P324 Biomarkers predict lack of response to anti-TNF in Moderate to Severe Ulcerative Colitis
J.F. Brandse*1, S. Singh2, M. Löwenberg1, C.Y. Ponsioen1, G.R. van den Brink1, G.R. D'Haens1
1Academic Medical Center, Inflammatory Bowel Disease Center, Amsterdam, Netherlands, 2Prometheus Laboratories, Therapeutics&Diagnostics, San Diego, California, United States
It is still poorly understood why certain patients with moderate to severe ulcerative colitis do not respond to anti-TNF antibody therapy. The availability of serum biomarkers allowing prediction of response would be of great clinical value.
We studied consecutive patients with moderate to severe ulcerative colitis (endoscopy Mayo grade ≥ 2) started on infliximab after failure of conventional treatment and collected serum samples at 10 serial time points between week 0 and week 6. IFX serum concentrations and ATI were measured with a homogeneous mobility shift assay (Prometheus Laboratories, San Diego, CA). In addition, serum TNF- α , IFN- γ , IL-6, IL-8, IL-10 and IL-12p40 levels were measured at baseline, week 2 and 6. Serum TNF- α was measured by a Collaborative Enzyme Enhanced immuno-Reactive (CEER) Assay, Interleukins by a high sensitive ELISA. The primary outcome was endoscopic response defined as improvement by at least 1 Mayo point at week 8.
Day 0 cytokines, chemokines and infliximab concentration in relation to ATI formation (up to week 6)
|Day 0 cytokines, chemokines, IFX||ATI- (N=13), Median (IQR)||ATI+ (N=7), Median (IQR)||P-value|
|IFN- γ (pg/mL)||9.83 (6.93–25.64)||19.81 (8.70–29.87)||P=0.52|
|IL-6 (pg/mL)||1.48 (0.21–3.13)||7.55 (0.71–8.05)||P=0.25|
|IL-8 (pg/mL)||75.9 (15.1–501.1)||49.9 (22.1–600)||P=0.98|
|IL-10 (pg/mL)||1.73 (0.81–3.47)||1.67 (1.13–2.31)||P=0.70|
|IL12p40 (pg/mL)||61.88 (28.38–160.8)||36.35 (14.81–63.05)||P=0.22|
|Infliximab [µg/mL]||126 (108–155)||88 (83–102)||P=0.002|
|TNF- α (pg/ml)||0.46 (0.31–0.65)||0.55 (0.34–1.69)||P=0.26|
|TNF- α /IFX||0.0031 (0.0026–0.0048)||0.009(0.004–0.017)||P=0.048|
Twenty patients were included, 19 of which completed a standard IFX induction regimen (5mg/kg at week 0,2,6). 11/19 patients had an endoscopic response at week 8. Antibodies to IFX (ATI) were detected in 7 patients as early as a median of 28 days (18-42 days) into treatment. 6/8 patients without endoscopic response tested ATI+ compared to 1/11 with response (P<0.01, OR:30, 95%CI:2.2-406.2) without clear impact of immunomodulators. Lower median levels of IFX at one hour after the end of the first infusion were associated with consecutive development of ATI after the second infusion: 93 (83-102) ug/ml in ATI+, versus 126 (106-155) ug/ml in ATI- patients (P<0.01). The ratio serum TNF/IFX one hour after the end of the first infusion was also associated with ATI formation(P<0.05). (TABLE 1.)
Patients with higher week 2 IL12/23 p40 and IL-8 levels were less likely to have an endoscopic response at week 8 (P=0.03 and 0.06).
Low IFX levels and higher TNF/IFX ratio one hour after the end of infusion were associated with early ATI formation and treatment failure. High IL12/23 p40 and IL8 levels at week 2 also predicted lack of response, suggesting early diversion of inflammation towards the IL12/23 pathway and enhanced recruitment of neutrophils, respectively. Further validation of this data in larger samples is warranted.