Ustekinumab Tissue and Serum Levels in Patients With Crohn’s Disease Are Closely Correlated Though Not Consistently Associated With Objective Response After Induction

Abstract

Background Ustekinumab (UST), which targets p40/interleukin (IL)-23 and IL-12, is an effective treatment for Crohn’s disease (CD). Therapeutic drug monitoring may optimize UST posology. The aim of this study was to investigate UST and IL-23 serum and tissue concentrations in relation to mucosal inflammation and treatment response at an early time point. Methods CD patients starting UST between December 2016 and November 2018 were prospectively enrolled. Endoscopies were performed at baseline and week 16. UST and IL-23 serum and tissue concentrations were measured at week 16. Clinical and biochemical response were defined as decline of ≥3 points in Harvey-Bradshaw Index and reduction of ≥50% in fecal calprotectin levels. Endoscopic response was defined as a ≥50% decline in Simple Endoscopic Score or a decline of ≥1 points in Rutgeerts score. Histological remission was defined as Global Histologic Disease Activity Score ≤4. Results Of 56 included patients, 17 (30%) of 56 showed clinical response, 16 (30%) of 53 showed biochemical response, and 20 (36%) of 56 showed endoscopic response. UST, but not IL-23, concentration in biopsies was correlated to levels in corresponding sera (P < .0001). No correlation was found between UST tissue levels and treatment response. Patients achieving biochemical response showed significantly higher UST serum levels (3.12 µg/mL vs 1.41 µg/mL; P = .01). Tissue IL-23-to-UST ratio correlated with mucosal inflammation (P = .01). Conclusions This is the first study to demonstrate a correlation between serum and tissue UST levels. While tissue IL-23-to-UST ratio correlated with mucosal inflammation, UST serum levels were more indicative for biochemical response. The role of UST levels for therapeutic drug monitoring in inflammatory bowel disease needs further research.

Systematic Review and Meta-analysis: The Association Between Serum Ustekinumab Trough Concentrations and Treatment Response in Inflammatory Bowel Disease

“…We only assessed serum levels and did not evaluate tissue drug levels, and reports evaluating this have suggested that serum levels rather than tissue levels correlate with biochemical response. 62 Additionally, although our analysis did not suggest the presence of publication bias, the number of studies included in the analysis was quite small, and hence, publication bias remains possible.…”

Association between Ustekinumab Trough Levels, Serum IL-22, and Oncostatin M Levels and Clinical and Biochemical Outcomes in Patients with Crohn’s Disease

“…Real-world studies have indicated a correlation between UST levels and clinical outcome measures [ 69 , 70 , 71 , 72 , 73 , 74 , 75 ], endoscopic outcomes [ 70 , 76 , 77 , 78 , 79 ], or biochemical ones [ 72 , 73 , 74 , 76 , 80 , 81 , 82 ]. Although these findings were not confirmed by evidence on clinical outcomes [ 80 , 81 , 82 , 83 ] or endoscopic outcomes [ 80 , 81 ], most real-world studies affirm the significance of trough concentrations in CD. It is worth mentioning that subsequent observational studies have individuated higher optimal TL concentrations than those identified in RCTs.…”

Extra intravenous Ustekinumab reinduction is an effective optimization strategy for patients with refractory Crohn’s disease

“…Our previous study demonstrated the drug exposure-response relationship in patients receiving UST therapy ( 3 ). UST trough concentration was closely associated with clinical and endoscopic remission rates ( 29 ), with underlying mechanisms focusing on the UST volume distribution ( 30 , 31 ). Patients with active disease activity always manifest higher levels of pro-inflammatory cytokines IL-12/23 detected, calling for more binding with UST, and resulting in lower drug concentrations ( 32 ).…”

“…A real-world analysis conducted in patients with ulcerative colitis confirmed a drug exposure-response relationship, but denied the utility of measuring tissue’s drug level, given its strong correlation with serum exposure ( 34 ). The other study demonstrated a strong correlation between serum and tissue UST levels in patients with CD and concluded that UST serum levels were more indicative of biochemical response ( 31 ). We detected the serum level, instead of tissue, UST levels in our clinical routine due to its less-invasiveness, convenience, and repeatability.…”