Explore the vast range of titles available.

A phase 3 trial of anifrolumab, a monoclonal antibody to type I interferon receptor subunit 1, showed benefit in a composite primary end point of lupus scores. A previous phase 3 trial failed to meet its primary objective but showed an effect in secondary end points.

Background Patients with SLE display marked clinical and immunlogical heterogeneity. The purpose of the study was to investigate patterns of serum cytokines in patients with active and stable systemic lupus erythematosus (SLE) and to determine how they relate to clinical phenotype. Methods Serum levels of 10 cytokines were measured retrospectively in a cohort of patients with SLE and in healthy controls using a high-sensitivity multiplex bead array. Disease activity was determined using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and British Isles Lupus Assessment Group (BILAG-2004) indices. Logistic regression models were used to determine the association between cytokine levels and active SLE. Principal component analysis (PCA) and cluster analysis was then used to identify subgroups of patients on the basis of cytokine levels. Results Serum chemokine (C-X-C motif) ligand 10 (CXCL10) and CXCL13 were significantly higher in patients with SLE compared to healthy controls. Two cytokines (pentraxin-related protein (PTX3) and CXCL10) were significantly higher in patients with active disease after adjustment for potential confounding factors. Measurement of four cytokines (CXCL10, IL-10, IL-21 and PTX3) significantly improved the performance of a model to identify patients with clinically active disease. Cluster analysis revealed that the patients formed 3 distinct groups, characterised by higher levels of interferon alpha (IFNα) and B lymphocyte stimulator (BLyS) (group 1), increased CXCL10 and CXCL13 (group 2) or low levels of cytokines (group 3). Group 2 had significantly lower serum complement and higher anti-double-stranded DNA antibodies and increased prevalence of inflammatory arthritis. Conclusions Multiplex analysis has identified a serum cytokine signature for active SLE. Within the SLE population distinct cytokine subgroups were identified, with differing clinical and immunological phenotypes that appeared stable over time. Assessment of cytokine profiles may reveal unique insights into disease heterogeneity.

Background Individual clinical trials and cohort studies are a useful source of data, often under-utilised once a study has ended. Pooling data from multiple sources could increase sample sizes and allow for further investigation of treatment effects; even if the original trial did not meet its primary goals. Through the MASTERPLANS (MAximizing Sle ThERapeutic PotentiaL by Application of Novel and Stratified approaches) national consortium, focused on Systemic Lupus Erythematosus (SLE), we have gained valuable real-world experiences in aligning, harmonising and combining data from multiple studies and trials, specifically where standards for data capture, representation and documentation, were not used or were unavailable. This was not without challenges arising both from the inherent complexity of the disease and from differences in the way data were captured and represented across different studies. Main body Data were, unavoidably, aligned by hand, matching up equivalent or similar patient variables across the different studies. Heterogeneity-related issues were tackled and data were cleaned, organised and combined, resulting in a single large dataset ready for analysis. Overcoming these hurdles, often seen in large-scale data harmonization and integration endeavours of legacy datasets, was made possible within a realistic timescale and limited resource by focusing on specific research questions driven by the aims of MASTERPLANS. Here we describe our experiences tackling the complexities in the integration of large, diverse datasets, and the lessons learned. Conclusions Harmonising data across studies can be complex, and time and resource consuming. The work carried out here highlights the importance of using standards for data capture, recording, and representation, to facilitate both the integration of large datasets and comparison between studies. Where standards are not implemented at the source harmonisation is still possible by taking a flexible approach, with systematic preparation, and a focus on specific research questions.

Key Points The prevalence and rate of progression of atherosclerosis is increased in rheumatoid arthritis (RA), and atherosclerotic plaques in patients with RA might have a rupture-prone phenotype Atherosclerosis is a chronic inflammatory condition, and similarities exist in the cellular processes and cytokines involved in both atherosclerosis and rheumatoid synovitis Cardiovascular disease (CVD) and RA share genetic and environmental risk factors, including polymorphisms in genes within the HLA region, smoking and obesity The prevalence of some traditional CVD risk factors is increased in patients with RA, but traditional risk-prediction models perform poorly in this population Chronic inflammation is closely linked with atherosclerosis in RA; burden of inflammation is associated with clinical and subclinical CVD, and PET can reveal arterial inflammation in patients with active RA Although treatments for RA seem to have beneficial effects on cardiovascular event rates, mortality remains increased and further work is required to better estimate and treat cardiovascular risk in RA Cardiovascular disease and rheumatoid arthritis (RA) share genetic and environmental risk factors, as well as pathological processes. This article outlines the mechanisms that might contribute to the prevalence and characteristic phenotype of atherosclerosis in RA, with an emphasis on inflammation. Rheumatoid arthritis (RA) has long been associated with increased cardiovascular risk, but despite substantial improvements in disease management, mortality remains high. Atherosclerosis is more prevalent in RA than in the general population, and atherosclerotic lesions progress at a faster rate and might be more prone to rupture, causing clinical events. Cells and cytokines implicated in RA pathogenesis are also involved in the development and progression of atherosclerosis, which is generally recognized as an inflammatory condition. The two diseases also share genetic and environmental risk factors, which suggests that patients who develop RA might also be predisposed to developing cardiovascular disease. In RA, inflammation and atherosclerosis are closely linked. Inflammation mediates its effects on atherosclerosis both through modulation of traditional risk factors and by directly affecting the vessel wall. Treatments such as TNF inhibitors might have a beneficial effect on cardiovascular risk. However, whether this benefit is attributable to effective control of inflammation or whether targeting specific cytokines, implicated in atherosclerosis, provides additional risk reduction is unclear. Further knowledge of the predictors of cardiovascular risk, the effects of early control of inflammation and of drug-specific effects are likely to improve the recognition and management of cardiovascular risk in patients with RA.

Objectives To investigate the relationships between interferon alpha (IFNα) and the clinical and serological phenotype of patients with systemic autoimmune rheumatic disease (SARDs) in order to determine whether a distinct subpopulation of patients can be identified. Methods We recruited patients with at least 1 SARD clinical feature and at least 1 SARD-related autoantibody from two NHS Trusts in Greater Manchester. A 6-gene interferon-stimulated gene (ISG) score was calculated in all patients, and in a subgroup, a 30-gene ISG score was produced using NanoString. A digital Single Molecule Array (Simoa) was used to measure plasma IFNα protein. In an exploratory analysis, whole blood RNA sequencing was conducted in 12 patients followed by RT-qPCR confirmation of expression of 6 nucleic acid receptors (NARs) in the whole cohort. Results Sixty three of 164 (38%) patients had a positive ISG score. The 3 measures of IFNα all correlated strongly with each other ( p  < 0.0001). There were no differences in mucocutaneous or internal organ involvement between the ISG subgroups. The ISG-positive group had increased frequency of specific autoantibodies and haematological abnormalities which remained significant after adjusting for the SARD subtype. Expression of DDX58, MB21D1 and TLR7 was correlated with the ISG score whilst TLR3, TLR9 and MB21D1 were associated with neutrophil count. Conclusion In SARD patients, IFNα-positivity was associated with specific autoantibodies and haematological parameters but not with other clinical features. The variable NAR expression suggests that different pathways may drive IFNα production in individual patients. The identification of an IFNα-positive subgroup within a mixed SARD cohort supports a pathology-based approach to treatment.

Background Systemic lupus erythematosus (SLE) is a heterogeneous systemic autoimmune condition for which there are limited licensed therapies. Clinical trial design is challenging in SLE due at least in part to imperfect outcome measures. Improved understanding of how disease activity changes over time could inform future trial design. The aim of this study was to determine whether distinct trajectories of disease activity over time occur in patients with active SLE within a clinical trial setting and to identify factors associated with these trajectories. Methods Latent class trajectory models were fitted to a clinical trial dataset of a monoclonal antibody targeting CD22 (Epratuzumab) in patients with active SLE using the numerical BILAG-2004 score (nBILAG). The baseline characteristics of patients in each class and changes in prednisolone over time were identified. Exploratory PK-PD modelling was used to examine cumulative drug exposure in relation to latent class membership. Results Five trajectories of disease activity were identified, with 3 principal classes: non-responders (NR), slow responders (SR) and rapid-responders (RR). In both the SR and RR groups, significant changes in disease activity were evident within the first 90 days of the trial. The SR and RR patients had significantly higher baseline disease activity, exposure to epratuzumab and activity in specific BILAG domains, whilst NR had lower steroid use at baseline and less change in steroid dose early in the trial. Conclusions Longitudinal nBILAG scores reveal different trajectories of disease activity and may offer advantages over fixed endpoints. Corticosteroid use however remains an important confounder in lupus trials and can influence early response. Changes in disease activity and steroid dose early in the trial were associated with the overall disease activity trajectory, supporting the feasibility of performing adaptive trial designs in SLE.

Objective We applied systems biology approaches to investigate circadian rhythmicity in rheumatoid arthritis (RA). Methods We recruited adults (age 16–80 years old) with a clinical diagnosis of RA (active disease [DAS28 > 3.2]). Sleep profiles were determined before inpatient measurements of saliva, serum, and peripheral blood mononuclear leukocytes (PBML). Transcriptome and proteome analyses were carried out by RNA-SEQ and LC-MS/MS. Serum samples were analysed by targeted lipidomics, along with serum from mouse collagen induced-arthritis (CIA). Bioinformatic analysis identified RA-specific gene networks and rhythmic processes differing between healthy and RA. Results RA caused greater time-of-day variation in PBML gene expression, and ex vivo stimulation identified a time-of-day-specific RA transcriptome. We found increased phospho-STAT3 in RA patients, and some targets, including phospho-ATF2, acquired time-of-day variation in RA. Serum ceramides also gained circadian rhythmicity in RA, which was also seen in mouse experimental arthritis, resulting from gain in circadian rhythmicity of hepatic ceramide synthases. Conclusion RA drives a gain in circadian rhythmicity, both in immune cells, and systemically. The coupling of distant timing information to ceramide synthesis and joint inflammation points to a systemic re-wiring of the circadian repertoire. Circadian reprogramming in response to chronic inflammation has implications for inflammatory co-morbidities and time-of-day therapeutics.

Disease modification has become a well-established concept in several therapeutic areas; however, no widely accepted definition of disease modification exists for SLE. We reviewed established definitions of disease modification in other conditions and identified a meaningful effect on ‘disease manifestations’ (ie, signs, symptoms and patient-reported outcomes) and on ‘disease outcomes’ (eg, long-term remission or progression of damage) as the key principles of disease modification, indicating a positive effect on the natural course of the disease. Based on these findings and the treatment goals and outcome measures for SLE, including lupus nephritis, we suggest a definition of disease modification based on disease activity indices and organ damage outcomes, with the latter as a key anchor. A set of evaluation criteria is also suggested. Establishing a definition of disease modification in SLE will clarify which treatments can be considered disease modifying, provide an opportunity to harmonise future clinical trial outcomes and enable comparison between therapies, all of which could ultimately help to improve patient outcomes. This publication seeks to catalyse further discussion and provide a framework to develop an accepted definition of disease modification in SLE.

ObjectiveTo obtain updated estimates on the incidence and prevalence of systemic lupus erythematosus (SLE) in the UK, over the period 1990–2020, using the Clinical Practice Research Datalink (CPRD).MethodsThis was a retrospective cohort study using the CPRD covering the period 1990–2020. A case ascertainment algorithm was developed in line with best practice recommendations for observational research. Incidence was calculated per 100 000 person-years and point prevalence (at the mid-year point) calculated per 100 000. Results were stratified by sex.Results9443 SLE cases were identified. 5278 incident cases were identified (4538 women, 740 men). The overall incidence rate was 5.47 (95% CI 5.33 to 5.62) cases per 100 000 person-years. Incidence rates decreased slightly across the study period, which was more pronounced for women than men. Point prevalence increased over time, from 21.4 (95% CI 17.68 to 25.67) per 100 000 in 1990 to 107.14 (95% CI 103.26 to 111.12) per 100 000 in 2020.ConclusionsThe observed fivefold increase in prevalence of SLE over the last 30 years, in the context of a modest decline in incidence rate, may suggest improved outcomes in SLE and has important implications for healthcare service delivery and planning in the UK.