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Remission is the established therapeutic goal for patients with systemic lupus erythematosus (SLE) and is currently defined by the widely adopted Definition Of Remission In SLE (DORIS) criteria. Attainment of remission is rare in the clinical setting, thus an alternative, pragmatic treatment target of low disease activity, as defined by the Lupus Low Disease Activity State (LLDAS), provides a less stringent and more attainable treatment goal for a wider proportion of patients compared with DORIS remission. Randomized controlled trials and real-world analyses have confirmed the positive clinical benefits of achieving either DORIS remission or LLDAS. The treat-to-target (T2T) approach utilizes practical clinical targets to proactively tailor individual treatment regimens. Studies in other chronic inflammatory diseases using the T2T approach demonstrated significantly improved clinical outcomes and quality-of-life measures compared with established standard of care. However, such trials have not yet been performed in patients with SLE. Here we review the evolution of DORIS remission and LLDAS definitions and the evidence supporting the positive clinical outcomes following DORIS remission or LLDAS attainment, before discussing considerations for implementation of these outcome measures as potential T2T objectives. Adoption of DORIS remission and LLDAS treatment goals may result in favorable patient outcomes compared with established standard of care for patients with SLE. Plain Language Summary Systemic lupus erythematosus (SLE) is a complex disease that can affect many organs. It can lead to life-threatening complications and poor quality of life. As SLE is very different in each person, it can be challenging to measure disease activity. Doctors are encouraged to set clinical targets to tailor treatment for each patient. Clinical targets include scoring systems that measure disease improvement. Remission is an established clinical target. When a patient is in remission, disease activity is controlled, and the patient does not experience any symptoms. As remission is difficult to achieve, experts developed a more realistic yet still favorable state. This is the lupus low disease activity state, when lupus symptoms are minimal on stable therapy. Doctors use remission and low disease activity in clinical trials to compare existing SLE drugs with new treatments, including biologic drugs. Biologics target key parts of the immune system to help suppress SLE. In this review, we looked at recent clinical trials and found that biologic drugs can help patients achieve remission or low disease activity. Patients who achieved these clinical targets had slower disease progression and improved quality of life. Clinical trials in SLE should continue to use remission and low disease activity targets to help compare treatments. Doctors are encouraged to use them in their routine clinics as treatment targets to measure SLE disease control. Low disease activity state may be particularly helpful as an initial target for patients who are not yet in remission.

The treat-to-target (T2T) concept has improved outcomes for patients with diabetes, hypertension and rheumatoid arthritis. This therapeutic strategy involves choosing a well-defined, relevant target, taking therapeutic steps, evaluating whether the target has been achieved, and taking action if it has not. The T2T principle has been embraced by systemic lupus erythematosus (SLE) experts, but measurable and achievable outcomes, and therapeutic options, are needed to make this approach possible in practice. Considerable evidence has been generated regarding meaningful ‘state’ outcomes for SLE. Low disease activity has been defined and studied, and the most aspirational goal, remission, has been defined by the Definition of Remission in SLE task force. By contrast, current therapeutic options in SLE are limited, and more effective and safer therapies are urgently needed. Fortunately, clinical trial activity in SLE has been unprecedented, and encouraging results have been seen for novel therapies, including biologic and small-molecule agents. Thus, with the expected advent of such treatments, it is likely that sufficiently diverse therapies for SLE will be available in the foreseeable future, allowing the routine implementation of T2T approaches in the care of patients with SLE.This Review discusses progress in identifying potential outcome measures and developing treatment options to achieve a treat-to-target approach in systemic lupus erythematosus, as well as the research advances that are needed to realize these objectives.

New biomarkers are needed for better stratification and personalized treatment of Systemic Lupus Erythematosus (SLE). Phosphoinositide 3-kinase δ (PI3Kδ) has been implicated in SLE pathogenesis. Here, we investigated whether a subset of SLE patients has increased PI3Kδ activity after T cell activation. T cells were isolated from frozen PBMCs of 108 SLE patients, 19 healthy controls, and one patient with Activated PI3K Delta syndrome (APDS), which provided a benchmark of increased PI3Kδ activity. After 90-minute anti-CD3/CD28 stimulation, phosphatidylinositol 3,4,5-trisphosphate (PIP3) and phosphatidylinositol 4,5-bisphosphate (PIP2) were measured using high-performance liquid chromatography-mass spectrometry. Higher levels of PIP3 (measured as the ratio of PIP3/PIP2) in stimulated T cells distinguished APDS patient from other subjects providing a useful biomarker of increased PI3Kδ activity. We observed no significant difference in T-cell PIP3 levels between SLE patients and healthy controls. However, a subset of SLE patients (n = 4) exhibited strong upregulation of PIP3 following T-cell stimulation, comparable to that observed in the APDS patient. PIP3 levels in stimulated T cells positively correlated with the frequency of CD4+ T cells and negatively correlated with the frequencies of CD8+, EMRA CD4+, and EMRA CD8+ T cells. We describe the range of variation of PI3Kδ activity in T cells from a large cohort of patients with SLE and from healthy subjects. Our findings suggest that increased PI3Kδ activity is not associated with SLE in general, although some SLE patients exhibit a particularly strong upregulation of PIP3 levels after T-cell stimulation. This subgroup of SLE patients warrants further investigation given the promising effect of PI3Kδ inhibitors in restoring normal immune regulation.

BackgroundTreat-to-target (T2T) is a therapeutic strategy currently being studied for its application in systemic lupus erythematosus (SLE). Patients and rheumatologists have little support in making the best treatment decision in the context of a T2T strategy, thus, the use of information technology for systematically processing data and supporting information and knowledge may improve routine decision-making practices, helping to deliver value-based care.ObjectiveTo design and develop an online Clinical Decision Support Systems (CDSS) tool “SLE-T2T”, and test its usability for the implementation of a T2T strategy in the management of patients with SLE.MethodsA prototype of a CDSS was conceived as a web-based application with the task of generating appropriate treatment advice based on entered patients’ data. Once developed, a System Usability Score (SUS) questionnaire was implemented to test whether the eHealth tool was user-friendly, comprehensible, easy-to-deliver and workflow-oriented. Data from the participants’ comments were synthesised, and the elements in need for improvement were identified.ResultsThe beta version web-based system was developed based on the interim usability and acceptance evaluation. 7 participants completed the SUS survey. The median SUS score of SLE-T2T was 79 (scale 0 to 100), categorising the application as ‘good’ and indicating the need for minor improvements to the design.ConclusionsSLE-T2T is the first eHealth tool to be designed for the management of SLE patients in a T2T context. The SUS score and unstructured feedback showed high acceptance of this digital instrument for its future use in a clinical trial.

IntroductionPregnant women with SLE have an increased risk of maternal complications and adverse fetal outcomes. These include pre-eclampsia, preterm birth and fetal growth restriction. Interestingly, this increased risk persists in subsequent pregnancies, whereas it decreases in healthy women due to the development of maternal–fetal tolerance. As maternal–fetal tolerance is crucial for a healthy pregnancy, we hypothesise that its failure contributes to the increased risk of pregnancy complications in women with SLE. Therefore, we initiated the failing maternal–fetal tolerance in SLE (FaMaLE) study to investigate the failure of maternal–fetal tolerance in pregnant women with SLE.Methods and analysisIn the FaMaLE study, women with SLE and healthy women are included in their first trimester of pregnancy (<14 weeks gestational age) at Amsterdam UMC. Throughout the pregnancy, data on SLE disease activity, pregnancy course and medication use are collected. Peripheral blood is collected once per trimester, within 48 hours before delivery and 5–12 weeks post partum. In addition, the placenta is collected after delivery. Whole blood, peripheral blood mononuclear cells and placenta samples are freshly analysed by flow cytometry to assess immune cell composition. The resulting data are analysed in relation to SLE disease course, pregnancy course and pregnancy outcomes.Ethics and disseminationThe study has been approved by the Amsterdam UMC Medical Ethics Committee and all participating women will be asked to provide informed consent. The findings will be disseminated through peer-reviewed publications, presentations at scientific meetings and via patient organisations.

ObjectiveTo evaluate the feasibility, usability and acceptability of implementing a treat-to-target (T2T) strategy supported by a Clinical Decision Support System (CDSS), in routine SLE outpatient care.MethodsA 24-week, non-randomised, multicentre, clustered pilot study was conducted across four rheumatology outpatient centres. Adult patients with SLE were allocated by centre to either a T2T strategy supported by a CDSS (T2T-CDSS) or a routine outpatient care (ROC) group. The CDSS provided evidence-based treatment recommendations based on disease activity measures. Feasibility outcomes included recruitment and retention rates. Usability was assessed with the System Usability Scale (SUS), completed by physicians in the T2T-CDSS group. Acceptability was evaluated using the Treatment Satisfaction Questionnaire (TSQ) and qualitative feedback. Exploratory outcomes included disease activity, remission rates and treatment modifications.ResultsOf 91 screened patients, 38 were enrolled (recruitment rate 42%) and 35 completed the study (retention rate 92%). The SUS score for the CDSS was 73.8, indicating good usability. Global satisfaction scores on the TSQ were stable over time and comparable between groups. Remission was achieved at least once by 61% (11/18) of patients in the T2T-CDSS group and 59% (10/17) in the ROC group. Both treatment intensifications and de-escalations occurred more frequently in the T2T-CDSS group compared with ROC (83% vs 47%). Treatment intensifications were observed in 61% of patients in the T2T-CDSS group vs 29% in the ROC group. Treatment de-escalation, represented by glucocorticoid tapering, occurred in 39% of T2T-CDSS patients compared with 18% in ROC. No statistically significant differences were observed between groups in disease activity outcomes or remission rates.ConclusionsImplementation of a T2T strategy supported by a CDSS in SLE outpatient care was feasible, usable and acceptable to patients and physicians. Although qualitative feedback revealed important implementation barriers that should be addressed in future trials, the intervention facilitated proactive, target-driven treatment adjustments without compromising patient satisfaction and shows promise for implementing goal-directed therapy in SLE management.

ObjectivesThe 2021 definition of remission in SLE (DORIS) has been widely used in clinical research. Since then, case series have suggested that a deeper state of remission is attainable for at least some patients. The DORIS Task Force committed itself to developing a suitable definition for a state of deep remission, entitled DORIS-PLUS (DORIS+).The objective of the Task Force was to obtain a consensus-based, data-driven definition of deep remission in systemic lupus erythematosus (SLE), for use in parallel with, not as a replacement for, the existing DORIS definition .MethodsFollowing initial literature surveys and preliminary work, the international DORIS+ Task Force, comprising patients and specialists in rheumatology, nephrology, dermatology and clinical immunology, held two plenary meetings, collected feedback through an international survey, and held live voting rounds applying an 80% consensus threshold.ResultsThe Task Force agreed on the following verbatim definition: ‘DORIS+ represents the state beyond clinical remission that is a meaningful outcome for patients with SLE and that may now be within reach for some.’ Consensus was also achieved that this definition will include specifications for clinical quiescence, immunological reset, limitations on treatment and a favorable patient experience. The Task Force remained divided on the inclusion of duration into the definition. The agreed-upon consensus statements, as well as statements on which consensus was not yet achieved, are shown in table 1. The Task Force also achieved consensus on definitions of remission in lupus arthritis, hematological lupus, cardiopulmonary lupus, and CNS lupus. For other organ systems no consensus was achieved, and the need for post-treatment renal biopsies emerged as the most controversial topic.Abstract LBS1:04 Table 1Statements and percentage agreement from the DORIS+ task force[Image Omitted. See PDF.]ConclusionsThe DORIS+ Task Force defined several important elements of the DORIS+ definition. A research agenda was defined that will help resolve several remaining issues. The final DORIS+ definition is anticipated in the academic year 2026-2027.

ObjectivesMethotrexate (MTX) is one of the most commonly used medications to treat rheumatoid arthritis (RA). However, the effect of MTX treatment on cellular immune responses remains incompletely understood. This raises concerns about the vulnerability of these patients to emerging infections and following vaccination.MethodsIn the current study, we investigated the impact of MTX treatment in patients with immune-mediated inflammatory disease on B and CD4 T cell SARS-CoV-2 vaccination responses. Eighteen patients with RA and two patients with psoriatic arthritis on MTX monotherapy were included, as well as 10 patients with RA without immunosuppressive treatment, and 29 healthy controls. CD4 T and B cell responses were analysed 7 days and 3–6 months after two SARS-CoV-2 messenger RNA vaccinations. High-dimensional flow cytometry analysis was used to analyse fresh whole blood, an activation-induced marker assay to measure antigen-specific CD4 T cells, and spike probes to study antigen-specific B cells.ResultsSeven days following two SARS-CoV-2 vaccinations, total B and T cell counts were similar between MTX-treated patients and controls. In addition, spike-specific B cell frequencies were unaffected. Remarkably, the frequency of antigen-specific CD4 T cells was reduced in patients using MTX and correlated strongly with anti-RBD IgG antibodies. These results suggest that decreased CD4 T cell activity may result in slower vaccination antibody responses in MTX-treated patients.ConclusionTaken together, MTX treatment reduces vaccine-induced CD4 T cell activation, which correlates with lower antibody responses.Trial registration numberNL8900.