Risk factors for anti-drug antibody formation to infliximab: Secondary analyses of a randomised controlled trial

Abstract

Background: Anti-drug antibodies (ADAb) frequently form early in the treatment course of infliximab and other tumour necrosis factor (TNF) inhibitors, leading to treatment failure and adverse events.

Objective: To identify risk factors for ADAb in the early phase of infliximab treatment.

Methods: Patients (n = 410) with immune-mediated inflammatory diseases who initiated infliximab treatment were included in the 38-week Norwegian Drug Monitoring Trial (NOR-DRUM) A and randomised 1:1 to therapeutic drug monitoring (TDM) or standard therapy. Serum levels of infliximab and ADAb were measured at each infusion. Possible risk factors for ADAb formation were assessed using logistic regression, adjusting for potential confounders.

Results: ADAb were detected in 78 (19%) patients. A diagnosis of rheumatoid arthritis (RA) (odds ratio [OR], 1.9 [95% confidence interval [CI] 1.0-3.6]) and lifetime smoking (OR, 2.0 [CI 1.1-3.6]) were baseline risk factors, while baseline use of concomitant immunosuppressors (OR, 0.4 [CI 0.2-0.8]) and a diagnosis of spondyloarthritis (SpA) (OR, 0.4 [CI 0.2-0.8]) reduced the risk of ADAb. Higher disease activity during follow-up (OR, 1.1 [CI 1.0-1.1]) and "drug holidays" of more than 11 weeks (OR, 4.1 [CI 1.2-13.8]) increased the risk of ADAb, whereas higher infliximab doses (OR, 0.1 [CI 0.0-0.3) and higher serum infliximab concentrations (OR, 0.7 [CI 0.6-0.8]) reduced the risk of immunogenicity.

Conclusion: Several risk factors for ADAb formation during early-phase infliximab treatment were identified. This knowledge provides a basis for treatment strategies to mitigate the formation of ADAb and identify patients in whom these measures are of particular importance.

Keywords: autoimmune disease; immunosuppressive treatment.

Fig. 1

Nelson‐Aalen plot showing the cumulative hazard of ADAb formation for each diagnosis. Each step indicates a new event. The slope of the curve indicates the hazard rate. ADAb, anti‐drug antibodies; w, weeks.

Fig. 2

Concentration–risk curves. Predicted probability of later ADAb formation with CI for infliximab trough serum concentrations before infusion 2 (a), before infusion 3 (b) and in the maintenance phase (c). Patients were sorted by infliximab concentrations (low to high) and divided into equally sized groups (n = 10). Mean values were calculated for each group. Predictive values were obtained from univariate regression analyses. ADAb, anti‐drug antibodies; CI, 95% confidence interval.

Fig. 3

Receiver operating characteristics curves with AUC to identify cut‐offs for infliximab trough serum concentrations for best discrimination of patients with and without later ADAb formation. Predictive values were obtained from univariate regression analyses. The optimal cut‐off point was defined by the point closest to 0.1 (i.e., 100% sensitivity and specificity). (a). Infliximab concentrations before infusion 2. AUC is 0.66 (CI 0.61–0.71) with optimal cut‐off at 26 mg/L with a sensitivity of 68.5% (CI 57.1–78.0) and specificity of 66.8% (CI 61.5–71.7). (b). Infliximab concentrations before infusion 3. AUC is 0.76 (CI 0.71–0.80) with optimal cut‐off at 19 mg/L with a sensitivity of 71.0% (CI 59.4–80.4) and a specificity of 75.9% (CI 71.0–80.3). (c). Infliximab concentrations in the maintenance phase (calculated mean for each patient). AUC is 0.79 (CI 0.74–0.83) with optimal cut‐off at 5 mg/L with a sensitivity of 71.1% (CI 55.2–83.0) and specificity of 74.3% (CI 69.0–79.0). AUC, area under the curve; ADAb, anti‐drug antibody; CI, 95% confidence interval.