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

Abstract

Background Optimizing therapy and monitoring response are integral aspects of inflammatory bowel disease treatment. We conducted a systematic review and meta-analysis to determine whether serum ustekinumab trough concentrations during maintenance therapy were associated with ustekinumab treatment response in patients with inflammatory bowel disease. Methods A systematic review was performed to March 21, 2022, to identify studies using MEDLINE, EMBASE, and the Cochrane library. We included studies that reported the association between serum ustekinumab trough concentrations with clinical or endoscopic remission. Outcome measures were combined across studies using the random-effects model with an odds ratio (OR) for binary outcomes of endoscopic and clinical remission. Results We identified 14 observational studies that were included in the analysis for clinical remission (919 patients, 63% with Crohn’s disease) or endoscopic remission (290 patients, all with Crohn’s disease). Median ustekinumab trough concentrations were higher amongst individuals achieving clinical remission compared with those not achieving remission (mean difference, 1.6 ug/mL; 95% confidence interval [CI], 0.21-3.01 ug/mL). Furthermore, individuals with median serum trough concentration in the fourth quartile were significantly more likely to achieve clinical (OR, 3.61; 95% CI, 2.11-6.20) but not endoscopic remission (OR, 4.67; 95% CI, 0.86-25.19) compared with those with first quartile median trough concentrations. Conclusion Based on the results of this meta-analysis primarily relating to patients with Crohn’s disease on maintenance ustekinumab treatment, it appears that there is an association between higher ustekinumab trough concentration and clinical outcomes. Prospective studies are required to determine whether proactive dose adjustments of ustekinumab therapy provides additional clinical benefit.

Postoperative Ustekinumab Drug Levels and Disease Activity in Patients with Crohn’s

“…The average post-operative HBI was signi cantly lower in the adequate ustekinumab group compared to the suboptimal group. This is in line with previous data showing that higher ustekinumab levels are associated with higher rates of clinical remission de ned as HBI < 5 [29]. Our study showed no difference in endoscopic scores (SES-CD or Rutgeerts) between the suboptimal and adequate ustekinumab level groups.…”

Approach to loss of response to advanced therapies in inflammatory bowel disease

“…Role of TDM: Despite some contrary findings regarding the association between trough levels and Crohn’s disease response (clinical or biochemical)[ 119 - 123 ], there is robust evidence to suggest that ustekinumab trough levels correlate with clinical, biomarker and/or endoscopic response in Crohn’s[ 124 - 139 ]. This was confirmed in meta-analysis which showed higher median ustekinumab trough concentrations occur in individuals who achieve clinical remission compared with those who do not achieve remission[ 140 ].…”

“…However, despite these findings the role of TDM to guide ustekinumab therapy is limited. The significant variations between studies in reported ustekinumab levels to achieve response in conjunction with the heterogeneity in methods of reporting ustekinumab levels do not currently permit a clear cutoff value for defining a response to therapy[ 140 ]. Furthermore, there is only sparse data evaluating ustekinumab levels following dose escalation[ 110 , 123 , 133 , 141 ] and endoscopic remission was associated with an increase in ustekinumab levels in only one of these observational studies[ 133 ].…”

Therapeutic Drug Monitoring for Biologic and Small-Molecule Therapies for Inflammatory Bowel Disease

“…Immunogenicity was noted to be low in the pivotal phase 3 trials for ustekinumab in both UC and CD [40]. A systematic review estimated the rate of ADA development on maintenance therapy to be between 4.2% and 5.6% [42]. It has been suggested that immunogenicity is transient with ustekinumab [40]; however, a recent study has shown that it may correlate to loss of response [43].…”

“…The majority of these studies evaluated serum trough levels via ELISA at the time of ustekinumab induction or mobility shift assay and at follow-up periods up to week 26. The identified target trough levels required on maintenance therapy to achieve a clinical response have varied substantially [42], with levels as low as 1.3 µg/mL [40] and up to levels of 4.5 µg/mL [15] being observed as targets to establish clinical response. The timing of drug level measurement is also likely to have an impact on these reported drug levels and may explain some of the variation in identified cut-off values [46].…”