P346 Single-centre experience of ustekinumab: Therapeutic drug monitoring in Crohn’s disease patients

Abstract

Background Therapeutic drug monitoring (TDM) is a diagnostic tool in the monitoring of anti-TNF therapies. Yet, the benefit for TDM of new biologics such as ustekinumab (USK) is still controversial in real-world experiences. Methods This monocentric retrospective study aims to correlate USK trough levels (TLs) with clinical and endoscopic data. All patients have given written consent to the Biobank (B2011/005). Endoscopic disease was defined as quiescent in absence of endoscopic lesions, mild disease in presence of few superficial ulcerations, moderate in presence of several ulcers and severe in presence of numerous deep ulcers and/or inflammatory stenosis. 313 serum USK samples from 67 Crohn’s disease patients were used to measure USK TL (USK ELISA, apDia) while 88 samples (at week 16, and before and after optimisation) were used to measure anti-drug antibody (ADA), using a drug-tolerant affinity capture elution anti-ustekinumab assay Results Demographic and baseline data of our population are presented in Table 1. The median follow-up was 73 weeks (IQR 39–92). An optimisation due to loss of response was required in 44.8% of patients (n = 30) after a median time of 38 weeks (IQR 24–55). To evaluate the drug efficacy, an endoscopy was performed in 61% of cases at a median time of 35 weeks (IQR 27–47). TLs were 5.2 µg/ml (IQR 2.1–8.8), 1.7 µg/ml (IQR 0.3–4.3) and 2.6 µg/ml (IQR 0.6–4.1) at week 8, 16 and 24, respectively. TLs at week 8 were correlated to the induction IV dose administrated (r = 0.3, p = 0.03). At week 16, low TLs were associated with higher endoscopic activity in the follow-up (p = 0.02), although this was not the case at week 8 (p = 0.5) (Figure 1). Patients not requiring an optimisation had higher TLs in maintenance than patients requiring optimisation (2.45 µg/ml (IQR 1.3–4.4) vs. 1.15 µg/ml (IQR 0.1–2.24), p = 0.008). Obviously, optimisation significantly increased TLs (1.15 µg/ml (IQR 0.1–2.24) vs. 6.6 µg/ml (IQR 2.3–11.3), p < 0.001). ADA were undetectable in all the measured samples in maintenance. Conclusion This real-world experience confirms a drug exposure-endoscopic response relationship. Week 16 seems to be an appropriate time point to monitor drug exposure. Earlier USK TLs, at week 8, appear less valuable to be monitored due to the influence of initial IV dose. The absence of immunogenicity suggests that it is not a key driver in the loss of response.

Systematic review with meta‐analysis: loss of response and requirement of ustekinumab dose escalation in inflammatory bowel diseases

“…39 Dose significantly increased ustekinumab trough levels; higher baseline and post-treatment ustekinumab levels were associated with better efficacy of dose escalation. 40 This supports the use of dose escalation in CD patients who lose response to ustekinumab and have low trough levels. Therapeutic drug monitoring may help to select which patients are most likely to benefit from dose escalation.…”

“…Trough concentrations of 0.8 μg/mL (or even up to 1.4 μg/mL) or greater were associated with higher rates of clinical remission 39 . Dose escalation significantly increased ustekinumab trough levels; higher baseline and post‐treatment ustekinumab levels were associated with better efficacy of dose escalation 40 . This supports the use of dose escalation in CD patients who lose response to ustekinumab and have low trough levels.…”

“…Although lower serum concentrations were observed among those who had antibodies to ustekinumab, there was no demonstrable effect of immunogenicity on its efficacy 39 . Moreover, Liefferinckx C, et al have reported that antibodies to ustekinumab were not detected in ustekinumab‐treated CD patients who lost their response, had an incomplete response or needed dose escalation 40 . These data suggest that immunogenicity may not be the main reason for LOR to ustekinumab, and it appears less valuable to monitor anti‐ustekinumab antibodies to detect early LOR to ustekinumab in CD patients.…”

“…39 Moreover, Liefferinckx C, et al have reported that antibodies to ustekinumab were not detected in ustekinumab-treated CD patients who lost their response, had an incomplete response or needed dose escalation. 40 These data suggest that immunogenicity may not be the main reason for LOR to ustekinumab, and it appears less valuable to moni- Very few studies have investigated the LOR or the need for dose escalation in patients with UC. The limited data showed that a relative proportion of these patients lost response to ustekinumab over time, and therapeutic benefits could also be obtained from dose escalation.…”

Predictors and Early Markers of Response to Biological Therapies in Inflammatory Bowel Diseases

“…Interestingly, in a retrospective analysis of IBD patients on maintenance therapy with vedolizumab, TLs <7.4 µg/mL, in patients experiencing LOR was associated with a significantly increased likelihood to respond to dose escalation compared to higher concentrations (OR 3.7, 95% CI 1.1–13, p = 0.04) [ 108 ]. A similar exposure-efficacy relationship has been observed for ustekinumab: early TLs (week 4 and 8) have been associated with clinical remission [ 109 , 110 ], decrease of faecal calprotectin [ 111 ] and biochemical remission [ 112 ], while TLs during maintenance have been correlated with clinical remission [ 109 , 110 ], endoscopic response [ 111 , 113 ] and need for optimization [ 114 ]. In a recent review, Alsoud et al [ 127 ] proposed target TLs for vedolizumab and ustekinumab.…”