VClin Gastroenterol Hepatol. 2015 Jan 3. pii: S1542-3565(14)01839-4.
Concentrations of 6-thioguanine nucleotide correlate with trough levels of infliximab in patients with inflammatory bowel disease on combination therapy.
Yarur AJ, Kubiliun MJ, Czul F, et al.
BACKGROUND & AIMS: In patients with inflammatory bowel diseases (IBD), the combination of infliximab and thiopurines (such as 6-thioguanine) is more effective than monotherapy. We assessed the correlation between serum levels of 6-thioguanine (6-TGN) and infliximab levels or antibodies to infliximab (ATI). METHODS: We performed a cross-sectional study of 72 patients receiving maintenance therapy with infliximab and a thiopurine for IBD at the Crohn's and Colitis Center of the University of Miami, FL. We collected clinical, endoscopic, biochemical data, and levels of thiopurine metabolites. The primary outcomes were trough level of infliximab and the presence of ATI. RESULTS: Levels of 6-thioguanine correlated with those of infliximab (ρ=0.53; P<0.0001). The cut point of 6-TGN that best predicted a higher level of infliximab was 125 pmol/8x108 red blood cells (RBC) (area under receiver operating characteristic=0.86; P<0.001). Patients in the lowest quartile of 6-TGN had infliximab levels that were similar to patients on no thiopurines (4.3 vs. 4.8 mcg/ml respectively [p=0.8]). A level of infliximab ≥ 8.3 mcg/mL was associated with mucosal healing. Only 8 patients (11%) had detectable ATI. Patients with levels of 6-thioguanine <125 pmol="" 8x108="" rbc="" were="" significantly="" more="" likely="" to="" have="" ati="" odds="" ratio="" 1="" 3="" 95="" ci="" 2="" 3-72="" 5="" p="" 0="" 01="">
CONCLUSIONS: Whereas 6-thioguanine levels of >230 pmol/8x108 RBC have been associated with improved outcomes in patients on monotherapy, a level of 6-thioguanine ≥125 pmol/8x108 RBC may be adequate to achieve therapeutic levels of infliximab. In the long term, this may minimize the toxicity for patients on combination therapy.
Eur J Gastroenterol Hepatol. 2015 Jan 7. [Epub ahead of print]
Therapeutic drug monitoring of infliximab in inflammatory bowel disease patients in a teaching hospital setting: results of a prospective cohort study.
Warman A, Straathof JW, Derijks LJ.
OBJECTIVE: Therapeutic drug monitoring (TDM) of infliximab (IFX) is not routinely implemented in our clinical practice. We therefore carried out a prospective cohort study measuring IFX trough levels in our total inflammatory bowel disease (IBD) population in relation to remission. METHODS: Patient demographics, and medication and clinical history were collected from the electronic hospital information system. Blood was drawn at one time point for the determination of IFX trough levels and antibodies to IFX (ATI). Disease activity indices [Crohn's disease activity index (CDAI) and the Truelove-Witts disease activity index (TWDAI) for Crohn's disease and ulcerative colitis, respectively] and quality-of-life scores (Visual Analog Scale) were obtained. RESULTS: We included 107 patients. IFX levels varied from less than 0.02 to 21.9 μg/ml. The median IFX level was 2.8 μg/ml [interquartile range (IQR) 1.37-5.13]. The IFX level was associated significantly with remission (P=0.007). The median IFX level was 3.9 μg/ml (IQR 1.9-6.53) in patients in remission and 2.1 μg/ml in patients with active disease (IQR 0.77-4.38) (P=0.074). Receiver operating charecteristic curve analysis indicated a cutoff value of 2.18 μg/ml for CD and 6.26 μg/ml for UC. Eleven patients (10.3%) had developed ATI. The appearance of ATI was associated with the disappearance of IFX [relative risk: 2.2 (95% confidence interval: 1.368-3.610) P<0.0001], but not with relapse. The presence of ATI induced more infusion reactions [relative risk: 11.7 (95% confidence interval: 2.74-49.60) P<0.001].
CONCLUSION: TDM of IFX in IBD outpatients in a teaching hospital setting showed large interindividual differences in IFX trough levels. Despite this, we still found a significant association between remission and IFX trough levels. We determined cutoff values for both IBD modalities. IFX trough levels were not detectable in a significant proportion of IBD patients; TDM is indicated to identify this group of patients.
Inflamm Bowel Dis. 2015 Jan 7. [Epub ahead of print]
Fecal calprotectin for evaluating postoperative recurrence of Crohn's disease: a meta-analysis of prospective studies.
Qiu Y, Mao R, Chen BL, et al.
BACKGROUND: Fecal calprotectin (FC) levels have been extensively reported to correlate with clinical and endoscopic activities in Crohn's disease (CD); however, the utility of FC levels in the postoperative setting remains to be determined. Using meta-analysis, we aimed to evaluate the utility of FC as a noninvasive marker of recurrence in patients with CD who had undergone previous surgical resection.
METHODS: An electronic search using keywords related to CD and FC was performed in multiple electronic resources from 1966 to March 2014. The extracted data were pooled using a hierarchical summary receiver operating curve model. RESULTS: Ten articles met the inclusion criteria, and methodological quality was determined in detail for each study. The 10 studies presented FC levels in 613 postoperative CD patients. The pooled sensitivity and specificity values for assessing suspected endoscopic recurrence were 0.82 (95% confidence interval (CI), 0.73-0.89, 8 studies, n = 391) and 0.61 (95% CI, 0.51-0.71), respectively. The overall positive and negative likelihood ratios were 2.11 (95% CI, 1.68-2.66) and 0.29 (95% CI, 0.197-0.44), respectively. The pooled sensitivity and specificity values for evaluating clinical relapse were 0.59 (95% CI, 0.47-0.71; 3 studies, n = 183) and 0.88 (95% CI, 0.80-0.93), respectively. The overall positive and negative likelihood ratios were 5.10 and 0.47, respectively.
CONCLUSIONS: As a simple and noninvasive marker, FC is useful in evaluating recurrence of postoperative patients with CD.
Inflamm Bowel Dis. 2015 Jan 9. [Epub ahead of print]
Change in erythrocyte mean corpuscular volume during combination therapy with azathioprine and infliximab is associated with mucosal healing: a post hoc analysis from SONIC.
Bouguen G, Sninsky C, Tang KL, et al.
BACKGROUND: The adequacy of exposure of purine analogs as measured by 6-thioguanine nucleotides concentrations in the setting of combination therapy remains poorly understood. The aim of this study was to investigate the relationship between the mean corpuscular volume (MCV) value (as a surrogate marker of 6-thioguanine nucleotides concentration) and Crohn's disease outcomes in the setting of combination therapy with infliximab.
METHODS: The SONIC trial was a randomized controlled trial comparing infliximab to azathioprine and to infliximab plus azathioprine in 508 Crohn's disease patients. An increase of at least 7 femtoliter (fL) of the MCV (ΔMCV) was used for statistical analysis. RESULTS: At week 26, the mean increase of MCV was similar among patients treated with azathioprine alone (mean of 7.9 fL) or in combination with infliximab (mean of 8.5 fL). In the azathioprine group, 63.6% of patients with ΔMCV >7 were in steroid-free clinical remission at week 26 as compared with 33.3% of patients without ΔMCV >7 (P = 0.0046). In the combination therapy group, ΔMCV above 7 was associated with mucosal healing (75.0% for ΔMCV >7 versus 47.1% for ΔMCV <7, P = 0.0172) but not with steroid-free clinical remission. Patients with a ΔMCV above 7 were more likely to have infliximab trough level above 3 μg/mL at week 30 (68.4% versus 38.8% for ΔMCV <7, P = 0.0032).
CONCLUSIONS: These results suggest that ΔMCV above 7 (which is a surrogate for a higher 6-thioguanine nucleotides concentration) leads to improved Crohn's disease outcomes, even when combined with infliximab. It also suggests the possibility that a lower azathioprine exposure might be less effective in combination therapy.
J Crohns Colitis. 2015 Jan 9. pii: jjv004. [Epub ahead of print]
Changes in serum trough levels of infliximab during treatment intensification but not in anti-infliximab antibody detection are associated with clinical outcomes after therapeutic failure in Crohn's disease.
Steenholdt C, Bendtzen K, Brynskov J, et al.
BACKGROUND: It is recommended to intensify the infliximab (IFX) regimen in case of inadequate treatment effect. However, the rationale is not well defined as underlying mechanisms varies. AIM: To explore the association between changes in serum IFX and anti-IFX antibodies (Abs) after IFX intensification and clinical outcomes. METHODS: Post hoc analysis of randomized clinical trial including 42 Crohn's disease patients with IFX treatment failure all treated by an intensified IFX regimen (5 mg/kg every 4 week) throughout 12 weeks. Trough serum IFX and anti-IFX Abs were measured by homogeneous mobility shift binding assay (HMSA) and functional cell-based reporter gene assay (RGA) at treatment failure and end of trial.
RESULTS: 21 patients (50%) regained clinical response on intensified IFX regimen. The increase in serum trough levels of IFX during treatment intensification was higher among responders than non-responders (RGA: 8.8 μg/ml vs. 3.0, p=0.035; HMSA: 9.9 μg/ml vs. 4.7, p=0.040), and differentiated patients by clinical outcome (AUCROC RGA 0.75 [0.53-0.97], p=0.035; AUCROC HMSA 0.74 [0.53-0.95], p=0.042). All responders exhibited IFX increase ≥2.6 μg/ml (sensitivity 100%, specificity 50%). Anti-IFX Abs detected by HMSA in 13 patients (32%) were often non-functional and became undetectable during IFX intensification. However, even functional anti-IFX Abs detected by RGA in 6 patients (15%) became undetectable.
CONCLUSION: Increase in IFX levels following treatment intensification associates with improved clinical outcomes indicating insufficient drug levels in a subgroup of patients. Anti-IFX Abs may become undetectable during treatment intensification suggesting lowered production or formation of immune complexes.
J Pediatr Gastroenterol Nutr. 2015 Jan 5. [Epub ahead of print]
Monotherapy with infliximab vs. combo therapy in the maintenance of clinical remission in children with moderate to severe Crohn's disease - a randomized study.
Kierkuś J, Iwańczak B, Wegner A, et al.
OBJECTIVES: To compare the efficacy and safety of two various protocols of maintenance therapy with infliximab (IFX) and immunomodulatory agent in pediatric Crohn's disease (CD) patients: withdrawal of immunomodulators vs. continuation of immunosupressants.
METHODS: This multicenter randomized open label trial included 99 CD patients (aged 14.5±2.6 years) who were administered IFX (5 mg/kg body weight, b.w.) along with immunomodulatory agent (azathioprine 1.5-3 mg/kg b.w. per day, methotrexate 10-25 mg per week). After 10 weeks of the induction therapy, 84 responders were centrally randomized into one of the following groups: group I (n=45) in which IFX and immunomodulatory agent were continued until week 54, and group II (n=39) in which immunomodulatory agent was discontinued after 26 weeks.
RESULTS: The induction therapy was reflected by significant decrease in Pediatric Crohn's Disease Activity Index (PCDAI) and Simplified Endoscopic Activity Score for Crohn's Disease (SES-CD) values. After the maintenance phase, the analyzed groups did not differ significantly in terms of the clinical response loss rates and final PCDAI and SES-CD scores. Furthermore, no significant intragroup differences were documented between mean PCDAI scores determined at the end of induction and maintenance phases. Intensification/modification of the treatment was required in 13/45 (29%) and 11/39 (28%) patients of group I and II, respectively. A total of 9 serious adverse events were documented; none of the patients died during the trial.
CONCLUSION: 26 weeks likely represent the safe duration of combined IFX/immunomodulatory therapy in our sample of pediatric CD patients.
Gut. 2015 Jan 7. pii: gutjnl-2014-308337.
Anrukinzumab, an anti-interleukin 13 monoclonal antibody, in active UC: efficacy and safety from a phase IIa randomised multicentre study.
Reinisch W, Panés J, Khurana S, et al.
OBJECTIVE: Interleukin 13 (IL-13) is thought to play a key role as an effector cytokine in UC. Anrukinzumab, a humanised antibody that inhibits human IL-13, was evaluated for the treatment of UC.
DESIGN: In a multicentre, randomised, double-blind, placebo-controlled study, patients with active UC (Mayo score ≥4 and <10) were randomised to anrukinzumab 200, 400 or 600 mg or placebo. Patients received five intravenous administrations over 14 weeks. The primary endpoint was fold change from baseline in faecal calprotectin (FC) at Week 14. Secondary endpoints included safety, pharmacokinetics and IL-13 levels.
RESULTS: The modified intention-to-treat population included 84 patients (21 patients/arm). Fold change of FC from baseline at Week 14 was not significantly different for any treatment groups compared with the placebo. The study had a high dropout rate, in part, related to lack of efficacy. The exploratory comparisons of each dose were not significantly different from placebo in terms of change from baseline in total Mayo score, clinical response, clinical remission and proportion of subjects with mucosal healing. An increase in serum total IL-13 (free and bound to anrukinzumab) was observed for all anrukinzumab groups but not with placebo. This suggests significant binding of anrukinzumab to IL-13. The safety profile was not different between the anrukinzumab and placebo groups. CONCLUSIONS: A statistically significant therapeutic effect of anrukinzumab could not be demonstrated in patients with active UC in spite of binding of anrukinzumab to IL-13.
TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number NCT01284062.
Clin Epidemiol. 2014 Dec 23;7:29-35.
Incorporating alternative design clinical trials in network meta-analyses.
Thorlund K, Druyts E, Toor K, et al.
INTRODUCTION: Network meta-analysis (NMA) is an extension of conventional pairwise meta-analysis that allows for simultaneous comparison of multiple interventions. Well-established drug class efficacies have become commonplace in many disease areas. Thus, for reasons of ethics and equipoise, it is not practical to randomize patients to placebo or older drug classes. Unique randomized clinical trial designs are an attempt to navigate these obstacles. These alternative designs, however, pose challenges when attempting to incorporate data into NMAs. Using ulcerative colitis as an example, we illustrate an example of a method where data provided by these trials are used to populate treatment networks.
METHODS: We present the methods used to convert data from the PURSUIT trial into a typical parallel design for inclusion in our NMA. Data were required for three arms: golimumab 100 mg; golimumab 50 mg; and placebo. Golimumab 100 mg induction data were available; however, data regarding those individuals who were nonresponders at induction and those who were responders at maintenance were not reported, and as such, had to be imputed using data from the rerandomization phase. Golimumab 50 mg data regarding responses at week 6 were not available. Existing relationships between the available components were used to impute the expected proportions in this missing subpopulation. Data for placebo maintenance response were incomplete, as all induction nonresponders were assigned to golimumab 100 mg. Data from the PURSUIT trial were combined with ACT-1 and ULTRA-2 trial data to impute missing information.
DISCUSSION: We have demonstrated methods for converting results from alternative study designs to more conventional parallel randomized clinical trials. These conversions allow for indirect treatment comparisons that are informed by a wider array of evidence, adding to the precision of estimates.
Gut. 2014 Dec 30. pii: gutjnl-2014-308839.
An endoscopic Mayo score of 0 is associated with a lower risk of colectomy than a score of 1 in ulcerative colitis.
Manginot C, Baumann C, Peyrin-Biroulet L.
No abstract available.