Rituximab in recalcitrant thrombotic thrombocytopenic purpura secondary to systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a typical autoimmune disease with manifestations due to unopposed production of autoantibodies against the patient's own cells. The clinical features are diverse, ranging from musculoskeletal involvement, lupus nephritis to cerebral and even haematological involvement. We report a case of a young woman with known SLE who developed thrombotic thrombocytopenic purpura (TTP) secondary to SLE resistant to conventional treatment with plasma exchange. She was then treated with rituximab (MabThera®), a CD20 monoclonal antibody, and showed remarkable improvement. To our best knowledge this is the first case reporting the use of rituximab in acute resistant TTP secondary to SLE.     

Anti-cytokine therapy in systemic lupus erythematosus

In the course of the disease, a wide variety of cytokines is dysregulated, many of which likely influence systemic lupus erythematosus (SLE) autoimmunity and/or lupus tissue inflammation. Proinflammatory cytokines in particular, such as TNF, IL-6, IL-18 or IFN-gamma, may play a major role in propagating the inflammatory processes responsible for tissue damage. These cytokines are overexpressed both systemically and locally, and preliminary results from open-label trials and/or animal studies suggest potential benefits of blocking either of these inflammatory mediators. Since new therapeutic agents may soon offer many ways to influence the process, controlled clinical trials following open-label safety studies are of central importance to arrive at optimized therapies for SLE patients.     

B-cell-depleting therapy in systemic lupus erythematosus

The emergence of a new class of agents (B-cell-depleting therapies) has opened a new era in the therapeutic approach to systemic lupus erythematosus, with belimumab being the first drug licensed for use in systemic lupus erythematosus in more than 50 years. Four agents deserve specific mention: rituximab, ocrelizumab, epratuzumab, and belimumab. Controlled trials have shown negative results for rituximab, promising results for epratuzumab, and positive results for belimumab. Despite these negative results, rituximab is the most-used agent in patients who do not respond or are intolerant to standard therapy and those with life-threatening presentations. B-cell-depleting agents should not be used in patients with mild disease and should be tailored according to individual patient characteristics, including ethnicity, organ involvement, and the immunological profile. Forthcoming studies of B-cell-directed strategies, particularly data from investigations of off-label rituximab use and postmarketing studies of belimumab, will provide new insights into the utility of these treatments in the routine management of patients with systemic lupus erythematosus.     

IgG therapy in systemic lupus erythematosus

Summary Two paediatric patients with systemic lupus erythematosus were treated with immunoglobulin G (IgG). In the first case treatment resulted in regression of the most acute symptoms and a long remission was achieved. In the second patient, who was treated during the chronic stage of the disease, there was no significant effect on the course of the SLE.Abbreviations ESR Erythrocyte sedimentation rate - T Thoracic vertebra - DNA Deoxyribonucleic acid - HLA HLA system (of histocompatibility loci) - IgG Immunoglobulin G - RES Reticuloendothelial system - SLE Systemic lupus erythematosus - CNS Central nervous system     

系统性红斑狼疮的药物治疗

系统性红斑狼疮(systemic lupus erythematosus,SLE)总体上来说是一种慢性风湿病,容易复发.因此其治疗应包括两个方面:一方面是急性加重期如何治疗;另一方面是在慢性期如何予以维持治疗.近几十年来,由于糖皮质激素及免疫抑制剂的应用,SLE的死亡率及致残率已经较前明显下降.但由于SLE病因未明,因此很难根治.目前对SLE的治疗目标是:保持患者临床缓解并能进行日常活动,或应用最低剂量皮质激素或甚至停用激素情况下参加工作.     

系统性红斑狼疮的非药物治疗

系统性红斑狼疮(systemic lupus erythematosus,SLE)是一种自身免疫性疾病, 长期以来临床治疗主要依赖于糖皮质激素和免疫抑制剂等药物治疗.临床上观察到重症SLE及难治性SLE, 药物治疗往往难以控制病情, 目前难治性及重症SLE的治疗仍然非常棘手,现将其中的非药物治疗方法简介如下.     

Anticytokine therapy in systemic lupus erythematosus

Systemic lupus erythematosus is a prototype of heterogeneous autoimmune disease. There have been few newly approved therapeutic agents in lupus treatment for many reasons. Several animal studies and human data have shown that many potential cytokines are related to the pathogenesis and disease activity of systemic lupus erythematosus. Cytokines are produced by many immune cell types and have variable functions in the immune system. Following the success of biological agents in the treatment of inflammatory arthritis, inflammatory bowel disease, and psoriasis, biological targeting to specific cytokines or receptor molecules is now promising in the treatment of systemic lupus erythematosus. In addition to B-cell deleting modalities, clinical trials targeting potential cytokines associated with disease pathogenesis are underway at various clinical stages. Among potential cytokines, targeting agents against B-cell activating factor and interferon-alpha are in the most advanced stage, and belimumab (anti-B-cell activating factor antibody) could be the first biological agent approved in the treatment of systemic lupus erythematosus. Anti-tumor necrosis factor was tried with some success, but with a potential risk of infection in a small number of patients. In this review, we discuss the rationale for anticytokine therapies and review agents currently in clinical trials, and those that could be developed in the near future for systemic lupus erythematosus. We present the results mostly from published trials and data from http://clinicaltrials.gov/ct2/     

Gene therapy in systemic lupus erythematosus

Preclinical studies have provided proof of concept for the feasibility and efficacy of gene therapy in human systemic lupus erythematosus (SLE). Successful efforts include gene constructs that alter the expression of cytokines or limit the cognate interaction of immune cells. Other efforts may include gene modified cell transfer such as autologous B cells transfected with tolerogenic constructs or T cells in which specific molecular aberrations have been corrected.     

Methotrexate therapy in systemic lupus erythematosus

There are 12 non-controlled and only two controlled studies using methotrexate (MTX) in a total of 207 SLE patients in the literature. The majority of these studies evaluated mainly cutaneous and/or articular involvement and attained good results. Two studies evaluated a small number of patients with lupus nephritis, achieving discordant results. Two other studies in pediatric onset systemic lupus erythematosus (SLE) also presented conflicting results, it being relevant that the one with poor response had the majority of patients with nephritis. One of the controlled trials was retrospective and concluded that MTX was effective in the treatment of antimalarial-resistant lupus arthritis and that toxicity leading to discontinuation of MTX was infrequent. The other controlled study was a double-blind, randomized, placebo-controlled clinical trial that evaluated SLE patients with mild activity. The authors concluded that MTX was effective in controlling cutaneous and articular activity and permitted prednisone dose reduction. The side effects were frequent but only 10% of patients needed to discontinue the medication. The accumulative evidence suggests that MTX in a low weekly dose may be effective in SLE patients with articular and/or cutaneous involvement with no response to antimalarials and low-dose prednisone and in patients in whom we can not reduce prednisone dose due to articular or cutaneous activity. Caution is required concerning the side effects.     

Frentizole therapy in systemic lupus erythematosus

Seven corticosteroid dependent patients with active systemic lupus erythematosus (SLE) were given frentizole in order to assess its effect on their clinical manifestations. Three patients exhibited slight clinical improvement, 2 patients did not change, and 2 deteriorated. Five of the 7 patients developed subclinical and reversible liver damage related to frentizole. This study, although preliminary and uncontrolled, suggests that frentizole is of limited value in the management of patients with SLE.     

Rituximab improves peripheral B cell abnormalities in human systemic lupus erythematosus

OBJECTIVE: B lymphocyte depletion has recently emerged as a promising approach to the treatment of systemic lupus erythematosus (SLE). As part of a phase I/II dose-ranging trial of rituximab in the treatment of SLE, we evaluated the fate of discrete B cell subsets in the setting of selective depletion by anti-CD20 monoclonal antibody and during the B cell recovery phase. METHODS: B cell depletion and phenotype were examined by flow cytometry of peripheral blood mononuclear cells for CD19, CD20, CD27, IgD, and CD38 expression. Changes in autoreactive B lymphocytes and plasma cells were assessed by determination of serum autoantibody levels (anti-double-stranded DNA and VH4.34) and by direct monitoring of a unique autoreactive B cell population bearing surface antibodies whose heavy chain is encoded by the VH4.34 gene segment. RESULTS: Compared with normal controls, SLE patients displayed several abnormalities in peripheral B cell homeostasis at baseline, including naive lymphopenia, expansion of a CD27-,IgD- (double negative) population, and expansion of circulating plasmablasts. Remarkably, these abnormalities resolved after effective B cell depletion with rituximab and immune reconstitution. The frequency of autoreactive VH4.34 memory B cells also decreased 1 year posttreatment, despite the presence of low levels of residual memory B cells at the point of maximal B cell depletion and persistently elevated serum autoantibody titers in most patients. CONCLUSION: This study is the first to show evidence that in SLE, specific B cell depletion therapy with rituximab dramatically improves abnormalities in B cell homeostasis and tolerance that are characteristic of this disease. The persistence of elevated autoantibody titers may reflect the presence of low levels of residual autoreactive memory B cells and/or long-lived autoreactive plasma cells.     

Novel approaches to therapy for systemic lupus erythematosus

Current therapies for systemic lupus erythematosus (SLE) are targeted at immunosuppression and at reducing inflammation. The current therapies are broad-spectrum and include steroids and cytotoxic agents that are counterbalanced by toxicity and side effects of the medications. Methotrexate can be utilized to reduce steroid requirements in mild to moderate SLE. Manipulation of the hormonal axis includes DHEA and bromocriptine. Mycophenolate mofetil is an immunosuppressive agent that is being investigated for SLE renal disease. Autologous stem cell transplantation or high-dose cyclophosphamide may be an option for severe refractory SLE. The aim of the future is to target therapies by altering specific known mechanisms of inflammation and autoimmunity. Although the inciting antigen is still unknown in SLE, it may be possible to alter the regulation of the immune response by targeted molecular therapy. Methods to do so would include manipulation of idiotypes, manipulation of second signal stimulation of the immune response, manipulation of cytokines, and the induction of tolerance by administration of blocking peptides. IVIg is an immunomodulator that has been successful in the treatment of SLE. Targeted molecular therapy is undergoing phase I trials with monoclonal anti-CD40L, a signaling inhibitor. Anti-CTLA4Ig, another signaling blocker, is presently being investigated for psoriasis, but may be a potential therapy for SLE. Finally, therapies may include the administration of peptides to induce tolerance.     

Modern therapy for systemic lupus erythematosus

Even though no new treatment for systemic lupus erythematosus (SLE) has been approved in over 40 years, the treatment possibilities have expanded decisively in this time. The available evidence for most forms of therapy is rather thin, yet there is a wide consensus on an individual immunosuppressive therapy that is adjusted to the illness activity and severity. Various new substances, e.g. other immunosuppressants and anti-cell therapies have been tested, mostly in open studies. Considering the experience in other indications, mycophenolate mofetil and rituximab have a very promising potential to be approved for therapy of SLE. Aside from these, "old medications" such as antimalarial drugs still possess a high value. Besides the effective suppression of the illness activity, this is especially decisive for the improvement of the long-term prognosis, the treatment of co-morbidities and secondary prevention and the avoidance of negative effects of the illness and therapy, such as infections, osteoporosis, and premature arteriosclerosis. As these "simple" measures often remain disregarded in modern therapy, they will be focused on in this overview on the current treatment concepts for SLE and these aspects will be discussed in greater depth. With regard to new future therapies, we refer the reader to other current publications.     

The future of the treatment of systemic lupus erythematosus

Despite recent advances, patients with systemic lupus erythematosus (SLE) still experience considerable morbidity and mortality. To try and improve their prognosis, varied novel biological interventions and immune manipulations are being developed. They may hold promise in particular for patients whose disease is organ-threatening and refractory to conventional treatment. In addition, awareness of the tendency of lupus patients to develop accelerated atherosclerosis as well as newly gained insights into the underlying mechanisms, may lead to better control of risk factors, earlier diagnosis of prevalent cardiovascular disease and more effective treatment. Infections also remain a significant threat that may be amenable to improved preventive measures. Evidence related to a better management of lupus patients by specialists, the need to address the impact of commonly associated stress and depression and other significant developments are also presented and discussed.