A B S T R A C TBackground: The clinical and pathologic diversity of systemic lupus erythematosus (SLE) hinders diagnosis, management, and treatment development. This study addresses heterogeneity in SLE through comprehensive molecular phenotyping and machine learning clustering. Methods: Adult SLE patients (n = 198) provided plasma, serum, and RNA. Disease activity was scored by modified SELENA-SLEDAI. Twenty-nine co-expression module scores were calculated from microarray geneexpression data. Plasma soluble mediators (n = 23) and autoantibodies (n = 13) were assessed by multiplex bead-based assays and ELISAs. Patient clusters were identified by machine learning combining K-means clustering and random forest analysis of co-expression module scores and soluble mediators. Findings: SLEDAI scores correlated with interferon, plasma cell, and select cell cycle modules, and with circulating IFN-a, IP10, and IL-1a levels. Co-expression modules and soluble mediators differentiated seven clusters of SLE patients with unique molecular phenotypes. Inflammation and interferon modules were elevated in Clusters 1 (moderately) and 4 (strongly), with decreased T cell modules in Cluster 4. Monocyte, neutrophil, plasmablast, B cell, and T cell modules distinguished the remaining clusters. Active clinical features were similar across clusters. Clinical SLEDAI trended highest in Clusters 3 and 4, though Cluster 3 lacked strong interferon and inflammation signatures. Renal activity was more frequent in Cluster 4, and rare in Clusters 2, 5, and 7. Serology findings were lowest in Clusters 2 and 5. Musculoskeletal and mucocutaneous activity were common in all clusters. Interpretation: Molecular profiles distinguish SLE subsets that are not apparent from clinical information. Prospective longitudinal studies of these profiles may help improve prognostic evaluation, clinical trial design, and precision medicine approaches.

Background: Decreased heart rate variability (HRV) is associated with adverse outcomes in cardiovascular diseases and has been observed in patients with systemic lupus erythematosus (SLE). We examined the relationship of HRV with SLE disease activity and selected cytokine pathways.

Despite rapid accumulation of knowledge about complex immune dysregulation in systemic lupus erythematosus (SLE) and major primary lupus syndromes, and a plethora of promising new treatments reaching preclinical and early clinical studies, advanced-phase trials of new biologic agents have repeatedly failed to achieve their clinical end points. It is possible that none of these agents work, but the accuracy of this suggestion is as unclear as the case for efficacy, owing to issues in the design of studies and the opacity of the data that have resulted. Disease heterogeneity and complexity might be a hurdle that is simply too high to overcome by existing methodological approaches, and the way forward to interpretable trial results remains unclear. Nonetheless, well-characterized patterns of immune pathology are shared by substantial subsets of patients, and selective targeting of one or more relevant immune system molecules seems to offer the promise of safer and more effective treatments. Evolution dictates a more personalized approach to therapy and trial design, but this option seems challenging in the current economic, regulatory and scientific environment. This Review addresses these concerns by considering the progress of some of the investigational treatments targeting key physiological abnormalities in lupus.

No abstract

ObjectiveTo evaluate the efficacy and safety of the immunotherapeutic vaccine interferon-α kinoid (IFN-K) in a 36-week (W) phase IIb, randomised, double-blind, placebo (PBO)-controlled trial in adults with active systemic lupus erythematosus (SLE) despite standard of care.MethodsPatients with SLE (185) with moderate to severe disease activity and positive interferon (IFN) gene signature were randomised to receive IFN-K or PBO intramuscular injections (days 0, 7 and 28 and W12 and W24). Coprimary endpoints at W36 were neutralisation of IFN gene signature and the BILAG-Based Composite Lupus Assessment (BICLA) modified by mandatory corticosteroid (CS) tapering.ResultsIFN-K induced neutralising anti-IFN-α2b serum antibodies in 91% of treated patients and reduced the IFN gene signature (p<0.0001). Modified BICLA responses at W36 did not statistically differ between IFN-K (41%) and PBO (34%). Trends on Systemic Lupus Erythematosus Responder Index-4, including steroid tapering at W36, favoured the IFN-K and became significant (p<0.05) in analyses restricted to patients who developed neutralising anti-IFN-α2b antibodies. Attainment of lupus low disease activity state (LLDAS) at W36 discriminated the two groups in favour of IFN-K (53% vs 30%, p=0.0022). A significant CS sparing effect of IFN-K was observed from W28 onwards, with a 24% prednisone daily dose reduction at W36 in IFN-K compared with PBO (p=0.0097). The safety profile of IFN-K was acceptable.ConclusionsIFN-K induced neutralising anti-IFN-α2b antibodies and significantly reduced the IFN gene signature with an acceptable safety profile. Although the clinical coprimary endpoint was not met, relevant secondary endpoints were achieved in the IFN-K group, including attainment of LLDAS and steroid tapering.Trial registration numberNCT02665364.