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

Metabolic syndrome in rheumatic diseases: epidemiology, pathophysiology, and clinical implications

Subjects with metabolic syndrome–a constellation of cardiovascular risk factors of which central obesity and insulin resistance are the most characteristic–are at increased risk for developing diabetes mellitus and cardiovascular disease. In these subjects, abdominal adipose tissue is a source of inflammatory cytokines such as tumor necrosis factor-alpha, known to promote insulin resistance. The presence of inflammatory cytokines together with the well-documented increased risk for cardiovascular diseases in patients with inflammatory arthritides and systemic lupus erythematosus has prompted studies to examine the prevalence of the metabolic syndrome in an effort to identify subjects at risk in addition to that conferred by traditional cardiovascular risk factors. These studies have documented a high prevalence of metabolic syndrome which correlates with disease activity and markers of atherosclerosis. The correlation of inflammatory disease activity with metabolic syndrome provides additional evidence for a link between inflammation and metabolic disturbances/vascular morbidity

Targeted Therapies for Systemic Lupus Erythematosus (SLE): A Critical Appraisal

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by a wide range of manifestations from mild to life-threatening. Prognosis has markedly improved in the last decades due to earlier diagnosis, prevention of comorbidities, and the use of more intensive treatment regimens. However, the high rates of morbidity, despite treatment, reflect the presence of numerous unmet medical needs in patients with SLE, calling for new, treat-to-target strategies. To date, only two biological agents, belimumab and recently anifrolumab, have been approved in patients with SLE with several others showing promising results. In this review, we critically review the data, with emphasis on the approved biologics

The genomic landscape of ANCA-associated vasculitis: Distinct transcriptional signatures, molecular endotypes and comparison with systemic lupus erythematosus

IntroductionAnti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) present with a complex phenotype and are associated with high mortality and multi-organ involvement. We sought to define the transcriptional landscape and molecular endotypes of AAVs and compare it to systemic lupus erythematosus (SLE).MethodsWe performed whole blood mRNA sequencing from 30 patients with AAV (granulomatosis with polyangiitis/GPA and microscopic polyangiitis/MPA) combined with functional enrichment and network analysis for aberrant pathways. Key genes and pathways were validated in an independent cohort of 18 AAV patients. Co-expression network and hierarchical clustering analysis, identified molecular endotypes. Multi-level transcriptional overlap analysis to SLE was based on our published data from 142 patients.ResultsWe report here that “Pan-vasculitis” signature contained 1,982 differentially expressed genes, enriched in leukocyte differentiation, cytokine signaling, type I and type II IFN signaling and aberrant B-T cell immunity. Active disease was characterized by signatures linked to cell cycle checkpoints and metabolism pathways, whereas ANCA-positive patients exhibited a humoral immunity transcriptional fingerprint. Differential expression analysis of GPA and MPA yielded an IFN-g pathway (in addition to a type I IFN) in the former and aberrant expression of genes related to autophagy and mRNA splicing in the latter. Unsupervised molecular taxonomy analysis revealed four endotypes with neutrophil degranulation, aberrant metabolism and B-cell responses as potential mechanistic drivers. Transcriptional perturbations and molecular heterogeneity were more pronounced in SLE. Molecular analysis and data-driven clustering of AAV uncovered distinct transcriptional pathways that could be exploited for targeted therapy.DiscussionWe conclude that transcriptomic analysis of AAV reveals distinct endotypes and molecular pathways that could be targeted for therapy. The AAV transcriptome is more homogenous and less fragmented compared to the SLE which may account for its superior rates of response to therapy

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