T Molnár

Early clinical remission and normalisation of CRP are the strongest predictors of efficacy, mucosal healing and dose escalation during the first year of adalimumab therapy in Crohn's disease

Aliment Pharmacol Ther 2011; 34: 911–922

Predictors of relapse in patients with Crohn's disease in remission after 1 year of biological therapy

Some of the most important questions relating to the use of biological therapy in inflammatory bowel diseases concern the duration of maintenance therapy.

Heterozygosity for IL23R p.Arg381Gln confers a protective effect not only against Crohn’s disease but also ulcerative colitis

Background  A recent study reported that a non‐synonymous single nucleotide polymorphism (rs11209026, p.Arg381Gln) located in the IL23R gene is a protective marker for inflammatory bowel disease.

DLG5 Variants in Inflammatory Bowel Disease

OBJECTIVES:Genetic variants within DLG5 were recently reported to be associated with inflammatory bowel disease (IBD). The aim of our study was to test for allelic and haplotype associations of six DLG5 variants in 668 IBD patients from two European populations. Furthermore, we evaluated whether DLG5 variants alter gastrointestinal permeability in Crohns disease (CD).METHODS:Six DLG5 variants (p.R30Q, p.P1371Q, p.G1066G, rs2289308, DLG_e26, p.D1507D) were genotyped in two study populations: (1) German IBD patients (CD n = 250; ulcerative colitis (UC) n = 150) and German healthy controls (n = 422); (2) Hungarian IBD patients (CD n = 144; UC n = 124) and Hungarian healthy controls (n = 205). Subtyping analysis was performed in respect of CARD15 mutations and clinical characteristics. We also tested for differences within DLG5 genotypes in German CD patients with respect to gastroduodenal and intestinal permeability measured by triple-sugar-test.RESULTS:Allele as well as genotype frequencies of DLG5 variants did not differ between IBD patients and controls in either study population. Indeed, the p.R30Q polymorphism was found more frequently in controls than in patients. The distribution of DLG5 genotypes in German and Hungarian CD patients with CARD15 mutations was not different from patients without mutated CARD15. We did also not observe any association between DLG5 variants and clinical parameters. Importantly, DLG5 variants were not associated with gastroduodenal or intestinal permeability.CONCLUSIONS:We could not replicate that DLG5 is a relevant disease susceptibility gene for IBD in German or Hungarian subjects. In addition, we have no evidence that DLG5 variants are involved in altered gastrointestinal permeability in CD.

The c.1-260C>T promoter variant of CD14 but not the c.896A>G (p.D299G) variant of toll-like receptor 4 (TLR4) genes is associated with inflammatory bowel disease.

Background: Inflammatory bowel disease (IBD) results from an aberrant immune response to the indigenous intestinal flora in genetically susceptible hosts. Therefore, the study of candidate genes involved in host pathogen interactions is of key interest. Methods: In this two-center, retrospective German and Hungarian cohort study, patients with Crohn’s disease (CD) (n = 379; German n = 235, Hungarian n = 144) and ulcerative colitis (UC) (n = 263; German n = 145, Hungarian n = 118) and healthy controls (n = 605; German n = 403, Hungarian n = 202) were genotyped for the presence of the CD14 c.1-260C>T promoter variant and the TLR4 c.896A>G (p.D299G) variant by melting curve analysis using fluorescence resonance energy transfer probes. Data were stratified according to the presence of NOD2 (CARD15) mutations and a detailed genotype-phenotype analysis was performed. Results: In the German cohort the CD14 single-nucleotide polymorphism was associated with UC, but not CD (UC p = 0.016 vs. CD p = 0.190), while the opposite was found in the Hungarian cohort (UC p = 0.083 vs. CD p = 0.019). No association of IBD with the TLR4 single-nucleotide polymorphism was found in either cohort (UC p = 0.430, CD p = 0.783 vs. UC p = 0.745, CD p = 0.383). Conclusion: IBD appears to be associated with the CD14 c.1-260C>T promoter variant in Germans and Hungarians, but not with the TLR4 c.896A>G (p.D299G) variant.

Letter: role of diet in the onset and relapse of inflammatory bowel disease from the patients' perspective.

SIRS, We read with interest the review article by Spooren et al. on the role of habitual diet in the onset and relapse in patients with ulcerative colitis (UC) or Crohn’s disease (CD). The paper confirmed that high intake of sugar and low intake of fruits and vegetables were associated with increased risk of onset of UC or CD, with a possible protective role for grain-derived products. However, despite the detailed analysis of 41 studies, the authors could not draw firm conclusions on the role of specific food components in the aetiology of inflammatory bowel diseases (IBD). As evidence about the role of diet is still missing, we agree that identifying dietary factors as predictors for IBD is very important in the current management of the disease. In particular, patients’ opinion and beliefs could also be informative on this topic. Using a structured questionnaire, we assessed our patients’ beliefs about the importance of diet in the relapse of IBD. A total of 154 IBD patients participated in our survey; 51%, and significantly more CD than UC patients, believed that lack of diet is a risk factor both for the development and for the relapse of IBD. Almost 70% thought diet to be as important as medical therapy; 86% of the patients could identify drinks and foods as determinant for relapse. The most ‘harmful’ were alcohol-containing drinks, soda, coffee, chilli, pepper, and curry, while rice, chicken, fish, and potatoes were the most favourable meals, with beneficial effect on disease activity; 49% of patients believed that certain foods could prevent disease relapse. Our survey showed that diet is more important for CD than UC patients. Patients can recognise and try to avoid foods they perceive to exacerbate their disease. These results also indicate the importance of further examinations of dietary factors to improve our therapeutic strategies in IBD.

Letter: factors that may predict response to ciclosporin in ulcerative colitis.

SIRS, We read with interest the recently published paper by Saito et al. The authors proposed a calculation formula to predict the response to ciclosporin treatment for severe ulcerative colitis (UC). Data of 52 patients with refractory UC treated with ciclosporin were analysed. Clinical response was achieved in 65.4% of the patients. Four independent predictive factors were identified: age at hospitalisation, platelet count (910/μL) on the first day (PLA), Lichtiger score on the third day (LIC) and total protein (g/dL) on the third day minus total protein on the first day (DTP). The calculation formula 8.5–0.16 9 age + 0.21 9 PLA 0.61 9 LIC + 2.3 9 DTP < 0 predicted colectomy with an accuracy of 88.5%. The aim of our study was to determine whether the calculation formula developed by Saito et al. showed any association with colectomy in our UC patients treated with ciclosporin. Seventy-three patients (40 women, 33 men) underwent ciclosporin therapy between 1998 and 2005 due to acute exacerbation of UC. Overall 29/73 (39.7%) patients needed either early (within 3 months) or late (over 3 months) colectomy during the 4.2 year follow-up period. The examined variables are summarised in Table 1. Multiple logistic regression analyses revealed LIC score on the third day to be the only significant of the examined variables. The sensitivity of the calculation formula in predicting the response to intravenous ciclosporin was 72.7%. Our results do not confirm the utility of this novel formula in the daily practice. It should be noted that we analysed the data of every patient who underwent colectomy during the mean follow-up period of more than 4 years not only those who were operated on within 3 months after ciclosporin therapy. Further studies are needed to validate the novel calculating formula proposed by Saito et al.

Infliximab rescue therapy in steroid‐refractory ulcerative colitis: is more really more?

SIRS, Everyone interested in the biological therapy of ulcerative colitis (UC) was looking forward to the long-term data of the only placebo-controlled, randomised study examining the efficacy of a single infliximab infusion in steroid-refractory UC. Five years after the publication of the pioneer study, Gustavsson et al. summarised the 3-year outcome of their 45 patients. The colectomy rate was significantly lower in the infliximab group (50% vs. 76%), although the fact that half of the treated patients had to be operated on despite that more than 40% (7 ⁄ 17) of the patients initially responding to the therapy were treated again with infliximab is disappointing. One of the clearest therapeutic lines of evidence of the last 5 years is that the three-infusion induction regime and the scheduled use of infliximab are more effective than a single infusion and episodic retreatment. Without doubt, a comparative study would answer the question whether more infusions save more bowels when using infliximab as rescue therapy; however, only some small studies have been published in the past years that make this suggestion. Let us start with our data: 5 of 20 (25%) patients with steroid refractory UC were operated on during the average follow-up period of 15 months. After 3 months, 3 of 20 patients underwent colectomy (15%). Another retrospective, single-centre study performed in Scandinavia presented a short-term colectomy rate of 11% (2 ⁄ 19) and a long-term rate of 37% (7 ⁄ 19). The average length of follow-up was 22 months. If we try to summarise these data, we can suggest that more is really more also in the case of infliximab therapy. However, the problem is always with children: a prospective, multicentre analysis of a paediatric cohort revealed a 24% acute and a 45% annual colectomy rate, which is similar to that in the Gustavsson study.

Every fourth patient with Crohn's disease has anti-TNF dependency.

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Infliximab safety profile and long-term applicability in inflammatory bowel disease: Clinical experiences from the Eastern side of Europe

Infliximab safety profile and long-term applicability in inflammatory bowel disease: clinical experiences from the Eastern side of Europe SIRS, We read with interest the article by Zabana et al. evaluating the long-term safety profile of infliximab (IFX) in inflammatory bowel disease [IBD-Crohn’s disease (CD), ulcerative colitis (UC)] in clinical practice. As the number of IFX-treated patients and the period of follow-up at our Department are similar to those in the above mentioned study, and considering that similar survey has not yet been performed in Eastern Europe, we assessed the safety and applicability of IFX treatment on the basis of our prospectively-recorded database. Data of 127 IBD patients [70 females, 57 males; mean age at the diagnosis 27 years (range 12–67)] infused for refractory or steroid-dependent CD (n = 81) or UC (n = 42) during a 7-year period between January 2003 and December 2009 were analysed. Of the patients, 26% received only three infusion induction, while 62.2% were on maintenance treatment. A total of 733 infusions were administered and the mean number of IFX infusions was 5.8 ⁄ patient. The mean length of follow-up was 2.3 years. Sixteen (12.6%) patients had 31 episodes of acute reaction, 7 (5.5%) patients had nine episodes of delayed infusion reaction. Of those with acute reaction, 68.8% were on concomitant immunomodulator and ⁄ or corticosteroid treatment. IFX had to be discontinued in 12 patients because of the allergic reactions. Listeria meningoencephalitis, sepsis of unknown origin and pulmonary TB, was the most severe infectious complications in three cases; all these patients were on concomitant immunosuppressive treatment. One patient with UC on IFX monotherapy developed primary colonic lymphoma diagnosed after