Persistent expression and function of P-glycoprotein on peripheral blood lymphocytes identifies corticosteroid resistance in patients with systemic lupus erythematosus

Abstract

Corticosteroids (CS) are the mainstay of treatment in systemic lupus erythematosus (SLE) patients. However, some patients have poor response to CS treatment. Among the multiple mechanisms of CS resistance, overexpression of P-glycoprotein (P-gp) on peripheral blood lymphocytes (PBL) may be one of them as this result in efflux of CS from lymphocytes. Thus, we evaluated the role of P-gp protein on PBLs in patients with SLE in its response to CS therapy. SLE patients (n = 42) (fulfilling ACR revised criteria) who were naïve to CS and immunosuppressive drugs were enrolled. Disease activity was assessed using SLE disease activity index (SLEDAI) and expression, and function of P-gp was evaluated by flow cytometry at baseline and after 3 months of therapy with CS. At 3 months, patients with SLEDAI >4 and SLEDAI ≤4 were grouped as nonresponders and responders, respectively. P-gp expression was significantly increased on PBLs of SLE patients as compared to healthy controls (p < 0.001). P-gp expression and function correlated with SLEDAI (r = 0.49, p = 0.005; and r = 0.49, p = 0.001, respectively). P-gp expression and function were not different in responders and nonresponders at baseline. However, at 3 months of CS therapy, P-gp expression and function decreased in responders (p < 0.001 and p < 0.005, respectively), whereas in nonresponders, it remained unchanged. Persistent overexpression and activity of P-gp are associated with poor response to CS in CS naïve patients of SLE.

Plant‐derived alkaloid sinomenine potentiates glucocorticoid pharmacodynamics in mitogen‐activated human peripheral blood mononuclear cells by regulating the translocation of glucocorticoid receptor

“…P‐glycoprotein (P‐gp) is known to be localized on the immune cell membrane and acts as “efflux pumps,” lowing the intracellular concentration of many lipophilic drugs and thus leading to glucocorticoid (GC) resistant (Garcia‐Carrasco et al, ). Persistent expression of P‐gp was identified on human peripheral blood lymphocytes (PBMCs) of GC resistant patients with systemic lupus erythematosus (Kansal, Tripathi, Rai, & Agarwal, ). GC resistant RA patients also companied with higher percentage of P‐gp expression (Maillefert et al, ).…”

Retracted: When doing the right thing is wrong: Drug efflux pumps in steroid‐resistant nephrotic syndrome

“…The major ABC superfamily transporters involved in MDR development in humans are P‐glycoprotein (P‐gp/ABCB1), multidrug resistance‐associated protein 2 (MRP2/ABCC2), and breast cancer resistance protein (BCRP/ABCG2). A role for MDR in treatment failure has been postulated in several diseases like asthma, ulcerative colitis, rheumatoid arthritis and systemic lupus …”

“…In this issue of International Journal of Rheumatic Diseases , Singh et al carried out a prospective study to understand the relationship between P‐gp, HDAC2 expression and functionality to steroid responsiveness in INS. Extensive work by this group previously has shown the important role of MDR‐1/P‐gp in childhood nephrotic syndrome and other autoimmune diseases . In a cohort of 216 North Indian children, G2677T/A polymorphism in MDR‐1 gene was associated with steroid resistance .…”

Interaction of Hydroxychloroquine with Pharmacokinetically Important Drug Transporters

“…Moreover, based on the assumption that hydroxychloroquine is a P-gp substrate, diminished intracellular concentration of hydroxychloroquine might also have contributed to the poor response in SLE patients with high P-gp activity in the cell membrane of leucocytes. These patients received a combination of prednisolone and hydroxychloroquine and originally the poor response in patients with high P-gp activity was attributed to corticosteroid resistance [ 42 ].…”