Emerging therapies for systemic lupus erythematosus — Focus on targeting interferon-alpha

Abstract

Current therapies for systemic lupus erythematosus (SLE), a debilitating, potentially lethal, multifactorial systemic autoimmune disease, are limited to suppressing disease activity and are associated with multiple adverse effects. Recent advances in basic and translational sciences have elucidated a crucial role for the interferon-alpha (IFNα) pathway in the pathogenesis of this enigmatic disease. The so-called “type I interferon signature” has emerged as a major risk factor for disease activity of SLE. Multiple genes encoding for molecules within the type I interferon pathway have been associated with SLE in genome wide association studies. In addition, innate immune receptors are thought to be triggered by either endogenous and/or exogenous stimuli that lead to hypersecretion of IFNα. We review the multiple emerging treatment strategies targeting IFNα-related pathways. These include monoclonal antibodies against IFNα, anti-IFNα antibody-inducing vaccines, and inhibitors of Toll-like receptors. We also summarize the current status of these pharmaceutical agents in early clinical trials.

Introduction

Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease with a wide range of clinical manifestations and a pathogenesis whose details have remained relatively elusive. Dysregulation of adaptive immune responses in SLE leads to autoantibody production and immune complex deposition in various tissues [1], [2]. Clinical manifestations commonly appear in the skin, kidney, musculoskeletal, and hematologic systems, but SLE can also affect the lungs, central nervous system, serous membranes and virtually every other organ system of the body [1], [3]. The disease is responsible for significant morbidity and mortality, with most recent studies showing a 10-year survival of approximately 70–90% [4], [5]. Both genetic and environmental factors have been linked to SLE [2], [6]. The genetic risk of developing SLE is generally thought to result from the aggregate effects of multiple polymorphisms (although rare single gene mutations also cause SLE-like disease) [7]. Environmental triggers include smoking [8], UV light [9], various medications [10], and possibly certain viruses [2].

Current therapies for SLE are generally lacking in effectiveness and/or safety, and include primarily nonspecific immunomodulatory, immunosuppressive or cytotoxic agents. These therapies inhibit broadly inflammatory mediators or pathways, including those that are not particularly relevant to SLE pathogenesis. Antimalarial agents and nonsteroidal anti-inflammatory drugs (NSAIDs) remain the first-line drugs for mild disease. Corticosteroids are the primary therapy for more serious disease or one that is resistant to first-line agents, as well as during a lupus flare. Other systemic treatments targeting inflammation include cyclophosphamide, mycophenolate mofetil, and azathioprine. Less commonly used immunosuppressive agents include methotrexate, cyclosporine, tacrolimus, and leflunomide [11], [12]. All of these therapies have a broad range of nonspecific effects and are associated with considerable toxicities [11], [12]. More recently developed biologic therapies have been studied in SLE patients and B cell targeted therapy appears to provide some benefit. Belimumab (an inhibitor of the molecule “B Lymphocyte Stimulator,” or BLyS) was recently given FDA-approval for use in treating SLE, the first drug in over 40 years to achieve this status [13]. The original FDA-approved disease-modifying drug for SLE, hydroxychloroquine, an antimalarial agent, has a lengthy track record in the treatment of lupus and has been shown to have an impact on survival [14]. Antimalarial agents have a variety of effects that may be relevant to their therapeutic benefit in SLE, including interference with Toll-like receptor (TLR) signaling pathways that induce interferon-alpha (IFNα) production [15]. Additional evidence has also implicated IFNα in SLE pathogenesis, heightening interest in the development of novel pharmaceutical agents that specifically target the IFNα pathway. The role of IFNα in disease pathogenesis and the current state of development of therapies targeting IFNα are discussed below.