Background/Purpose: 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^¥. 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 an observational 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 (15-17.5 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 = 0.0003) being significant since 0.5years (60% with MTX ≥ 20 mg / week vs 39% without MTX; p = 0.003). To analyze the ADA development, patients treated with Ifx and Ada were grouped and we observed a low development of immunogenicity in the group which did not receive MTX (n = 37) compared to those who received high-dose MTX (n =27) close to significance (32% vs 19%, p = 0.05). Analysing by separate drugs MTX significantly reduced the immunogenicity of Ada, (53% in patients with MTX vs 12% in monotherapy; p <0.0001).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 <0.0001) .This effect was significant since 0.5 years of treatment (16% MTX ≥ 20 mg / week vs 3% without MTX; p =0.001)

Conclusion: 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.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/effect-of-methotrexate-in-the-presence-of-drug-and-the-appearance-of-antibodies-against-tumour-necrosis-factor-inhibitors-in-patients-with-rheumatoid-arthritis/