The HBsAg-HBcAg vaccine candidate was safe, well tolerated and immunogenic in this phase I study in healthy adults. To our knowledge, this is the first demonstration of safety and immunogenicity for a nasal vaccine candidate comprising HBV antigens.
Background
Is not uncommon to observe that an important number of patients with rheumatoid arthritis (RA) have to withdraw or change treatment because of lack or loss of efficacy. Several mechanisms of treatment resistance, including the drug-uptake and drug-efflux transporters belonging to the superfamily of transporters multidrug-resistance (MDR) has been described that might explain this status. Among these transporters, ABCB1 (P- gp) and ABCG2 (BCRP) may have an important role for among its substrates some disease-modifying drugs such as prednisone and chloroquine (for ABCB1) and methotrexate and sulfasalazine (for ABCG2) are included.
Objectives
To determine the ABCB1 and ABCG2 transporters activity in RA patients in remission compared with those that do not achieve remission.
Methods
Patients at the early RA clinic cohort of our Institute, who meet the ACR/EULAR 2010 diagnosis criteria, were included. ABCB1 (P-gp) and ABCG2 (BCRP) functional activity was measured in peripheral mononuclear cells by flow cytometry. The percentage of cells able to extrude specific substrates for ABCB1 (daunorubicin) and ABCG2 (mitoxantrone) were recorded. The specificity of the assay was confirmed with specific inhibitors (verapamil for ABCB1 and KO143 for ABCG2). Thirty healthy controls were also evaluated to established normal values. The study was approved by our local ethics committee. Statistical analysis: Continuous variables were compared with Student t or Mann -Whitney U tests and categorical variables with chi square or Fisher exact test as appropriate.
Results
We included 21 patients (all women) with a mean age of 36.9±11.7 years, with disease duration of 4.67±3.59 years. Ten patients had active and 11 inactive disease determined by DAS28 (mean 4.22±0.92 vs 1.25±0.66, p<0.001). There were no significant differences in age, disease duration (5.4±3.5 vs 4±3.7 years) or the use of methotrexate (80 vs 100%), antimalarials (30 vs 36.4%), sulfasalazine (40 vs 27.3%) or PDN (70 vs 72%) among active vs inactive patients.Only one inactive patient was positive for ABCB1 and none for ABCG2 while 5 active patients were positive for ABCB1 and ABCG2. The median percentage value of cells able to extrude daunorubicin in active patients was 3% (IQR 1-15.5%) vs 1 (IQR 0-1) in inactive patients (p=0.036) while the median percentage of cells that extruded mitoxantrone in active patients was 3% (IQR 0-10.5%) vs 0% (IQR 0-1) in the inactive patients (p=0.05).
Conclusions
Patients with active RA have a higher functional activity of ABCB1 and ABCG2 transporters compared with those in remission independently of treatment and disease duration. Follow up of these patients is currently ongoing –and will be presented- to determine if the functional activity of these efflux pumps entails a higher risk of persistent activity or risk of RA reactivation.
Disclosure of Interest
None declared
DOI
10.1136/annrheumdis-2014-eular.5268
BackgroundABCB1 (P-gp) and ABCG2 (BCRP1) are part of the adenine triphosphate (ATP)-binding cassette (ABC) transporter proteins. These proteins mediate efflux of drugs from inside the cells and can confer a multidrug resistance phenotype. Drugs included among its substrates are indicated in RA patients. Accordingly, an association between disease activity and ABCB1 and ABCG2 function might be hypothesized.ObjectivesThe study was undertaken to compare the drug efflux function of both transporters in patients with active and inactive RA and to define the impact of disease activity on transporter function.MethodsWe included 17 active RA patients (DAS28≥3.2), paired (age, gender and disease duration) to 17 patients in remission (DAS28<2.6), from an early RA cohort. All patients had a complete medical evaluation and serum sample obtained at study inclusion and 27 of them had an additional sample and evaluation at six-month follow-up.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.For 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.ResultsData from 34 patients (94.1% women) were analyzed. Their mean age was 41.6±11 years and disease duration was 6.3±3.5 years; 85.3% had RF and 97.5% ACCP. Patients with active disease ([mean ± SD] DAS28: 4.8±1.3) had significantly higher cumulative corticosteroids doses than inactive patients ([mean ± SD] DAS28: 1.2±0.6). The formers had also higher efflux function of both transporters: median (25-75 IQR) ABCB1: 7.1% (1.4-29.3) vs. 1.6% (0.7-3.5), p=0.02 and ABCG2 6.2% (1.3-22.4) vs. 1.3% (0.7-2), p=0.007. Percentage of cells able to extrude daunorubicin or mitoxantrone 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.Finally, 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.ConclusionsPatients with active RA have a higher efflux function of ABCB1 and ABCG2 compared with those in remission at baseline. What seems to be conclusive is that ABCB1 and ABCG2 beh...
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