Abetimus sodium: a new therapy for delaying the time to, and reducing the incidence of, renal flare and/or major systemic lupus erythematosus flares in patients with systemic lupus erythematosus who have a history of renal disease

The safety and efficacy of abetimus sodium (abetimus) has been evaluated in 13 controlled and uncontrolled clinical trials involving > 800 patients or subjects. The two pivotal trials enrolled a total of 547 patients with systemic lupus erythematosus (SLE) who had a history of lupus nephritis. Evidence of clinical effectiveness of abetimus comes from analyses of data from patients with SLE and high-affinity antibodies to the DNA epitope of abetimus at baseline; a retrospective subgroup in the pivotal Phase II/III LJP-394-90-05 trial (90-05 trial) and the intent-to-treat population in the Phase III LJP-394-90-09 trial (90-09 trial). These studies enrolled SLE patients who had experienced prior renal manifestations of their disease and had elevated anti-dsDNA antibodies at baseline by Farr assay. Both were long-term studies, with a mean duration of treatment participation of 371 days in 90-05 and 310 days in 90-09 for the population of patients with high-affinity antibodies at baseline. The 90-05 and 90-09 studies, as well as all other clinical studies of abetimus, consistently showed that treatment with abetimus resulted in durable and persistent reductions in anti-dsDNA antibodies in SLE patients. Treatment with abetimus was associated with statistically significant decreases in anti-dsDNA antibody levels from baseline compared with placebo in both the 90-09 and 90-05 trials. Positive trends were noted for the incidence of renal flares and major SLE flares in patients treated with abetimus. Abetimus appeared to be well tolerated for treatment periods of < or = 22 months.     

Clinical and pharmacological experience with LJP-394

LJP-394 is a synthetic biological with immunomodulatory functions. Composed of four double-stranded oligodeoxynucleotides attached to a central branched platform, the drug acts as an anti-‘anti-ds-DNA’ B-cell toleragen by rendering specific B-lymphocytes unresponsive to immunogen so they do not produce autoantibodies. Extensive animal studies and Phase II clinical trials suggested that the effects of LJP-394 are effective and safe when used as a weekly dose of 100 mg intravenously. Analysis of a multicentre, international Phase II/III clinical trial showed that patients with lupus nephritis and high affinity IgG antibodies to LJP-394 have clinical benefits. This includes increased time to renal flares, reduced number of renal flares, time to institution of high-dose corticosteroids and/or cyclophosphamide and lower anti-ds-DNA levels. A definitive trial is in progress. LJP-394 appears to be free of serious adverse reactions. Though promising, the role of LJP-394 in patients with active, organ-threatening lupus is still not known.     

Clinical and pharmacological experience with LJP-394

LJP-394 is a synthetic biological with immunomodulatory functions. Composed of four double-stranded oligodeoxynucleotides attached to a central branched platform, the drug acts as an anti-"anti-ds-DNA" B-cell toleragen by rendering specific B-lymphocytes unresponsive to immunogen so they do not produce autoantibodies. Extensive animal studies and Phase II clinical trials suggested that the effects of LJP-394 are effective and safe when used as a weekly dose of 100 mg intravenously. Analysis of a multicentre, international Phase II/III clinical trial showed that patients with lupus nephritis and high affinity IgG antibodies to LJP-394 have clinical benefits. This includes increased time to renal flares, reduced number of renal flares, time to institution of high-dose corticosteroids and/or cyclophosphamide and lower anti-ds-DNA levels. A definitive trial is in progress. LJP-394 appears to be free of serious adverse reactions. Though promising, the role of LJP-394 in patients with active, organ-threatening lupus is still not known.     

B细胞耐受原阿贝莫司钠的研究现状及启示

阿贝莫司钠(abetimus sodium,LJP-394)是美国La Jolla制药公司历时20多年研究开发的拟用于治疗系统性红斑狼疮的新药。阿贝莫司钠属于B细胞耐受原,可与B细胞抗dsDNA抗体交联而诱导B细胞产生免疫耐受。在Ⅲ期临床试验中,阿贝莫司钠能降低部分狼疮性肾炎患者抗dsDNA抗体水平,但对肾炎复发无明显的保护作用。因此,2009年La Jolla制药公司宣布终止了阿贝莫司钠的临床试验。本文对就阿贝莫司钠的作用特点和研究脉络作一综述,为研究开发治疗系统性红斑狼疮的新药提供借鉴。     

Emergence of targeted immune therapies for systemic lupus

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease, characterised by flares of rampant inflammation that can threaten, in an unpredictable manner, almost any organ in the body. Current standard of care is largely empiric, involving the use of corticosteroids and toxic immune suppressive agents that are widely acknowledged to have unacceptable side effects for long-term use. Recently, there have been significant advances in understanding the nature of some fundamental immune imbalances underlying the complicated clinical manifestations of SLE. Nevertheless attempts to develop and test more targeted, and potentially safer immune-modulating drugs for lupus have encountered significant obstacles, due to the lack of validated biological markers for disease flare and remission, and difficulties in the clinical assessment of the heterogeneous patients. In support of renewed interest in drug development for lupus, large collaborative groups have formed, and efforts are underway to develop objective biomarkers for SLE as well as to improve the standardisation and reproducibility of clinical outcome measures in multi-centre trials.     

Serum and urinary cytokine levels of SLE patients

Systemic lupus erythematosus (SLE) is a chronic, relapsing, polysystemic autoimmune disease with various clinical signs. The prognosis of SLE patients is influenced by neuropsychiatric and renal involvement. Lupus nephritis (LN) is present in 40-60% of patients. Classical laboratory parameters are not sensitive and specific in prediction renal flares, over the last few years there has been a growing interest in searching novel lupus biomarkers predicting future flares. Our goal was to detect serum and urinary level of cytokines in 36 patients with lupus nephritis (34 female and 2 male, mean age: 43.36 +/- 11.53 years), 23 patients with SLE without renal involvement (19 women and 4 men, mean age: 54 +/- 8.71) (both groups followed by the 3rd Department of Internal Medicine, Division of Clinical Immunology, University of Debrecen) and 30 healthy controls (23 female and 7 male, mean age: 45.5 +/- 12.4). Serum IL-1 (interleukin), IL-2 (both p < 0.05), IL-6, IL-13 and IFN-gamma (p < 0.001) levels were significantly higher in lupus nephritis patients, as compared to patients with SLE without renal involvement and healthy controls. Urinary level of IL-1 and TNF-alpha were significantly higher in SLE patients without renal disease (p = 0.012 and p < 0.001), while urinary IFN-gamma was significantly higher in LN patients (p = 0.002). Measurement of IL-6 level in SLE patients could help to predict future renal involvement of SLE patients.     

系统性红斑狼疮合并感染的诊断与鉴别的研究进展

系统性红斑狼疮(SLE) 是一种慢性自身免疫性疾病,可累及多个系统。SLE病人具有较高的感染率,可能是因为长期的免疫抑制治疗以及疾病本身造成的免疫系统异常等综合因素所致,但鉴别SLE发热是感染还是病情活动是极其困难的。活动指数对判断狼疮病人疾病活动是有用的,但临床和生物学的异常可能很难区别疾病活动还是合并感染。几种生物标志物被认为是鉴别SLE活动或者感染的潜在工具,如C-反应蛋白和原降钙素。但仅使用一种生物标志物去确认或者否认感染是不可行的,这就需要新的评分包含多种生物标志物,这可能是区分感染和病情活动新的方法,该文综述了近年关于SLE合并感染的诊断与鉴别的研究进展。     

Targeted B-cell depletion therapy in childhood-onset systemic lupus erythematosus: progress to date

Childhood-onset systemic lupus erythematosus (SLE) is a multisystemic autoimmune disease associated with significant morbidity and mortality with lupus nephritis being a major prognostic factor. Children with SLE tend to have more severe hematologic and renal involvement compared with adults. Although the morbidity and mortality have greatly improved over the last 20 years, recent studies show that there are still associated major risks from under treatment (with resultant severe flares of disease activity) and over treatment (with additional medication adverse effects including risks of severe infection; many of these patients have inherent abnormal complement pathways).Therapies used to treat children with SLE need to be individualized based on multiorgan involvement, severity of disease, history of disease flares, and knowledge of recent relevant clinical, hematologic, and immunologic parameters. These medications need to be the most effective treatments, allowing normal growth, development, fertility, and the avoidance of severe toxicity and future malignancies. Many toxic effects of current medications range from the well described Cushingoid features of corticosteroids to the gastrointestinal adverse effects of mycophenolate mofetil.In vitro studies have shown that rituximab causes B-cell depletion by mechanisms involving antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and direct signaling leading to apoptosis. As the adverse effect profile of B-cell depletion with rituximab has been well described in adults and children with oncologic and other autoimmune diseases, initial pilot studies using rituximab in patients with refractory SLE have been carried out according to different protocols. Evidence to date in open studies demonstrates that targeted B-cell depletion therapy can be safe and efficacious as an addition to standard immunosuppressant agents in refractory childhood-onset and adult-onset disease. Although there are positive outcomes in using this therapy, caution is necessary with respect to minimizing the number of doses and treatments given to reduce the incidence of developing human anti-chimeric antibodies.The next phase for the clinical and research community are multicenter randomized controlled trials of rituximab in severe childhood SLE, such as a comparative trial of rituximab versus intravenous cyclophosphamide in patients both at presentation and with exacerbations of disease activity.     

利妥昔单抗治疗难治性重症系统性红斑狼疮的临床初步观察

目的初步观察利妥昔单抗治疗难治性重症系统性红斑狼疮(SLE)的疗效及不良反应。方法难治性重症SLE 15例(神经精神狼疮6例,狼疮肾炎4例,免疫性血小板减少5例),予静脉滴注利妥昔单抗500mg,使用1～4次,同时依据病情联合使用激素等免疫抑制剂。采用BILAG和系统性红斑狼疮疾病活动指数(SLEDAI)积分对病情进行评价,监测不良反应及外周血B细胞清除情况和血清学指标变化。结果利妥昔单抗治疗难治性重症SLE,至随访终点BILAG临床完全缓解、部分缓解和无缓解分别占总例数的33%,40%和27%。其中神经精神狼疮和免疫性血小板减少临床改善显著,起效时间≤1个月,部分患者可获得长期缓解(>12个月);入组狼疮肾炎患者效果不佳。研究期间共发生4例严重感染,并导致2例死亡。结论初步提示利妥昔单抗对部分难治性重症SLE有效,该生物制剂可能成为SLE新的诱导缓解手段之一。由于尚缺乏有力的循证医学指导,临床应用需谨慎从事。尤需警惕免疫抑制状态继发感染问题。     

Treat-to-target in systemic lupus erythematosus: are we there yet?

The treat-to-target (T2T) strategy has proven benefits in several chronic medical illnesses including rheumatoid arthritis. Whether the T2T principle can be applied to SLE has become a recent topic of discussion. A European panel of rheumatologists agrees that treatment of SLE should target at multiple goals that include control of disease activity, prevention of disease flares, minimization of disease or treatment related comorbidity, and improvement of quality of life. Therapy of SLE should aim at remission or when remission cannot be achieved, the lowest possible disease activity that is assessed by a validated lupus activity index and/or organ-specific markers. However, owing to the clinical heterogeneity of SLE, there is still no consensus on the definition of remission or low disease activity state in individual organ-systems. In real life, agents readily available for therapy switching in SLE are limited. Moreover, no disease activity index is universally agreed upon for disease monitoring to make therapeutic decisions. Currently, clinical parameters for the assessment and monitoring of lupus renal disease appear to be more objective and evidence-based. A therapeutic target in terms of proteinuria and/or other renal parameters should be tested in randomized controlled trials for the proof of the T2T concept in SLE.     

Late-onset systemic lupus erythematosus: epidemiology, diagnosis and treatment

Systemic lupus erythematosus (SLE) is usually described as a disease that most often strikes reproductive-age women. However, the onset of SLE beyond the age of 50 years is reported to occur in 3-18% of patients. This later age at onset has a strong modifying effect on the clinical presentation, disease course, response to treatment and prognosis of SLE. In comparison with younger patients, patients with late-onset SLE often have delayed diagnosis and less common occurrence of severe manifestations. For instance, literature data suggest that pulmonary involvement and serositis are more frequent in late-onset SLE, whereas malar rash, photosensitivity, arthritis and nephropathy occur less commonly. Furthermore, some distinct aspects of late-onset SLE may be influenced by the association with Sj?gren's syndrome, which is more frequent in the elderly. Not only clinical features but also serological manifestations of SLE change with aging. In comparison with early-onset SLE patients, older patients have a higher frequency of rheumatoid factor and of antinuclear antibody positivity, and a lower frequency of anti-ribonucleoprotein (anti-RNP) and anti-Sm antibody positivity. The major challenge for physicians managing patients with SLE is to treat the active phase without allowing the treatment itself to cause long-term damage. This is especially true in older and often polymedicated patients, in whom side effects of treatments are more frequent. Another important issue is that possible drug interactions should always be considered in the elderly. The management of the disease in these older patients depends on the type and severity of disease manifestations. The use of antimalarial agents such as hydroxychloroquine is an important aspect of SLE treatment, unless contraindicated. Other treatments mostly include NSAIDs, corticosteroids and immunosuppressive agents, depending on which organs are involved. Survival data may be used as an indirect way to assess the changes in the severity of SLE with aging, but the few studies available conclude that late-onset SLE is associated with poorer survival than early-onset SLE, which likely reflects the consequences of aging rather than true differences in survival. Importantly, the cause of death in late-onset SLE patients is usually not SLE itself, but rather the more frequent occurrence of infections, cardiovascular disorders, malignancies or drug-induced complications.     

Novel therapies in the treatment of systemic lupus erythematosus

This review highlights the advances made in the use of biological and immunomodulatory agents in systemic lupus erythematosus. Although there have been disappointments (eg, anti-CD40 ligand, DNAse), it is clear that DHEA and mycophenolate mofetil will have a place in the management of the disease. In our opinion, leflunomide and LJP-394 are the most promising therapies currently, under study.     

狼疮性肾炎的生物靶向治疗

狼疮性肾炎(LN)的治疗药物主要为糖皮质激素及免疫抑制药,但其存在不同程度的不良反应,且部分患者无效或反复复发。生物制剂为LN的治疗提供了新的选择,本文对此进行综述。     

Antimalarial drugs in systemic lupus erythematosus: use in pregnancy.

The 4-aminoquinoline radical containing antimalarial drugs are also used in the management of various connective tissue diseases including systemic lupus erythematosus (SLE) and rheumatoid arthritis. These agents are particularly useful for the management of inflammatory polyarthritis and skin disease. By raising the pH in intracellular compartments, these drugs interfere with normal phagocytic function which consequently enables them to interfere with antigen processing. Other actions include inhibition of platelet aggregation, this is advantageous in patients with phospholipid antibodies (aPL) which are known to predispose patients to recurrent arterial and venous clinical thrombotic events. Hydroxychloroquine has also been demonstrated to reduce serum lipid levels including cholesterol, triglycerides and low density lipoproteins. As it is now known that patients with SLE are at risk for accelerated artherogenesis and premature heart disease, this action may be an added benefit for these patients. The use of the 4-aminoquinoline radical containing antimalarial drugs during pregnancy is controversial. It is known that these agents can cross the placenta and are deposited in fetal pigmented tissues. These findings have led to the recommendation that these agents should be discontinued in pregnancy for patients with connective tissue diseases even though they have long been recommended for malarial prophylaxis in pregnant women travelling to malarial infested areas. Flares of SLE disease have been documented when these agents are discontinued and as flares of SLE disease activity are known to be detrimental to pregnancy outcome in patients with SLE, it is our opinion that these drugs should not be discontinued during pregnancy in a patient with lupus, particularly when the known terminal elimination half life is 1 to 2 months.     

Lupus, the current therapeutic approaches

The management of systemic lupus erythematosus (SLE) is challenging due to the heterogenous presentation and clinical manifestations of the disease. Standard therapies for SLE use immunosuppressive drugs with significant side effects. Advanced knowledge of the pathogenesis of SLE has led to new therapeutic approaches targeting specific molecules, pathways and cells. Factors intimately involved in the chronic inflammatory response to SLE have been studied in animal models of the disease and tested in clinical trials. Here we review the topic discussing the agents currently used in the induction and maintenance therapy of SLE. In addition, the emerging therapeutic modalities in SLE that use biologics such as monoclonal antibodies to immune cell surface molecules or cytokines, synthetic peptides, oligonucleotides and cell-based therapies are discussed here.     

Upcoming biological therapies in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a chronic autoimmune condition with unpredictable course, intermingled with flares and periods of remission. Although the prognosis of the disease has improved in the past decades, current therapies are still associated with treatment-related complications. Recently, there has been major progress in the understanding of the pathogenesis of SLE, paving the way for the development of new biological agents, potentially revolutionizing the treatment of SLE.This review summarizes available data on novel biological therapies for SLE, focusing on recent results from clinical trials.As a result of treatment strategies based upon an individualized therapeutic approach, it is hoped that the clinical view of SLE will change from a severe autoimmune disease to a condition in which significant damage, mortality and treatment related complications can be prevented in the majority of SLE patients.     

Type I interferon as a target of treatment in SLE

Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease characterized by the production of antibodies against a spectrum of autoantigens. Recent evidence suggests that type-I interferons (IFN-I) are critically involved in the pathogenesis of SLE. Initially recognized for their anti-viral properties, IFN-I play important roles in immunity and autoimmunity by promoting DC maturation, T cell survival, and antibody production. Onset of SLE has been reported in patients with hepatitis or neoplastic diseases undergoing treatment with recombinant IFN-I while elevated serum IFN-I and IFN-stimulated gene expression are found in approximately 2/3 of SLE patients. This interferon signature is clinically important as it correlates with disease activity and renal as well as CNS involvement. Supporting these findings, genetic abnormalities resulting in increased IFN-I production and/or signaling are associated with SLE. In view of the accumulating evidence linking IFN-I to the pathogenesis of SLE, targeting of IFN-I may be beneficial therapeutically while avoiding the side effects associated with conventional immunosuppressive therapy. To this end, IFN-I and IFN-producing cells as well as IFN-inducers and molecules of the IFN signaling pathway may all serve as potential therapeutic targets. Several anti-IFN-I approaches have already shown promising effects in animal studies and clinical trials will likely begin in the near future.     

Drugs in early clinical development for Systemic Lupus Erythematosus

Introduction: While immunosuppressive therapy has positively impacted the prognosis of systemic lupus erythematosus (SLE), many patients still do not respond to traditional therapy. Thus, active SLE disease remains a significant problem. Furthermore, conventional immunosuppressive treatments for SLE are associated a high risk of side effects. These issues call for improvement in our current therapeutic armamentarium.

Areas covered: In this review, the authors highlight the recent developments in therapies for SLE, and present an overview of drugs which are in early clinical development for SLE. There are many new therapeutic approaches being developed, including those focused on B-cell targets, T-cell downregulation, co-stimulatory blockade, anti-cytokine agents, and kinase inhibition, and Toll-like receptor inhibition. They also discuss peptide therapy as a potential method to re-establish immune tolerance, and some of the challenges ahead in developing and testing novel agents for SLE.

Expert opinion: Many novel agents are currently in development for SLE, but this encouraging news is tempered by several disappointments in clinical trials and provides a timely moment to reflect on the future of therapeutic development in SLE. It seems likely that biological heterogeneity between patients is a major contributor to difficulty in drug design in SLE.     

Targeting BLyS in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a chronic disabling autoimmune disease that significantly impacts the quality of life of patients, and can associate with several complications including end-stage renal disease and shortened lifespan. A central component in the pathogenesis of SLE is the B-cell production of autoantibodies to multiple self-antigens. Since, B lymphocyte stimulator (BLyS) plays a key role in the selection, differentiation and survival of most B cells, it has been studied as a therapeutic target in SLE. After a gap of more than fifty years without new drugs being approved for this disease, the human neutralizing anti-BLyS monoclonal antibody belimumab has recently been approved by the FDA for SLE therapy. This review provides an overview on the targeting of BLyS in lupus animal models, the use of belimumab in human SLE, and relevant patents.     

系统性红斑狼疮并发真菌感染的临床回顾性分析

目的探讨系统性红斑狼疮(SLE)并发真菌感染的危险因素、临床特点及防治措施。方法回顾性分析56例SLE合并真菌感染的临床资料。结果SLE并发真菌感染主要发生在消化道、皮肤及呼吸道(83.3%),患者的免疫功能低下、疾病的活动以及激素、免疫抑制剂、抗生素的不合理应用是其发病的主要危险因素。结论早期诊断及合理的治疗有助于改善SLE合并真菌感染患者的预后。