Background/Purpose Up to 40% of RA patients on anti-TNF treatment fail to respond either due to primary inefficacy or loss of response. One explanation is immunogenicity leading to the development of anti-drug antibodies (ADAb) and low drug levels, however the clinical utility of pharmacological monitoring is debated. One challenge is the practicality of obtaining trough drug levels in patients and the impact that would have on service delivery. Our aim was to evaluate whether the presence of ADAb and/or non-trough drug levels may predict treatment response in patients with RA treated with anti-TNF drugs.

Methods 331 patients were selected from the Biologics in RA Genetics and Genomics Study Syndicate prospective cohort [n=160 adalimumab (ADL); n=171 etanercept (ETA)]. Serum samples  were collected at 3, 6 and 12 months following initiation of therapy. ADAb were measured using RIA and drug levels using ELISA assays at 3, 6 and 12 months. Disease activity (DAS28) scores were measured at each visit. Multiple linear regression, logistic regression, generalised estimating equation and ROC curves were used to test the association and predictive value of ADAb and/or non-trough drug levels on treatment response as assessed by the change in DAS28 score between pre-treatment and 12 months post-treatment (ΔDAS28).

Results

835 serial samples were suitable for pharmacological testing (n= 414 ADL; n=421 ETA). Mean age: 56±13 years; 75% female; baseline DAS28 score 5.9±0.8; median BMI 27.5 (IQR 23.6-32.3). 85% were on a DMARD (56% MTX). ADAbs to ADL were detected in 24.8% (31/125 patients at ≥1 time points by 12 months) and in none of the ETA patients. The presence of ADAbs were significantly associated with lower ADL drug levels (ADAb titres>100AU p=0.0041; Spearman’s rho -0.66). At 3 months, ADAb formation and low ADL levels were a significant predictor of no EULAR response at 12 months [ROC curve analysis, area under curve (AUC) 0.71, 95% confidence intervals (CI) 0.57-0.85]. Patients who developed ADAbs received lower median doses of concomitant MTX therapy (15mg/wk [IQR 10-20]) and had longer disease duration (14.0 years [6.7-19.4]) vs. patients who did not (20mg/wk [15-20] p= 0.01); (7.7 years [3.6-16.0] p=0.03). ADL drug level was the most significant independent predictor of ΔDAS28 at all time points after adjusting for confounders (p= 0.003, regression coefficient (RC) 0.12, CI: 0.06-0.18). Patients on ETA with higher drug levels (>15μg/mL) were more likely to achieve a good EULAR response than patients with sub-therapeutic levels (<0.035 μg/mL) (p=0.01). However low ETA levels at 3 months were not a significant predictor of no EULAR response at 12 months (AUC 0.51; CI 0.41-0.61). BMI was the strongest predictor of low drug levels (ETA, p<0.001, RC - 5.97; CI -8.75 to -3.19; ADL, p<0.001, RC-3.86; CI -5.72 to -2.00). Patients with a BMI>30 had significantly lower drug levels compared to those with a BMI<30 in both ADL and ETA cohorts (p<0.01).

Conclusion Pharmacological testing in anti-TNF initiated patients is clinically useful even in the absence of trough levels. At 3 months ADAb formation and low ADL drug levels are a significant predictor for poor treatment response at 12 months. Patients with a BMI>30 were less likely to have therapeutic drug levels.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/clinical-utility-of-random-anti-tnf-drug-level-testing-and-measurement-of-anti-drug-antibodies-on-long-term-treatment-response-in-rheumatoid-arthritis/