Background: Ustekinumab (UST) has been shown to be effective in refractory Crohn's disease (CD) in phase III trials. The aim of the present study was to prospectively evaluate the association between UST trough levels and anti-ustekinumab antibodies, with the response and the remission to induction and maintenance UST treatment in CD patients.
Methods: We performed a prospective study including all CD patients refractory to anti-TNF who received subcutaneous UST from September 2015 to October 2016 in the tertiary French referral center of Gastroenterology in Claude Huriez hospital in Lille. During induction, patients received 90mg of SC UST at week 0, 4 and 12. During the maintenance phase, patients received 90mg of SC UST every 8 weeks that could be optimized by shortening injection interval to every 4 weeks in case of loss of response. Clinical response was defined by a decreased Harvey Bradshaw Index (HBI) by 3 points, clinical remission by HBI <5, loss of response by new increase of HBI. UST trough levels and antibodies were dosed at 12 weeks, and at a single time-point for patients who had received more than 3 months of UST. The results of dosage were obtained by enzyme-Linked ImmunoSorbent Assay technique. We evaluated the correlation between clinical and biological response and remission to UST, and UST through levels and antibodies concentrations. Differences between independent groups were traced with the use of the Mann–Whitney exact test.
Results: Forty-two patients with active disease received at least three UST injections and were prospectively included. At time of ustekinumab introduction, 62% of patients received concomitant immunosuppressant and 43% received corticosteroids. At the end of the induction phase (week 12), clinical response was observed in 57% patients. There was no significant difference in mean UST trough levels in patients who responded to UST induction (median 1160ng/ml; IQR: 603–1644) as compared to patients who did not respond (median 1556ng/ml; IQR: 494–2758, p=0.24). Thirty-two (76%) patients received at least 4 injections of UST, with 11 patients who were optimized at the time of dosages. Clinical response was observed in 23/32 (72%) patients. Median UST concentration in clinical responder was 1398ng/ml (IQR: 477–1979) and 1548ng/ml in non-responder (IQR: 453–2392), with no significant difference between the two groups of patients (p=0.77). UST antibodies were undetectable for the 42 patients.
Conclusions: We confirmed that UST treatment is effective in the majority of CD patients refractory to anti-TNF agents. Median trough levels to UST are not correlated to response and remission to UST induction and maintenance treatment, with no antibodies developed against UST.