Background Several factors influence pharmacokinetics of TNFinhibitors (TNFi). One relevant factor is the formation of anti drug- antibodies (ADA) associated with low drug levels and a worse clinical response. Recent publications in rheumatoid arthritis (RA) 1,2 have demonstrated a beneficial effect of concomitant use of anti-TNF drugs and methotrexate (MTX), with a dose-dependent effect.
Objectives To analyze the MTX influence on the presence of drug and appearance of ADA in a cohort of RA patients treated with Infliximab (Ifx), Adalimumab (Ada) or Etanercept (Etn) with a long follow-up (3 years).
Methods This is a retrospective study that analyzed patients with RA treated with Ifx (112 patients), Ada (71 patients) and Etn (110 patients), in a prospective observational biological cohort from the University Hospital La Paz, Madrid, Spain. Patients were grouped according to the use of MTX: no MTX, low dose (≤12.5 mg/week), intermediate dose (12.5–20 mg/week) and high dose (≥20 mg/week). Levels of drug and ADA were measured by capture and bridging ELISA respectively at baseline, 0.5, 1, 2 and 3 years. All samples were obtained just before drug administration. Statistical analysis was performed using GraphPad Prism 5.0 software.
Results Out of 293 RA patients with a TNFi treatment; 184 (71 with Ifx, 40 with Ada and 73 with Etn) were included. In this cohort, 111 (61%) were on MTX and 72 (39%) were on monotherapy. Most patients with high dose of MTX had levels of drug over 3 years of treatment (93% with MTX ≥20 mg/week vs 77% without MTX; p=0.01) being significant since 0.5 years (≥60% with MTX 20 mg/week vs 39% without MTX; p=0.02)
To analyze the ADA development, patients treated with Ifx and Ada were grouped and we observed a trend to a higher percentage of ADA in the group which did not receive MTX (n=37) compared to those who received high-dose MTX (n=27) although not statistically significant (32% vs 19%, p=0.21). Analysing by separate drugs MTX significantly reduced the immunogenicity of Ada, (53% in patients with MTX vs 15% in monotherapy; p=0.02).
When we study the lack of circulating drug (Ifx, Ada and Etn) as an indicator of immunogenicity, patients who did not receive MTX (n=56) had higher absence of drug than patients with high-dose MTX (n=61) (34% vs 10%, respectively; p<0.01). This effect was significant since 0.5 years of treatment (16% MTX ≥20 mg/week vs 3% without MTX; p=0.017)
Conclusions In our cohort of RA patients the concomitant use of MTX has a positive effect in the persistence of TNFi levels together with a decrease of immunogenicity. Furthermore, the MTX has a dose-dependent effect being greater at high dose of MTX.
Krickaert C et al.ARD 2012; 71:11.
Vogelzang E H et al.ARD 2015; 74:2
Acknowledgement This work is partially funded by a non restricted grant from Pfizer
Disclosure of Interest None declared