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.

Emerging clinical phenotypes associated with anti-cytokine autoantibodies

“…The protective role of neutralizing anti-IFNα AAbs in SLE was confirmed in a recent survey showing higher anti-IFNα AAb prevalence in patients with a clinically quiescent disease [53]. These results highlight the potential therapeutic utility of antibodies directed to either type I IFN or their receptors (IFNAR1/IFNAR2) in SLE [54][55][56][57][58].…”

B cell epitope spreading: Mechanisms and contribution to autoimmune diseases

“…Epitope spreading has been thoroughly studied in EAE mice, which serve as a model for multiple sclerosis. Other drugs such as interferon pathway regulatory agents could provide a further targeted approach to management of autoimmune activity [112,113]. Most recently researchers are working to develop Th2 bystander suppression drugs to combat epitope spreading, disease-specific immunologic drugs, and targeted cytokine inhibitors [2].…”

Autophagy Is an Inflammation-Related Defensive Mechanism Against Disease

“…Interestingly, autophagy is involved in interferon (IFN) secretion. Elevated levels of IFN-α are the hallmark of systemic lupus erythematosus, and ongoing clinical trials are testing the effectiveness of monoclonal antibodies against IFN-α [ 48 ]. The paucity of data in humans using agents that modulate autophagy is intriguing.…”