Background/Purpose: ABCB1 (P-gp) and ABCG2 (BCRP1) are part of the adenine triphosphate (ATP)-binding cassette transporter proteins. These proteins can modulate inflammatory responses and mediate efflux of drugs from cells. Several disease modifying anti-rheumatic drugs are among the substrates of ABC transporters.

The objectives of this study were to compare drug efflux function of ABCB1 and ABCG2 transporters in patients with active and inactive RA and investigate the impact of disease activity and treatment on transporter function. 

Methods: Seventeen patients with RA (ACR/EULAR criteria) active (DAS28 ≥3.2 at study inclusion) and 17 with inactive RA (DAS28<2.6) were selected from the Early Arthritis Clinic (Dec 2013-January 2015). Patients were paired according to age, gender and disease duration. All patients had medical evaluation and serum sample at study inclusion. Furthermore, 27 of them had an additional sample and clinical evaluation after six-months.

ABCB1 and ABCG2 functional activity was measured in peripheral mononuclear cells by flow cytometry. The percentage of cells able to extrude substrates for ABCB1 (daunorubicin) and ABCG2 (mitoxantrone) were recorded in the presence or absence of the selective ABCB1 (verapamil) or ABCG2 (KO143) inhibitors. Efflux activity was defined as a percentage greater than the mean in 30 healthy controls plus two standard deviations, i.e. 1.67% (range 0.26% to 1.98%).

The study was approved by our internal review board. All patients signed informed consent.

Statistical analysis. Appropriate tests were used according to variable distribution and linear regression model to establish the association between disease activity and transporter´s function.

Results:

Data from 34 patients (94.1% women) were analyzed. Mean ± SD age: 41.6 ± 11 years, disease duration was 6.3 ± 3.5 years; patients with active disease (DAS28: 4.8 ± 1.3) had significantly higher baseline and cumulative corticosteroids doses than inactive patients (DAS28: 1.2 ± 0.6): 10.1±5 vs. 6.3±2.1 mg/day, p=0.03 and 4041±1849 vs. 2348.5±859.5 mg, p=0.004, respectively. No other remarkable differences were seen.

Active patients had higher ABCB1 activity, median (25-75 IQR): 7.1% (1.4-29.3) vs. 1.6% (0.7-3.5); p=0.02 and ABCG2 activity: 6.2% (1.3-22.4) vs. 1.3% (0.7-2); p=0.007.

The ABCB1 and ABCG2 activity correlated with DAS28: rho=0.45, p=0.008 for ABCB1 and rho=0.52, p=0.002, for ABCG2. No correlation was found with cumulative corticosteroids or other treatment.

Linear regression model applied to the 34 patients at baseline showed DAS28 as the only predictor of both ABCB1 (beta coefficient: 0.50; 95%CI: 1.6-6.7; p=0.002; R2=0.23) and ABCG2 (beta coefficient: 0.48; 95CI%: 1.4-6.8; p=0.004; R2=0.21) function.

Disease activity increased in 14.8% of the patients at 6 month follow-up, while 48.1% remained stable and 37.1% improved. DAS28 changes at this time correlated with shift in ABCB1 (r=0.35, p=0.07) and ABCG2 (r=0.33, p=0.09) function.

Conclusion:

Patients with active RA have a higher efflux function of ABCB1 and ABCG2 compared with those in remission at baseline. ABCB1 and ABCG2 behavior is conditioned by disease activity.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/disease-activity-predicts-abcb1-and-abcg2-drug-efflux-transporters-function-in-rheumatoid-arthritis-ra-patients/