Defining Biological Subsets in Systemic Lupus Erythematosus: Progress Toward Personalized Therapy

Abstract

Systemic lupus erythematosus (SLE) is a heterogeneous disease with respect to disease severity, response to treatment, and organ damage. The pathogenesis of SLE includes immunological mechanisms which are driven by both genetic and environmental factors. There are clear differences in the pathogenesis of SLE between patients of different ancestral backgrounds, including differences in genetic risk factors, immunological parameters, and clinical manifestations. Patients with high vs. low levels of type I interferon (IFN) in circulation represents one major biological subset within SLE, and these two groups of patients are present in all ancestral backgrounds. Genetic factors, autoantibodies, and levels of other cytokines all differ between high and low IFN patients. This distinction has also been important in predicting response to treatment with anti-type I IFN therapies, providing a precedent in SLE for biological subsets predicting treatment response. This review will highlight some recent developments in defining biological subsets of SLE based on disease pathophysiology, and the idea that improved knowledge of disease heterogeneity will inform our efforts to personalize therapy in this disease.

SLE, An Overlooked Disease: Possibilities for Early Rescue by Early Diagnosis

“…SLE is actually a highly representative model for diseases that are in crucial need for personalized therapies as it is one of the highly heterogeneous and complex human diseases with chaotic pathogenesis [1,4]. Although under the same disease umbrella, SLE patients are not homogenous cohorts that can be classified, treated, or managed equally as they show marked discrepancies in their responses to the same treatment, manifestations of disease severity, type and levels of circulating biomarkers, organ involvement, and the underlying pathogenic mechanisms that are highly influenced by genetic, environmental, and other risk factors [1,118]. Currently, SLE patients are routinely treated with potent immunosuppressive agents that can cause adverse side effects which tend to be even more aggressive than the disease itself [41].…”

“…With the aim of achieving optimum management of SLE patients, it is therefore very wise to stratify these patients into subsets that share common pathogenic pathways which can be best accommodated with targeted or personalized therapeutic approaches that do not only increase treatment efficacy but also present safer alternatives to the nonselective immune-toxic steroids that are currently employed for the management of SLE patients [3,118].…”

“…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].…”

“…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].…”

“…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.…”