Methods The study included SLE patients who attended a single-center rheumatology clinic between 2013 and 2017. Patients completed both specific (SLEQOL) and generic (SF36) surveys and rated their GRC compared to the previous visit using a 7-point Likert scale on the same day of routine visits. Based on GRC scores, patients’ change in HRQoL was categorized as “no change,” “deterioration,” or “improvement.” Disease activity (SLEDAI-2K), flare, and lupus low disease activity state (LLDAS) were assessed at each visit, and organ damage (SDI) was determined annually. Pairwise correlations between SLEQOL and SF36 components were examined, and associations between GRC status and SLE disease indicators were compared using generalized estimating equations (GEE). Results Three hundred thirty-seven patients with 2062 visits were included in the analysis. SLEQOL correlated significantly with SF36. Patients reported improvements in HRQoL in 58%, deterioration in 15%, and “no change” in 27% of all visits. Compared to the “no change” group, mean SF36 and SLEQOL scores were significantly lower in the deterioration group and higher in the improvement group. The magnitude of changes observed with SLEQOL and SF36 in the deterioration and improvement groups was similar. Patients in LLDAS had significantly higher mean scores in both SLEQOL and SF36. In contrast, patients with active disease, especially those with cutaneous, renal, central nervous system, and musculoskeletal activity, had significantly lower SLEQOL and SF36. Flare and organ damage were also associated with lower SLEQOL and SF36-PCS (physical component) but not with SF36-MCS (mental component). Conclusion SLEQOL and SF36 similarly describe HRQoL in SLE. Both instruments demonstrated strong associations with GRC-based deterioration or improvement as well as SLE disease status. LLDAS was associated with improved HRQoL.

ObjectivesThis study examined if lowering the glucocorticoid (GC) ceiling in the definition of lupus low disease activity state (LLDAS) from 7.5 mg/day to 5 mg/day (LLDAS-5) was associated with better outcomes in patients with systemic lupus erythematosus (SLE).MethodsData from a 13-country longitudinal SLE cohort (American College of Rheumatology/Systemic Lupus International Collaborating Clinics criteria), collected prospectively between 2013 and 2020, were analysed. Survival analyses were used to examine the longitudinal associations of LLDAS definitions with flare, organ damage accrual (frailty models) and mortality (Cox regression models).Results3801 patients with ≥2 visits were studied, with a median of 2.8 years (IQR: 1.0–5.4) of follow-up data (total visits: 40 949). 2141 (56.3%) patients experienced mild–moderate/severe flares; 717 (20.8%) accrued organ damage, and 80 (2.1%) died. 3072 (80%) patients attained LLDAS in 19 293 (47%) visits, while 2858 (75%) patients attained LLDAS-5 in 17 403 (42%) visits. Most patients in LLDAS were also in LLDAS-5; 214 patients (5.6%) attained LLDAS on at least one occasion, but never attained LLDAS-5. The magnitude of protection provided by LLDAS attainment against flare, irreversible organ damage accrual and mortality was similar with both GC thresholds. HRs (95% CIs) of damage accrual subsequent to spending 12 months in sustained LLDAS and LLDAS-5 were 0.42 (0.33 to 0.54, p<0.0001) and 0.43 (0.34 to 0.55, p<0.001), respectively. Likewise, HRs of flare and mortality corresponding to 12 months in LLDAS and LLDAS-5 were similar.ConclusionsNo evidence was found to support revising the GC dose threshold of the LLDAS definition. Regardless, minimising GC exposure remains a key goal of SLE management.Trial registration numberNCT03138941.

ObjectiveTo report the prevalence of disease activity in individual SLE organ domains, including prevalence stratified by the most common disease activity cut-off score for clinical trial eligibility (SLE Disease Activity Index 2000; SLEDAI-2K ≥6).MethodsWe used data from a multinational longitudinal SLE cohort, prospectively collected between 2013 and 2020. Disease activity was categorised by the SLEDAI-2K into nine organ systems. We calculated proportions of organ-specific disease activity in the overall cohort and stratified by SLEDAI-2K ≥6 or <6, on both a per-patient and per-visit level.ResultsWe included 4102 patients (92.0% female, 88.9% Asian) contributing 42 345 eligible visits. Serological disease activity was most prevalent, affecting 75.5% of patients at least once during follow-up, followed by renal (41.6%), cutaneous (36.5%), musculoskeletal (20.1%) and haematological (19.1%) activity. Serositis (3.4%), vasculitis (3.4%), central nervous system activity (3.0%) and fever (2.9%) occurred infrequently. In patient visits with an SLEDAI-2K ≥6 (n=10 031), the most common active manifestations were serological (89.8%), renal (72.9%), cutaneous (26.4%) and musculoskeletal (14.3%). In patient visits with an SLEDAI-2K <6 (n=32 314), renal (7.3%), cutaneous (6.7%), haematological (5.8%) and musculoskeletal (1.3%) disease activity were still present.ConclusionSerological, renal, cutaneous, musculoskeletal and haematological manifestations predominate in patients with active SLE; other organs are affected infrequently. Trial outcome measures could focus on measuring change in these systems and omit detailed analysis of rare events. Conversely, some patients with active disease in common domains would be ineligible for clinical trials based on an SLEDAI-2K <6. Use of organ-specific activity measures and inclusion criteria may overcome this limitation.

Objective In contrast to relapsing‐remitting patterns, persistently active disease (PAD) is a disease activity pattern in patients with systemic lupus erythematosus (SLE) that is inadequately studied. We sought to identify the frequency and determinants of flare and PAD in SLE. Methods Flare was defined using the Safety of Estrogens in Lupus Erythematosus National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index (SELENA–SLEDAI flare index), and PAD was defined as an SLEDAI‐2K score of ≥4, excluding serology only, on two or more consecutive visits with a maximum six‐month interval. Multivariable logistic regression was used to develop predictive models for flare and PAD, which were tested in an independent validation subset. Results Among 3,811 patients over 2.8 (interquartile range 1.0–5.3) years of follow‐up, 2,142 (56.2%) experienced flare and 1,786 (46.9%) had PAD, with 368 (9.7%) experiencing PAD but not flare. The most common flare features were nephritis and arthritis, whereas PAD was most commonly characterized by renal or mucocutaneous activity. After adjusting for prednisone dose and use of antimalarials and immunosuppressants, low gross domestic product in country of residence, smoking, arthritis, nephritis, and low complement levels were predictive for flare, whereas being in a low disease activity state for ≥50% of follow‐up time (LLDAS50) was a protective factor. Renal activity and higher time‐adjusted mean SLEDAI‐2K were predictive of PAD, whereas LLDAS50 was protective. The models developed gave 72.1% and 83.8% correct classification of flare and PAD, respectively, in the validation cohort. Conclusion Both flare and PAD are common disease activity patterns in SLE; both predict organ damage accrual but differ in disease features and predictive factors. Because 9.7% of patients experience PAD but not flare, flare measures alone do not adequately capture all patients in whom disease control is suboptimal.

Objectives Systemic sclerosis (SSc) is an autoimmune disease characterised by fibrosis, vascular dysfunction and immune dysregulation. The pathogenesis of SSc remains poorly understood, although studies have indicated a role for the innate immune response. Methods Here, we measured serum interleukin (IL)‐1α, IL‐1β and IL‐18 levels in 105 SSc patients and 47 healthy controls (HC) and analysed them with respect to multiple clinical parameters. Results Serum IL‐18 concentrations were significantly higher in SSc patients than in HC, while no significant differences in concentrations of IL‐1α and IL‐1β were observed between SSc and HC. In both SSc and HC serum, IL‐1α and IL‐1β were positively correlated, while in SSc, both cytokines negatively correlated with IL‐18. Serum IL‐18 was significantly negatively correlated with both carbon monoxide transfer coefficient (KCO) and diffusing capacity of the lungs for carbon monoxide (DLCO). Serum IL‐1β was positively correlated with the modified Rodnan skin score (mRSS), particularly in patients with limited subtype. DLCO, KCO and tricuspid regurgitation (TR) velocity were significantly higher in patients with high serum IL‐1β. Serum IL‐1α was significantly lower in SSc patients with low KCO and positively correlated with KCO. SSc patients with high serum IL‐1α concentrations were more likely to have digital ulcers. Conclusions Our data suggest that these IL‐1 family cytokines may have different roles in the pathogenesis of SSc fibrotic complications. Serum levels of IL‐1α, IL‐1β and IL‐18 were measured in patients with systemic sclerosis (SSc) and analysed with respect to multiple clinical parameters. The data suggest potentially different roles for each cytokine in SSc.

Objectives To determine the presence and clinical associations of the soluble receptors of B cell‐activating factor from the tumor necrosis factor family (BAFF) in serum of patients with systemic lupus erythematosus (SLE). Methods Serum BAFF and soluble BAFF receptor (sBAFF‐R) were quantified using ELISA, and soluble B cell maturation antigen (sBCMA) and transmembrane activator and cyclophilin ligand interactor (sTACI) by Luminex, in 87 SLE patients and 17 healthy controls (HC). Disease activity and organ damage were assessed using SLE Disease Activity Index 2000 (SLEDAI‐2K) and Systemic Lupus International Collaborating Clinics (SLICC) SLE Damage Index (SDI), respectively. Results BAFF and all receptors were detectable in all serum samples. Serum sBCMA and sTACI, but not sBAFF‐R, were significantly higher in SLE than in HC. Serum BAFF was also increased in SLE, but this association was attenuated after adjusting for age and ethnicity. Increased serum BAFF was associated with flare and organ damage. Increased serum sBCMA was associated with the presence of anti‐dsDNA, but not with overall or organ‐specific disease activity, flare or organ damage. Neither sTACI nor sBAFF‐R was associated with any SLE clinical parameters in multivariable analysis. While serum BAFF correlated negatively with sBAFF‐R in HC, no statistically significant correlations were observed between BAFF and its receptors in SLE patients. Conclusion Serum BAFF was associated with flare and organ damage independent of the presence of its soluble receptors. While sBCMA was associated with anti‐dsDNA positivity, other soluble BAFF receptors were not associated with SLE clinical indicators. We found that serum soluble B cell maturation antigen (sBCMA) and transmembrane activator and cyclophilin ligand interactor (sTACI), but not BAFF receptor (sBAFF‐R), were significantly higher in systemic lupus erythematosus (SLE) patients than in healthy controls (HC). Serum B cell‐activating factor from the tumor necrosis factor family (BAFF) was associated with flare and organ damage independent of the presence of its soluble receptors. While sBCMA was associated with anti‐dsDNA positivity, other soluble BAFF receptors were not associated with SLE clinical indicators.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the development of autoantibodies to nuclear antigens and inflammatory responses mediated by multiple cytokines. Although previous studies have determined clinical associations between SLE and the anti-inflammatory cytokines IL-10 and IL-37, their role in the disease, or their potential as biomarkers, remains unclear. We examined serum levels of IL-10 and IL-37 in a large cohort of SLE patients, with detailed longitudinal clinical data. We demonstrate a statistically significant association of serum IL-10 with disease activity, with higher levels in active compared to inactive disease. High first visit IL-10 was predictive of high subsequent disease activity; patients with IL-10 in highest quartile at first visit were 3.6 times more likely to have active disease in subsequent visits. Serum IL-37 was also higher in SLE patients compared to control, and was strongly associated with Asian ethnicity. However, IL-37 was not statistically significantly associated with disease activity. IL-37 was significantly reduced in patients with organ damage but this association was attenuated in multivariable analysis. The data suggest that IL-10, but not IL-37, may have potential as a biomarker predictive for disease activity in SLE.