Immunosuppressant exposure confounds gene expression analysis in systemic lupus erythematosus.

Objectives: The analysis of gene module expression in SLE is emerging as a tool to identify active biological pathways, with the aim of developing targeted therapies for subsets of patients. Detailed information on the effect of immunosuppressants on gene module expression is lacking. We aimed to examine the impact of medication exposure on gene module expression. Methods: A set of commercially available disease-relevant gene modules were measured in 730 whole blood samples from a dedicated lupus clinic on whom prospectively collected, contemporaneous clinical data including medication exposure were available. Results: Compared to heathy controls, SLE patients showed over-expression of IFN and under-expression of B cell, T cell and pDC modules. Neutrophil module over-expression and under-expression of B and T cell modules were observed in patients with active lupus nephritis or highly active disease (SLEDAI-2K > 8), while Lupus Low Disease Activity State (LLDAS) had inverse associations. Disease activity in other organ domains was not associated with specific gene modules. In contrast, medications were associated with multiple effects. Glucocorticoid use was associated with under-expression of T cell, B cell and plasmablast modules, and over-expression of neutrophil modules. Mycophenolate and azathioprine exposure were associated with plasmablast module and B cell module under-expression respectively. Disease activity associations with neutrophil over-expression and lymphocyte module under-expression were attenuated by multivariable adjustment for medication exposure. Conclusion: Medications have significant effect on gene module expression in SLE patients. These findings emphasize the need to control for medications in studies of gene expression in SLE.

The performance of different classification criteria for systemic lupus erythematosus in a real-world rheumatology department.

OBJECTIVE: New classification criteria have been proposed to improve classification of systemic lupus erythematosus (SLE). We aimed to evaluate their performance by determining their sensitivity, specificity and accuracy in a real-world rheumatology department. METHODS: SLE patients who were enrolled in the Australian Lupus Registry and Biobank were included and compared with controls recruited from other rheumatology clinics. Clinical and immunological features were reviewed, according to ACR 1997, SLICC 2012, EULAR/ACR 2019, or Systemic Lupus Erythematosus Risk Probability Index (SLERPI). Performance of each set of criteria was evaluated for the overall cohort and in a subgroup of patients with early SLE. RESULTS: The study included 394 SLE and 123 control patients with other rheumatological conditions. Sensitivity was highest using SLICC 2012 or SLERPI 2020 criteria. Specificity was highest using ACR 1997 criteria. The SLICC 2012 criteria had the highest overall accuracy at 94.4% (95% CI: 91.7, 97.1%). In the subgroup analysis of SLE patients with early disease, SLICC 2012 performed similarly well. CONCLUSIONS: The sensitivity and specificity of each set of classification criteria vary slightly, with SLICC 2012 and SLERPI 2020 having the highest sensitivities and the ACR 1997 criteria having the highest specificity in our patient cohort. All classification criteria serve as good instructional aids for clinicians to understand SLE manifestations. For the Australian Lupus Registry and Biobank, we will continue to use the ACR 1997 and/or SLICC 2012 as entry to the observational cohort.

Type 1 interferon status in systemic lupus erythematosus: a longitudinal analysis.

OBJECTIVES: Type 1 interferon (IFN) is key to the pathogenesis of SLE, evidenced by the expression of IFN-stimulated genes (ISGs) in most patients, but the clinical utility of serial ISG assessment remains unknown. With the emergence of IFN-blocking drugs, we aimed to examine IFN status in relation to clinical findings longitudinally to provide insights into the value of testing ISG levels over time. METHODS: Clinical data and whole blood were collected prospectively on adult patients with SLE from a single tertiary lupus centre. IFN status was measured using a panel of ISGs. FINDINGS: 729 samples were analysed from 205 patients. At baseline, 62.9% of patients were IFN high, 30.2% IFN low and 6.8% borderline. 142 patients had multiple samples collected, and 87.3% of these demonstrated stable ISG status over time. In longitudinal follow-up, IFN high patients had higher activity in multiple organ domains and spent less time in Lupus Low Disease Activity State, but IFN score did not correlate with SLE Disease Activity Index in individual patients. In the small subset of patients who had large fluctuations in ISG across the observation period, most had high-dose glucocorticoids that correlated with ISG suppression. However, low-moderate-dose glucocorticoids did not suppress ISG expression. CONCLUSION: Although IFN high status is associated with indicators of more severe SLE, in the majority of patients, ISGs are stable across time and do not correlate with disease activity. Changes in ISG expression may be seen with high-dose, but not routine dose, glucocorticoid exposure. These findings suggest baseline but not serial ISG measurement may be of value in the management of SLE.

Disease course following High Disease Activity Status revealed patterns in SLE.

BACKGROUND: We sought to examine the disease course of High Disease Activity Status (HDAS) patients and their different disease patterns in a real-world longitudinal cohort. Disease resolution till Lupus Low Disease Activity State (LLDAS) has been a general treatment goal, but there is limited information on this subset of patients who achieve this. METHODS: All consenting patients of the Monash Lupus Cohort who had at least 12 months of observation were included. HDAS was defined as SLEDAI-2K ≥ 10 ever, and HDAS episode as the period from the first HDAS clinic visit until attainment of LLDAS. We examined the associations of different HDAS patterns with the likelihood of damage accrual. RESULTS: Of 342 SLE patients, 151 experienced HDAS at least once, accounting for 298 HDAS episodes. The majority of HDAS patients (76.2%) experienced Recurrent HDAS (> 1 HDAS visit), and a smaller subset (47.7%) had Persistent HDAS (consecutive HDAS visits for longer than 2 months). Recurrent or Persistent HDAS patients were younger at diagnosis and more likely to experience renal or serositis manifestations; persistent HDAS patients were also more likely to experience neurological manifestations. Baseline SLEDAI greater than 10 was associated with longer HDAS episodes. Recurrent and Persistent HDAS were both associated with an increased likelihood of damage accrual. The total duration of HDAS episode greater than 2 years and experiencing multiple HDAS episodes (≥4) was also associated with an increased likelihood of damage accrual (OR 1.80, 95% CI 1.08-2.97, p = 0.02, and OR 3.31, 95% CI 1.66-13.26, p = 0.01, respectively). CONCLUSION: HDAS episodes have a highly variable course. Recurrent and Persistent HDAS, and longer duration of HDAS episodes, increased the risk of damage accrual. In addition to a major signifier of severity in SLE, its resolution to LLDAS can determine the subsequent outcome in SLE patients.