Childhood-onset systemic lupus erythematosus: characteristics and the prospect of glucocorticoid pulse therapy

Abstract

Childhood-onset systemic lupus erythematosus (cSLE) is an autoimmune disease that results in significant damage and often needs more aggressive treatment. Compared to adult-onset SLE, cSLE has a stronger genetic background and more prevalent elevated type I Interferon expression. The management of cSLE is more challenging because the disease itself and treatment can affect physical, psychological and emotional growth and development. High dose oral glucocorticoid (GC) has become the rule for treating moderate to severe cSLE activity. However, GC-related side effects and potential toxicities are problems that cannot be ignored. Recent studies have suggested that GC pulse therapy can achieve disease remission rapidly and reduce GC-related side effects with a reduction in oral prednisone doses. This article reviews characteristics, including pathogenesis and manifestations of cSLE, and summarized the existing evidence on GC therapy, especially on GC pulse therapy in cSLE, followed by our proposal for GC therapy according to the clinical effects and pathogenesis.

Keywords: childhood-onset systemic lupus erythematosus; genetic factors; glucocorticoids; intravenous methylprednisolone pulse therapy; type I interferon.

Figure 1

Susceptibility genes related to the production of IFN-I and IFN-I signaling pathway in SLE. Red italics represent susceptibility genes, and blue arrows represent proteins in the pathway affected by the susceptibility genes. UBE2L3 regulate the degradation of TLR4/9. High IFN-α in SLE patients is related to the risk allele of PTPN22 though TRAF3. TNFAIP3 and TNIP1 encode regulatory factors in IFN-I pathway, NF-κB activation. DDX58 is related to RIG1 hyperactivation. IFIH1 encodes MDA5 and is involved in elevated expression of IFN-induced genes. ETS1 is a negative regulator in SLE. IRF5/7/8 can directly induce transcription of proteins in IFN-I signaling pathway. IRAK1, TRAF6, STAT4 and TYK2 are related to the production of IFN-I. UBE2L3, ubiquitin-conjugating enzyme E2 L3; PTPN22, protein tyrosine phosphatase non-receptor type 22.

Figure 2

The central role of type I IFN in SLE. Interferogenic ICs stimulate pDCs and produce type I IFN. The secreted type I IFN acted on innate and adaptive immune cells to amplify the autoimmune response. B, T and NK enhanced type I IFN production by activated pDCs via PECAM, GM-CSF and LFA-1, respectively. In contrast, activated monocytes suppressed the secreted type I IFN by pDC via ROS and PGE2. GM-CSF, Granulocyte-macrophage colony stimulating factor; PGE2, Prostaglandin E2; NE, neutrophil.

Figure 3

The anti-inflammatory/immunosuppressive effects of GC and difference between oral and pulsed GC. The effects of GC are transmitted intracellularly through the binding of GR to GRE/nGRE to suppress the expression of pro-inflammatory genes. Furthermore, GR can interact with p65 subunit of NF-κB to repress NF-κB regulated gene expression. GR can also interact with c-Jun to repress AP-1 regulated gene transcription. Then the synthesis of IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-12, IL-18, GM-CSF, TNF-α, IFN-γ are decreased. The decreased IL-12 further reduced the secretion of TNF-α by NK cells. GR negatively regulates CXCL5, which in turn decreases NE migration. On the other hand, GR suppress the excessive inflammatory response mediated by T cell response by inhibiting COX-2. Finally, GC directly decreased the number of multiple immune cells including NK, CD8⁺ T cells, B cells, Th1 cells and monocytes. Pathway marked by red asterisks and red arrows is the different pathway affected by oral and pulse GC. The GC pulse regimen affects TLR7/9 in the IFN pathway, thereby affecting the activation of NF-κB, which in turn mediates pDC apoptosis and reduces IFN-α production. IFN pathway is not significantly affected by oral GCs. GRE, glucocorticoid response elements; nGRE, negative GRE; GM-CSF, granulocyte macrophage-colony stimulating factor; NE, neutrophil; TNF-α, tumor necrosis factor-α.

Figure 4

Pattern-trend plot of GC therapy. The red line represents the repeated IVMP pulses combined with low-dose oral prednisone therapy. The blue line represents the daily oral prednisone therapy. In daily oral therapy, prednisone doses decreased gradually but mostly remained at higher levels. In intermittent IVMP pulses combined with low-dose oral prednisone therapy, MP doses were high during the pulses, and intermittent and maintenance periods were given a low dose of GCs.