SAT0052 Influence of Immunogenicity and Drug Levels on the Efficacy of Long-Term Treatment of Rheumatoid Arthritis with Adalimumab and Etanercept: A Uk-Based Prospective Study

Abstract

Background The introduction of tumour necrosis factor inhibitors represents a major advance in the treatment of rheumatoid arthritis (RA). Despite this, up to 40% of patients 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. Radioimmunoassay (RIA) is a sensitive method to detect ADAb and is less prone to drug interference vs. ELISA. The clinical utility of pharmacological monitoring in routine rheumatology practice is still debated with conflicting opinions. Objectives To evaluate whether ADAb formation and serum drug levels may predict future treatment response of anti-TNF initiated RA patients. Methods 331 patients were selected from the Biologics in RA Genetics and Genomics Study Syndicate prospective cohort [n=160 adalimumab (AD); 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 at 3, 6 and 12 months; the timing of blood samples was not consistently pre-dose. Disease activity (DAS28) scores were measured at each visit. Descriptive statistics, multiple linear regression and generalised estimating equation were used as appropriate. Results 835 serial samples were suitable for pharmacological testing (n=414 AD; 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 AD 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 AD drug levels (p <0.0001; rs -0.51; if ADAb titres>100AU p=0.0041; rs-0.66). At 3 months, ADAb formation and low drug levels were a significant predictor of poor ΔDAS28 at 6 and 12 months (p<0.0001, RC -0.0048 95% confidence intervals (CI) -0.0071 to -0.0025). By 12 months, patients who developed ADAbs showed less improvement in disease activity (mean ΔDAS28 2.35; CI 1.67-3.03) than patients without (mean ΔDAS28 3.15; CI 2.86-3.35; p=0.022). Patients who did not develop ADAbs were more likely to be co-treated with MTX (61.4% vs. 43.7% p=0.01). AD drug level was the most significant independent predictor of ΔDAS28 at all time points after adjusting for confounders (p <0.0001, RC 0.12, CI: 0.06-0.18). At 12 months, patients on ETA with higher drug levels (>15μg/mL) were more likely to achieve a good EULAR response than patients with sub-therapeutic levels (<0.0035 μg/mL) (p=0.01). High BMI was the strongest predictor of low drug levels (ETA, p<0.0001, RC -5.97; CI -8.75 to -3.19; AD, p<0.0001, RC-3.86; CI -5.72 to -2.00). Conclusions At 3 months ADAb formation and low AD drug levels are a significant predictor for poor treatment response at 6 and 12 months. In addition low AD drug levels were the strongest independent predictor of poor treatment response at all time points. Acknowledgements Supported by Medical Research Council [grant...

Immunoassay methods used in clinical studies for the detection of anti-drug antibodies to adalimumab and infliximab

“…In many of the included studies in which the type of immunoassay was identified and pharmacokinetic or clinical outcomes evaluated, the presence of ADA was associated with decreased efficacy [20 of 38 (53%) adalimumab studies and 26 of 62 (42%) infliximab studies; Tables and ]. In adalimumab studies conducted in patients with RA using several different assay formats, ADA‐positive patients had significantly less improvement in clinical symptoms with treatment , were significantly more likely to have poor response or treatment failure and were significantly less likely to achieve clinical remission or low disease activity compared with ADA‐negative patients. Similar results were observed in infliximab studies in RA regardless of immunoassay type .…”

“…In many of the included studies in which the type of immunoassay was identified and pharmacokinetic or clinical outcomes evaluated, the presence of ADA was associated with decreased efficacy [20 of 38 (53%) adalimumab studies and 26 of 62 (42%) infliximab studies; Tables 2 and 3]. In adalimumab studies conducted in patients with RA using several different assay formats, ADA-positive patients had significantly less improvement in clinical symptoms with treatment [45,46], were significantly more likely to 100…”

“…Bubble size denotes the number of patients assessed for ADA. Summary of efficacy outcomes in ADA-positive and -negative patients treated with adalimumab et al 2014[46] Jani et al 2015[230] clinical trialsV C 2018 The Authors. Clinical & Experimental Immunology published by John Wiley & Sons Ltd on behalf of British Society for Immunology, Clinical and Experimental Immunology, 192: 348-365…”

Laboratory Monitoring of Biological Therapies in Rheumatology: The Role of Immunogenicity

“…Moreover, the complex formed by an anti-TNF drug and its specific antibody may affect its pharmacokinetics by increasing its clearance and lowering its serum level, thus having a potentially negative impact on clinical responses. A recently reported randomized controlled trial (RCT) and real-life data showed that anti-drug antibody-positive patients treated with ADA, IFX, CZP, or GLM had lower serum bD-MARD levels than those who are anti-drug antibody-negative [21,[30][31][32][33]. However, although one study found that serum IFX levels were low ( < 0.5 µg/mL) in one-quarter of RA patients, no more than 11% had detectable anti-IFX antibodies, suggesting that additional factors may be responsible for the reduced efficacy of IFX [34].…”

The potential value of blood monitoring of biologic drugs used in the treatment of rheumatoid arthritis

“…In a UK study of over 300 RA patients, body mass index (BMI) was the strongest predictor of low drug levels and subsequent poor response. 40 Overweight patients are recognized to be underdosed on subcutaneous anti-TNF drugs. 41 The sampling date within a 2-week drug injection interval to obtain a trough measurement in TDM could be important: is within 3 days of drug administration acceptable, or could this be extended to up to 1 week?…”