The Use of Glucocorticoids in Lupus Nephritis: New Pathways for an Old Drug

Abstract

Glucocorticoids therapy has greatly improved the outcome of lupus nephritis patients. Since their discovery, their adverse effects have counterbalanced their beneficial anti-inflammatory effects. Glucocorticoids exert their effects through both genomic and non-genomic pathways. Differential activation of these pathways is clinically relevant in terms of benefit and adverse effects. Ongoing aims in lupus nephritis treatment development focus on a better use of glucocorticoids combined with immunosuppressant drugs and biologics. Newer regimens aim to decrease the peak glucocorticoid dose, allow a rapid glucocorticoid tapering, and intend to control disease activity with a lower cumulative glucocorticoid exposure. In this review we discuss the mechanisms, adverse effects and recent strategies to limit glucocorticoid exposure without compromising treatment efficacy.

Keywords: adverse effect; glucocorticoids; lupus nephritis; methylpredisolone; prednisone; steroids; systemic lupus erythematosus.

Figure 1

Genomic and non-genomic mechanisms of glucocorticoids. Glucocorticoid genomic pathway is mediated through the cytoplasmic glucocorticoid receptor (cGR) leading to the mechanisms of gene transactivation and transrepression. The non-genomic pathway is mediated through the membrane glucocorticoid receptor (mGR), inhibition of the phospholipase A2, and changes in cell membranes. The arrow in the left depicts the dose of prednisone required to activate these pathways. The upper and lower gray zones represent the doses were genomic (lower gray zone) and non-genomic (upper gray zone) are fully saturated without added benefit and with higher incidence of adverse effects. mGR, membrane glucocorticoid receptor; PLA2, phospholipase A2; cGR, cytoplasmic glucocorticoid receptor; GRE, glucocorticoid response element; Hsp70·HOP·Hsp90, multiprotein complex including chaperones such as heat shock proteins and the glucocorticoid receptor; Hsp90·FKBP52·p23, multiprotein complex including chaperones, co-chaperones, and the glucocorticoid receptor.

Figure 2

Glucocorticoid dosing in induction of remission schemes. High-dose oral glucocorticoid schemes (blue) apply starting doses of oral glucocorticoids at 0.8–1.0 mg/kg/day, with slow tapering, reaching low glucocorticoid doses by 24 weeks of therapy. Recent schemes (green) apply methylprednisolone pulses followed by medium starting doses of oral glucocorticoids (<0.5 mg/kg/day) with a faster tapering, reaching low glucocorticoid doses by 12 weeks of therapy.

Figure 3

Induction of remission schemes in several studies. (A) Euro Lupus Nephritis Trial low-dose cyclophosphamide arm; (B) MYLUPUS reduced-dose glucocorticoid arm; (C) Lupus-Cruces protocol; (D) RITUXILUP protocol; (E) AURA-LV study voclosporin-treated arm; (F) NOBILITY study obinutuzumab-treated arm.