Developing novel drugs for systemic lupus erythematosus. Lessons learned from the belimumab trials

Systemic lupus erythematosus is the prototypic autoimmune disease with a broad range of clinical manifestations and a complex pathogenesis. B-cells hold a central role in its pathogenesis, not only as autoantibody producing cells, but also by producing other inflammatory mediators and by presenting autoantigens to autoreactive T cells. BlyS, a soluble ligand of the TNF cytokine family, is a key factor affecting B-cell homeostasis and survival and its blockade ameliorated the disease in animal models and preclinical studies of SLE. Following an unsuccessful phase II trial of belimumab, a monoclonal antibody targeting BlyS, two large phase III studies in patients with mild-to-moderate disease, BLISS-52 and BLISS-76, met their primary endpoints showing better efficacy of the drug over standard of care alone. To this end, development of a novel more sensitive responder index and improvements in study designs were crucial. As a result, belimumab became the first drug to get approval for the treatment of SLE after more than 50 years. In this paper we discuss the rationale, development, indications, lessons learned, pitfalls and challenges for this novel therapy and point-out to additional issues that need to be addressed in the future.http://dx.doi.org/10.7175/rhc.v3i3.20

Editorial: Lupus and the Brain: Advances in Neuropsychiatric Systemic Lupus Erythematosus

Editorial on the Research Topic Lupus and the Brain: Advances in Neuropsychiatric Systemic Lupus Erythematosu

Management of lupus nephritis: a systematic literature review informing the 2019 update of the joint EULAR and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations.

OBJECTIVES: To analyse the current evidence for the management of lupus nephritis (LN) informing the 2019 update of the EULAR/European Renal Association-European Dialysis and Transplant Association recommendations. METHODS: According to the EULAR standardised operating procedures, a PubMed systematic literature review was performed, from January 1, 2012 to December 31, 2018. Since this was an update of the 2012 recommendations, the final level of evidence (LoE) and grading of recommendations considered the total body of evidence, including literature prior to 2012. RESULTS: We identified 387 relevant articles. High-quality randomised evidence supports the use of immunosuppressive treatment for class III and class IV LN (LoE 1a), and moderate-level evidence supports the use of immunosuppressive treatment for pure class V LN with nephrotic-range proteinuria (LoE 2b). Treatment should aim for at least 25% reduction in proteinuria at 3 months, 50% at 6 months and complete renal response (<500-700 mg/day) at 12 months (LoE 2a-2b). High-quality evidence supports the use of mycophenolate mofetil/mycophenolic acid (MMF/MPA) or low-dose intravenous cyclophosphamide (CY) as initial treatment of active class III/IV LN (LoE 1a). Combination of tacrolimus with MMF/MPA and high-dose CY are alternatives in specific circumstances (LoE 1a). There is low-quality level evidence to guide optimal duration of immunosuppression in LN (LoE 3). In end-stage kidney disease, all methods of kidney replacement treatment can be used, with transplantation having the most favourable outcomes (LoE 2b). CONCLUSIONS: There is high-quality evidence to guide the initial and subsequent phases of class III/IV LN treatment, but low-to-moderate quality evidence to guide treatment of class V LN, monitoring and optimal duration of immunosuppression

Anxiety and depression severity in neuropsychiatric SLE are associated with perfusion and functional connectivity changes of the frontolimbic neural circuit: a resting-state f(unctional) MRI study.

peer reviewed[en] OBJECTIVE: To examine the hypothesis that perfusion and functional connectivity disturbances in brain areas implicated in emotional processing are linked to emotion-related symptoms in neuropsychiatric SLE (NPSLE). METHODS: Resting-state fMRI (rs-fMRI) was performed and anxiety and/or depression symptoms were assessed in 32 patients with NPSLE and 18 healthy controls (HC). Whole-brain time-shift analysis (TSA) maps, voxel-wise global connectivity (assessed through intrinsic connectivity contrast (ICC)) and within-network connectivity were estimated and submitted to one-sample t-tests. Subgroup differences (high vs low anxiety and high vs low depression symptoms) were assessed using independent-samples t-tests. In the total group, associations between anxiety (controlling for depression) or depression symptoms (controlling for anxiety) and regional TSA or ICC metrics were also assessed. RESULTS: Elevated anxiety symptoms in patients with NPSLE were distinctly associated with relatively faster haemodynamic response (haemodynamic lead) in the right amygdala, relatively lower intrinsic connectivity of orbital dlPFC, and relatively lower bidirectional connectivity between dlPFC and vmPFC combined with relatively higher bidirectional connectivity between ACC and amygdala. Elevated depression symptoms in patients with NPSLE were distinctly associated with haemodynamic lead in vmPFC regions in both hemispheres (lateral and medial orbitofrontal cortex) combined with relatively lower intrinsic connectivity in the right medial orbitofrontal cortex. These measures failed to account for self-rated, milder depression symptoms in the HC group. CONCLUSION: By using rs-fMRI, altered perfusion dynamics and functional connectivity was found in limbic and prefrontal brain regions in patients with NPSLE with severe anxiety and depression symptoms. Although these changes could not be directly attributed to NPSLE pathology, results offer new insights on the pathophysiological substrate of psychoemotional symptomatology in patients with lupus, which may assist its clinical diagnosis and treatment

Converging evidence of impaired brain function in systemic lupus erythematosus: changes in perfusion dynamics and intrinsic functional connectivity.

peer reviewed[en] PURPOSE: Τhe study examined changes in hemodynamics and functional connectivity in patients with systemic lupus erythematosus (SLE) with or without neuropsychiatric manifestations. METHODS: Participants were 44 patients with neuropsychiatric SLE (NPSLE), 20 SLE patients without such manifestations (non-NPSLE), and 35 healthy controls. Resting-state functional MRI (rs-fMRI) was used to obtain whole-brain maps of (a) perfusion dynamics derived through time shift analysis (TSA), (b) regional functional connectivity (intrinsic connectivity contrast (ICC) coefficients), and (c) hemodynamic-connectivity coupling. Group differences were assessed through independent samples t-tests, and correlations of rs-fMRI indices with clinical variables and neuropsychological test scores were, also, computed. RESULTS: Compared to HC, NPSLE patients demonstrated intrinsic hypoconnectivity of anterior Default Mode Network (DMN) and hyperconnectivity of posterior DMN components. These changes were paralleled by elevated hemodynamic lag. In NPSLE, cognitive performance was positively related to higher intrinsic connectivity in these regions, and to higher connectivity-hemodynamic coupling in posterior DMN components. Uncoupling between hemodynamics and connectivity in the posterior DMN was associated with worse task performance. Non-NPSLE patients displayed hyperconnectivity in posterior DMN and sensorimotor regions paralleled by relatively increased hemodynamic lag. CONCLUSION: Adaptation of regional brain function to hemodynamic changes in NPSLE may involve locally decreased or locally increased intrinsic connectivity (which can be beneficial for cognitive function). This process may also involve elevated coupling of hemodynamics with functional connectivity (beneficial for cognitive performance) or uncoupling, which may be detrimental for the cognitive skills of NPSLE patients

EULAR recommendations for the management of systemic lupus erythematosus : 2023 update

To update the EULAR recommendations for the management of systemic lupus erythematosus (SLE) based on emerging new evidence.An international Task Force formed the questions for the systematic literature reviews (January 2018-December 2022), followed by formulation and finalisation of the statements after a series of meetings. A predefined voting process was applied to each overarching principle and recommendation. Levels of evidence and strengths of recommendation were assigned, and participants finally provided their level of agreement with each item.The Task Force agreed on 5 overarching principles and 13 recommendations, concerning the use of hydroxychloroquine (HCQ), glucocorticoids (GC), immunosuppressive drugs (ISDs) (including methotrexate, mycophenolate, azathioprine, cyclophosphamide (CYC)), calcineurin inhibitors (CNIs, cyclosporine, tacrolimus, voclosporin) and biologics (belimumab, anifrolumab, rituximab). Advice is also provided on treatment strategies and targets of therapy, assessment of response, combination and sequential therapies, and tapering of therapy. HCQ is recommended for all patients with lupus at a target dose 5 mg/kg real body weight/day, considering the individual's risk for flares and retinal toxicity. GC are used as 'bridging therapy' during periods of disease activity; for maintenance treatment, they should be minimised to equal or less than 5 mg/day (prednisone equivalent) and, when possible, withdrawn. Prompt initiation of ISDs (methotrexate, azathioprine, mycophenolate) and/or biological agents (anifrolumab, belimumab) should be considered to control the disease and facilitate GC tapering/discontinuation. CYC and rituximab should be considered in organ-threatening and refractory disease, respectively. For active lupus nephritis, GC, mycophenolate or low-dose intravenous CYC are recommended as anchor drugs, and add-on therapy with belimumab or CNIs (voclosporin or tacrolimus) should be considered. Updated specific recommendations are also provided for cutaneous, neuropsychiatric and haematological disease, SLE-associated antiphospholipid syndrome, kidney protection, as well as preventative measures for infections, osteoporosis, cardiovascular disease.The updated recommendations provide consensus guidance on the management of SLE, combining evidence and expert opinion

Educational needs and preferences of young European clinicians and physician researchers working in the field of rheumatology

Funding Information: CB: Grant BE 5191/1-1 of the Deutsche Forschungsgemeinschaft.Objectives: To understand the educational needs and preferences of young clinicians and physician researchers in the field of rheumatology in Europe. Methods: An international online survey was performed as a joint venture of ESCET and EMEUNET. The survey assessed the acceptance of and the access to the current European League Against Rheumatism (EULAR) educational portfolio, as well as the unmet educational needs and learning preferences among individuals below the age of 40 years working in rheumatology in Europe. Results: Among 568 European clinicians and physician researchers, 65% indicated that the existing EULAR educational portfolio adequately covers their educational needs. Within the EULAR portfolio, the online course on rheumatic diseases and the postgraduate course were the most appreciated. Participants were very much in favour of new educational courses on imaging techniques, and 63% of participants indicated a particular interest in musculoskeletal ultrasound. A strong interest in refresher (60%) and general review (55%) courses was observed. Lack of funding was considered the major obstacle to participating in existing EULAR programmes. Finally, participants showed diverse preferences regarding learning modalities with common interests in live courses and conferences. Conclusions: EULAR's training opportunities are well appreciated among young clinicians and physician researchers in rheumatology. The results from this survey will help to develop EULAR's future educational portfolio.publishersversionPeer reviewe

Rheumatology training experience across Europe : Analysis of core competences

Publisher Copyright: © 2016 The Author(s). Copyright: Copyright 2019 Elsevier B.V., All rights reserved.Background: The aim of this project was to analyze and compare the educational experience in rheumatology specialty training programs across European countries, with a focus on self-reported ability. Method: An electronic survey was designed to assess the training experience in terms of self-reported ability, existence of formal education, number of patients managed and assessments performed during rheumatology training in 21 core competences including managing specific diseases, generic competences and procedures. The target population consisted of rheumatology trainees and recently certified rheumatologists across Europe. The relationship between the country of training and the self-reported ability or training methods for each competence was analyzed through linear or logistic regression, as appropriate. Results: In total 1079 questionnaires from 41 countries were gathered. Self-reported ability was high for most competences, range 7.5-9.4 (0-10 scale) for clinical competences, 5.8-9.0 for technical procedures and 7.8-8.9 for generic competences. Competences with lower self-reported ability included managing patients with vasculitis, identifying crystals and performing an ultrasound. Between 53 and 91 % of the trainees received formal education and between 7 and 61 % of the trainees reported limited practical experience (managing ≤10 patients) in each competence. Evaluation of each competence was reported by 29-60 % of the respondents. In adjusted multivariable analysis, the country of training was associated with significant differences in self-reported ability for all individual competences. Conclusion: Even though self-reported ability is generally high, there are significant differences amongst European countries, including differences in the learning structure and assessment of competences. This suggests that educational outcomes may also differ. Efforts to promote European harmonization in rheumatology training should be encouraged and supported.publishersversionPeer reviewe

Proceedings of the 24th Paediatric Rheumatology European Society Congress: Part three

From Springer Nature via Jisc Publications Router.Publication status: PublishedHistory: collection 2017-09, epub 2017-09-0