Cognitive dysfunction (CD) is a common yet often clinically subtle manifestation that considerably impacts the health-related quality of life in patients with systemic lupus erythaematosus (SLE). Given the inconsistencies in CD assessment and challenges in its attribution to SLE, the reported prevalence of CD differs widely, ranging from 3 to 88%. The clinical presentation of CD in SLE is non-specific and may manifest concurrently with overt neuropsychiatric illness such as psychosis or mood disorders or as isolated impairment of attention, working memory, executive dysfunction or processing speed. Despite the lack of standardized and sensitive neuropsychological tests and validated diagnostic biomarkers of CD in SLE, significant progress has been made in identifying pathogenic neural pathways and neuroimaging. Furthermore, several autoantibodies, cytokines, pro-inflammatory mediators and metabolic factors have been implicated in the pathogenesis of CD in SLE. Abrogation of the integrity of the blood-brain barrier (BBB) and ensuing autoantibody-mediated neurotoxicity, complement and microglial activation remains the widely accepted mechanism of SLE-related CD. Although several functional neuroimaging modalities have consistently demonstrated abnormalities that correlate with CD in SLE patients, a consensus remains to be reached as to their clinical utility in diagnosing CD. Given the multifactorial aetiology of CD, a multi-domain interventional approach that addresses the risk factors and disease mechanisms of CD in a concurrent fashion is the favourable therapeutic direction. While cognitive rehabilitation and exercise training remain important, specific pharmacological agents that target microglial activation and maintain the BBB integrity are potential candidates for the treatment of SLE-related CD.

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.

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.

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. 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. 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. 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.