Leveraging Heterogeneity in Systemic Lupus Erythematosus for New Therapies

Abstract

Systemic lupus erythematosus (SLE) is a multisystem, chronic autoimmune disease where treatment varies by patient and disease activity. Strong preclinical results and clinical correlates have motivated development of many drugs, but many of these have failed to achieve efficacy in clinical trials. FDA approval of belimumab in 2011 was the first successful SLE drug in nearly six decades. In this article, we review insights into the molecular and clinical heterogeneity of SLE from transcriptomics studies and detail their potential impact on drug development and clinical practices. We critically examine the pipeline of SLE drugs, including past failures and their associated lessons and current promising approaches. Finally, we identify opportunities for integrating these findings and drug development with new multidisciplinary advances to enhance future SLE treatment.

Keywords: patient heterogeneity; personalized medicine; systemic lupus erythematosus; systems immunology; therapies; transcriptomics.

Figure 1.. Heterogeneity in SLE [182].

A broad range of clinical manifestations and immunological abnormalities in SLE underlies patient heterogeneity. Patients may present any combination of characteristics and these may change over the course of disease and treatment.

Figure 2.. Patient Profiling for Personalized SLE Medicine [182].

Constructing profiles from multiple -omics approaches (i.e. transcriptomics, metabolomics, proteomics, epigenomics, and genomics) can highlight key players in each individual patient’s clinical and molecular manifestations. Interpretation of these profiles within the context of patient medical history and clinician monitoring can inform personalized medicine regimens. Specific drug targets and mechanisms can be matched to patient characteristics to optimize the likelihood of treatment success. Abbreviations used: BDCA2, blood DC antigen 2; BLyS, B lymphocyte stimulator; CaN, calcineurin, CAR, chimeric antigen receptor; IFN, interferon; IFNAR, interferon alpha and beta receptor; IFN-K, IFN-α kinoid; JAK/STAT, Janus kinase/signal transducer and activator of transcription; pDC, plasmacytoid dendritic cell; TACI, transmembrane activator and calcium modulator and cyclophylin ligand interactor; TYK2, tyrosine kinase 2

Figure 3.. Pathologic mechanisms andemerging therapies in SLE [182].

1) Autoimmune responses are initiated by immune recognition of autoantigens derived from apoptotic material from dead and dying cells and neutrophil extracellular trap debris. These autoantigens include dsDNA, histones, snRNP, Ro/SSA, and La/SSB.2) Autoantigens are presented to self-reactive T cells which provide help to B cells, resulting in cellular activation and the production of pathogenic autoantibodies by plasma cells. 3) Autoantibodies bind to circulating autoantigens to form immune complexes that engage Fc gamma receptors (FcγRs) on plasmacytoid dendritic cells (pDCs), leading to internalization via endocytosis. 4) Intracellular toll-like receptors (TLRs) 7 and 9 are activated by nucleic acids in immune complexes, resulting in type I interferon (IFN) production. 5) Immune complexes and chronic immune activation contribute to excessive production of proinflammatory cytokines. IFNα is one major cytokine in this milieu, which promotes production of pro-B cell survival cytokines (e.g., APRIL, BLyS) via the innate immune system to support B cell maturation. IFNα can also contribute to pathogenic activation of T cells and differentiation of monocytes into dendritic cells. 6) Many cytokine receptors, including type I and II IFNs, transduce signals using the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. Type I IFN receptors activate JAK/STAT to drive transcription of IFN-stimulated genes to create a positive feedback loop for inflammation. Immunological networks are shown with arrows. Preclinical and clinical therapeutics are highlighted in boxes and are expanded upon in the text. Abbreviations used: APRIL, a proliferation-inducing ligand; BLyS, B lymphocyte stimulator; IFNAR, interferon alpha and beta receptor; NFAT, nuclear factor of activated T cells; TACI, transmembrane activator and calcium modulator and cyclophilin ligand interactor