Impact of disease location on fecal calprotectin levels in Crohn's disease.

OBJECTIVE: The correlation between the Simple Endoscopic Score for Crohn's Disease (SES-CD) and fecal calprotectin is well established in (ileo)colonic Crohn's disease (CD). However, for ileal CD, existing data are conflicting. The aim of this study is to evaluate the biomarker profile in CD patients with varying severity and location of mucosal ulceration. MATERIALS AND METHODS: An electronic patient database search identified CD patients in whom ileocolonoscopy, fecal calprotectin (CALPRO), serum C-reactive protein (CRP) and blood leukocyte counts (LEU) were measured within a 4-week interval without changes in medication. Ileocolonoscopies were scored for the presence of ulcers in each segment as defined by the SES-CD and the sum of segmental ulcer scores resulted in a partial SES-CD (pSES-CD). RESULTS: Fourty-four patients were identified, of whom 9/44 had ileal CD, 20/44 colonic and 15/44 ileocolonic CD based on the Montreal classification. In the total study population CALPRO correlated best with pSES-CD (r = 0.76, p < 0.0001), followed by LEU (r = 0.54, p = 0.0004) and CRP (r = 0.45, p = 0.0026). Patients with ileal CD had significantly lower CALPRO level than those with (ileo)colonic disease even in the presence of large and/or very large ulcers (mean +/- SEM: 297 +/- 81 mug/g vs. 1523 +/- 97 mug/g, p < 0.0001). LEU was also significantly lower in the presence of large and/or very large ulcers in ileal CD compared to those with (ileo)colonic disease (mean +/- SEM: 6.7 +/- 0.9 x 10(9)/l vs. 10.6 +/- 0.8 x 10(9)/l, p = 0.02). A similar trend was identified regarding CRP levels. CONCLUSIONS: Even in the presence of large or very large ulcers, patients with ileal Crohn's may not have markedly elevated fecal calprotectin levels

Tumor necrosis factor-mediated disposition of infliximab in ulcerative colitis patients

Ulcerative Colitis (UC) is an inflammatory bowel disease typically affecting the colon. Patients with active UC have elevated tumor necrosis factor (TNF) concentrations in serum and colonic tissue. Infliximab is a monoclonal antibody directed against TNF and binds with high affinity. Target-mediated drug disposition (TMDD) is reported for monoclonal antibodies meaning that their pharmacokinetics are affected by high target affinity. Here, a TMDD model is proposed to describe the interaction between infliximab and TNF in UC patients. Data from 20 patients with moderate to severe UC was used. Patients received standard infliximab induction therapy (5 mg kg−1) at week 0, followed by infusions at week 2 and 6. IFX, anti-drug antibodies and TNF serum concentrations were measured at day 0 (1 h after infusion), 1, 4, 7, 11, 14, 18, 21, 28 and 42. A binding model, TMDD model, and a quasi-steady state (QSS) approximation were evaluated using nonlinear mixed effects modeling (NONMEM). A two-compartment model best described the concentration–time profiles of infliximab. Typical clearance of infliximab was 0.404 L day−1 and increased with the presence of anti-drug antibodies and with lower albumin concentrations. The TMDD-QSS model best described the pharmacokinetic and pharmacodynamics data. Estimate for TNF baseline (Bmax was 19.8 pg mL−1 and the dissociation constant (Kss) was 13.6 nM. This model could eventually be used to investigate the relationship between suppression of TNF and the response to IFX therapy

Serum Concentration of Anti-TNF Antibodies, Adverse Effects and Quality of Life in Patients with Inflammatory Bowel Disease in Remission on Maintenance Treatment

Background and aims: High serum concentrations of infliximab [IFX] and adalimumab [ADA] may be associated with adverse effects in patients with inflammatory bowel disease [IBD]. We aimed to investigate whether high anti-tumour necrosis factor [TNF] trough levels [TLs] were associated with toxicity and impaired quality of life [QoL]. Methods: We conducted a prospective cohort study in IBD patients in clinical and biochemical remission on IFX or ADA maintenance therapy. Trough serum concentrations and antidrug antibodies were measured in addition to biochemical markers of inflammation in serum and stool to confirm quiescent disease. QoL was assessed using the Inflammatory Bowel Disease Questionnaire and 36-item short form]. Side effects such as fatigue and arthralgia were measured with a visual analogue score [VAS]. Skin toxicity was reported with a European Organization for Research and Treatment of Cancer-derived score. Results: In all, 252 IBD patients on maintenance anti-TNF therapy were screened, of whom 95 [73 with Crohn's disease, 22 with ulcerative colitis; 72 on IFX, 23 on ADA] were in clinical and biochemical remission and were included. Median TLs were 5.5 mu g/ml and 6.6 mu g/ml for IFX and ADA, respectively. Patients with anti-TNF TLs above median had lower IBDQ scores than patients with lower TLs [IBDQ 176 vs 187, p = 0.02], particularly regarding systemic symptoms and emotional status. A trend towards lower SF-36 and higher fatigue scores was observed in the higher anti-TNF TL group. Skin and arthralgia scores were not significantly different between the groups. Conclusions: IBD patients with higher anti-TNF serum concentrations had significantly lower disease-specific QoL. Fatigue, arthralgia, and skin lesions do not occur more often in these patients. These data are reassuring that high serum concentrations of anti-TNF antibodies are not toxi