FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
For patients with Crohn’s disease, therapeutic drug monitoring helped identify early primary nonresponders to induction with ustekinumab, according to researchers. The report is in Clinical Gastroenterology and Hepatology.
At week 8, median trough levels of ustekinumab were 6.0 mcg per mL (interquartile range, 3.1-8.0) among patients who achieved a primary response to induction at week 16, versus 1.3 mcg/mL (IQR, 0.9-5.6 ) among primary nonresponders (P = .03). An 8-week ustekinumab trough level cutoff of 2.0 mcg/mL distinguished week 16 responders from nonresponders with an area under the receiver operating curve (AUROC) of 0.75, wrote Ninon Soufflet of University Claude Bernard Lyon 1 in France, and associates. The researchers recommended “dedicated studies” to assess whether escalating the dose of ustekinumab can benefit patients with lower trough levels at week 8.
Few studies have explored biomarkers for response to ustekinumab induction therapy. Hence, the researchers assessed the relative utility of ustekinumab trough levels, C-reactive protein (CRP) levels, and fecal calprotectin levels for predicting early primary nonresponse. All 51 study participants had active luminal Crohn’s disease and received body weight–based intravenous infusions of ustekinumab at baseline, followed by subcutaneous injections of 90 mg. Primary nonresponders did not achieve steroid-free clinical and biochemical remission at week 16, defined as a Harvey-Bradshaw Index (HBI) of 4 points or less, a CRP level under 5 mg/L, and a fecal calprotectin level under 250 mcg/g. Week 16 was chosen to account for any delayed responders, the researchers noted.
A total of 32 patients (63%) achieved remission to ustekinumab induction therapy by week 16. An 8-week trough level of 2.0 mcg/mL was found to be optimal and distinguished primary nonresponders from responders with a sensitivity of 87%, a specificity of 66%, a positive predictive value of 82%, and a negative predictive value of 75%. In prior studies, optimal thresholds exceeded 3.3 mcg/mL for achieving remission and 4.5 mcg/mL at week 26 for achieving endoscopic response, the researchers noted. They said that this discrepancy might reflect different time points for evaluation, assays for measuring ustekinumab, patient populations, and a lack of endoscopic data in their study. “The relatively small sample size and the short period of follow-up evaluation [were] substantial limitations” they acknowledged.
FromRESULTS: At week 26 or beyond, 80.7% of patients had a clinical response, 66.1% were in clinical remission, 50.0% were in steroid-free clinical remission, 58.9% had an endoscopic response, and 19.6% were in endoscopic remission. The mean trough concentration of ustekinumab at this time point was higher in patients with an endoscopic response (4.7 μg/mL) than without (3.8 ug/mL; P = .03). An optimal ustekinumab threshold trough concentration at week 26 or later was found to be 4.5 μg/mL (area under the curve, 0.67). A greater proportion of patients with trough concentrations of ustekinumab above 4.5 μg/mL at week 26 or later had an endoscopic response (75.9%) than did patients with trough concentrations below this level (40.7%; P = .008). Patients with trough concentrations of ustekinumab above 4.5 μg/mL at week 26 or later also had a lower mean level of CRP (12.6 mg/L) than did patients with trough concentrations below this level (mean level of CRP, 23.9 mg/L; P = .04). We did not detect antibodies against ustekinumab in any patient.
CONCLUSIONS: Ustekinumab therapy was effective in patients with CD who had not responded to or were intolerant to treatment with a TNF antagonist. Maintenance trough concentrations of ustekinumab above 4.5 μg/mL at 26 weeks or later were associated with biomarker reduction and endoscopic response.