Clinical utility of measuring adalimumab trough levels and antibodies to adalimumab in patients with inflammatory bowel diseases

Monday, 28 October, 2013
  • MG Ward ,
  • VC Kariyawasam,
  • SB Mogan,
  • PA Blaker,
  • KP Patel,
  • M Pantelidou,
  • S Anderson,
  • JD Sanderson,
  • Nick Unsworth,
  • Zehra Arkir,
  • PM Irving

Abstract

Adalimumab (ADA) is an effective therapy for inducing and maintaining response in patients with inflammatory bowel disease (IBD). Nevertheless a considerable proportion of patients develop secondary loss of response. The measurement of drug levels (DL) and antibodies to ADA (ATA) may be useful in this situation. Where as good data exists defining therapeutic DL and antibodies to infliximab, little is known of absolute values that are associated with active disease and clinical remission in patients treated with ADA.

Aims: To describe initial clinical experience with a commercially available ELISA kit for the measurement of DL and ATA in a tertiary IBD centre. Methods: Patients with IBD who underwent DL and ATA testing between February 2012 and March 2013 were reviewed. LISA-TRACKER Premium ELISA kits (Theradiag, Marne La Vallee, France) were used to determine free DL and ATA. Measurement range was 0.1 to 5 ug/mL for DL and 10 to 160 ng/mL for ATA (>10 ng/mL considered positive). Samples with DL above 5 ug/mL were diluted 1:3 or 1:4 to derive absolute values. Clinical details were obtained from the electronic patient record. Patients were classified as in remission or as active disease after review by two IBD physicians blinded to DL/ATAresults. Anti-TNF resistant disease was defined as active disease with DL >5 ug/mL despite dose escalation to 40 mg weekly.

Results: 31 patients (19 male, median 33 years) had 32 samples collected; 27 with Crohn’s disease, 3 IBD – unclassified and 1 ulcerative colitis. Median duration ADA treatment was 26 months (4–48). 12/32 (38%) patients had active disease. 20/32 (63%) samples had DL above upper limit of detection, of which 11 were diluted to derive absolute values. Hence 23 patients had absolute DL available for analysis. DL were significantly higher in patients in remission (median 8.3 ug/mL, IQR 4.9–17.9) compared to active disease (median 4.6 ug/mL, IQR 3.2–9.6,p = 0.45). This significance was further strengthened when patients with anti-TNF resistant disease (n = 4) were excluded (remission DL median 8.3 ug/mL, IQR 4.9–17.9 vs active disease DL median 3.5 ug/mL, IQR 1.4– 4.8,p < 0.001), (Fig 1). ROC analysis identified an optimal AD DL > 4.9 ug/mL (sensitivity 83%, specificity 65%, AUC 0.75) to predict clinical remission (Fig 2). The association between this therapeutic DL (4.9 ug/mL) and clinical remission remained statistically significant (p = 0.03) when samples with undiluted DL > 5 ug/mL were also considered, (Fig 3). 1/32 (3%) samples were ATA positive; (undetectable DL); this patient had active disease.

Conclusions: As has been demonstrated with drug level testing for infliximab, initial experience suggests that measuring DL in adalimumabtreated patients may be clinically useful. The significance of antibodies is less clear given their low prevalence, however it is important to note bridging ELISA detects free ATA only, hence undetectable ATA may have contributed to the lower DL seen in non-responders in this study. A therapeutic level of approximately 5 μg/ml concurs with data from other centres using this assay.

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Clinical utility of measuring adalimumab trough levels and antibodies to adalimumab in patients with inflammatory bowel diseases.
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Published: Journal of Gastroenterology and Hepatology 2013; 28 (Suppl. 2): 82–111.