The proinflammatory cytokines IL12 and IL23 have been implicated in the pathophysiology of CD with multiple lines of evidence suggesting that CD is mediated by Th1 and/or Th17 cells [6, 7]. UST prevents IL12 and IL23 bioactivity by preventing their interaction with their cell surface receptor protein IL12Rb1. Through this mechanism of action, UST effectively neutralizesIL12 (Th1)- and IL23 (Th17)-mediated cellular responses. UST binds with high affinity to the p40 subunit of human IL12 and IL23 and has recently been approved for the treatment of moderately to severely active CD in adults.
Currently, UST is an effective treatment for anti-TNF-αrefractory CD patients. As it has been shown to be useful in the management of patients with a loss of response to anti-TNF-α agents. However, there are limited data on the association of UST drug concentrations on CD patient outcomes. Understanding UST pharmacokinetic characteristics and the relationship between clinical outcomes and UST concentration is important for prescribers to optimize efficacy of UST therapy.
The main finding of this study is that anti-TNF-α refractory CD patients treated with UST achieved in 54% and 33% of cases clinical and corticosteroid-free remission over a treatment period of 32 to 40 weeks. In addition, the UST trough level decreased significantly during the maintenance therapy just above the detection limit. The mean UST concentration at week 8 in our study was similar to the value reported by Adedokun et al.: 2.0(IQR 1.2-4.0 µg/mL) . Interestingly, the present real-life study does not report a positive relationship between USTTL and clinical disease outcomes during UST therapy. In addition, the levels of proinflammatory biochemical parameters such as CRP and FC neither decreased during the treatment period nor were associated with treatment outcome. The majority of the included patients were treated with a12-week interval during the maintenance therapy.
Our findings show discrepancy from those found in previous studies in which an UST trough level of higher than 4.5 µg/mL at week 26 was associated with endoscopic response  or a trough level of 3.3 µg/mL at week 8 was associated with clinical remission . In line with our results, the study by Battat et al. also failed to identify an association of UST trough level with clinical outcomes . Another study by Thomann et al. also identified that serum UST level at week 8 was moderately effective to predict clinical response for week 16 .
The pharmacokinetics post hoc analysis of the approval studies of UST published by Adedokun et al. showed that during the maintenance study period UST concentration reached a steady state after the second maintenance dose. Moreover, the median trough concentration in patients given UST every 8-weeks compared to patients every 12-weekswas approximately threefold higher . UST serum concentrations were significantly associated with rates of clinical remission only in patients treated with an 8-week interval (p = 0.006) but not with a 12-week interval application (p = 0.08). In contrast to the results of the present study, they could show that trough concentrations of UST of 0.8 µg/mL or greater were associated with maintenance of clinical remission. In addition, the UST concentration cutoffs obtained from the receiver operator curve analyses were based on statistically significant but modest area under the curve and specificity values . Because the level of significance could only be achieved only in the 8-week interval treatment, this result has no general validity in a real-life setting, as the majority of patients may be treated with a 12-week interval.
In accordance with our results, Peinchart et al. showed, by studying on 49 Patients within maintenance therapy, that USTTL did not correlate with clinical, biological or endoscopic response .
There are various factors that may account for such differences including distinct treatment regimens and disease outcome assessments, different assays of measuring UST, and distinct patient populations. Only studies by Adedokan et al., Thomann et al., Soufflet et al. and ours evaluated CD patients after intravenous induction and subcutaneous maintenance therapy [5, 10, 12] while other published studies evaluated different modes of induction and maintenance therapy [11, 9].
There are different assay techniques available on the market to determine the UST drug concentration and the above mentioned studies did not use the same assay to determine the UST cutoffs, which may explain the different results that were obtained. The assays in the previous works are using laboratory techniques like ELISA, a drug-tolerant liquid-phase homogeneous mobility shift assay, or an electrochemiluminescent immunoassay [5, 9, 11]. In our study we used an ELISA essay. Thus, other prospective studies are needed to confirm therapeutic UST trough levels.
In our cohort, all patients were previously treated or were intolerant to anti-TNF-α. The anti-TNF-α therapy was changed due to anaphylaxis, primary and secondary nonresponse or side effects. In the UST-approval studies the medical history of anti-TNF-α therapy of the patients was associated with lower rates of clinical remission . The fact that we have only included ant-TNF-α exposed patients in our study with high inflammatory burden and complex pathophysiology could explain the contrasting results of our study.
In contrast to the experience with anti-TNF-α there was no significant impact of immunomodulators such as azathioprine or tacrolimus on serum UST concentration in the present study as well as previously published [5, 9].
We acknowledge the limitations of our study, such as the retrospective characteristic, the small number of patients in our cohort and the fact that not all patients received endoscopic observation or FC monitoring in the analyzed period. Due to the small number of patients, we could not calculate the UST trough level for the group of patients treated with an 8-week interval compared to the 12-week interval. However, we strongly believe that our results bring important clinical information, which could potentially help gastroenterologists treating CD with UST make important decisions.