5.1. New potential therapeutic targets in SLE

As previously learnt, type I IFNs including IFN-α are greatly implicated in SLE pathogenesis and mediate a variety of downstream-deregulated immune responses including the release of autoantibodies [4]. However, highly elevated levels of type I INFs are only found in 40–50% of SLE patients constituting a subset of patients that can be particularly responsive to therapies targeting type I INFs and other mediators implicated in their pathway such as TLRs and IFN receptors [118, 121, 122]. One such agent is the anti-IFN-α monoclonal antibody sifalimumab which showed promising clinical activity in phase I and phase II clinical trials with high tolerance and safety profile [3, 123]. Other agents include the monoclonal anti-IFN-α antibodies rontalizumab [124] and AGS-009 which have finished phase II and phase I studies, respectively, with promising clinical results [3].

Another promising target is BAFF cytokine (also called BLyS) which is essential for B-cell maturation and function [4]. Differential circulating levels of this cytokine have been observed among SLE patients of different ethnic backgrounds where it was particularly elevated in SLE, An Overlooked Disease: Possibilities for Early Rescue by Early Diagnosis 81 http://dx.doi.org/10.5772/intechopen.74803

Figure 6. Several therapeutic approaches target distinct immune modulators in the pathogenesis of systemic lupus erythematosus. Deregulated immune cascade in SLE involves activation of TLRs in plasmacytoid dendritic cells mediated by internalized nucleic acids that are released from dead cells. Activated TLR induces potent release of type I INF such as INF-α which activates myeloid cells that act to release elevated amounts of the B-cell activator factor BAFF (also called BLyS). BLyS stimulates B-cell maturation and release of autoantibodies. Further activation of B cells is mediated via B-cell and T-cell interactions that can ultimately lead to loss of immune tolerance. Several agents have been described for targeting key players in the above immune cascade where some have paved their way in clinical use; others are still under clinical investigations, while some were not met with clinical successes [3].

patients of African background in comparison to patients of European background [125]. One of the agents that has gained approval in many countries for the treatment of SLE patients is the anti-BAFF monoclonal antibody belimumab [3] that has shown considerable efficacy and tolerability in randomized placebo-controlled phase III clinical trials in SLE patients against a control group [55, 126]. Many other agents that target BAFF are also still under clinical investigations and have shown promising results including blisibimod which has currently passed phase II clinical trials for SLE [3, 127]. Another agent that target B cells and showed highly encouraging early results for the treatment of SLE but has unfortunately failed in advanced stages of clinical trials is the chimeric antibody Rituximab [3]. Rituximab showed highly promising results in reducing SLE activity particularly in patients with lupus nephritis [128, 129] and has been largely prescribed to SLE patients all over the world with a decision that was mainly based on clinical experience and open-label studies [3]. However, in randomized placebo-controlled clinical trials, rituximab failed to provide efficacy in moderate to severe SLE patients with and without renal nephritis [130, 131]. Nevertheless, these results could be potentially misleading owing to some issues in the study design as it was shown that both test and control groups were receiving strong immunosuppressive agents including high doses of glucocorticoids [3, 118]. Nevertheless, rituximab is still prescribed by some clinicians, which also suggests the probability that this treatment works best at certain subsets of lupus patients, and further investigations should be implemented [118].

Finally, T cells and associated stimulatory pathways play a key role in the deregulated immune cascade in SLE pathogenesis [1, 4] and are thus highly promising therapeutic targets in SLE. Many attempts have been made in generating therapeutics targeting T cells including anti-CD40 ligand antibodies such as CDP7657 which is currently under clinical investigations in phase I study for SLE [3]. Other anti-T-cell approaches are being attempted including small molecule inhibitor drugs such as quinoline-3-carboxamide derivatives [132] and analogues of sphingosine-1-phosphate [133] which are still under clinical developments.
