Authors
A. GILS (1), E. DREESEN (1), G. COMPERNOLLE (1), M. PEETERS (1), E. BROUWERS (1), S. TOPS (1), V. BALLET (2), M. NOMAN (2), M. FERRANTE (2), G. VAN ASSCHE (2), S. VERMEIRE (2) / [1] Katholieke Universiteit Leuven, Leuven, Belgium, Department of Pharmaceutical and Pharmacological Sciences, [2] University Hospitals Leuven, Leuven, Belgium, Department of Gastroenterology and Hepatology
Introduction Vedolizumab (VDZ) specifically inhibits the α4β7 integrin interaction with mucosal addressin cell adhesion molecule (MAdCAM)-1 and has been approved for the treatment of patients with moderate to severe Crohn’s disease (CD) and ulcerative colitis (UC). We have previously shown that anti-tumor necrosis factor-alpha (anti-TNF) treatment influences MAdCAM-1 expression in gut biopsies.
Aim
We studied the impact of recent anti-TNF exposure on the VDZ trough concentrations (TC) and response.
Methods From 75 patients (46 CD, 29 UC) starting IV VDZ therapy in a tertiary referral center, VDZ and anti-TNF serum concentrations (median [IQR]) were measured at trough during VDZ induction (w2 and w6) and early maintenance therapy (w10 only for patients with CD, w14 and w22) using in-house developed ELISAs. Clinical response was evaluated by clinical symptoms and physician global assessment. Biological response (CRP decrease ≥50% from baseline) and remission (CRP ≤5 mg/L) were assessed at w6 and w22 in patients with CD who had a baseline CRP >5 mg/L (n = 25). All patients underwent endoscopy at baseline. Twenty-eight patients with CD underwent endoscopy after w22 to assess mucosal healing and all patients with UC received sigmoidoscopy at w10 (mucosal healing was defined as a Mayo endoscopic sub-score of 0 or 1).
Results Clinical response was achieved in 46% (21/46) and 66% (19/29) of the patients with CD and UC. Only in patients with UC, a significant exposure-response correlation was found between VDZ TC up to w22 and clinical response (data not shown, p<.0001). Biological response and remission at w6 were achieved in 48% (12/25) and 28% (7/25) of the patients with CD. Patients with biological response and remission had significantly higher VDZ TC at w6 (p=.002 and p=.0007, resp.). At w22, 48% (12/25) and 32% (8/25) of the patients with CD were in biological response and remission. Patients in biological remission had significantly higher TC at w6, w10 and w22 (data not shown, p=.02, p=.04 and p=.01). Mucosal healing was achieved in 18% (5/28) of the patients with CD and in 66% (19/29) of the patients with UC. Patients with UC with mucosal healing had significantly higher VDZ TC up to w22 compared to patients with no healing (p=.02 and p=.006, p=.03 and p=.04 for w2, w6, w14 and w22, resp.). Patients with CD with mucosal healing had significantly higher VDZ TC at w6 and w10 (p=.006, p=.03, resp.). Most patients (93%, 70/75) were previously exposed to anti-TNF. Of these, 30 (43%) had still detectable anti-TNF concentrations at the first VDZ infusion. Patients with CD who were recently exposed to anti-TNF (<16 weeks before the start of VDZ therapy, n=38) had significantly lower VDZ TC at all time points, compared to patients with no recent anti-TNF exposure (w2: 22.7 µg/mL [19.3 – 31.6], n=18 vs. 31.6 µg/mL [23.7 – 38.1], n=28, p=.05; w6: 16.8 µg/mL [10.7 – 23.2], n=18 vs. 28.5 µg/mL [20.6 – 38.8], n=28, p=.006; w10: 16.4 µg/mL [9.6 – 24.4], n=18 vs. 27.6 µg/mL [16.5 – 42.2], n=26, p=.03; w14: 19.5 µg/mL [11.6 – 22.8], n=16 vs. 26.7 µg/mL [17.7 – 40.8], n=28, p=.005; w22: 6.8 µg/mL [3.2 – 11.2], n=16 vs. 15.5 µg/mL [9.9 – 22.3], n=27, p=.005). We observed numerical though non-significant lower response rates in patients with recent anti-TNF exposure (data not shown, p>.1).
Conclusions A clear exposure-response correlation was observed as early as w2 and up to w22, with significant impact of higher VDZ TC on meaningful outcomes such as clinical response, biological response and remission and endoscopic healing. The inverse association between recent anti-TNF exposure and VDZ TC in patients with CD is intriguing and might be explained by a residual effect of anti-TNF treatment on MAdCAM-1 expression.
