Assessment of the Influence of Inflammation and FCGR3A Genotype on Infliximab Pharmacokinetics and Time to Relapse in Patients with Crohn's Disease.
; ; et al
in Clinical pharmacokinetics (2015)
BACKGROUND AND OBJECTIVES: Infliximab is a monoclonal anti-tumor necrosis factor-alpha (anti-TNFalpha) antibody that profoundly modified the treatment of Crohn's disease (CD). The polymorphism of Fc ... [more ▼]
BACKGROUND AND OBJECTIVES: Infliximab is a monoclonal anti-tumor necrosis factor-alpha (anti-TNFalpha) antibody that profoundly modified the treatment of Crohn's disease (CD). The polymorphism of Fc fragment of IgG, low affinity IIIa, receptor (CD16a) [FCGR3A] influences the biological response to infliximab in patients with CD. Our aim was to study its influence on infliximab pharmacokinetics and risk of relapse after infliximab discontinuation. METHODS: In 111 CD patients in remission, infliximab was discontinued and its concentrations were measured for 30 months or until relapse. Infliximab pharmacokinetics were described using monocompartmental population modeling. RESULTS: The elimination rate of infliximab increased with C-reactive protein (CRP) [p = 0.00018] and was 16 % higher in FCGR3A-158V/V patients than in F carriers (p = 0.0028). Risk of relapse was higher in patients with baseline CRP >/=5 mg/L than in those with a lower value (p = 0.0000029). In addition, there was a first-order interaction between CRP and the FCGR3A genotype; in patients with high CRP, risk of relapse was higher for V/V patients than for F carriers (hazard ratio 4.80 and 2.84 for V/V and F carriers, respectively; p = 0.013). CONCLUSION: Both increased inflammation and FCGR3A-158V/V genotype are associated with increased infliximab elimination and risk of relapse after infliximab discontinuation in patients with CD. [less ▲]Detailed reference viewed: 36 (8 ULg)
Systematic Review of Effects of Withdrawal of Immunomodulators or Biologic Agents From Patients With Inflammatory Bowel Disease
; ; et al
in Gastroenterology (2015), 149(7), 1716-1730Detailed reference viewed: 44 (4 ULg)
Development of the lemann index to assess digestive tract damage in patients with Crohn's disease.
; ; et al
in Gastroenterology (2015), 148(1), 52-63
BACKGROUND & AIMS: There is a need for a scoring system that provides a comprehensive assessment of structural bowel damage, including stricturing lesions, penetrating lesions, and surgical resection, for ... [more ▼]
BACKGROUND & AIMS: There is a need for a scoring system that provides a comprehensive assessment of structural bowel damage, including stricturing lesions, penetrating lesions, and surgical resection, for measuring disease progression. We developed the Lemann Index and assessed its ability to measure cumulative structural bowel damage in patients with Crohn's disease (CD). METHODS: We performed a prospective, multicenter, international, cross-sectional study of patients with CD evaluated at 24 centers in 15 countries. Inclusions were stratified based on CD location and duration. All patients underwent clinical examination and abdominal magnetic resonance imaging analyses. Upper endoscopy, colonoscopy, and pelvic magnetic resonance imaging analyses were performed according to suspected disease locations. The digestive tract was divided into 4 organs and subsequently into segments. For each segment, investigators collected information on previous operations, predefined strictures, and/or penetrating lesions of maximal severity (grades 1-3), and then provided damage evaluations ranging from 0.0 (no lesion) to 10.0 (complete resection). Overall level of organ damage was calculated from the average of segmental damage. Investigators provided a global damage evaluation (from 0.0 to 10.0) using calculated organ damage evaluations. Predicted organ indexes and Lemann Index were constructed using a multiple linear mixed model, showing the best fit with investigator organ and global damage evaluations, respectively. An internal cross-validation was performed using bootstrap methods. RESULTS: Data from 138 patients (24, 115, 92, and 59 with upper tract, small bowel, colon/rectum, and anus CD location, respectively) were analyzed. According to validation, the unbiased correlation coefficients between predicted indexes and investigator damage evaluations were 0.85, 0.98, 0.90, 0.82 for upper tract, small bowel, colon/rectum, anus, respectively, and 0.84 overall. CONCLUSIONS: In a cross-sectional study, we assessed the ability of the Lemann Index to measure cumulative structural bowel damage in patients with CD. Provided further successful validation and good sensitivity to change, the index should be used to evaluate progression of CD and efficacy of treatment. [less ▲]Detailed reference viewed: 104 (7 ULg)
Alterations in the intestinal microbiome (dysbiosis) as a predictor of relapse after infliximab withdrawal in Crohn's disease.
; ; Louis, Edouard et al
in Inflammatory bowel diseases (2014), 20(6), 978-86
BACKGROUND: Crohn's disease (CD)-associated dysbiosis could predispose patients to relapse. Gut microbiota composition of patients from the prospective cohort study designed to identify predictive factors ... [more ▼]
BACKGROUND: Crohn's disease (CD)-associated dysbiosis could predispose patients to relapse. Gut microbiota composition of patients from the prospective cohort study designed to identify predictive factors of clinical relapse after infliximab discontinuation (STORI Study) was investigated to determine the impact of dysbiosis in CD relapse. METHODS: Fecal samples from 33 patients with CD in this cohort were collected at baseline, 2 months, 6 months, and at the end of the follow-up period (19 relapsers and 14 nonrelapsers). Healthy volunteers subjects (n = 29) were used as a control group. The fecal microbiota composition was assessed using quantitative PCR, and comparisons between the patient groups were made at different time points using the Wilcoxon test. The analysis of the time-to-relapse was performed according to the baseline median level of each bacterial signal. RESULTS: Dysbiosis was observed in patients with CD compared with healthy subjects, and it was characterized by low mean counts of Firmicutes (Clostridium coccoides [P = 0.0003], C. leptum [P < 0.0001], and Faecalibacterium prausnitzii [P = 0.003]). Lower rates of Firmicutes were seen in relapsers compared with nonrelapsers. Moreover, a low rate of F. prausnitzii (P = 0.014) and a low rate of Bacteroides (P = 0.030) predicted relapse independently from high C reactive protein level (P = 0.0001). CONCLUSIONS: In this work, we report that CD-associated dysbiosis, characterized by a decrease in Firmicutes, correlates with the time-to-relapse after infliximab withdrawal. A deficit in some bacterial groups or species, such as F. prausnitzii, may represent a predictive factor for relapse. Restoring normobiosis in CD could be a new goal for optimal CD management. [less ▲]Detailed reference viewed: 24 (0 ULg)
Vedolizumab as induction and maintenance therapy for Crohn's disease.
; ; et al
in The New England journal of medicine (2013), 369(8), 711-21
BACKGROUND: The efficacy of vedolizumab, an alpha4beta7 integrin antibody, in Crohn's disease is unknown. METHODS: In an integrated study with separate induction and maintenance trials, we assessed ... [more ▼]
BACKGROUND: The efficacy of vedolizumab, an alpha4beta7 integrin antibody, in Crohn's disease is unknown. METHODS: In an integrated study with separate induction and maintenance trials, we assessed intravenous vedolizumab therapy (300 mg) in adults with active Crohn's disease. In the induction trial, 368 patients were randomly assigned to receive vedolizumab or placebo at weeks 0 and 2 (cohort 1), and 747 patients received open-label vedolizumab at weeks 0 and 2 (cohort 2); disease status was assessed at week 6. In the maintenance trial, 461 patients who had had a response to vedolizumab were randomly assigned to receive placebo or vedolizumab every 8 or 4 weeks until week 52. RESULTS: At week 6, a total of 14.5% of the patients in cohort 1 who received vedolizumab and 6.8% who received placebo were in clinical remission (i.e., had a score on the Crohn's Disease Activity Index [CDAI] of </=150, with scores ranging from 0 to approximately 600 and higher scores indicating greater disease activity) (P=0.02); a total of 31.4% and 25.7% of the patients, respectively, had a CDAI-100 response (>/=100-point decrease in the CDAI score) (P=0.23). Among patients in cohorts 1 and 2 who had a response to induction therapy, 39.0% and 36.4% of those assigned to vedolizumab every 8 weeks and every 4 weeks, respectively, were in clinical remission at week 52, as compared with 21.6% assigned to placebo (P<0.001 and P=0.004 for the two vedolizumab groups, respectively, vs. placebo). Antibodies against vedolizumab developed in 4.0% of the patients. Nasopharyngitis occurred more frequently, and headache and abdominal pain less frequently, in patients receiving vedolizumab than in patients receiving placebo. Vedolizumab, as compared with placebo, was associated with a higher rate of serious adverse events (24.4% vs. 15.3%), infections (44.1% vs. 40.2%), and serious infections (5.5% vs. 3.0%). CONCLUSIONS: Vedolizumab-treated patients with active Crohn's disease were more likely than patients receiving placebo to have a remission, but not a CDAI-100 response, at week 6; patients with a response to induction therapy who continued to receive vedolizumab (rather than switching to placebo) were more likely to be in remission at week 52. Adverse events were more common with vedolizumab. (Funded by Millennium Pharmaceuticals; GEMINI 2 ClinicalTrials.gov number, NCT00783692.). [less ▲]Detailed reference viewed: 52 (1 ULg)
Evolving definitions of remission in Crohn's disease.
; ; Louis, Edouard et al
in Inflammatory bowel diseases (2013), 19(8), 1645-53
BACKGROUND: Using clinical symptoms alone to inform treatment decisions in Crohn's disease (CD) may increase the risk of disease progression and complications. Treatment beyond symptoms may offer improved ... [more ▼]
BACKGROUND: Using clinical symptoms alone to inform treatment decisions in Crohn's disease (CD) may increase the risk of disease progression and complications. Treatment beyond symptoms may offer improved outcomes. METHODS: We explore alternative definitions of remission, beyond traditional clinical remission, incorporating more objective parameters of inflammation control, which may support prevention or delay the disease progression. These definitions could serve as a platform for future clinical research, evaluating whether treating beyond symptoms alters the natural history of CD. RESULTS: Proposed definitions may include endoscopic remission (mucosal healing), normalization of serologic or fecal markers of inflammation, and even radiographic remission, in addition to clinical remission (symptom control). Endoscopic remission is the leading candidate for inclusion because it is the best studied. The definition should include considerations for both early and late disease given that in late disease, which may be associated with operation-related symptoms or irreversible bowel damage, symptomatic remission may not achievable. Desired outcomes in early disease are complete absence of symptoms, no disease progression, no complications or disability, and normal quality of life. In late disease, there are stabilization of noninflammatory symptoms, no progression of damage or disability, and improved quality of life. CONCLUSIONS: Over time, we anticipate that a working definition of remission that includes both biological remission and clinical remission will evolve and be evaluated in clinical trials. Our proposed definition is a possible starting point for that evolution. Ultimately, the goal in evolving the definition of remission is to improve the outcomes in patients with CD. [less ▲]Detailed reference viewed: 23 (0 ULg)
Optimising monitoring in the management of Crohn's disease: a physician's perspective.
; ; et al
in Journal of Crohn's & colitis (2013), 7(8), 653-69
Management of Crohn's disease has traditionally placed high value on subjective symptom assessment; however, it is increasingly appreciated that patient symptoms and objective parameters of inflammation ... [more ▼]
Management of Crohn's disease has traditionally placed high value on subjective symptom assessment; however, it is increasingly appreciated that patient symptoms and objective parameters of inflammation can be disconnected. Therefore, strategies that objectively monitor inflammatory activity should be utilised throughout the disease course to optimise patient management. Initially, a thorough assessment of the severity, location and extent of disease is needed to ensure a correct diagnosis, identify any complications, help assess prognosis and select appropriate therapy. During follow-up, clinical decision-making should be driven by disease activity monitoring, with the aim of optimising treatment for tight disease control. However, few data exist to guide the choice of monitoring tools and the frequency of their use. Furthermore, adaption of monitoring strategies for symptomatic, asymptomatic and post-operative patients has not been well defined. The Annual excHangE on the ADvances in Inflammatory Bowel Disease (IBD Ahead) 2011 educational programme, which included approximately 600 gastroenterologists from 36 countries, has developed practice recommendations for the optimal monitoring of Crohn's disease based on evidence and/or expert opinion. These recommendations address the need to incorporate different modalities of disease assessment (symptom and endoscopic assessment, measurement of biomarkers of inflammatory activity and cross-sectional imaging) into robust monitoring. Furthermore, the importance of measuring and recording parameters in a standardised fashion to enable longitudinal evaluation of disease activity is highlighted. [less ▲]Detailed reference viewed: 92 (1 ULg)
Effects of infliximab therapy on transmural lesions as assessed by magnetic resonance enteroclysis in patients with ileal Crohn's disease.
; ; Louis, Edouard et al
in Journal of Crohn's & colitis (2013), 7(12), 950-7
BACKGROUND AND AIMS: Anti TNF therapy induces mucosal healing in patients with Crohn's disease, but the effects on transmural inflammation in the ileum are not well understood. Magnetic resonance ... [more ▼]
BACKGROUND AND AIMS: Anti TNF therapy induces mucosal healing in patients with Crohn's disease, but the effects on transmural inflammation in the ileum are not well understood. Magnetic resonance-enteroclysis (MRE) offers excellent imaging of transmural and peri-enteric lesions in Crohn's ileitis and we aimed to study its responsiveness to anti TNF therapy. METHODS: In this multi-center prospective trial, anti TNF naive patients with ileal Crohn's disease and with increased CRP and contrast enhanced wall thickening received infliximab 5 mg/kg at weeks 0, 2 and 6, and q8 weeks maintenance MRE was performed at baseline, 2 weeks and 6 months and assessed based on a predefined MRE score of severity in ileal Crohn's Disease. RESULTS: Twenty patients were included; of those, 18 patients underwent MRE at week 2 and 15 patients at weeks 2 and 26 as scheduled. Inflammatory components of the MRE index decreased by >/=2 points and by >/=50% at week 26 (primary endpoint) in 40% and 32% of patients (per protocol and intention to treat analysis, respectively). The MRE index improved in 44% at week 2 and in 80% at week 26. Complete absence of inflammatory lesions was observed in 0/18 at week 2 and 13% (2/15) at week 26. The obstructive elements did not change. Clinical and CRP improvement occurred as early as wk 2, but only CDAI correlated with the MRE index. CONCLUSION: Improvement of MRE occurs from 2 weeks after infliximab therapy onwards and correlates with clinical response but normalization of MRE is rare. [less ▲]Detailed reference viewed: 38 (5 ULg)
Vedolizumab as induction and maintenance therapy for ulcerative colitis.
; ; et al
in The New England journal of medicine (2013), 369(8), 699-710
BACKGROUND: Gut-selective blockade of lymphocyte trafficking by vedolizumab may constitute effective treatment for ulcerative colitis. METHODS: We conducted two integrated randomized, double-blind ... [more ▼]
BACKGROUND: Gut-selective blockade of lymphocyte trafficking by vedolizumab may constitute effective treatment for ulcerative colitis. METHODS: We conducted two integrated randomized, double-blind, placebo-controlled trials of vedolizumab in patients with active disease. In the trial of induction therapy, 374 patients (cohort 1) received vedolizumab (at a dose of 300 mg) or placebo intravenously at weeks 0 and 2, and 521 patients (cohort 2) received open-label vedolizumab at weeks 0 and 2, with disease evaluation at week 6. In the trial of maintenance therapy, patients in either cohort who had a response to vedolizumab at week 6 were randomly assigned to continue receiving vedolizumab every 8 or 4 weeks or to switch to placebo for up to 52 weeks. A response was defined as a reduction in the Mayo Clinic score (range, 0 to 12, with higher scores indicating more active disease) of at least 3 points and a decrease of at least 30% from baseline, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1. RESULTS: Response rates at week 6 were 47.1% and 25.5% among patients in the vedolizumab group and placebo group, respectively (difference with adjustment for stratification factors, 21.7 percentage points; 95% confidence interval [CI], 11.6 to 31.7; P<0.001). At week 52, 41.8% of patients who continued to receive vedolizumab every 8 weeks and 44.8% of patients who continued to receive vedolizumab every 4 weeks were in clinical remission (Mayo Clinic score </=2 and no subscore >1), as compared with 15.9% of patients who switched to placebo (adjusted difference, 26.1 percentage points for vedolizumab every 8 weeks vs. placebo [95% CI, 14.9 to 37.2; P<0.001] and 29.1 percentage points for vedolizumab every 4 weeks vs. placebo [95% CI, 17.9 to 40.4; P<0.001]). The frequency of adverse events was similar in the vedolizumab and placebo groups. CONCLUSIONS: Vedolizumab was more effective than placebo as induction and maintenance therapy for ulcerative colitis. (Funded by Millennium Pharmaceuticals; GEMINI 1 ClinicalTrials.gov number, NCT00783718.). [less ▲]Detailed reference viewed: 33 (2 ULg)
Development of the paris definition of early Crohn's disease for disease-modification trials: results of an international expert opinion process.
; ; et al
in American Journal of Gastroenterology (2012), 107(12), 1770-6
We report the findings and outputs of an international expert opinion process to develop a definition of early Crohn's disease (CD) that could be used in future disease-modification trials. Nineteen ... [more ▼]
We report the findings and outputs of an international expert opinion process to develop a definition of early Crohn's disease (CD) that could be used in future disease-modification trials. Nineteen experts on inflammatory bowel diseases held an international expert opinion meeting to discuss and agree on a definition for early CD to be used in disease-modification trials. The process included literature searches for the relevant basic-science and clinical evidence. A published preliminary definition of early CD was used as the basis for development of a proposed definition that was discussed at the expert opinion meeting. The participants then derived a final definition, based on best current knowledge, that it is hoped will be of practical use in disease-modification trials in CD. [less ▲]Detailed reference viewed: 43 (3 ULg)
Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47.
; ; et al
in Nature Genetics (2011), 43(3), 246-52
Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association ... [more ▼]
Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 x 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis. [less ▲]Detailed reference viewed: 40 (11 ULg)
Resequencing of positional candidates identifies low frequency IL23R coding variants protecting against inflammatory bowel disease.
Momozawa, Yukihide ; Mni, Myriam ; Nakamura, Kayo et al
in Nature Genetics (2011), 43(1), 43-7
Genome-wide association studies (GWAS) have identified dozens of risk loci for many complex disorders, including Crohn's disease. However, common disease-associated SNPs explain at most approximately 20 ... [more ▼]
Genome-wide association studies (GWAS) have identified dozens of risk loci for many complex disorders, including Crohn's disease. However, common disease-associated SNPs explain at most approximately 20% of the genetic variance for Crohn's disease. Several factors may account for this unexplained heritability, including rare risk variants not adequately tagged thus far in GWAS. That rare susceptibility variants indeed contribute to variation in multifactorial phenotypes has been demonstrated for colorectal cancer, plasma high-density lipoprotein cholesterol levels, blood pressure, type 1 diabetes, hypertriglyceridemia and, in the case of Crohn's disease, for NOD2 (refs. 14,15). Here we describe the use of high-throughput resequencing of DNA pools to search for rare coding variants influencing susceptibility to Crohn's disease in 63 GWAS-identified positional candidate genes. We identify low frequency coding variants conferring protection against inflammatory bowel disease in IL23R, but we conclude that rare coding variants in positional candidates do not make a large contribution to inherited predisposition to Crohn's disease. [less ▲]Detailed reference viewed: 107 (39 ULg)
Development of the Crohn's disease digestive damage score, the Lemann score.
; ; et al
in Inflammatory Bowel Diseases (2011), 17(6), 1415-22
Crohn's disease (CD) is a chronic progressive destructive disease. Currently available instruments measure disease activity at a specific point in time. An instrument to measure cumulative structural ... [more ▼]
Crohn's disease (CD) is a chronic progressive destructive disease. Currently available instruments measure disease activity at a specific point in time. An instrument to measure cumulative structural damage to the bowel, which may predict long-term disability, is needed. The aim of this article is to outline the methods to develop an instrument that can measure cumulative bowel damage. The project is being conducted by the International Program to develop New Indexes in Crohn's disease (IPNIC) group. This instrument, called the Crohn's Disease Digestive Damage Score (the Lemann score), should take into account damage location, severity, extent, progression, and reversibility, as measured by diagnostic imaging modalities and the history of surgical resection. It should not be "diagnostic modality driven": for each lesion and location, a modality appropriate for the anatomic site (for example: computed tomography or magnetic resonance imaging enterography, and colonoscopy) will be used. A total of 24 centers from 15 countries will be involved in a cross-sectional study, which will include up to 240 patients with stratification according to disease location and duration. At least 120 additional patients will be included in the study to validate the score. The Lemann score is expected to be able to portray a patient's disease course on a double-axis graph, with time as the x-axis, bowel damage severity as the y-axis, and the slope of the line connecting data points as a measure of disease progression. This instrument could be used to assess the effect of various medical therapies on the progression of bowel damage. [less ▲]Detailed reference viewed: 96 (2 ULg)
Familial aggregation and antimicrobial response dose-dependently affect the risk for Crohn's disease.
; Van Steen, Kristel ; et al
in Inflammatory Bowel Diseases (2010), 16(1), 58-67
BACKGROUND:: An increased risk of Crohn's disease (CD) has been reported consistently in first-degree relatives of patients. Our aim was to test whether a combination of CD-associated genes involved in ... [more ▼]
BACKGROUND:: An increased risk of Crohn's disease (CD) has been reported consistently in first-degree relatives of patients. Our aim was to test whether a combination of CD-associated genes involved in innate immunity and/or antibody responses to microbial antigens may be valuable in identifying healthy relatives at risk. METHODS:: We investigated 86 families from Belgium and northern France, 45 with at least 3 first-degree relatives with CD, 24 with a single case, and 17 control families without inflammatory bowel disease (IBD). The cohort consisted of 186 CD patients, 290 healthy relatives, and 142 controls (total 618). Genetic (NOD2, NOD1, TLR4, CARD8) and serologic markers (ASCA, ACMA, ALCA, ACCA, ASigmaMA, OmpC, CBir1, I2) were determined in all subjects. All Belgian families were prospectively followed up for 54 months. RESULTS:: In multiple-affected families, an increment of affected first-degree relatives and of positive antibodies were additive risks factors for CD (P < 0.0001), independent of NOD2 mutations. When comparing subjects from multiple-affected families, having 3 additional first-degree relatives with CD and 1 additional positive antibody increased the odds for CD to 9.19 (95% confidence interval [CI]: 4.07-20.80). After a follow-up of 54 months among all Belgian families, a total of 4 new diagnoses of IBD were confirmed in the multiple-affected families only, resulting in a 57-fold increase in incidence within multiple-affected families compared to the known incidence of IBD in our region. CONCLUSIONS:: We found an additive risk increment for CD in subjects from multicase families per additional affected relative and per additional positive antibody, independent of NOD2. Furthermore, a very high disease incidence was observed in these multiple-affected families. Inflamm Bowel Dis 2010. [less ▲]Detailed reference viewed: 33 (3 ULg)
Severe skin lesions cause patients with inflammatory bowel disease to discontinue anti-tumor necrosis factor therapy.
; ; et al
in Clinical Gastroenterology and Hepatology : the Official Clinical Practice Journal of The American Gastroenterological Association (2010), 8(12), 1048-55
BACKGROUND & AIMS: Psoriasiform and eczematiform lesions are associated with anti-tumor necrosis factor (TNF)-alpha therapies. We assessed clinical characteristics, risk factors, and outcomes of skin ... [more ▼]
BACKGROUND & AIMS: Psoriasiform and eczematiform lesions are associated with anti-tumor necrosis factor (TNF)-alpha therapies. We assessed clinical characteristics, risk factors, and outcomes of skin disease in patients with inflammatory bowel diseases that presented with psoriasiform and eczematiform lesions induced by anti-TNF-alpha agents. METHODS: We studied 85 patients (69 with Crohn's disease, 15 with ulcerative colitis, and 1 with indeterminate colitis; 62 women) with inflammatory skin lesions (62 psoriasiform and 23 eczematiform lesions). RESULTS: Twenty-four patients had a history of inflammatory skin lesions and 15 had a familial history of inflammatory skin disease. Locations of eczematiform lesions varied whereas scalp and flexural varieties were mostly psoriasiform. Skin lesions emerged but inflammatory bowel disease was quiescent in 69 patients following treatment with any type of anti-TNF-alpha agent (60 with infliximab, 20 with adalimumab, and 5 with certolizumab). Topical therapy resulted in partial or total remission in 41 patients. Patients with psoriasiform lesions that were resistant to topical therapy and that changed anti-TNF-alpha therapies once or twice developed recurring lesions. Overall, uncontrolled skin lesions caused 29 patients to stop taking TNF-alpha inhibitors. CONCLUSIONS: Inflammatory skin lesions following therapy with TNF-alpha inhibitors occurred most frequently among women and patients with a personal or familial history of inflammatory skin disease; lesions did not correlate with intestinal disease activity. Recurring and intense skin lesions caused 34% of patients in this study to discontinue use of anti-TNF-alpha agents. [less ▲]Detailed reference viewed: 49 (3 ULg)
Fibrin glue is effective healing perianal fistulas in patients with Crohn's disease.
; ; et al
in Gastroenterology (2010), 138(7), 2275-8122811
BACKGROUND & AIMS: Fibrin glue is a therapeutic for fistulas that activates thrombin to form a fibrin clot, which mechanically seals the fistula tract. We assessed the efficacy and safety of a ... [more ▼]
BACKGROUND & AIMS: Fibrin glue is a therapeutic for fistulas that activates thrombin to form a fibrin clot, which mechanically seals the fistula tract. We assessed the efficacy and safety of a heterologous fibrin glue that was injected into the fistula tracts of patients with Crohn's disease (ClinicalTrials.gov No. NCT00723047). METHODS: This multicenter, open-label, randomized controlled trial included patients with a Crohn's disease activity index < or =250 and fistulas between the anus (or low rectum) and perineum, vulva, or vagina, that drained for more than 2 months. Magnetic resonance imaging or endosonography was performed to assess fistula tracts and the absence of abscesses. Patients were stratified into groups with simple or complex fistulas and randomly assigned to receive fibrin glue injections (n = 36) or only observation (n = 41) after removal of setons. The primary end point was clinical remission at week 8, defined as the absence of draining, perianal pain, or abscesses. At week 8, a fibrin glue injection was offered to patients who were not in remission. RESULTS: Clinical remission was observed in 13 of the 34 patients (38%) of the fibrin glue group compared with 6 of the 37 (16%) in the observation group; these findings demonstrate the benefit of fibrin glue (odds ratio, 3.2; 95% confidence interval: 1.1-9.8; P = .04). The benefit seemed to be greater in patients with simple fistulas. Four patients in the fibrin glue group and 6 in the observation group had adverse events. CONCLUSIONS: Fibrin glue injection is a simple, effective, and well-tolerated therapeutic option for patients with Crohn's disease and perianal fistula tracts. [less ▲]Detailed reference viewed: 50 (0 ULg)
Efficacy and safety of a third anti-TNF monoclonal antibody in Crohn's disease after failure of two other anti-TNF.
; ; et al
in Alimentary Pharmacology & Therapeutics (2009)
Adalimumab (ADA) and certolizumab pegol (CZP) have demonstrated efficacy in Crohn's disease (CD) patients previously treated with infliximab (IFX). Aim: To assess the efficacy and tolerability of a third ... [more ▼]
Adalimumab (ADA) and certolizumab pegol (CZP) have demonstrated efficacy in Crohn's disease (CD) patients previously treated with infliximab (IFX). Aim: To assess the efficacy and tolerability of a third anti-TNF in CD after failure of and/or intolerance to two different anti-TNF. Methods: CD patients who received ADA or CZP after loss of response and/or intolerance to two anti-TNF were included in this retrospective study. Data were collected using a standardized questionnaire. Clinical response, duration, safety and reasons for discontinuation were assessed. Results: Sixty-seven patients treated with CZP (n=40) or ADA (n=27) were included. A clinical response was observed in 41 (61%) at week 6 and 34 patients (51%) at week 20. The probability of remaining under treatment at 3 months, 6 months and 9 months was 68%, 60% and 45%, respectively. At the end of follow-up, the third anti-TNF had been stopped in 36 patients for intolerance (n=13), or failure (n=23). Two deaths were observed. Conclusion: Treatment, with a third anti-TNF (CZP or ADA) agent, of CD patients who have experienced loss of response and/or intolerance to two anti-TNF antibodies, has favorable short- and long-term efficacy and is an option to be considered in patients with no other therapeutic options. [less ▲]Detailed reference viewed: 39 (5 ULg)
Polymorphism in IgG Fc receptor gene FCGR3A and response to infliximab in Crohn's disease: a subanalysis of the ACCENT I study.
Louis, Edouard ; ; et al
in Pharmacogenetics and Genomics (2006), 16(12), 911-4
Recently, it has been shown that FCGR3A-158 gene polymorphism is associated with biological and possibly clinical response to infliximab in Crohn's disease. We further assessed this association in a ... [more ▼]
Recently, it has been shown that FCGR3A-158 gene polymorphism is associated with biological and possibly clinical response to infliximab in Crohn's disease. We further assessed this association in a subset of 344 patients from the large and well-defined cohort of 573 patients with Crohn's disease from the ACCENT I study. No association could be observed between FCGR3A-158 gene polymorphism and the clinical response to infliximab, which was primarily defined as a decrease of >or=70 points in the Crohn's disease activity index or clinical remission (Crohn's disease activity index <150). We did, however, confirm a trend towards a greater decrease in C-reactive protein after infliximab in V/V homozygotes as compared with V/F heterozygotes and F/F homozygotes (-79.4, -76.5, and -64.3%, respectively, at week 6; P=0.085; one-tailed P=0.043). This finding has no immediate clinical impact but may enhance the understanding of the complex mechanisms of action of anti-tumor necrosis factor agents in Crohn's disease. [less ▲]Detailed reference viewed: 31 (0 ULg)