Vera Ballet

A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis

Objective Bacteria play an important role in the onset and perpetuation of intestinal inflammation in inflammatory bowel disease (IBD). Unlike in Crohns disease (CD), in which dysbiosis has been better characterised, in ulcerative colitis (UC), only small cohorts have been studied and showed conflicting data. Therefore, we evaluated in a large cohort if the microbial signature described in CD is also present in UC, and if we could characterise predominant dysbiosis in UC. To assess the functional impact of dysbiosis, we quantified the bacterial metabolites. Design The predominant microbiota from 127 UC patients and 87 age and sex-matched controls was analysed using denaturing gradient gel electrophoresis (DGGE) analysis. Differences were quantitatively validated using real-time PCR. Metabolites were quantified using gas chromatography–mass spectrometry. Results Based on DGGE analysis, the microbial signature previously described in CD was not present in UC. Real-time PCR analysis revealed a lower abundance of Roseburia hominis (p<0.0001) and Faecalibacterium prausnitzii (p<0.0001) in UC patients compared to controls. Both species showed an inverse correlation with disease activity. Short-chain fatty acids (SCFA) were reduced in UC patients (p=0.014), but no direct correlation between SCFA and the identified bacteria was found. Conclusions The composition of the fecal microbiota of UC patients differs from that of healthy individuals: we found a reduction in R hominis and F prausnitzii, both well-known butyrate-producing bacteria of the Firmicutes phylum. These results underscore the importance of dysbiosis in IBD but suggest that different bacterial species contribute to the pathogenesis of UC and CD.

Outcome of pregnancy in women with inflammatory bowel disease treated with antitumor necrosis factor therapy

Background: Infliximab (IFX) and adalimumab (ADA) are attractive treatment options in patients with inflammatory bowel disease (IBD) also during pregnancy but there is still limited data on the benefit/risk profile of IFX and ADA during pregnancy. Methods: This observational study assessed pregnancy outcomes in 212 women with IBD under antitumor necrosis factor alpha (TNF) treatment at our IBD unit. Pregnancy outcomes in 42 pregnancies with direct exposure to anti‐TNF treatment (35 IFX, 7 ADA) were compared with that in 23 pregnancies prior to IBD diagnosis, 78 pregnancies before start of IFX, 53 pregnancies with indirect exposure to IFX, and 56 matched pregnancies in healthy women. Results: Thirty‐two of the 42 pregnancies ended in live births with a median gestational age of 38 weeks (interquartile range [IQR] 37–39). There were seven premature deliveries, six children had low birth weight, and there was one stillbirth. One boy weighed 1640 g delivered at week 33, died at age of 13 days because of necrotizing enterocolitis. A total of eight abortions (one patient wish) occurred in seven women. Trisomy 18 was diagnosed in one fetus of a mother with CD at age 37 under ADA treatment (40 mg weekly) and pregnancy was terminated. Pregnancy outcomes after direct exposure to anti‐TNF treatment were not different from those in pregnancies before anti‐TNF treatment or with indirect exposure to anti‐TNF treatment but outcomes were worse than in pregnancies before IBD diagnosis. Conclusions: Direct exposure to anti‐TNF treatment during pregnancy was not related to a higher incidence of adverse pregnancy outcomes than IBD overall. (Inflamm Bowel Dis 2011;)

Levels of C-reactive protein are associated with response to infliximab therapy in patients with Crohn's disease.

BACKGROUND & AIMS Infliximab is an antibody against tumor necrosis factor-α that is used to treat patients with moderate to severe Crohns disease (CD). C-reactive protein (CRP) is a marker used to identify and follow individuals with CD. We analyzed changes in levels of CRP in a large cohort of patients with CD undergoing treatment with infliximab. METHODS Serial levels of CRP were analyzed in 718 CD patients. Blood was collected before each infusion; a total of 8845 CRP levels were available for analysis. The correlations between CRP levels and need for dose adjustment, outcomes, and mucosal healing (based on endoscopic analysis of 253 patients) were evaluated. Therapy adjustment was considered successful if therapy continued without need for change. Subgroup analysis was performed by using data from 268 patients who received 8 weeks of maintenance therapy. RESULTS More patients with high baseline levels of CRP responded to infliximab than patients with normal levels (90.8% vs 82.6%; P = .014). Early normalization of CRP levels correlated with sustained long-term response (P < .001). CRP levels remained significantly higher among patients who lost their response to infliximab, compared with those with a sustained response (P = .001). At time of loss of response, CRP levels were significantly increased (median, 11.2 mg/L) and did not return to baseline levels (median, 18.2 mg/L; P = .039). CRP correlated with mucosal healing (P = .033). CONCLUSIONS CRP is a good marker of disease activity in patients treated with infliximab. Increased levels of CRP indicate mucosal inflammation and a likelihood of clinical relapse.

Switch to adalimumab in patients with Crohn's disease controlled by maintenance infliximab: prospective randomised SWITCH trial

Background Elective switching between anti-tumour necrosis factor (TNF) agents not necessarily dictated by efficacy or tolerability occurs in clinical practice. A study was undertaken to evaluate prospectively the impact of elective switching of patients with Crohns disease well controlled with intravenous infliximab to subcutaneous adalimumab in a controlled trial. Methods An open-label randomised single-centre trial recruited 73 patients with ongoing response to at least 6 months of scheduled maintenance infliximab. Patients were randomised to continue intravenous 5 mg/kg infliximab or to switch to subcutaneous adalimumab 80 mg at baseline followed by 40 mg every other week for 1 year. Dose optimisation was allowed for intermittent flares, and patients with loss of response or intolerance could cross over to the alternative treatment group. Tolerability, patient preference and efficacy of both treatment options were the primary outcomes. Results Dose optimisation or interruption of treatment occurred in 17/36 patients (47%) in the adalimumab group and in 6/37 patients (16%) in the infliximab group (p=0.006). One patient interrupted infliximab treatment and 10 patients interrupted adalimumab treatment (p=0.003), mostly for loss of tolerance. Overall, patients preferred adalimumab treatment. All five serious adverse events were related to complicated Crohns disease and occurred in patients randomised to adalimumab. Injection site reactions were more frequent than infusion reactions (8 vs 1, p=0.01), but only the latter caused cessation of further dosing. Anti-TNF serum levels were stable throughout the 1-year period in both groups. Conclusion Elective switching from infliximab to adalimumab is associated with loss of tolerance and loss of efficacy within 1 year. Adherence to the first anti-TNF agent is recommended.

Primary sclerosing cholangitis is characterised by intestinal dysbiosis independent from IBD

Objective Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease often leading to end-stage liver disease. Its pathogenesis remains largely unknown, although frequent concomitant IBD hints towards common factors underlying gut and bile duct inflammation. Considering the mounting evidence on the involvement of the intestinal microbiota in initiating and determining IBD phenotype, we investigated intestinal microbiota composition in patients with PSC. Design Stool samples were collected from 147 individuals (52 patients with PSC, 52 age, gender and body mass index-matched healthy volunteers, 13 UC and 30 patients with Crohns disease). An independent validation cohort of 14 PSC and 14 matched controls was recruited. 16S rDNA sequencing of faecal DNA was performed (Illumina MiSeq). Results The microbiota of patients with PSC was characterised by decreased microbiota diversity, and a significant overrepresentation of Enterococcus (p=3.76e-05), Fusobacterium (p=3.76e-05) and Lactobacillus (p=0.0002) genera. This dysbiosis was present in patients with PSC with and without concomitant IBD and was distinct from IBD, and independent of treatment with ursodeoxycholic acid. A decision tree based on abundances of these three genera allowed reliable classification in the validation cohort. In particular, one operational taxonomic unit belonging to the Enterococcus genus was associated with increased levels of serum alkaline phosphatase (p=0.048), a marker of disease severity. Conclusions We here present the first report of PSC-associated faecal dysbiosis, independent from IBD signatures, suggesting the intestinal microbiota could be a contributing factor in PSC pathogenesis. Further studies are needed to confirm these findings and assess causality.

Early serial trough and antidrug antibody level measurements predict clinical outcome of infliximab and adalimumab treatment

We read with great interest the recent article by Ben-Horin et al which concludes that the measurement of trough levels of infliximab (TLI) combined with the measurement of antibodies to infliximab (ATI) is highly correlated with the clinical response to the therapeutic.1 Infliximab (Remicade) and adalimumab (Humira), both monoclonal antibodies towards TNF-α, are widely used in the treatment of Crohns disease and ulcerative colitis. Loss of efficacy, infusion and injection-site reactions and hypersensitivity reactions have been described due to the development of antibodies towards these agents.2 We agree with Ben-Horin et al that the interpretation of ATI with TLI is important to document the clinical response of a patient to infliximab. However, we urge that these measurements are performed early in the treatment. Previously it was stated that the TLI measured early after …

Effect of oligofructose-enriched inulin (OF-IN) on bacterial composition and disease activity of patients with Crohn's disease: results from a double-blinded randomised controlled trial

With great interest, we have read the manuscript by Benjamin et al 1 on the effect of fructo-oligosaccharides in patients with active Crohns disease (CD). We recently completed a single-centre randomised placebo-controlled trial with a similar study design. In our study, 67 patients with inactive and mild to moderately active CD were randomised to receive oligofructose-enriched inulin (OF-IN) or placebo 10 g twice daily for 4 weeks. Clinical disease activity was assessed …

Characteristics of Skin Lesions Associated With Anti–Tumor Necrosis Factor Therapy in Patients With Inflammatory Bowel Disease: A Cohort Study

Context Tumor necrosis factor (TNF) antagonists are effective for the treatment of inflammatory bowel disease (IBD) that does not respond to conventional therapy. Some patients, however, have discontinued anti-TNF therapy because of the development of psoriasiform lesions. Contribution In this large study from a tertiary care center, nearly one third of patients with IBD who initiated anti-TNF therapy developed skin lesions. With dedicated dermatologic care, most were able to continue therapy without interruption. Caution Patients with IBD not receiving anti-TNF therapy were not studied. Implication Skin lesions seem to be commonly associated with anti-TNF therapy in patients with IBD but typically do not require treatment discontinuation for successful management. In the late 1990s, tumor necrosis factor (TNF) antagonists were introduced as treatment for several inflammatory disorders, including rheumatoid arthritis, ankylosing spondylitis, psoriasis, Crohn disease, and ulcerative colitis. Whereas conventional therapy primarily targets symptom control, anti-TNF therapy has been shown to reduce symptoms, heal mucosal ulcers, reduce hospitalizations and surgeries, and spare corticosteroids (110). Infliximab, the first biological agent targeted against TNF, was followed by other anti-TNF biologics, including adalimumab, golimumab, certolizumab pegol, and etanercept (which is not used for inflammatory bowel disease [IBD]). Anti-TNF therapy has also proved to have a favorable safety profile with respect to serious infections, cancer, and mortality as long as it is given for the right indication and comorbidities are taken into account (1120). However, psoriasiform skin manifestations have been reported (long after the completion of randomized, controlled trials) as adverse events associated with anti-TNF therapy (2130). The appearance of psoriasiform skin manifestations is intriguing and seems paradoxical because anti-TNF therapy is also successfully used in psoriasis treatment. Inflammatory bowel disease shares several pathophysiologic characteristics with psoriasis and atopic dermatitis. All of these conditions have a strong genetic component, with 163 loci identified for IBD, 36 identified for psoriasis, and 11 identified for atopic dermatitis thus far (3133). Of note, the reported regions of association overlap substantially (32, 34, 35). Because skin lesions may represent a significant burden to patients, it is important to advise patients on preventive measures or alternative therapeutic options, especially when they are at increased risk. This study aimed to accurately describe patients with IBD treated with anti-TNF therapy who did and did not develop skin lesions. We investigated the development of skin lesions in a retrospective cohort of such patients. We also looked at specific patient characteristics, autoimmune and genetic factors, and infliximab cumulative dose and trough levels (TLs) in patients with and without skin lesions. Methods Study Participants and Design We retrospectively analyzed a consecutive cohort of 917 patients with IBD for the occurrence of skin lesions during anti-TNF therapy. Diagnosis of IBD was well-established according to conventional endoscopic, radiologic, and histologic criteria (36, 37). A total of 955 patients initiated infliximab treatment at the University Hospitals Leuven between December 1994 and January 2009, of whom 917 agreed to participate in our research projects. At the time of initiation of infliximab treatment, they were naive to any other anti-TNF agent. A subset of patients were noted to have switched to another anti-TNF agent (adalimumab or certolizumab pegol) when they showed loss of response to infliximab. The Ethics Board of the University Hospitals Leuven approved the study before data collection (institutional review board approval number B322201213950/S53684). All participants provided written informed consent agreeing to take part in our current and future research projects when they were included in our ongoing patient registry. Diagnostic and Therapeutic Criteria for Patients With Skin Lesions At the Leuven IBD center, all patients were seen by the IBD gastroenterologists (S.V., G.V.A., P.R., and M.F.) every 8 weeks or more frequently if needed. Patients with skin symptoms (especially itching) or skin lesions that occurred during and were possibly linked to anti-TNF therapy were referred to a dermatologist (S.S.) experienced in anti-TNF therapies. Beginning in 2000, when the phenomenon of skin lesions associated with anti-TNF treatment became more clear, patients who came to consultation were systematically checked for lesions and referred to a dermatologist. We classified the patients in the following categories (listed in descending order of severity) according to the predominant or most distressing lesions (if 1 type of lesion was identified, the patient was placed in the most-severe category): palmoplantar pustulosis (pustules of the palms and soles with or without surrounding erythema or erythematosquamous lesions), psoriasis (sharply demarcated erythematosquamous lesion covered with silvery-white scales; histologic evaluation [when performed] showed psoriasis), psoriasiform eczema (dermatitis with some features of psoriasis, especially the orange-red color, but unsharply defined lesions, often superinfected; histologic evaluation [when performed] showed dermatitis), eczema (dermatitis without features of psoriasis), or xerosis (dryness of the skin without signs of inflammation). In cases of diagnostic uncertainty (especially psoriasis vs. psoriasiform eczema) (Appendix Figure 1), skin biopsy specimens were taken and histologic evaluation was done. Skin lesions that could not be classified into one of these categories, including infections, inflammatory skin disease, tumors, and alopecia areata, were classified as other. A full list of skin lesion types is provided in Appendix Table 1. Appendix Figure 1. Hematoxylin and eosin staining of psoriasis (top), psoriasiform eczema (middle), and eczema (bottom). All histologic pictures are original magnification50. Top. A skin lesion showing irregular acanthosis, focal parakeratosis, and crust/scale formation, resembling psoriasiform eczema. Middle. A skin lesion showing regular elongation and clubbing of rete ridges, thinning of suprapapillary epidermis, confluent parakeratosis, and superficial perivascular inflammation, resembling psoriasis. Bottom. A skin lesion showing irregular and plump acanthosis, multifocal parakeratosis and spongiosis, and superficial perivascular inflammation, resembling spongiotic eczema. Appendix Table 1. Types of Skin Lesions For dermatologic treatment of the most frequently occurring skin lesions, we used a standard protocol, which is provided in the Appendix. Patient Characteristics The medical records of the patients were systematically reviewed up to 1 July 2014. For each patient, sex, diagnosis, smoking (ever vs. never), age at diagnosis and at the start of infliximab treatment, start and stop dates of infliximab treatment, infliximab infusion dates, switch to other anti-TNF agent (adalimumab or certolizumab pegol) with respective start and stop dates, reason for discontinuing anti-TNF therapy, and cumulative infliximab dose (until development of skin lesion, discontinuation of therapy, or end of analysis) were retrieved. To correct for different durations of exposure to infliximab, the cumulative infliximab dose was divided by the duration of treatment. When the interval between infliximab infusions was more than 16 weeks (as happened in the first patients treated in the 1990s), the time between infusions was not included in the calculations of total duration of treatment. Loss of response to infliximab was assessed and was defined as the need to stop infliximab therapy or the need for surgery despite an attempt to optimize treatment. If a skin lesion was reported, date of onset, type, location, history of atopic dermatitis or psoriasis, and initiated treatment were obtained. Case patients who stopped anti-TNF treatment because of a lesion were also noted. For all patients with skin lesions, we noted at their last consultation whether they showed complete, partial, or no resolution of the lesions and whether they were still receiving treatment for them at that time. For patients in whom anti-TNF treatment was stopped because of lesions, we noted how the lesions subsequently evolved and, in cases of complete resolution, in what time frame. Measurement of Serum Trough Levels of Infliximab Infliximab TLs and anti-infliximab antibodies (ATIs) were measured at several time points during treatment by using enzyme-linked immunosorbent assays developed in-house (38, 39). We considered only samples from week 14 onward in patients receiving infliximab maintenance therapy (defined as receipt of 4 infliximab infusions and 6 months of therapy). A total of 8350 TL measurements in 433 patients were available (median, 18 [interquartile range {IQR}, 5 to 32] per patient). A patient was considered to have subtherapeutic TLs when at least 2 measurements were less than 3 g/mL and supratherapeutic TLs when at least 2 measurements were greater than 7 g/mL (40). A total of 2770 ATI measurements in 325 patients were available (median, 5 [IQR, 3 to 13] per patient). Anti-infliximab antibodies were evaluated only when TLs were not detectable. Patients were considered ATI-positive when they had at least 1 ATI concentration greater than 1 g/mL. Measurement of Antinuclear Antibodies and Double-Stranded DNA Antibodies Measurements at baseline (3 months before the first infliximab dose) and at several time points during follow-up were included. Antinuclear antibodies (ANAs) were determined on 1:40 diluted sera by an indirect immunofluorescent technique on Sjgren syndrome Atransfected HEp-2 cells. A total of 3820 ANA measurements in 847 patients were available (median, 3 [IQR, 1 to 5] per patien

Efficacy and safety of anti-TNF therapy in elderly patients with inflammatory bowel disease

The general increased life expectancy is reflected in the age of patients with inflammatory bowel disease (IBD). The knowledge about efficacy and safety of anti‐tumour necrosis factor (TNF) therapy in elderly is scarce and conflicting.

OP11 Individualised infliximab treatment using therapeutic drug monitoring: A prospective controlled Trough level Adapted infliXImab Treatment (TAXIT) trial

OP11 Individualised infliximab treatment using therapeutic drug monitoring: A prospective controlled Trough level Adapted infliXImab Treatment (TAXIT) trial N. Vande Casteele1 *, G. Compernolle1, V. Ballet2, G. Van Assche2, A. Gils1, S. Vermeire2, P. Rutgeerts2. 1Katholieke Universiteit Leuven, Laboratory for Pharmaceutical Biology, Belgium, 2University Hospitals Leuven, Department of Gastroenterology, Leuven, Belgium