Nicolas Williet

Guidelines on the diagnosis and treatment of iron deficiency across indications: a systematic review

BACKGROUND Guidelines on the diagnosis and treatment of iron deficiency (ID) vary widely across indications. OBJECTIVE We reviewed all available guidelines on the management of ID worldwide. DESIGN A literature search was conducted in PubMed, Cochrane, and EMBASE and in main professional association websites, limited to documents published between 1 January 2004 and 30 June 2014. RESULTS Of 127 guidelines identified, 29 were selected, involving 29 professional associations and issued from the United States (n = 8), Europe (n = 6), Britain (n = 4), Canada (n = 3), international organizations (n = 2), France (n = 2), Poland (n = 1), Australia (n = 1), Mexico (n = 1), and Japan (n = 1). A total of 22 and 27 guidelines provided recommendations on diagnosis and treatment of ID, respectively. To define ID, all guidelines recommended a concentration for serum ferritin. One-half of them (10 of 22) proposed transferrin saturation (TSAT) as an alternative or complementary diagnostic test. To treat ID, most of the guidelines (18 of 27) recommended preferentially the oral route if possible, particularly in children and in women in the pre- or postpregnancy period. Iron supplementation should be administered intravenously according to 13 of 27 guidelines, particularly in patients with chronic kidney disease (CKD) (n = 7) and chemotherapy-induced anemia (n = 5). Treatment targets for ID included an increase in hemoglobin concentrations to 10-12 g/dL or normalization (n = 8) and serum ferritin >100 μg/L (n = 7) or 200 μg/L (n = 4). For the latter, in some situations, such as CKD, ferritin concentrations should not exceed 500 μg/L (n = 5) or 800 μg/L (n = 5). Only 9 guidelines recommended TSAT as a target, proposing various thresholds ranging from 20% to 50%. CONCLUSIONS It appears that for the diagnosis of ID, a cutoff of 100 μg/L for serum ferritin concentration should be considered in most conditions and 20% for TSAT, except in particular situations, including young healthy women with heavy menstrual flow. New indications of intravenous iron supplementation are emerging.

Incidence of and impact of medications on colectomy in newly diagnosed ulcerative colitis in the era of biologics

Background: The cumulative incidence of colectomy and the impact of 5‐aminosalicylates (5‐ASA), azathioprine, and antitumor necrosis factor (TNF) treatment on the long‐term need for surgery are unknown in ulcerative colitis (UC) in the era of biologics. Methods: This was an observational study of a referral center cohort. The cumulative incidence of UC‐related colectomy was estimated using the Kaplan–Meier method. Independent predictors of surgery were identified using Cox proportional hazards regression with propensity scores adjustment. The electronic charts of 151 incident cases of UC from Nancy University Hospital, France, diagnosed between 2000 and 2008, were reviewed through January 2010. Results: The median follow‐up time per patient was 58 months. Twenty‐one (14%) underwent surgery. The cumulative probabilities of colectomy were respectively 1.3% and 13.5% at 1 and 5 years from the time of diagnosis. The probability of receiving oral mesalamine at 5 years was 68.1%. The corresponding figures were 48.9% for azathioprine and 29.0% for infliximab. For corticosteroids, methotrexate, and cyclosporin these figures were 75%, 8.8%, and 11.5%, respectively. Using multivariate Cox proportional hazards regression analysis after propensity score adjustment, previous use of cyclosporin was the only independent predictor for colectomy (hazard ratio = 4.41; 95% confidence interval 1.75–1.13). Conclusions: About one‐tenth of patients still require colectomy for UC at 5 years in the era of biologics. Oral 5‐ASA, azathioprine, and anti‐TNF therapy are not associated with a reduced need for colectomy. (Inflamm Bowel Dis 2012)

Association Between Low Trough Levels of Vedolizumab During Induction Therapy for Inflammatory Bowel Diseases and Need for Additional Doses Within 6 Months

BACKGROUND & AIMS: We investigated whether serum trough levels of vedolizumab, a humanized monoclonal antibody against integrin &agr;4&bgr;7, during the induction phase of treatment can determine whether patients will need additional doses (optimization of therapy) within the first 6 months. METHODS: We conducted an observational study of 47 consecutive patients with Crohn’s disease (CD; n = 31) or ulcerative colitis (UC; n = 16) who had not responded to 2 previous treatment regimens with antagonists of tumor necrosis factor and were starting therapy with vedolizumab at 2 hospitals in France, from June 2014 through April 2016. All patients were given a 300‐mg infusion of vedolizumab at the start of the study, Week 2, Week 6, and then every 8 weeks; patients were also given corticosteroids during the first 4–6 weeks. Patients not in remission at Week 6 were given additional doses of vedolizumab at Week 10 and then every 4 weeks (extended therapy or optimization). Remission at Week 6 of treatment was defined as CD activity score below 150 points for patients with CD and a partial Mayo Clinic score of <3 points, without concomitant corticosteroids, for patients with UC. Blood samples were collected each week and serum levels of vedolizumab and antibodies against vedolizumab were measured using an enzyme‐linked immunosorbent assay. Median trough levels of vedolizumab and interquartile ranges were compared using the nonparametric Mann‐Whitney test. The primary objective was to determine whether trough levels of vedolizumab measured during the first 6 weeks of induction therapy associated with the need for extended treatment within the first 6 months. RESULTS: Based on response to therapy at Week 6, extended treatment was required for 30 of the 47 patients (23 patients with CD and 7 patients with UC). At Week 2, trough levels of vedolizumab for patients selected for extended treatment were 23.0 &mgr;g/mL (interquartile range, 14.0–37.0 &mgr;g/mL), compared with 42.5 &mgr;g/mL in patients who did not receive extended treatment (interquartile range, 33.5–50.7; P = .15). At Week 6, trough levels of vedolizumab <18.5 &mgr;g/mL were associated with need for extended therapy (100% positive predictive value, 46.2%; negative predictive value; area under the receiver operating characteristic curve, 0.72) within the first 6 months. Among patients who required extended treatment at Week 10, all of those with trough levels of vedolizumab <19.0 &mgr;g/mL at Week 6 had achieved clinical remission 4 weeks later (secondary responders). CONCLUSIONS: In a prospective study of patients with CD or UC receiving induction therapy with vedolizumab, low trough levels of vedolizumab at Week 6 (<19.0 &mgr;g/mL) are associated with need for additional doses (given at Week 10 and then every 4 weeks). All patients receiving these additional doses achieved a clinical response 4 weeks later.

Azathioprine dose reduction in inflammatory bowel disease patients on combination therapy: an open-label, prospective and randomised clinical trial

Infliximab (IFX) combined with azathioprine (AZA) is more effective than IFX monotherapy in inflammatory bowel disease (IBD).

Distribution of Cytomegalovirus DNA Load in the Inflamed Colon of Ulcerative Colitis Patients.

Distribution of Cytomegalovirus DNA Load in the Inflamed Colon of Ulcerative Colitis Patients

Development and Internal Validation of a Model Using Fecal Calprotectin in Combination with Infliximab Trough Levels to Predict Clinical Relapse in Crohnʼs Disease

Background: The best noninvasive method predicting clinical relapse remains undetermined in infliximab (IFX)-treated patients with Crohns disease. Methods: All patients with CD on IFX maintenance treatment and in clinical remission for at least 16 weeks, between 2011 and 2014, were enrolled in a prospective single-center study. The Crohns Disease Activity Index (CDAI), fecal calprotectin, C-reactive protein levels, antibodies (ATI), and trough level (TLI) of IFX were measured at every IFX infusion. The best thresholds of TLI (2 versus 3 &mgr;g/mL) and calprotectin (50 versus 250 &mgr;g/g stools) were identified across four logistic regression models. Results: One hundred nineteen patients (mean age: 34 ± 12 yrs, mean disease duration: 7.8 yrs) were included. Mean follow-up was 20.4 months, and 17% of the patients were on IFX and azathioprine at inclusion. During follow-up, 37 patients (31.1%) relapsed, 78% within the first 6 months. The clinical characteristics of the relapsed and nonrelapsed patients were similar. After logistic regression, fecal calprotectin >250 &mgr;g/g stools (OR: 4.09; 95% CI, 1.01–16.21; P = 0.049) and TLI <2 &mgr;g/mL (OR: 14.85; 95% CI, 3.67–60; P < 0.0001) were associated with loss of response. A training cohort of 55 patients was isolated randomly to implement prediction rules for loss of response. The best predictive rules were the combination of a TLI <2 &mgr;g/mL and a fecal calprotectin level >250 &mgr;g/g stools (78.3%). These rules were validated on a test cohort of 64 patients with an accuracy of 87%, (sensitivity = 0.94, specificity = 0.84, positive predictive value = 0.73, and negative predictive value = 0.97). Conclusions: In IFX-treated patients with CD in clinical remission, a combination of TLI (<2 &mgr;g/mL) and fecal calprotectin (>250 &mgr;g/g of stools) is a good model for predicting loss of response. In contrast with previous data, low TLIs ranging from 2 to 3 &mgr;g/mL should neither systematically lead to the optimization of IFX use nor a switch in the treatment.

Difficult endoscopic diagnosis of a pancreatic plasmacytoma: Case report and review of literature

A 71-year-old man, with history of plasmacytoma in relapse since one year, was hospitalized for a initial presentation of acute pancreatitis and hepatitis. Although there was a heterogeneous infiltration around the pancreas head, the diagnosis of an extramedullary localization of his plasmacytoma was not made until later. This delayed diagnosis was due to the lack of specific radiologic features and the lack of dilatation of biliary ducts at the admission. A diagnosis was made with a simple ultrasound guided paracentesis of the low abundance ascites after a transjugular hepatic biopsy, an endoscopic ultrasound-guided fine needle aspiration of the pancreatic mass, and a failed attempt of biliary drainage through endoscopic retrograde cholangiopancreatography. In order to document the difficulty of this diagnosis, characteristics of 63 patients suffering from this condition and diagnosis were identified and discussed through a systematic literature search.

Golimumab pharmacokinetics in ulcerative colitis: a literature review

Golimumab (GLM) is the latest anti-tumor necrosis factor (TNF) that gained its marketing license. Thanks to the PURSUIT induction and maintenance trials, it was approved for the treatment of ulcerative colitis (UC) in 2013. The other anti-TNF drugs available are infliximab and adalimumab. These two drugs have validated algorithms concerning prescription and therapeutic drug monitoring (TDM) but little is known about GLM. The available data on GLM’s exposure–response relationship in UC are from the PURSUIT trials and are recently published. The data reveal all the factors that may impact the pharmacokinetic (PK) parameters: dosage, body weight (BW), concomitant drugs, the presence of anti-drug antibodies (ADAbs), sex and age. In addition, the GLM trough level at steady-state appears to be correlated with the patient’s improvement which may make it a precious indicator to predict the clinical response. There is, however, no consensus on a possible therapeutic level or cutoff associated with clinical response, remission, or any other outcome measure such as endoscopic healing in UC. This lack of a threshold value, and its validation with different assay techniques, makes it difficult to use GLM TDM in clinical practice. As with other anti-TNF agents, GLM is associated with development of ADAbs, of which the prevalence and effects are still insufficiently described. The objective of this review is to describe current data and understanding of the PK of GLM including serum concentrations of GLM and ADAbs in UC patients. Better understanding of these parameters could lead to improved patient care with GLM.

Effect of Endocuff-assisted colonoscopy on adenoma detection rate: meta-analysis of randomized controlled trials

BACKGROUND Yield of Endocuff-assisted colonoscopy (EAC) compared with standard colonoscopy is conflicting in terms of adenoma detection rate (ADR). A meta-analysis of randomized controlled trials (RCTs) appears necessary. METHODS PubMed and Google Scholar were searched in December 2017. Abstracts from Digestive Disease Week and United European Gastroenterology Week meetings were also searched to 2017. All RCTs comparing EAC with standard colonoscopy were included. Analysis was conducted by using the Mantel-Haenszel models. Heterogeneity was quantified using the I2 test. RESULTS Of the 265 articles reviewed, 12 RCTs were included, with a total of 8376 patients (EAC group 4225; standard colonoscopy group 4151). In the meta-analysis, ADR was significantly increased in the EAC group vs. the standard colonoscopy group (41.3 % vs. 34.2 %; risk ratio [RR] = 1.20, 95 % confidence interval [CI] 1.06 to 1.36; P = 0.003; I2 = 79 %), especially for operators with low-to-moderate ADRs (< 35 %): RR = 1.51, 95 %CI 1.35 to 1.69; P < 0.001; I2 = 43 %). In contrast, this benefit was not reached for operators with high ADRs (> 45 %): RR = 1.01, 95 %CI 0.93 to 1.09; P = 0.87; I2 = 0.0 %). The mean number of adenomas per patient tended to be higher with EAC (mean difference = 0.11 adenomas/patient, 95 %CI - 0.17 to 0.38). Similar results were shown for polyp detection rates (61.6 % vs. 51.4 %; RR = 1.20, 95 %CI 1.06 to 1.36; P = 0.004). Use of the Endocuff did not impact the cecal intubation rate (95.1 % vs. 95.7 %; P = 0.08), or the procedure time compared with standard colonoscopy. Adverse events related to Endocuff were rare and exclusively mild mucosal erosion (4.0 %; 95 %CI 2.0 % to 8.0 %). CONCLUSION With moderate-quality evidence, this study showed an improvement in ADR with EAC without major adverse events, especially for operators with low-to-moderate ADRs.

Trastuzumab beyond progression in patients with HER2-positive advanced gastric adenocarcinoma: a multicenter AGEO study

Introduction Trastuzumab in combination with platinum-based chemotherapy is the standard first-line regimen in HER2-positive advanced gastric cancer. However, there are very few data concerning efficacy of continuing trastuzumab beyond first-line progression. Methods This retrospective multicenter study included all consecutive patients with HER2-positive advanced gastric or gastro-esophageal junction (GEJ) adenocarcinoma who received a second-line of chemotherapy with or without trastuzumab after progression on platinum-based chemotherapy plus trastuzumab. Progression-free survival (PFS) and overall survival (OS) were estimated from the start of second-line chemotherapy using the Kaplan-Meier method and compared using log-rank test. The prognostic variables with P values ≤ 0.05 in univariate analysis were eligible for the Cox multivariable regression model. Results From May 2010 to December 2015, 104 patients were included (median age, 60.8 years; male, 78.8%; ECOG performance status [PS] 0-1, 71.2%). The continuation (n=39) versus discontinuation (n=65) of trastuzumab beyond progression was significantly associated with an improvement of median PFS (4.4 versus 2.3 months; P=0.002) and OS (12.6 versus 6.1 months; P=0.001. In the multivariate analysis including the ECOG PS, number of metastatic sites and measurable disease, the continuation of trastuzumab beyond progression remained significantly associated with longer PFS (HR, 0.56; 95% CI, 0.35-0.89; P=0.01) and OS (HR, 0.47; 95% CI, 0.28-0.79; P=0.004). Conclusion This study suggests that continuation of trastuzumab beyond progression has clinical benefit in patients with HER2-positive advanced gastric cancer. These results deserve a prospective randomized validation.