A Meeting ReviewImmunotherapy of systemic lupus erythematosus
Introduction
Systemic lupus erythematosus (SLE) is an autoimmune disorder that can produce inflammation in many organ systems. It ranges from a mild illness involving skin and joints only to a life threatening condition affecting kidneys and brain. This variability in clinical expression as well as its relative rarity has limited the conduct of clinical trials. The vast majority of these trials have been undertaken in patients with lupus nephritis using corticosteroids and immunosuppressive drugs, particularly cyclophosphamide. While the latter is highly effective in lupus nephritis, this comes at the price of high toxicity. Accordingly, efforts are being made to identify more selective, less toxic agents. Significant advances in our understanding of the immunopathogenesis of SLE have led to the development of specific targeted therapies. This article reviews recent advances in the management of SLE, focusing on immunotherapy (Table 1). Where possible we have included references published in peer-reviewed journals. However, in order to provide as up-to-date a review as possible we have included material from abstracts presented at the 7th International Congress on SLE and Related Conditions in New York on May 2004, most of which have not yet been published in peer-reviewed journals. While non-pharmacological approaches, such as restricting exposure to sunlight, are important in patient management, this topic is beyond the scope of this review.
Section snippets
Nonsteroidal antiinflammatory drugs and Plaquenil
Nonsteroidal antiinflammatory drugs (NSAIDs) and anti-malarial drugs, particularly hydroxychloroquine (HCQ), remain established as first line treatment for patients with mild SLE, i.e. involving skin and/or joints only. There is recent evidence demonstrating the safety of HCQ in pregnancy [1] (although some guidelines still recommend its cessation). Furthermore, a beneficial effect of HCQ on dyslipidaemia has been reported [2].
Corticosteroids
Prednisone is standard therapy for the management of patients with
Plasmapheresis
Plasmapheresis (or plasma exchange) remains a controversial treatment modality in severe SLE. Its mechanism of action is uncertain but includes the physical removal of pathogenic autoantibodies and circulating inflammatory mediators such as activated complement components. Several trials in the 1990s failed to show a benefit of plasmapheresis in lupus nephritis [6]. An antibody rebound phenomenon was often noted after treatment with plasmapheresis was completed. B cells, which have been primed
LJP 394
This agent has shown promise in mouse models of SLE and in early human trials. LJP 394 consists of four double-stranded oligonucleotides conjugated to an ethylene glycol carrier [25]. The agent decreases dsDNA antibody levels by two or more mechanisms. Its initial action is through forming soluble complexes with pathogenic dsDNA antibodies, without activating the complement system. In animal models of lupus it leads to B cell anergy or apoptosis by crosslinking surface immunoglobulin receptors
Il10
There is increasing evidence of a role for IL-10 in the pathogenesis of SLE—which is intriguing given that it is thought to be an anti-inflammatory cytokine [32]. In the only published human trial anti-IL-10 murine antibody was administered intravenously to six patients for 21 consecutive days. There was improvement in all patients, which was maintained in 5 out of 6 patients for over 6 months. This is the first demonstration of the effective use of an anti-IL10 antibody in humans [33].
TNF alpha
Agents
Conclusions
After two decades of study into the immunopathogenesis of SLE, a new era is emerging in which knowledge acquired about its pathogenesis is being translated into new therapies. Clinical investigators supported by pharmaceutical and biotechnology companies have demonstrated an interest in conducting clinical trials, including phase III studies in patients with SLE. It is premature to conclude which of these treatment strategies will prove to be the most effective. However, one should not
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The administration of low doses of rituximab followed by hydroxychloroquine, prednisone and low doses of mycophenolate mofetil is an effective therapy in Latin American patients with active systemic lupus erythematosus
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Recent advances in therapeutic strategies for SLE
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