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.
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.
ObjectivesTo compare two measures of systemic lupus erythematosus (SLE) response: the British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA) and the Systemic Lupus Responder Index (SRI) against a clinician's assessment of improvement.MethodsNinety-one lupus patients were identified with two visits at which Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and BILAG had been scored and with active disease (SLEDAI≥6) at the first visit. A physician rated the disease activity at the second visit as clinically significant improvement, no change or worsening. SRI and BICLA were scored both with and without the medication criteria often used in trials to restrict response definitions.Results68 patients were considered improved, 17 same and 6 worse at follow-up. SRI versus BICLA, performed without considering medication changes, captured physician-rated improvement with 85% vs 76% sensitivity and 74% vs 78% specificity. With medication limits both instruments had 37% sensitivity and 96% specificity for physician-assessed improvement. Seven patients considered improved by the clinician met the BICLA but not the SRI definition of improvement by failing to achieve a four-point improvement in SLEDAI. 13 clinician-rated responders met SRI but not BICLA by improving in less than all organs.ConclusionsShortfalls of SRI and BICLA may be due to BICLA only requiring partial improvement but in all organs versus SRI requiring full improvement in some manifestation(s) and not all organs. SRI and BICLA with medication restrictions are less likely to denote response when the physician disagrees and could provide stringent proof of efficacy in appropriately powered clinical trials.
Objectives Molecular medicine raised expectations for strategically targeted biologics in systemic lupus erythematosus (SLE), but clinical trials have been disappointing and difficult to interpret. Most studies add investigational agents to various, often effective, standard of care (SoC) immunosuppressants used at baseline, with unknown treatment interactions. Eliminating polypharmacy in trials of active lupus patients remains controversial. The BOLD study tested immunosuppressant withdrawal as a novel approach to interpretable SLE trials. Methods In 41 patients with active, non-organ threatening SLE flare (Group A), temporary steroids were given while background immunosuppressants were withdrawn. Time to loss of disease suppression (“flare”) and safety were evaluated; SoC was immediately resumed when symptoms recurred. Immunologic impacts of SoC treatments were studied at baseline by multiplex assay, ELISA, and mRNA array in Group A plus 62 additional patients donating a single sample (Group B). Results Patients with lower or higher baseline disease had median times-to-flare of 71 or 45 days, respectively; 98% (40/41) flared by six months. All flares were treated and resolved within six weeks. No serious adverse events occurred from flare or infection. Type I interferon, TH17, and BLyS pathways tracked together. Baseline immunosuppressants had distinct impacts on TH17 and BLyS, depending on interferon signature. Conclusion Trials in active, non-organ-threatening SLE can safely withdraw background treatments if patients who flare are designated non-responders and returned to SoC. Immunologic effects of SoC vary between interferon-defined subsets. These findings provide a strategy for minimizing or optimizing treatment combinations in lupus trials and clinical care.
ObjectiveTo develop a simple systemic lupus erythematosus (SLE) severity index that requires knowledge of only American College of Rheumatology (ACR) criteria and subcriteria.MethodsThis study used demographic, mortality and medical records data of 1915 patients with lupus from the Lupus Family Registry and Repository. The data were randomly split (2:1 ratio) into independent training and validation sets. A logistic regression with ridge penalty was used to model the probability of being prescribed major immunosuppressive drugs—a surrogate indicator of lupus severity. ACR criteria and subcriteria were used as predictor variables in this model, and the resulting regression coefficient estimates obtained from the training data were used as item weightings to construct the severity index.ResultsThe resulting index was tested on the independent validation dataset and was found to have high predictive accuracy for immunosuppressive use and early mortality. The index was also found to be strongly correlated with a previously existing severity score for lupus. In addition, demographic factors known to influence lupus severity (eg, age of onset, gender and ethnicity) all showed robust associations with our severity index that were consistent with observed clinical trends.ConclusionsThis new index can be easily computed using ACR criteria, which may be among the most readily available data elements from patient medical records. This tool may be useful in lupus research, especially large dataset analyses to stratify patients by disease severity, an important prognostic indicator in SLE.
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