Clinical relevance of P-glycoprotein activity on peripheral blood mononuclear cells and polymorphonuclear neutrophils to methotrexate in systemic lupus erythematosus patients

Abstract

To elucidate the relationship between P-glycoprotein activity on peripheral blood leukocytes of systemic lupus erythematosus (SLE) patients with lupus arthritis and the clinical response to methotrexate. An observational study was made in patients with SLE according to ACR criteria 1997 who had arthralgia and arthritis and received methotrexate for ≥3 months. Methotrexate responders and non-responders were compared according to the Clinical Disease Activity Index. Mononuclear cells and polymorphonuclear neutrophils were isolated from SLE patients and P-glycoprotein expression was measured using the relative fluorescence index and percentage of positive cells. The chi-square test was used to compare P-glycoprotein activity between responders and non-responders. Thirty-two patients with a mean age of 45.4 ± 10.7 years were included: 34.4% had a response to methotrexate and 65.6% did not. Mean relative fluorescence units of both mononuclear cells and polymorphonuclear neutrophils were significantly lower in patients with a good response (7.0 ± 4.3 vs. 9.6 ± 3.8; p = 0.041 and 4.2 ± 3.5 vs. 7.6 ± 4.0; p = 0.004). The prevalence of low fluorescence levels (<6 relative fluorescence units), signifying higher P-glycoprotein activity of both mononuclear cells and polymorphonuclear neutrophils, was higher in methotrexate responders than in non-responders (27.3 vs. 4.8%; p = 0.10 and 81.8 vs. 23.8%; p = 0.003, respectively). In SLE patients with joint involvement treated with methotrexate, P-glycoprotein activity was higher in responders to methotrexate than in non-responders. Further studies are required to determine the mechanisms behind this finding and whether P-glycoprotein activity mediates alterations in methotrexate efficacy.

RETRACTED: Toxicité aiguë du méthotrexate lors d’un traitement à faible dose

“…La Pgp est une molécule de transport appartenant à la superfamille des transporteurs ABC (transporteurs à cassettes liant l'ATP). Elle est codée par le gène humain MDR1 (Multidrug Resistance Gen 1) [7,8]. Environ 10% du MTX sont métabolisés dans le foie [3].…”

ABCB1 in dermatology: roles in skin diseases and their treatment

“…Other investigations involving methotrexate and ABCB1 have mainly focused on rheumatoid arthritis and malignancy. Surprisingly, in patients with systemic lupus erythematosus, relative to methotrexate nonresponders, those that responded to methotrexate exhibited a higher ABCB1 expression level in polymorphous neutrophils and mononuclear cells [ 98 ]. By contrast, in a series of studies with subcutaneous rheumatoid nodules, no correlation was observed between ABCB1 expression and methotrexate treatment responses [ 99 ].…”

Acute Methotrexate Toxicity under Low Dose Therapy

“…Intracellular accumulation of these MTX polyglutamates occurs primarily in the liver, kidney and spleen, which may persist for weeks to months [3,6]. MTX can however be transported outside the cell by the drug efflux transporter P-glycoprotein (P-gp) [7,8]. P-gp inhibitors can therefore prolong the intracellular retention of MTX [7].…”

“…MTX can however be transported outside the cell by the drug efflux transporter P-glycoprotein (P-gp) [7,8]. P-gp inhibitors can therefore prolong the intracellular retention of MTX [7]. The plasma protein binding of MTX is approximately 50% [3].…”