Unmet Needs in the Pathogenesis and Treatment of Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease with a prevalence of approximately 1 in 1000. Over the last 30 years, advances in treatment such as use of corticosteroids and immunosuppressants have improved life expectancy and quality of life for patients with lupus and the key unmet needs have therefore changed. With the reduced mortality from disease activity, development of cardiovascular disease (CVD) has become an increasingly important cause of death in patients with SLE. The increased CVD risk in these patients is partly, but not fully explained by standard risk factors, and abnormalities in the immune response to lipids may play a role. Invariant natural killer T cells, which are triggered specifically by lipid antigens, may protect against progression of subclinical atherosclerosis. However, currently our recommendation is that clinicians should focus on optimal management of standard CVD risk factors such as smoking, blood pressure and lipid levels. Fatigue is one of the most common and most limiting symptoms suffered by patients with SLE. The cause of fatigue is multifactorial and disease activity does not explain this symptom. Consequently, therapies directed towards reducing inflammation and disease activity do not reliably reduce fatigue and new approaches are needed. Currently, we recommend asking about sleep pattern, optimising pain relief and excluding other causes of fatigue such as anaemia and metabolic disturbances. For the subgroup of patients whose disease activity is not fully controlled by standard treatment regimes, a range of different biologic agents have been proposed and subjected to clinical trials. Many of these trials have given disappointing results, though belimumab, which targets B lymphocytes, did meet its primary endpoint. New biologics targeting B cells, T cells or cytokines (especially interferon) are still going through trials raising the hope that novel therapies for patients with refractory SLE may be available soon.     

B cells in SLE: different biological drugs for different pathogenic mechanisms

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease characterized by a complex multi-factorial pathogenesis and a great clinical polymorphism. SLE is considered to be a B cell disease in which autoantibodies are the major players. Recently, the central role of B cells has been confirmed and it has been shown that that the relative frequency of B cells subsets is altered in SLE patients. Conventional immunosuppressive therapies such as azathioprine, cyclophosphamide or methotrexate, reduce disease activity and improves the patient's general health conditions. These treatments have possible side effects; in fact they could compromise liver function, fertility and innate and adaptive immune responses. Moreover, for unknown reasons a small group of SLE patients is refractory to immunosuppressive therapy. In these cases finding an effective treatment becomes a challenge. The progress in therapeutic antibody technology has led to the production of a wide array of humanized monoclonal antibodies, targeting specific cell types or pathways, initiating a new era in the treatment of autoimmune disorders. In contrast to general immuno-suppression, the availability of drugs interfering with specific pathogenetic pathways gives the possibility to choose therapies tailored to each disease in each patient.     

The 2018 pipeline of targeted therapies under clinical development for Systemic Lupus Erythematosus: a systematic review of trials

Currently, Systemic Lupus Erythematosus (SLE) therapies range from antimalarials to glucocorticoids, in addition to immunosupressive agents or biologics such as rituximab or belimumab, when needed. Several unmet needs remain in the treatment SLE and more targeted drugs with improved safety profiles are expected. Based on recent advances in the understanding of the complex pathogenesis of SLE, several targeted treatments are currently assessed in clinical trials. In this study, we performed a systematic review of all targeted therapies under clinical development in SLE in 17 online registries of clinical trials. The search yielded a total of 1140 trials, from which we identified 74 targeted therapies for SLE. Those treatments target inflammatory cytokines, chemokines, or their receptors (n?=?17), B cells or plasma cells (n?=?17), intracellular signalling pathways (n?=?10), T/B cells costimulation molecules (n?=?8), interferons (n?=?7), plasmacytoid dendritic cells (pDC) (n?=?3), as well as various other targets (n?=?12). Not all these candidate drugs will reach phase III, but the broad spectrum of drugs being investigated may satisfy the urgent need for improved lupus medications. The identification of biomarkers that would allow adequate prediction of response-to-therapy remains high, but when solved will allow a more rationale selection of the optimal pharmacological agent at the patient level.     

The efficacy of novel B cell biologics as the future of SLE treatment: A review

Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease with wide ranging multi-systemic effects. Current understanding centralises B cells in SLE pathogenesis with clinical features resulting from autoantibody formation, immune complex deposition, antigen presentation and cytokine activation. Existing standard of care therapies generates adverse side effects; secondary to corticosteroid use and untargeted immunosuppression. The inability to uphold remission and abolish the disease process, in addition to the increasing numbers of patients seen with refractory disease with these therapies, has provoked the development of novel B cell biologics targeting specific pathogenic pathways fundamental to the SLE disease process.     

Success and failure of biological treatment in systemic lupus erythematosus: A critical analysis

Patients affected with systemic lupus erythematosus (SLE) still display increased mortality and decreased quality of life in respect to general population. The major determinant of poor long term prognosis is organ damage, which is predictive of more damage and death. Damage is in turn triggered by uncontrolled disease activity and especially by the long-standing corticosteroid use which often accompanies SLE patients over their disease course, owing both to the need of reaching disease remission and to the habit of keeping patients on a small steroid dose for an indefinite period of time. Hence, the need for new drugs and therapeutic strategies aiming at minimizing damage accrual through a better control of disease activity and a steroid-sparing potential is paramount. So far, however, the therapeutic strategy in SLE requires a multitarget approach which is not devoid of widespread immunesuppression. In fact, several studies have been carried out in recent years targeting both the adaptive and the innate immune system, the majority of which did not achieve their primary endpoint, being often divergent from successful clinical experience and thereby committing physician to off-label use of targeted therapies in face of refractory SLE manifestations. The study designs and the chosen endpoints were often blamed for inadequacy, being at least in part responsible for study failures. In this review, we go over major clinical trials conducted in SLE by analyzing any critical aspects related to study design, predefined endpoints and biological activity of novel compounds that may have hampered study outcome, despite the great effort of providing less toxic drugs within a targeted, pathogenic-based approach.     

造血干细胞移植治疗系统性红斑狼疮的进展

系统性红斑狼疮是一种病因未明的自身免疫性疾病,基本上由自身抗体和免疫复合物介导致病.随着医学在基因水平上不断发展,对于重症SLE不能耐受传统疗法,HSCT目前已是公认的潜在治疗手段之一.从报道HSCT治疗严重AID至今,大约有20个国家的700个患者接受了临床Ⅰ/Ⅱ试验.研究认为,大剂量免疫抑制和移植后免疫重建可能是使SLE缓解的机制.经过10年的临床试验,国内对HSCT治疗手段不断成熟,以北京协和医院为首.虽有明显改善SLE病情,但随诊时期不长,仍存在着许多需要进一步解决的问题,HSCT给予那些难治的其他疗法无效的患者提供了"补救疗法",是否更有效,仍需要进一步进行随机化控制实验.     

Management of systemic lupus erythematosus in Chinese patients

Systemic lupus erythematosus (SLE) is a worldwide disease with prevalence figures ranging from nine to 130 per 100,000 individuals. SLE appears to be more prevalent in certain ethnic groups, such as the African–Americans, African–Caribbeans and Asians. The prevalence of SLE in Hong Kong Chinese was estimated to be 59 out of 100,000 (104/100,000 among women), which is mid-way between that of the Caucasians and African–Americans. Certain organ manifestations, such as lupus nephritis, are more common in Chinese than Caucasians. A recent prospective study reported that the cumulative incidence of renal disease within 5 years of diagnosis of SLE in Chinese patients was 60%. Despite the improvement in survival of SLE in the past few decades, manifestations that are refractory to conventional therapies and treatment related complications are still major challenges in the management of SLE. Novel-therapeutic modalities for SLE should aim at targeting more specifically the immunopathogenetic pathways to achieve higher efficacy and reduce short- and long-term therapy-related toxicities. This review summarizes the management strategies and novel therapeutic modalities in SLE.     

Cutaneous lupus erythematosus: understanding of clinical features, genetic basis, and pathobiology of disease guides therapeutic strategies

Cutaneous features of the protean disease lupus erythematous (LE) constitute 4 of 11 diagnostic criteria for systemic lupus erythematosus (SLE) and are exhibited by approximately 3/4 of patients during the course of their disease. Because the pathogenesis of LE is multifactorial and polygenic, many of the details of the pathogenesis remain unclear. We review here the clinical features of cutaneous lupus and recent genetic data that elucidate potential candidate genes for both cutaneous lupus erythematosus (CLE) and SLE. We discuss advances in elucidating the autoimmune pathogenesis of CLE and SLE. Furthermore, promising experimental therapies based on these advances are reviewed in the context of B cell directed therapies, T cell directed therapies, disruption of B and T cell interactions, cytokine directed therapies and finally, end-effector targeted therapies.     

Induction of immune tolerance by activation of CD8+ T suppressor/regulatory cells in lupus-prone mice

Multiple CD8(+) suppressive T cell (Ts) subtypes are now recognized as essential regulators of the immune system that prevent autoimmunity through secretion of multiple cytokines and the subsequent inhibition of effector lymphocyte function. CD8(+) Ts are an exciting area of study because of the possible therapeutic implications of inducing suppressive cells that are able to subdue or anergize autoimmune manifestations. Current research in systemic lupus erythematosus (SLE), a disease in which most effective therapies are widely immunosuppressive, is often focused on novel and highly targeted ways in which to treat this multiorgan disease. CD8(+) Ts have been impaired in human and murine SLE. Our group and others have utilized tolerogenic peptides to induce and study CD8(+) Ts to understand their function, as well as investigate a possible new SLE therapy. This review will discuss the similarities and differences in CD8(+) Ts subsets, the concept of tolerance as a therapy, and the current understanding of CD8(+) Ts in mouse SLE models.     

Regulatory T cells in systemic lupus erythematosus

Systemic lupus erythematosus (SLE), an autoimmune disease, develops when immunologic self‐tolerance fails. Treg cells are a subset of CD4⁺ T cells that maintain self‐tolerance by suppressing autoreactive lymphocytes. Defects in Treg cells are therefore considered to be an aspect of SLE pathogenesis. Nevertheless, reports on the numbers and function of Treg cells in SLE are contradictory and the definitive role of Treg cells in SLE remains unclear. In this review, we summarize findings from murine models and ex vivo experiments, which provide insights into the mechanisms that result in the breakdown of tolerance. We also include recent findings about Treg‐cell subsets and their markers in human SLE. The identification of unique markers to identify bona fide Treg cells, as well as therapies to reconstitute the balance between Treg cells and autoreactive T cells in SLE, are the future challenges for SLE research.     

Dissecting the immune cell mayhem that drives lupus pathogenesis

The autoimmune disease systemic lupus erythematosus (SLE) results from an inability of the immune system to discriminate between certain self-antigens and foreign ones. The most common treatment of SLE involves the use of immunosuppressive drugs to reduce inflammation, but these therapies have serious side effects. Three recent papers in Science Translational Medicine redirect focus on neutrophils, platelets, and interferon-α in the pathogenesis of SLE and reinforce the notion that researchers should seek to discover and devise combination therapies that target these processes.     

Prognosis in systemic lupus erythematosus

Conclusions In SLE, morbidity is universal and fatality is significant. One cannot learn too much about the prognostic markers for this disorder. The identification by means of renal biopsy of subclasses of lupus nephritis spurred the development of new treatment regimens that have improved outcomes. While proliferative nephritis remains a marker of serious renal involvement, the newer indices that attempt to quantify the activity and chronicity of the renal lesion, as well as greater awareness of the importance of tubulointerstitial involvement and improvement in the amount of subendothelial electron-dense deposits with therapy, will likely permit further fine-tuning of the treatment of individual patients with lupus nephritis.Neuropsychiatric involvement in SLE is another major determinant of financial costs, morbidity and death. Unfortunately, our knowledge of the prognostic markers for this more heterogeneous group of manifestations is less advanced than for lupus renal involvement. Additional studies are needed urgently to determine the factors that predict the subsequent development of the different forms of neuropsychiatric lupus. The determinants will likely differ among the various forms of neuropsychiatric lupus, thereby permitting different preventative or treatment regimens to be developed.The role of social factors, particularly socioeconomic status, has attracted attention in the United States. The lessons are likely applicable elsewhere. Additional studies to identify social factors that can be modified may bring tangible benefits to SLE patients in this decade.Although not universally accepted, it does appear that as more SLE patients survive the acute disease, there is an inordinately high risk of developing vascular diseases, including coronary artery disease, stroke and peripheral vascular disease. As with neuropsychiatric lupus, the determinants may differ depending on the specific vascular disease. Better knowledge of these determinants will permit a further improvement in the overall prognosis for patients with SLE.     

Cutaneous lupus erythematosus: Understanding of clinical features,genetic basis,and pathobiology of disease guides therapeutic strategies

Cutaneous features of the protean disease lupus erythematous (LE) constitute 4 of 11 diagnostic criteria for systemic lupus erythematosus (SLE) and are exhibited by approximately 3/4 of patients during the course of their disease. Because the pathogenesis of LE is multifactorial and polygenic, many of the details of the pathogenesis remain unclear. We review here the clinical features of cutaneous lupus and recent genetic data that elucidate potential candidate genes for both cutaneous lupus erythematosus (CLE) and SLE. We discuss advances in elucidating the autoimmune pathogenesis of CLE and SLE. Furthermore, promising experimental therapies based on these advances are reviewed in the context of B cell directed therapies, T cell directed therapies, disruption of B and T cell interactions, cytokine directed therapies and finally, end-effector targeted therapies.     

Novel approaches to the development of targeted therapeutic agents for systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a chronic multisystem disease in which various cell types and immunological pathways are dysregulated. Current therapies for SLE are based mainly on the use of non-specific immunosuppressive drugs that cause serious side effects. There is, therefore, an unmet need for novel therapeutic means with improved efficacy and lower toxicity. Based on recent better understanding of the pathogenesis of SLE, targeted biological therapies are under different stages of development. The latter include B-cell targeted treatments, agents directed against the B lymphocyte stimulator (BLyS), inhibitors of T cell activation as well as cytokine blocking means. Out of the latter, Belimumab was the first drug approved by the FDA for the treatment of SLE patients. In addition to the non-antigen specific agents that may affect the normal immune system as well, SLE-specific therapeutic means are under development. These are synthetic peptides (e.g. pConsensus, nucleosomal peptides, P140 and hCDR1) that are sequences of conserved regions of molecules involved in the pathogenesis of lupus. The peptides are tolerogenic T-cell epitopes that immunomodulate only cell types and pathways that play a role in the pathogenesis of SLE without interfering with normal immune functions. Two of the peptides (P140 and hCDR1) were tested in clinical trials and were reported to be safe and well tolerated. Thus, synthetic peptides are attractive potential means for the specific treatment of lupus patients. In this review we discuss the various biological treatments that have been developed for lupus with a special focus on the tolerogenic peptides.     

Therapeutic effect of retinoic acid in lupus nephritis

Lupus nephritis is a major cause of morbidity and mortality among patients with systemic lupus erythematosus (SLE). In these patients, treatment with immunosuppressive agents can significantly improve the outcome of lupus nephritis. However, these agents have severe adverse reactions and some patients are refractory to those therapies. Retinoids, a group of natural and synthetic derivatives of vitamin A, play important regulatory roles of cellular proliferation, differentiation and apoptosis. They have been used for the treatment of acute promyelocytic leukemia and inflammatory disorders such as psoriasis and acne. It has also been shown that retinoids have therapeutic effects in various animal models of kidney disease, including lupus nephritis. Based on these findings, retinoids are a promising agent for the treatment of lupus nephritis. We studied the clinical effects of retinoid therapy in patients with lupus nephritis. In open clinical trial, 7 patients with active lupus nephritis that was refractory to steroid therapy were studied. In all these patients, retinoid was added to the immunosuppressive therapy and its therapeutic effects were evaluated. As a result, 4 out of 7 patients showed improvement of the clinical symptoms and laboratory findings, including urinary protein and anti-dsDNA antibody levels. No important adverse effects of ATRA therapy were observed in all patients. Thus, retinoids might be indicated in cases of lupus nephritis that are refractory to conventional immunosuppressive therapy.     

CD38, CD81 and BAFFR combined expression by transitional B cells distinguishes active from inactive systemic lupus erythematosus

In view of its heterogeneous presentation and unpredictable course, clinical management of systemic lupus erythematosus (SLE) is difficult. There is a need for biomarkers and diagnostic aids to monitor SLE disease activity and severity prior to, during and after treatment. We undertook this study to search for unique phenotypic patterns in each peripheral blood (PB) B cell subset, capable of distinguishing SLE patients with inactive disease versus SLE patients with active disease versus controls by using an automated population separator (APS) visualization strategy. PB was collected from 41 SLE patients and 28 age- and gender-matched controls. We analyzed the cell surface markers (in a tube CD20/CD27/CD19/CD45/CD38/CD81/BAFFR combination) expression on PB B cell subsets using principal component analysis, implemented in the APS software tool. Overall, our analysis indicates that active SLE can be distinguished from inactive SLE on the basis of a single tube analysis, focused on the decreased expression of CD38, CD81 and BAFFR in transitional B cells. The cluster analysis of immunophenotypic profiles of B cell subsets highlighted disease-specific abnormalities on transitional B cells that emerge as promising surrogate markers for disease activity. Further validation is needed with larger samples and prospective follow-up of patients.     

Interplay of Infections,Autoimmunity, and Immunosuppression in Systemic Lupus Erythematosus

Infectious agents are considered to be crucial environmental factor in the etiopathogenesis of systemic lupus erythematosus (SLE). Infections may serve as initial trigger to the development of autoimmunity and carry an overall greater risk of morbidity and mortality than the general population. Initial presentation of SLE can mimic infections, and in turn infections can mimic disease flares in established SLE. Infections due to predisposition by commonly used immunosuppressive therapies are a significant cause of morbidity and mortality. In this review, viral, bacterial, fungal, and parasitic infections that contribute to the etiology of SLE, potentially mimic or precipitate flares, create diagnostic dilemmas, complicate treatment, or protect against disease, are discussed. Infection risks of current immunosuppressive therapies used in the treatment of SLE are outlined. Strategies to prevent infection, including vaccines, prophylactic antibiotic therapies, toll-like receptor antagonism, and antioxidant treatment that may decrease disease burden and improve quality of life in lupus patients will be discussed.     

The Systemic Lupus Erythematosus Responder Index (SRI); a new SLE disease activity assessment

Systemic Lupus Erythematosus (SLE), because of its complex and multisystemic presentation, lacks a reliable and sensitive gold standard for measuring disease activity. In addition, there is no standardized method for defining response to therapy. Several disease activity indices have been developed over the years, each with their own positive and negative aspects. Growing insight in the pathogenesis of inflammatory diseases like SLE leads to the introduction of specific targeted biologic therapies. To investigate the efficacy of these new biologic agents, disease activity must be monitored regularly by a reliable and validated instrument. Recent studies on new biologics for treatment of SLE use a new composite measurement for disease activity and response in SLE. This new disease activity assessment, called SLE Responder Index (SRI), comprises criteria from three different internationally validated indices, SELENA-SLE Disease Activity Index (SELENA-SLEDAI), Physician Global Assessment (PGA) and the British Isles Lupus Assessment Group (BILAG) 2004. This review gives an overview of current available disease activity indices in relation to the newly developed composite SRI.     

Clinical manifestations of cutaneous lupus erythematosus

The skin findings seen in lupus erythematosus can present with either lupus-specific or lupus-nonspecific findings, with lupus-specific skin disease showing findings histopathologically distinct for cutaneous lupus erythematosus. Lupus-specific skin diseases include chronic cutaneous, subacute cutaneous, and acute cutaneous lupus erythematosus. The types of skin lesions in each group are clinically distinct and recognizing the specific subsets helps in prognosticating the likelihood of underlying systemic lupus. A number of medications are associated with cutaneous lupus, in particular with subacute cutaneous lupus erythematosus. Lupus nonspecific skin lesions are not histopathologically distinct for cutaneous lupus and/or may be seen as a feature of another disease process. Nonspecific disease-related skin lesions are frequently seen in patients with SLE, usually in the active phase of the disease. The current ACR classification criteria for SLE include four somewhat overlapping dermatologic criteria, butterfly rash, discoid lupus, photosensitivity, and oral ulcers and thus patients can be classified as having SLE with only skin manifestations.