Events In Systemic Lupus Erythematosus Research Articles

Impact of the new American College of Cardiology/American Heart Association definition of hypertension on atherosclerotic vascular events in systemic lupus erythematosus

BackgroundThe 2017 American College of Cardiology/American Heart Association guidelines defined hypertension at ≥130/80 mm Hg. Studies on patients with connective tissue diseases were not considered. Our aim was to assess...

Neuropsychiatric events in systemic lupus erythematosus: a longitudinal analysis of outcomes in an international inception cohort using a multistate model approach

ObjectivesUsing a reversible multistate model, we prospectively examined neuropsychiatric (NP) events for attribution, outcome and association with health-related quality of life (HRQoL), in an international, inception cohort of systemic lupus...

Towards a pro-resolving concept in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with prominent chronic inflammatory aspects. SLE most often affects women (9:1) in childbearing age. The multifactorial nature of the etiopathogenesis of SLE involves a deficient clearance of dead and dying cells. This is supported by the occurrence of autoantibodies directed against autoantigens modified in dying and dead cells (dsDNA, high mobility group box 1 protein, apoptosis-associated chromatin modifications, e.g., histones H3-K27-me3; H2A/H4 AcK8,12,16; and H2B-AcK12) that are deposited in various tissues, including skin, kidneys, joints, muscles, and brain. The subsequent hyperinflammatory response often leads to irreparable tissue damage and organ destruction. In healthy individuals, dead and dying cells are rapidly removed by macrophages in an anti-inflammatory manner, referred to as efferocytosis. In SLE, extensive and prolonged cell death (apoptosis, necrosis, neutrophil extracellular trap (NET) formation) leads to autoantigens leaking out of the not cleared cell debris. These neo-epitopes are subsequently presented to B cells by follicular dendritic cells in the germinal centers of secondary lymphoid tissues conditioning the break of self-tolerance. Activation of autoreactive B cells and subsequent production of autoantibodies facilitate the formation of immune complexes (ICs) fueling the inflammatory response and leading to further tissue damage. ICs may also be ingested by phagocytes, which then produce further pro-inflammatory cytokines. These processes establish a vicious circle that leads to sustained inflammation. This review highlights the cell death-related events in SLE, the protagonists involved in SLE pathogenesis, the resolution of inflammation in various tissues affected in SLE, and explores strategies for intervention to restore hemostasis in a hyperinflammatory state.

Altered body composition and increased visceral adipose tissue in premenopausal and late postmenopausal patients with SLE

ObjectiveVisceral adipose tissue (VAT) is becoming a recognized cardiovascular (CV) risk factor. This study aimed to evaluate body composition, especially VAT, in systemic lupus erythematosus (SLE) and to explore the association between VAT and SLE disease-related factors.MethodNinety-eight inpatients with SLE and 108 age- and body mass index (BMI)–matched healthy controls were included. Demographic and clinical parameters were recorded. The VAT was measured by dual-energy x-ray absorptiometry.ResultThe mean age and disease duration of patients were 46.4 ± 13.0 years and 8.0 ± 7.0 years, respectively. Patients with SLE had higher VAT volume (p = 0.0015) and mass (p = 0.0017) than controls, especially in premenopausal and postmenopausal groups. The subanalysis of subjects with BMI less than 25 kg/m2 indicated that patients had lower lean mass (p = 0.0005), fat-free mass (p = 0.0005), and fat-free mass index (p = 0.0001), but increased adiposity distribution than controls, including VAT volume and mass. However, overweight/obese patients had similar body composition with controls. The VAT volume correlated with BMI, age, menopausal status, hypertension, uric acid, creatinine, non-high-density lipoprotein cholesterol, and triglyceride in both groups. In the patient group, the VAT volume correlated with disease duration, Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC/ACR-DI), and low serum complement, but not with SLEDAI and glucocorticoid dose.ConclusionThis study suggested that SLE patients had some traditional CV risk factors such as altered body composition and increased VAT. The higher VAT in patients with SLE was associated with traditional cardiometabolic risks, which may contribute to CV events in SLE populations.Key Points• Patients with SLE had increased VAT volume and mass than controls.• The VAT volume correlated with traditional cardiometabolic risk factors.• In SLE patient group, the VAT volume correlated with disease duration, SLICC/ACR-DI, and low serum complementC3/C4, but not with SLEDAI and glucocorticoid dose.

Blood Pressure Variability and Age-related Blood Pressure Patterns in Systemic Lupus Erythematosus.

Despite the high prevalence of cardiovascular (CV) disease among patients with systemic lupus erythematosus (SLE), the relationship between age, blood pressure (BP), and BP variability (BPV) is not well understood. We studied visit-to-visit BPV, its relationship to age, clinical, and demographic characteristics, and its potential role as a CV risk factor in patients with SLE. We analyzed systolic (SBP) and diastolic BP (DBP) measures in our cohort using mixed-effects regression models. From these models, we then obtained estimates of the mean BP, the visit-to-visit SD, and the between-person SD. The estimated means were compared to the general population using data from the National Health Statistics Reports from 2001 to 2008. In addition, we examined the relationship between BP (means, variances), patient demographic and clinical characteristics, and subsequent CV events. The mean SBP in SLE increased with age and was significantly higher in younger patients compared to the general population. BPV in SLE was elevated across all ages. BPV was significantly higher in African Americans, in patients with traditional CV risk factors, those with high disease activity, and in patients taking prednisone. Hydroxychloroquine was associated with significantly lower BPV. Within-person variability in DBP of ≥ 9 mmHg was highly associated with CV events in a multivariate analysis. Age-related BP patterns in SLE differ from the general population. Increased visit-to-visit BPV is affected by many disease-specific and traditional CV factors. Increased DBP variability is highly associated with CV events in SLE.

Progressive Multifocal Leukoencephalopathy in Systemic Lupus Erythematosus

Here, progressive multifocal leukoencephalopathy (PML) and PML in systemic lupus erythematosus (SLE) are reviewed. Disease-modifying therapy (DMT) associated PML is an emerging condition, particularly in multiple sclerosis patients. Although PML is a rare adverse event in SLE, we should consider development of PML more carefully in not only conventional drug-induced PML but also DMT associated PML during SLE treatment in the era of DMT associated PML.

A Meta-Analysis of Cardiovascular Events in Systemic Lupus Erythematosus

ABSTRACTObjective: To identify accurate occurrence and risk of cardiovascular (CV) events (stroke and myocardial infarction [MI]) in patients with systemic lupus erythematosus (SLE).Methods: Systemic literature search in PubMed and additional manual search were performed to obtain interested studies until March 31, 2018. The pooled incidences and risk of stroke and MI were calculated.Results: A total of 24 studies were included in this meta-analysis. For MI, a total of 1,516 SLE patients were reported to had MI (n = 96,154) over a mean follow-up of 9.98 years: incidence 2.0% (95% CI: 1.7–2.4%), i.e. 0.20/100 pyrs; in the five studies, 360 SLE patients (n = 18,943) and 817 controls had MI (n = 111,525), revealing that the risk of MI in SLE population was 3.04 times higher than in the general population (RR = 3.04, 95% CI: 1.81–5.11). For stroke, the incidence of 17 studies during the 10.09 follow-up period using random model was 4.4% (95% CI: 3.6–5.1%), i.e. 0.44/100 pyrs; in the 7 studies, 694 SLE patients (n = 22,594) and 4,034 controls had stroke (n = 255,023), indicating that the risk of MI in SLE population was 1.95 times higher than that in the general population (RR = 1.95, 95% CI: 1.52–2.53).Conclusion: Based on the findings from previous reports, our meta-analysis showed that patients with SLE have been at higher risk of CV events.

Cerebrovascular Events in Systemic Lupus Erythematosus: Diagnosis and Management.

Stroke is a major cause of morbidity, mortality and disability in systemic lupus erythematosus (SLE). Patients with SLE have a two-fold increase in the risk of stroke with younger patients (ie, less than 50 years of age) having an ever-higher risk (up to 10-fold). Although the prognosis of SLE has improved, mortality due to cerebrovascular events (CVE) remains unchanged. Cerebrovascular disease may be directly attributed to the disease per se, as a manifestation of neuropsychiatric SLE, or be the result of traditional cardiovascular risk factors accompanying the disease. Elucidation of the underlying mechanism(s) of CVE is essential as it may guide the type of therapy (ie, antithrombotic or anticoagulant therapy versus immunosuppressive). Strokes attributed to lupus usually occur early in the course of the disease and are often accompanied by evidence of activity in other organs; those related to antiphospholipid antibodies can occur at any time, in patients with either active or inactive SLE. In this review, we discuss the epidemiology, work-up, management and primary prevention of CVE in patients with lupus. In view of the effectiveness of thrombolysis, physicians need to educate lupus patients and their families for the early recognition of the signs of stroke and the need to seek prompt attention. To this end acronyms, such as FAST (Facial drooping, Arm weakness, Speech difficulties and Time to call emergency service) can be used as a mnemonic to help detect and enhance responsiveness to the needs of a person having a stroke.

Cerebrovascular Events in Systemic Lupus Erythematosus: Results From an International Inception Cohort Study.

To determine the frequency, characteristics, and outcomes of cerebrovascular events (CerVEs), as well as clinical and autoantibody associations in a multiethnic/racial inception cohort of patients with systemic lupus erythematosus (SLE). A total of 1,826 patients were assessed annually for 19 neuropsychiatric (NP) events, including 5 types of CerVEs: 1) stroke, 2) transient ischemia, 3) chronic multifocal ischemia, 4) subarachnoid/intracranial hemorrhage, and 5) sinus thrombosis. Global disease activity (Systemic Lupus Erythematosus Disease [SLE] Activity Index 2000), damage scores (SLE International Collaborating Clinics/American College of Rheumatology Damage Index), and Short Form 36 (SF-36) scores were collected. Time to event, linear and logistic regressions, and multistate models were used as appropriate. CerVEs were the fourth most frequent NP event: 82 of 1,826 patients had 109 events; of these events, 103 were attributed to SLE, and 44 were identified at the time of enrollment. The predominant events were stroke (60 of 109 patients) and transient ischemia (28 of 109 patients). CerVEs were associated with other NP events attributed to SLE, non-SLE-attributed NP events, African ancestry (at US SLICC sites), and increased organ damage scores. Lupus anticoagulant increased the risk of first stroke and sinus thrombosis and transient ischemic attack. Physician assessment indicated resolution or improvement in the majority of patients, but patients reported sustained reduction in SF-36 summary and subscale scores following a CerVE. CerVEs, the fourth most frequent NP event in SLE, are usually attributable to lupus. In contrast to good physician-reported outcomes, patients reported a sustained reduction in health-related quality of life following a CerVE.

Nitrated nucleosome levels and neuropsychiatric events in systemic lupus erythematosus; a multi-center retrospective case-control study

Nitrated nucleosome levels and neuropsychiatric events in systemic lupus erythematosus; a multi-center retrospective case-control study

Nitrated nucleosome levels and neuropsychiatric events in systemic lupus erythematosus; a multi-center retrospective case-control study

BackgroundIn patients with systemic lupus erythematosus (SLE) there is no serological test that will reliably distinguish neuropsychiatric (NP) events due to active SLE from those due to other causes. Previously we showed that serum levels of nitrated nucleosomes (NN) were elevated in a small number of patients with NPSLE. Here we measured serum NN in samples from a larger population of patients with SLE and NP events to see whether elevated serum NN could be a marker for NPSLE.MethodsWe obtained serum samples from patients in the Systemic Lupus International Collaborative Clinics (SLICC) inception cohort. This included 216 patients with NP events and two matched controls with SLE but no NP events for each of these patients. For the NP patients we tested samples taken before, during and after the NP event.ResultsTwenty-six patients had events attributed to SLE according to the most stringent SLICC attribution rule. In these patients there was no association between onset of event and elevated serum NN. In 190 patients in whom events were not attributed to SLE by the SLICC rules, median serum NN was elevated at the onset of event (P = 0.006). The predominant clinical features in this group of 190 patients were headache, mood disorders and anxiety.ConclusionsSerum NN levels rise at the time of an NP event in a proportion of patients with SLE. Further studies are needed to determine the value of serum NN as a biomarker for NPSLE.

Relationship between glucocorticoid dose and adverse events in systemic lupus erythematosus: data from a randomized clinical trial

Objective: The aim was to obtain a better understanding of the relationship between exposure to glucocorticoids (GCs) and adverse events (AEs) reported in a randomized controlled trial (RCT) in systemic lupus erythematosus (SLE) patients.Method: We used data from the BLISS-76 trial on belimumab. The data were accessed through an agreement under the SHARE mechanism. AEs were grouped according to medical relevance, i.e. based on similarity of symptoms and pathophysiology. We studied the relationship between AEs and exposure to GCs at baseline and at any time-point, and compared the frequencies of each AE and groups of AEs between tertiles of cumulative GC dose.Results: In total, 991 AEs were reported in the 819 patients of the trial. The frequencies of anaemia, pyrexia, oral herpes, and malaise were significantly higher (p < 0.05) in patients who were on GCs at baseline than in those who were not. The frequencies of several other AEs, including nausea, seasonal allergy, bacterial sinusitis, and viral upper respiratory infection, were significantly higher in patients without GCs. For cumulative GCs, tachycardia and proteinuria were significantly more frequent in the highest tertile than in the lowest tertile, but other AEs and groups of AEs were significantly more frequent in the lowest tertile.Conclusion: This study highlights the feasibility of post-hoc analyses of RCTs using the SHARE mechanism and demonstrates the association of GCs with various AEs. Contrary to expectations, there were also associations between lower cumulative GC dose and several other AEs.

Validity of the Italian algorithm for the attribution of neuropsychiatric events in systemic lupus erythematosus: a retrospective multicentre international diagnostic cohort study

ObjectiveTo validate the Italian algorithm of attribution of neuropsychiatric (NP) events to systemic lupus erythematosus (SLE) in an external international cohort of patients with SLE.MethodsA retrospective cohort diagnostic accuracy design...

Outcomes of neuropsychiatric events in systemic lupus erythematosus based on clinical phenotypes; prospective data from the Leiden NP SLE cohort.

Objective The objective of this study was to assess whether clinical and patient's reported outcomes are associated with a different pathophysiological origin of neuropsychiatric events presenting in systemic lupus erythematosus. Methods A total of 232 neuropsychiatric events presenting in 131 systemic lupus erythematosus patients were included. Neuropsychiatric systemic lupus erythematosus diagnosis was established per event by multidisciplinary evaluation. All neuropsychiatric events were divided according to a suspected underlying pathophysiological process into one of the following: non-neuropsychiatric systemic lupus erythematosus related, inflammatory and ischaemic neuropsychiatric systemic lupus erythematosus. The clinical outcome of all neuropsychiatric events was determined by a physician-completed four-point Likert scale. Health-related quality of life was measured with the subscales of the patient-generated Short Form 36 (SF-36) health survey questionnaire. The change between scores at paired visits of all domain scores, mental component summary (SF-36 MCS) and physical component summary (SF-36 PCS) scores were retrospectively calculated and used as patient-reported outcome. The association among these outcomes and the different origin of neuropsychiatric events was obtained using multiple logistic regression analysis. Results The clinical status of 26.8% non-neuropsychiatric systemic lupus erythematosus events, 15.8% ischaemic neuropsychiatric systemic lupus erythematosus and 51.6% inflammatory neuropsychiatric systemic lupus erythematosus improved after re-assessment. Almost all SF-36 domains had a positive change at re-assessment in all groups independently of the origin of neuropsychiatric events. Neuropsychiatric systemic lupus erythematosus ( B = 0.502; p < 0.001) and especially inflammatory neuropsychiatric systemic lupus erythematosus ( B = 0.827; p < 0.001) had better clinical outcome, with change in disease activity being the only important predictor. The change in SF-36 MCS was also independently associated with neuropsychiatric systemic lupus erythematosus ( B = 5.783; p < 0.05) and inflammatory neuropsychiatric systemic lupus erythematosus ( B = 11.133; p < 0.001). Disease duration and change in disease activity were the only predictors in both cases. The change in SF-36 PCS was only negatively associated with age. Conclusion Inflammatory neuropsychiatric systemic lupus erythematosus events have better clinical outcome and meaningful improvement in SF-36 MCS than ischaemic neuropsychiatric systemic lupus erythematosus or non-neuropsychiatric systemic lupus erythematosus.

Mapping eQTLs with RNA-seq reveals novel susceptibility genes, non-coding RNAs and alternative-splicing events in systemic lupus erythematosus.

Studies attempting to functionally interpret complex-disease susceptibility loci by GWAS and eQTL integration have predominantly employed microarrays to quantify gene-expression. RNA-Seq has the potential to discover a more comprehensive set of eQTLs and illuminate the underlying molecular consequence. We examine the functional outcome of 39 variants associated with Systemic Lupus Erythematosus (SLE) through the integration of GWAS and eQTL data from the TwinsUK microarray and RNA-Seq cohort in lymphoblastoid cell lines. We use conditional analysis and a Bayesian colocalisation method to provide evidence of a shared causal-variant, then compare the ability of each quantification type to detect disease relevant eQTLs and eGenes. We discovered the greatest frequency of candidate-causal eQTLs using exon-level RNA-Seq, and identified novel SLE susceptibility genes (e.g. NADSYN1 and TCF7) that were concealed using microarrays, including four non-coding RNAs. Many of these eQTLs were found to influence the expression of several genes, supporting the notion that risk haplotypes may harbour multiple functional effects. Novel SLE associated splicing events were identified in the T-reg restricted transcription factor, IKZF2, and other candidate genes (e.g. WDFY4) through asQTL mapping using the Geuvadis cohort. We have significantly increased our understanding of the genetic control of gene-expression in SLE by maximising the leverage of RNA-Seq and performing integrative GWAS-eQTL analysis against gene, exon, and splice-junction quantifications. We conclude that to better understand the true functional consequence of regulatory variants, quantification by RNA-Seq should be performed at the exon-level as a minimum, and run in parallel with gene and splice-junction level quantification.

Deciphering systemic lupus erythematosus-associated serum biomarkers reflecting apoptosis and disease activity.

Systemic lupus erythematosus (SLE) is a severe chronic inflammatory autoimmune connective tissue disease. Despite major efforts, SLE remains a poorly understood disease with unpredictable course, unknown etiology and complex pathogenesis. Apoptosis combined with deficiency in clearing apoptotic cells is an important etiopathogenic event in SLE, which could contribute to the increased load of potential autoantigen(s); however, the lack of disease-specific protein signatures deciphering SLE and the underlying biological processes is striking and represents a key limitation. In this retrospective pilot study, we explored the immune system as a specific sensor for disease, in order to advance our understanding of SLE. To this end, we determined multiplexed serum protein expression profiles of crude SLE serum samples, using antibody microarrays. The aim was to identify differential immunoprofiles, or snapshots of the immune response modulated by the disease, reflecting apoptosis, a key process in the etiology of SLE and disease activity. The results showed that multiplexed panels of SLE-associated serum biomarkers could be decoded, in particular reflecting disease activity, but potentially the apoptosis process as well. While the former biomarkers could display a potential future use for prognosis, the latter biomarkers might help shed further light on the apoptosis process taking place in SLE.

Lupus and fractures.

The article reviews recent advances in the research of fractures in patients with systemic lupus erythematosus (SLE), highlighting their clinical, scientific, and economic impact. Recent studies demonstrated an increased incidence of osteoporosis and symptomatic fractures in patients with SLE and age, disease duration, disease severity, and glucocorticoid use are important risk factors. A high prevalence of vertebral fractures was demonstrated, while one in three of these patients has normal bone density, which illustrates the multifactorial cause of fractures in SLE. Screening for vertebral fractures is important, as they often occur asymptomatically, but are associated with a reduced quality of life, increased future fracture risk, an increased mortality risk, and may have therapeutic implications. A recently developed Delphi consensus revealed the high economic burden of fractures as a glucocorticoid-related adverse event in SLE, whereas the majority of patients use glucocorticoids. Recent studies revealed an increased incidence of symptomatic fractures and a relatively high prevalence of vertebral fractures in patients with SLE, and provided new insights into their multifactorial aetiology. The clinical consequences and high economic burden of fractures as glucocorticoid-related adverse events underline the importance of reducing glucocorticoid therapy and use of steroid-sparing agents.

Low-dose aspirin as primary prophylaxis for cardiovascular events in systemic lupus erythematosus: a long-term retrospective cohort study.

Cardiovascular (CV) morbidity and mortality are significantly greater in SLE patients than in the general population. ASA is known to be associated with a decrease in the incidence of CV events in high-risk patients from the general population, but its efficacy as primary prophylaxis in SLE patients has not yet been investigated. The clinical charts of SLE patients consecutively admitted to a tertiary centre who, at admission, satisfied 1992 ACR and/or 2012 SLICC classification criteria for SLE and had not experienced any CV event, were reviewed. The occurrence of any CV event was recorded at each visit. ASA was prescribed to all patients at first visit. The rate and reasons for ASA discontinuation were also recorded at each visit. One hundred and sixty-seven consecutive SLE patients were enrolled and followed up for a median of 8 years (range 1-14 years). Among them, 146 regularly took the medication (ASA-treated patients) and 21 refused to take or discontinued it (non-ASA-treated patients). Five CV events occurred in the 146 ASA-treated patients (4.2 per 1000 person-years) and four in the 21 non-ASA-treated patients (30 per 1000 person-years; P = 0.0007). The CV event-free rate was higher in ASA-treated than in non-ASA-treated patients (log-rank test χ(2) = 15.74; P = 0.0001). No relevant side-effect related to ASA was recorded. Low-dose ASA is a safe treatment and may be beneficial in the primary prophylaxis of CV events in SLE patients. Controlled, prospective studies are needed to provide a better definition of its role in these patients.

Venous and Arterial Thrombotic Events in Systemic Lupus Erythematosus.

The incidence of thrombosis in patients with systemic lupus erythematosus (SLE) is 25 to 50-fold higher than in the general population; we aimed to define the characteristics of venous thrombotic events (VTE) and arterial thrombotic events (ATE) to identify the patients at highest risk. The study included 219 patients with recent-onset SLE. At baseline, standardized medical history and laboratory tests were done. Followup visits occurred quarterly, and information about damage accrual, comorbidities, and cardiovascular risk factors was updated annually. Main outcome was development of TE after SLE diagnosis. Thirty-five patients (16%) developed TE (27 VTE, 8 ATE) during 5.21 years of followup; incidence rate 31/1000 patient-years. Most events (57%) developed within the first year of diagnosis, and 69% were not associated with lupus anticoagulant (LAC), determined with 1 method. VTE developed earlier than ATE (2.0 vs 57.5 mos, p = 0.02). In the multivariate analysis, variables preceding VTE included cutaneous vasculitis, nephrotic syndrome, dose of prednisone, and LAC in combination with anti-RNP/Sm antibodies (p < 0.03). Patients with ATE were older (median age 44 vs 29 yrs, p = 0.04), smokers, and had hypertension, diabetes mellitus, dyslipidemia, at least 2 traditional risk factors, nephrotic syndrome, chronic damage, and a higher cumulative dose of prednisone (p < 0.05). LAC in combination with anti-RNP/Sm antibodies was associated with VTE and improved the accuracy for predicting it. Our study suggests that in SLE, VTE and ATE have different risk factors. Understanding these differences is helpful for identifying patients at highest risk. The use of LAC plus anti-RNP/Sm for predicting VTE deserves further study.

Pathogenic immunity in systemic lupus erythematosus and atherosclerosis: common mechanisms and possible targets for intervention.

Systemic lupus erythematosus (SLE) is an autoimmune disorder that primarily affects young women and is characterized by inflammation in several organs including kidneys, skin, joints, blood and nervous system. Abnormal immune cellular and humoral responses play important roles in the development of the disease process. Impaired clearance of apoptotic material is a key factor contributing to the activation of self-reactive immune cells. The incidence of atherosclerotic cardiovascular disease (CVD) is increased up to 50-fold in patients with SLE compared to age- and gender-matched controls, and this can only partly be explained by traditional risk factors for CVD. Currently, there is no effective treatment to prevent CVD complications in SLE. Traditional preventive CVD therapies have not been found to significantly lower the incidence of CVD in SLE; therefore, there is a need for novel treatment strategies and increased understanding of the mechanisms involved in the pathogenesis of CVD complications in SLE. The pathogenic immune responses in SLE and development of atherosclerotic plaques share some characteristics, such as impaired efferocytosis and skewed T-cell activation, suggesting the possibility of identifying novel targets for intervention. As novel immune-based therapies for CVD are being developed, it is possible that some of these may be effective for the prevention of CVD and for immunomodulation in SLE. However, further understanding of the mechanisms leading to an increased prevalence of cardiovascular events in SLE is critical for the development of such therapies.