Eric F. Morand

Description:Objective: To identify candidate Systemic Lupus Erythematosus (SLE) domains from the literature for consideration towards the development of the SLE Core Outcome Set. Methods: This was a comprehensive scoping literature review of SLE clinical trials and systematic reviews published since 2010. Studies were identified from 5 databases and were screened for eligibility. Candidate domains were extracted from the included studies. Candidate domains were winnowed and binned by the Outcome Measures in Rheumatology (OMERACT) SLE Advisory Group. Results: Of the 4063 studies identified, 507 met inclusion criteria and proceeded to data extraction. Multiple domains and items were extracted, which winnowing and binning reduced to 25 candidate domains. Conclusions: The 25 candidate domains cover the important aspects of SLE and the 4 core areas of disease impact according to OMERACT framework. The 25 candidate domains constitute a feasible and manageable number of domains to proceed with to the core domain consensus stage that covers the wide range of impact of SLE. The candidate domains will be supplemented by ongoing qualitative research with patients living with SLE to identify additional domains before proceeding to the consensus stage.

Description:The successful clinical trials of the type I interferon (IFN) receptor monoclonal antibody, anifrolumab, have proven the benefit of IFN blockade in systemic lupus erythematosus (SLE), and paved the way for novel therapies targeting this pathway. This review will cover the updated evidence regarding the efficacy and safety of anifrolumab since its positive phase III trial in 2020. In addition, indications of the clinical benefit of emerging IFN-targeting therapies, such as monoclonal antibodies targeting IFN-producing cells and small molecule inhibitors of IFN signaling, currently in phase II/III clinical trials will be discussed. Evidence from clinical trials and real-world studies have revealed the potential for IFN blockade to reduce disease activity and flares, improve glucocorticoid (GC) tapering and increase the attainment of treat-to-target goals in SLE, including in refractory patients. The efficacy of IFN blockade across different SLE disease manifestations and patient subgroups remains under investigation, as well as the ability of such treatments to reduce end organ damage. Regardless, it is clear that IFN blockade has earned a place as part of the standard of care in SLE. Future studies are needed to define whether IFN blockade moves toward being a first line treatment.

Description:Background: Emerging therapies have the potential to be used in patients with severe refractory systemic lupus erythematosus (srSLE), but no agreed definition of srSLE exists. We evaluated a pilot srSLE definition to assess whether a set of disease activity and treatment thresholds could identify patients with poor outcomes. Methods: Data from a 13-country longitudinal SLE cohort, collected prospectively between 2013 and 2020 were analysed. srSLE was defined if a patient was in high disease activity (SLEDAI-2K ≥ 10) despite combination use of at least glucocorticoids (GC) and immunosuppressants (IS) at both the index and preceding visit. Synchronised to the index srSLE visit, we assessed disease activity, medication use and treat-to-target (T2T) endpoint attainment over 12 months (m). Results: Of 3,744 patients studied, 578 (14%) had srSLE, in 1,810 visits. The median [IQR] SLEDAI-2K at the srSLE index visit was 12 [10, 14], which decreased to 6 [4, 10] at 6m and 12m. Most patients remained on combination anti-malarial, GC, and IS at all follow-up time points. The median [IQR] GC dose at the index visit was 10 [5, 20] mg/day; this reduced to 8 mg [5.0, 12.9] at 6m and 5 mg [5.0, 10.0] at 12m. Less than a quarter of patients attained LLDAS and only 1% attained GC-free remission over 12 months. Conclusions: A draft definition of srSLE was clearly associated with poor outcomes. Work to evaluate multiple thresholds with which to define srSLE, and their outcomes, is warranted.

Description:Objective: To 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). Methods: We 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. Results: We 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. Conclusions: Serological, 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.

Description:Systemic lupus erythematosus (SLE, lupus) remains an enigmatic diagnosis with a poor prognosis. SLE is characterised by complex biology and heterogeneous clinical manifestations that create a major hurdle to the approval of new medicines and contribute to multiple trial failures. While the pace of research has accelerated, drugs currently in development target a limited spectrum of mechanisms, tempering hope that any will be a panacea. The pace of translation lags behind advances in basic science, and this continues to cost patients dearly. The unacceptable metabolic adverse effects of glucocorticoids have rightly driven treatment guidelines towards ever more stringent dose-reduction targets, and new research is ongoing to develop a safe and reliable glucocorticoid replacement that will be active across a breadth of inflammatory pathways.