Anifrolumab-FNIA

Understanding the molecular events underlying systemic lupus erythematosus (SLE) onset and progression can facilitate early intervention strategies. We explored transcriptomic changes during progression from preclinical to clinical and advanced SLE, and assessed their potential reversibility by targeted agents.

This includes multicentre prospective study of individuals with nondiagnostic features suggestive of SLE. Baseline blood RNA-sequencing was performed in groups who progressed to classifiable SLE or not (n = 36 each), and compared with healthy (n = 42) and early SLE (n = 43). Transcriptome analysis included supervised methods, gene module-based clustering, and drug reversibility/repurposing pipelines with publicly available data. An independent at-risk cohort (n = 15 progressors, n = 20 nonprogressors) was used to validate molecular classifiers.

At-risk individuals exhibited deregulated metabolic, cytokine signalling, haematologic, and stress-response pathways. Progressors vs nonprogressors showed heightened interferon (IFN)-alpha (α)/gamma (γ) and inflammatory cytokine activity, corroborated by Gene Set Enrichment Analysis and coexpression analysis, and intensified during SLE classification. Unsupervised modelling of gene module-eigengene patterns revealed molecular heterogeneity among progressors, differing in p53/insulin activity and Toll-like receptor (TLR) signalling. Importantly, we characterised a 17-gene susceptibility signature that predicted transition with an area under the curve 0.80 of the receiver operating characteris (95% CI: 0.65-0.94) in the external cohort. Analysis across the continuum-from healthy and at-risk states to early SLE and lupus nephritis-revealed stepwise upregulation of IFN-α/γ, haem metabolism, and oxidative phosphorylation pathways, with additional IFN-related genes activated in established disease. SLE susceptibility and progression signatures demonstrated in silico reversibility by anifrolumab and belimumab.

IFN-α/γ and inflammatory cytokine signatures characterise evolving/early SLE, whereas amplification of IFN signalling and oxidative phosphorylation denotes severity. Blood molecular profiling may aid risk stratification and rationalise early biologic approaches.

Anifrolumab is a type I interferon receptor antagonist approved for the treatment of systemic lupus erythematosus (SLE). However, real-world evidence on its use, especially from large, unselected cohorts, is scarce. The ongoing REVEAL study is designed to collect real-world data on anifrolumab use. The data reported here are the pre-specified 6-month interim analysis, which aims to provide a phenotypic characterisation of a large real-world cohort of patients with SLE initiating anifrolumab, and to evaluate early treatment response in routine clinical practice.

REVEAL is a 5-year, multicentre, prospective observational study conducted in 25 tertiary rheumatology centres across Italy. A pre-specified interim analysis was planned when the first 50 patients completed the first 6 months of follow-up; this analysis includes all patients who initiated anifrolumab by the data cutoff of Feb 10, 2025. Patients with SLE were consecutively enrolled on the day of their first infusion of anifrolumab, prescribed according to clinical judgement and Italian indications for use. Eligible patients were aged 18 years or older, had a clinical diagnosis of SLE fulfilling at least one set of established classification criteria valid at the time of diagnosis (1997 American College of Rheumatology [ACR], 2012 Systemic Lupus International Collaborating Clinics, or 2019 European Alliance of Associations for Rheumatology-ACR), had active disease warranting anifrolumab treatment (including compassionate use programmes), and were naive to anifrolumab. Data were collected at baseline and at 1 month, 3 months, and 6 months. The primary outcome was the number of patients reaching remission (defined according to the Definition of Remission in SLE criteria as a clinical SLEDAI-2K score of 0, physician global assessment score of <0·5 [on a 0-3 scale], with a prednisone-equivalent dose ≤5 mg per day, and stable antimalarials or immunosuppressants), Lupus Low Disease Activity State (LLDAS; defined as a SLEDAI-2K ≤4 [with no activity in major organ systems and no new disease activity], physician global assessment ≤1·0, and a prednisone-equivalent dose ≤7·5 mg per day), and LLDAS5 (a modified version of the LLDAS with a prednisone-equivalent dose ≤5 mg per day) at 6 months. Adverse and serious adverse events were also recorded. No people with lived experience of SLE were involved in designing or conducting the study. This study is registered with ClinicalTrials.gov (NCT07215754) and with the Italian Medicines Agency (Agenzia Italiana del Farmaco; ID number 247) and recruitment is ongoing.

Between May 25, 2023, and Feb 10, 2025, 236 patients were recruited and included in this interim analysis. Of these, 219 (93%) were female, 17 (7%) were male, 218 (92%) were White, and the median age was 46·9 years (IQR 36·0-53·6). At baseline, the median SLEDAI-2K was 7 (IQR 6-9), and the main indications for anifrolumab were mucocutaneous (157 [67%]) and articular (116 [49%]) involvement. At 6 months, 37 (26%) of 140 patients reached remission, 80 (57%) reached LLDAS5 and 93 (66%) reached LLDAS. One patient was excluded from the outcome analysis due to missing physician global assessment data. 108 adverse events were recorded during the 6-month follow-up period; of these, 83 (77%) were infections. Five serious adverse events occurred, resulting in six hospitalisations.

This study provides the first large-scale real-world evidence of anifrolumab use in patients with SLE, supporting its clinical benefit and rapid onset of action in routine care.

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