Adalimumab produces clinical remission and reduces extraintestinal manifestations in Crohn's disease: Results from CARE.
; Louis, Edouard ; et al
in Inflammatory Bowel Diseases (2011)
BACKGROUND: Data regarding the effectiveness of anti-tumor necrosis factor (TNF) agents for resolution of extraintestinal manifestations (EIMs) are scarce. The CARE study evaluated clinical effectiveness ... [more ▼]
BACKGROUND: Data regarding the effectiveness of anti-tumor necrosis factor (TNF) agents for resolution of extraintestinal manifestations (EIMs) are scarce. The CARE study evaluated clinical effectiveness, EIM resolution, and safety of adalimumab in a large pan-European cohort of patients with moderate to severe Crohn's disease (CD). METHODS: In all, 945 patients with a Harvey-Bradshaw Index (HBI) >/=7 enrolled in this multicenter, open-label phase IIIb trial. Patients received subcutaneous adalimumab, 160/80 mg at weeks 0/2, then 40 mg every other week. Dose adjustments were allowed for CD-related concomitant medications (from week 8) and adalimumab (from week 12). Clinical endpoints were analyzed through week 20 for all patients, and after stratification by prior infliximab exposure and by reason for discontinuing infliximab (primary nonresponse [PNR] or other). RESULTS: The remission rate (HBI <5) at week 20 was 52% (95% confidence interval, 49%-55%) overall, and was higher for infliximab-naive versus infliximab-exposed patients (62% versus 42%, P < 0.001). Remission rates were similar for PNR (37%) and other reasons (43%; P = 0.278). Of 497 patients with baseline EIMs, 51% were free of EIM signs and symptoms at week 20. Serious infectious adverse events were reported in 5% of patients. Opportunistic infections and malignancies were rare (</=1%). There was one case of demyelinating disease, but no occurrences of lupus, tuberculosis, or death. CONCLUSIONS: In this large cohort of patients, adalimumab treatment resulted in rates of clinical remission and EIM resolution exceeding 50%, and substantial rates of effectiveness in patients who had PNR to infliximab. Adalimumab was well tolerated, with safety consistent with prior reports. (Inflamm Bowel Dis 2011). [less ▲]Detailed reference viewed: 37 (5 ULg)
H1N1 vaccines in a large observational cohort of patients with inflammatory bowel disease treated with immunomodulators and biological therapy.
; ; et al
in Gut (2011), 60(4), 456-62
BACKGROUND: Safety data are lacking on influenza vaccination in general and on A (H1N1)v vaccination in particular in patients with inflammatory bowel disease (IBD) receiving immmunomodulators and/or ... [more ▼]
BACKGROUND: Safety data are lacking on influenza vaccination in general and on A (H1N1)v vaccination in particular in patients with inflammatory bowel disease (IBD) receiving immmunomodulators and/or biological therapy. AIMS AND METHODS: The authors conducted a multicentre observational cohort study to evaluate symptoms associated with influenza H1N1 adjuvanted (Pandemrix, Focetria, FluvalP) and non-adjuvanted (Celvapan) vaccines and to assess the risk of flare of IBD after vaccination. Patients with stable IBD treated with immunomodulators and/or biological therapy were recruited from November 2009 until March 2010 in 12 European countries. Harvey-Bradshaw Index and Partial Mayo Score were used to assess disease activity before and 4 weeks after vaccination in Crohn's disease (CD) and ulcerative colitis (UC). Vaccination-related events up to 7 days after vaccination were recorded. RESULTS: Of 575 patients enrolled (407 CD, 159 UC and nine indeterminate colitis; 53.9% female; mean age 40.3 years, SD 13.9), local and systemic symptoms were reported by 34.6% and 15.5% of patients, respectively. The most common local and systemic reactions were pain in 32.8% and fatigue in 6.1% of subjects. Local symptoms were more common with adjuvanted (39.3%) than non-adjuvanted (3.9%) vaccines (p < 0.0001), whereas rates of systemic symptoms were similar with both types (15.0% vs 18.4%, p = 0.44). Among the adjuvanted group, Pandemrix more often induced local reactions than FluvalP and Focetria (51.2% vs 27.6% and 15.4%, p < 0.0001). Solicited adverse events were not associated with any patient characteristics, specific immunomodulatory treatment, or biological therapy. Four weeks after vaccination, absence of flare was observed in 377 patients with CD (96.7%) and 151 with UC (95.6%). CONCLUSION: Influenza A (H1N1)v vaccines are well tolerated in patients with IBD. Non-adjuvanted vaccines are associated with fewer local reactions. The risk of IBD flare is probably not increased after H1N1 vaccination. [less ▲]Detailed reference viewed: 24 (3 ULg)
Characterization of bacteria in biopsies of colon and stools by high throughput sequencing of the V2 region of bacterial 16S rRNA gene in human.
; Deffontaine Deurbroeck, Valérie ; Louis, Edouard et al
in PloS one (2011), 6(2), 16952
BACKGROUND: The characterization of the human intestinal microflora and their interactions with the host have been identified as key components in the study of intestinal disorders such as inflammatory ... [more ▼]
BACKGROUND: The characterization of the human intestinal microflora and their interactions with the host have been identified as key components in the study of intestinal disorders such as inflammatory bowel diseases. High-throughput sequencing has enabled culture-independent studies to deeply analyze bacteria in the gut. It is possible with this technology to systematically analyze links between microbes and the genetic constitution of the host, such as DNA polymorphisms and methylation, and gene expression. METHODS AND FINDINGS: In this study the V2 region of the bacterial 16S ribosomal RNA (rRNA) gene using 454 pyrosequencing from seven anatomic regions of human colon and two types of stool specimens were analyzed. The study examined the number of reads needed to ascertain differences between samples, the effect of DNA extraction procedures and PCR reproducibility, and differences between biopsies and stools in order to design a large scale systematic analysis of gut microbes. It was shown (1) that sequence coverage lower than 1,000 reads influenced quantitative and qualitative differences between samples measured by UniFrac distances. Distances between samples became stable after 1,000 reads. (2) Difference of extracted bacteria was observed between the two DNA extraction methods. In particular, Firmicutes Bacilli were not extracted well by one method. (3) Quantitative and qualitative difference in bacteria from ileum to rectum colon were not observed, but there was a significant positive trend between distances within colon and quantitative differences. Between sample type, biopsies or stools, quantitative and qualitative differences were observed. CONCLUSIONS: Results of human colonic bacteria analyzed using high-throughput sequencing were highly dependent on the experimental design, especially the number of sequence reads, DNA extraction method, and sample type. [less ▲]Detailed reference viewed: 23 (3 ULg)
The Thyro-gastric syndrome : its prevalence, clinical, pathological and predictive factors in a prospective series of 360 patients with Hashimoto's Thyroiditis
; VALDES SOCIN, Hernan Gonzalo ; LUTTERI, Laurence et al
in Abstract book - 21st Meeting of the Belgian Endocrine Society (2011)Detailed reference viewed: 190 (5 ULg)
Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci.
; ; et al
in Nature Genetics (2010), 42(12), 1118-25
We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in ... [more ▼]
We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 x 10). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease. [less ▲]Detailed reference viewed: 103 (11 ULg)
Vaccinations in patients with immune-mediated inflammatory diseases.
; Moutschen, Michel ; et al
in Rheumatology (2010), 49(10), 1815-27
Patients with immune-mediated inflammatory diseases (IMID) such as RA, IBD or psoriasis, are at increased risk of infection, partially because of the disease itself, but mostly because of treatment with ... [more ▼]
Patients with immune-mediated inflammatory diseases (IMID) such as RA, IBD or psoriasis, are at increased risk of infection, partially because of the disease itself, but mostly because of treatment with immunomodulatory or immunosuppressive drugs. In spite of their elevated risk for vaccine-preventable disease, vaccination coverage in IMID patients is surprisingly low. This review summarizes current literature data on vaccine safety and efficacy in IMID patients treated with immunosuppressive or immunomodulatory drugs and formulates best-practice recommendations on vaccination in this population. Especially in the current era of biological therapies, including TNF-blocking agents, special consideration should be given to vaccination strategies in IMID patients. Clinical evidence indicates that immunization of IMID patients does not increase clinical or laboratory parameters of disease activity. Live vaccines are contraindicated in immunocompromized individuals, but non-live vaccines can safely be given. Although the reduced quality of the immune response in patients under immunotherapy may have a negative impact on vaccination efficacy in this population, adequate humoral response to vaccination in IMID patients has been demonstrated for hepatitis B, influenza and pneumococcal vaccination. Vaccination status is best checked and updated before the start of immunomodulatory therapy: live vaccines are not contraindicated at that time and inactivated vaccines elicit an optimal immune response in immunocompetent individuals. [less ▲]Detailed reference viewed: 44 (8 ULg)
The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Definitions and diagnosis.
; ; et al
in Journal of Crohn’s and Colitis [=JCC] (2010), 4(1), 7-27Detailed reference viewed: 12 (1 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: 25 (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: 27 (0 ULg)
Report of the ECCO pathogenesis workshop on anti-TNF therapy failures in inflammatory bowel diseases: definitions, frequency and pharmacological aspects.
; ; Louis, Edouard et al
in Journal of Crohn’s and Colitis [=JCC] (2010), 4(4), 355-66
The first ECCO pathogenesis workshop focused on anti-TNF therapy failures in inflammatory bowel diseases (IBDs). The overall objective was to better understand and explore primary non response and loss of ... [more ▼]
The first ECCO pathogenesis workshop focused on anti-TNF therapy failures in inflammatory bowel diseases (IBDs). The overall objective was to better understand and explore primary non response and loss of response to anti-TNF agents in IBD. The outcome of this workshop is presented into two parts. This first section addresses definitions, frequency and pharmacological aspects of anti-TNF therapy failure, including pharmacokinetics of anti-TNF monoclonal antibodies and immune and non-immune mediated clearance of anti-TNF mAbs. The second section concerns the biological roles of TNF and TNF antagonists, including mechanisms of action of anti-TNF agents, and discuss hypothesis regarding their failures and phenomenon of paradoxical inflammation, including the potential role of TNF independent inflammatory pathways. [less ▲]Detailed reference viewed: 29 (0 ULg)
Do clinical factors help to predict disease course in inflammatory bowel disease?
Louis, Edouard ; Belaiche, Jacques ; Reenaers, Catherine
in World Journal of Gastroenterology (2010), 16(21), 2600-3
While therapeutic strategies able to change the natural history of the disease are developing, it is of major importance to have available predictive factors for aggressive disease to try and target these ... [more ▼]
While therapeutic strategies able to change the natural history of the disease are developing, it is of major importance to have available predictive factors for aggressive disease to try and target these therapeutic strategies. Clinical predictors have probably been the most broadly studied. In both Crohn's disease (CD) and ulcerative colitis (UC), age at diagnosis, disease location and smoking habit are currently the strongest predictors of disease course. A younger age at onset is associated with more aggressive disease both in CD and UC. Disease location in CD is associated with different types of complications: surgery and recurrence in upper gastrointestinal and proximal small bowel disease; and surgery in distal small bowel disease and peri-anal lesions in rectal disease. In UC, extensive colitis is clearly been associated with more severe disease. Finally, active smoking globally increases disease severity in CD but decreases it in UC. Besides these important factors, others may predispose to some specific disease evolution and complications, and are also reviewed in the present paper. [less ▲]Detailed reference viewed: 28 (6 ULg)
Should patients under long-term anti-TNF therapies be followed for tuberculosis contamination?
Reenaers, Catherine ; Belaiche, Jacques ; Louis, Edouard
in Inflammatory Bowel Diseases (2010), 16(8), 1271-2Detailed reference viewed: 21 (5 ULg)
Immunosuppressant combined with infliximab in Crohn's Disease: For 6 months, for 2 years, or forever?
in Inflammatory Bowel Diseases (2010)Detailed reference viewed: 13 (5 ULg)
Dissection moléculaire de la prédisposition innée aux maladies inflamatoires chroniques de l'intestin: liason génétique, gènes candidats et études d'association du génome entier.
Georges, Michel ; LIBIOULLE, Cécile ; Louis, Edouard
in Maladies inflamatoires chroniques de l'instestin. Progrès en hépatho-Gastroentérologie (2010)Detailed reference viewed: 27 (12 ULg)
Comparison of three methods for fractionation and enrichment of low molecular weight proteins for SELDI-TOF-MS differential analysis
De Bock, Muriel ; De Seny, Dominique ; Meuwis, Marie-Alice et al
in Talanta (2010), 82
In most diseases, the clinical need for serum/plasma markers has never been so crucial, not only for diagnosis, but also for the selection of the most efficient therapies, as well as exclusion of ... [more ▼]
In most diseases, the clinical need for serum/plasma markers has never been so crucial, not only for diagnosis, but also for the selection of the most efficient therapies, as well as exclusion of ineffective or toxic treatment. Due to the high sample complexity, prefractionation is essential for exploring the deep proteome and finding specific markers. In this study, three different sample preparation methods (i.e., highly abundant protein precipitation, restricted access materials (RAM) combined with IMAC chromatography and peptide ligand affinity beads) were investigated in order to select the best fractionation step for further differential proteomic experiments focusing on the LMW proteome (MW inferior to 40,000 Da). Indeed, the aim was not to cover the entire plasma/serum proteome, but to enrich potentially interesting tissue leakage proteins. These three methods were evaluated on their reproducibility, on the SELDI-TOF-MS peptide/protein peaks generated after fractionation and on the information supplied. The studied methods appeared to give complementary information and presented good reproducibility (below 20%). Peptide ligand affinity beads were found to provide efficient depletion of HMW proteins and peak enrichment in protein/peptide profiles. [less ▲]Detailed reference viewed: 84 (19 ULg)
Génomique des maladies inflammatoires intestinales
Louis, Edouard ; Libioulle, Cécile ; Reenaers, Catherine et al
in Revue Médicale de Liège (2009), 64Detailed reference viewed: 127 (20 ULg)
The Role of PET/CT in the Monitoring and Diagnosis of Pediatric Inflammatory Bowel Disease.
Hustinx, Roland ; Louis, Edouard
in PET Clinics (2009), 3Detailed reference viewed: 22 (4 ULg)
Anti-TNF and Crohn's Disease: When Should We Stop?
Louis, Edouard ; Belaiche, Jacques ; Reenaers, Catherine
in Current Drug Targets (2009), 11(2), 148-51
When to stop anti-TNF therapy in Crohn's disease (CD)? This is a very important question both for patients and physicians. There is no published evidence to clearly and definitely answer this question ... [more ▼]
When to stop anti-TNF therapy in Crohn's disease (CD)? This is a very important question both for patients and physicians. There is no published evidence to clearly and definitely answer this question. However data on natural history of CD, long term safety of biologics, outcome after immunosuppressors (IS) cessation and some preliminary studies on biologics cessation may help us to discuss this topic. One could argue that there is currently no good reason to stop anti-TNF therapy in a patient who is in stable remission and tolerate this drug very well. The decision to stop an anti-TNF treatment is thus currently based on a compromise between the benefits/risks and cost of such long term treatment. While it appears now clearly that prolonged anti-TNF therapy is associated with favourable outcome with sustained remission, reduced surgeries and hospitalisation as well as absence of significant increase in mortality or cancers, the cost-effectiveness which is probably favourable for short and mid-term treatment (up to one year), may be less optimal for very long term treatment. In this perspective however, prospective studies should be performed to adequately assess long term evolution, disease outcome, safety and global cost of strategies based on treatment reduction with IS maintenance alone or even full treatment cessation. [less ▲]Detailed reference viewed: 66 (6 ULg)
Common variants in the NLRP3 region contribute to Crohn's disease susceptibility.
; ; et al
in Nature Genetics (2009), 41(1), 71-6
We used a candidate gene approach to identify a set of SNPs, located in a predicted regulatory region on chromosome 1q44 downstream of NLRP3 (previously known as CIAS1 and NALP3) that are associated with ... [more ▼]
We used a candidate gene approach to identify a set of SNPs, located in a predicted regulatory region on chromosome 1q44 downstream of NLRP3 (previously known as CIAS1 and NALP3) that are associated with Crohn's disease. The associations were consistently replicated in four sample sets from individuals of European descent. In the combined analysis of all samples (710 father-mother-child trios, 239 cases and 107 controls), these SNPs were strongly associated with risk of Crohn's disease (P(combined) = 3.49 x 10(-9), odds ratio = 1.78, confidence interval = 1.47-2.16 for rs10733113), reaching a level consistent with the stringent significance thresholds imposed by whole-genome association studies. In addition, we observed significant associations between SNPs in the associated regions and NLRP3 expression and IL-1beta production. Mutations in NLRP3 are known to be responsible for three rare autoinflammatory disorders. These results suggest that the NLRP3 region is also implicated in the susceptibility of more common inflammatory diseases such as Crohn's disease. [less ▲]Detailed reference viewed: 94 (18 ULg)
Genetic variation in the familial Mediterranean fever gene (MEFV) and risk for Crohn's disease and ulcerative colitis.
; ; Louis, Edouard et al
in PLoS ONE (2009), 4(9), 7154
BACKGROUND AND AIMS: The familial Mediterranean fever (FMF) gene (MEFV) encodes pyrin, a major regulator of the inflammasome platform controlling caspase-1 activation and IL-1beta processing. Pyrin has ... [more ▼]
BACKGROUND AND AIMS: The familial Mediterranean fever (FMF) gene (MEFV) encodes pyrin, a major regulator of the inflammasome platform controlling caspase-1 activation and IL-1beta processing. Pyrin has been shown to interact with the gene product of NLRP3, NALP3/cryopyrin, also an important active member of the inflammasome. The NLRP3 region was recently reported to be associated with Crohn's disease (CD) susceptibility. We therefore sought to evaluate MEFV as an inflammatory bowel disease (IBD) susceptibility gene. METHODOLOGY AND RESULTS: MEFV colonic mucosal gene expression was significantly increased in experimental colitis mice models (TNBS p<0.0003; DSS p<0.006), in biopsies from CD (p<0.02) and severe ulcerative colitis (UC) patients (p<0.008). Comprehensive genetic screening of the MEFV region in the Belgian exploratory sample set (440 CD trios, 137 UC trios, 239 CD cases, 96 UC cases, and 107 healthy controls) identified SNPs located in the MEFV 5' haplotype block that were significantly associated with UC (rs224217; p = 0.003; A allele frequency: 56% cases, 45% controls), while no CD associations were observed. Sequencing and subsequent genotyping of variants located in this associated haplotype block identified three synonymous variants (D102D/rs224225, G138G/rs224224, A165A/rs224223) and one non-synonymous variant (R202Q/rs224222) located in MEFV exon 2 that were significantly associated with UC (rs224222: p = 0.0005; A allele frequency: 32% in cases, 23% in controls). No consistent associations were observed in additional Canadian (256 CD trios, 91 UC trios) and Scottish (495 UC, 370 controls) sample sets. We note that rs224222 showed marginal association (p = 0.012; G allele frequency: 82% in cases, 70% in controls) in the Canadian sample, but with a different risk allele. None of the NLRP3 common variants were associated with UC in the Belgian-Canadian UC samples and no significant interactions were observed between NLRP3 and MEFV that could explain the observed flip-flop of the rs224222 risk allele. CONCLUSION: The differences in association levels observed between the sample sets may be a consequence of distinct founder effects or of the relative small sample size of the cohorts evaluated in this study. However, the results suggest that common variants in the MEFV region do not contribute to CD and UC susceptibility. [less ▲]Detailed reference viewed: 66 (14 ULg)