Impact of patient characteristics on the clinical efficacy of mongersen (GED-0301), an oral Smad7 antisense oligonucleotide, in active Crohn's disease.

BACKGROUND: In a phase 2 study, mongersen, an oral antisense oligonucleotide targeting Smad7, was effective in inducing clinical remission in approximately 60% of patients with active Crohn's disease (CD). AIM: In a post hoc analysis to evaluate those patient disease characteristics that may have influenced the efficacy and safety of mongersen therapy. METHODS: Patients with steroid-dependent/resistant, active CD were randomised to mongersen 10, 40 or 160 mg/day or placebo for 2 weeks; patients were followed for 10 weeks. Clinical remission [Crohn's Disease Activity Index (CDAI) score <150] and clinical response (CDAI score reduction ≥100 points) were assessed at weeks 2, 4 and 12 for these subgroups: disease duration <5/≥5 years, human serum C-reactive protein (hsCRP) <3/≥3 mg/L, and CDAI at baseline ≤260/>260. Additional patient baseline and disease characteristics were explored. RESULTS: Clinical remission and response rates were significantly higher in patients receiving mongersen 40 and 160 mg/day but not 10 mg/day vs. placebo and independent of disease duration and hsCRP. Patients with baseline CDAI ≤260 had significantly higher remission rates with 40 and 160 mg/day. In patients with baseline CDAI >260, remission rates were statistically greater with 160 mg/day and numerically better with 40 mg/day vs. placebo. Adverse event rates were similar across treatment groups. Mongersen was safe and well tolerated. CONCLUSIONS: Patients with higher CDAI scores achieved clinical remission most frequently with the highest mongersen dose. Disease duration and baseline human serum C-reactive protein did not appear to significantly impact efficacy of mongersen in this study (EudraCT Number: 2011-002640-27.).

Hazardous o-toluidine mineralization by photocatalytic bismuth doped ZnO slurries.

Photocatalytic mineralization of o-toluidine in aqueous media under UV/solar irradiation was achieved by bare and bismuth doped zinc oxide nanoparticles. By adopting different analytical approaches a reaction mechanism is proposed, explaining the differences in photodetoxification performances.

Patterning of polymer brushes made easy using titanium dioxide: direct and remote photocatalytic lithography.

Photocatalytic lithography is proved for the realization of micropatterned polymer brushes. Initiator-functionalized titanium dioxide or silicon surfaces are respectively exposed directly to near-UV light through a photomask (direct approach) or through a transparent photoactive TiO2 film (remote approach). Initiator patterns are then amplified as polymer brushes with SI-ATRP. Features down to 10 µm could be obtained using simple equipment. The process is intrinsically parallel, has high throughput and scalable to wafer size, making it powerful for microfabrication purposes.

The second European evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease.

Trying to conceive and being pregnant is an emotional period for those involved. In the majority of patients suffering from inflammatory bowel disease, maintenance therapy is required during pregnancy to control the disease, and disease control might necessitate introduction of new drugs during a vulnerable period. In this updated consensus on the reproduction and pregnancy in inflammatory bowel disease reproductive issues including fertility, the safety of drugs during pregnancy and lactation are discussed.

Imaging techniques for assessment of inflammatory bowel disease: joint ECCO and ESGAR evidence-based consensus guidelines.

The management of patients with IBD requires evaluation with objective tools, both at the time of diagnosis and throughout the course of the disease, to determine the location, extension, activity and severity of inflammatory lesions, as well as, the potential existence of complications. Whereas endoscopy is a well-established and uniformly performed diagnostic examination, the implementation of radiologic techniques for assessment of IBD is still heterogeneous; variations in technical aspects and the degrees of experience and preferences exist across countries in Europe. ECCO and ESGAR scientific societies jointly elaborated a consensus to establish standards for imaging in IBD using magnetic resonance imaging, computed tomography, ultrasonography, and including also other radiologic procedures such as conventional radiology or nuclear medicine examinations for different clinical situations that include general principles, upper GI tract, colon and rectum, perineum, liver and biliary tract, emergency situation, and the postoperative setting. The statements and general recommendations of this consensus are based on the highest level of evidence available, but significant gaps remain in certain areas such as the comparison of diagnostic accuracy between different techniques, the value for therapeutic monitoring, and the prognostic implications of particular findings.

Wettability of bare and fluorinated silanes: a combined approach based on surface free energy evaluations and dipole moment calculations.

The assessment of the surface free energy (SFE) of a material permits to control and predict a large number of physicochemical properties of a solid surface and its reactivity. Here, the surface energies of a series of bare and fluorinated silanes are determined by means of different semi-empirical models on the grounds of contact angle determinations for different solvents. Literature data are also considered in order to produce a series of films with increasing SFE. Wetting envelopes (WE) are obtained for the various surfaces in order to predict the wettability of the films by numerous commonly employed solvents. The polar and disperse components of the surface energies are obtained by the Owens-Wendt-Rabel-Kaelbe (OWRK) method; the values of the polar components are compared with gas-phase dipole moments obtained by theoretical calculations employing semi-empirical Hamiltonians. The sequences of the polar components of the SFE and of the calculated dipole moments for the different molecules are strictly the same. The interplay between theoretical and experimental approaches proves efficient in predicting the behavior of different systems and it could be employed in tuning the SFE of a solid surface with respect to its final applications.

Immunogenicity and autoimmunity during anti-TNF therapy.

The introduction of anti-tumour necrosis factor (TNF) agents for the treatment of rheumatoid arthritis (RA), Crohn's disease (CD) or spondyloarthritis (SpA) has revolutionised the therapeutic approach to patients with active disease failing to respond to conventional therapy. However, some of the patients treated with selective TNF inhibitors may develop autoantibodies, such as antinuclear antibodies (ANAs) and anti-double-stranded DNA (anti-dsDNA) antibodies. Furthermore, anti-phospholipid antibodies, which are mainly detected by means of anti-cardiolipin assays, have been found in RA patients receiving TNF blockers. There have also been a number of reports of the development of anti-drug antibodies, of which those against infliximab can interfere with the drug's pharmacokinetics (and therefore its effects), and may also cause acute and delayed infusion and injection site reactions. The onset of autoimmune diseases during biological treatment is rare, but it needs to be promptly recognised in order to plan appropriate patient management. The addition of an immunosuppressive drug can reduce the induction of anti-TNF antibodies.

Haematopoietic SCT in severe autoimmune diseases: updated guidelines of the European Group for Blood and Marrow Transplantation.

In 1997, the first consensus guidelines for haematopoietic SCT (HSCT) in autoimmune diseases (ADs) were published, while an international coordinated clinical programme was launched. These guidelines provided broad principles for the field over the following decade and were accompanied by comprehensive data collection in the European Group for Blood and Marrow Transplantation (EBMT) AD Registry. Subsequently, retrospective analyses and prospective phase I/II studies generated evidence to support the feasibility, safety and efficacy of HSCT in several types of severe, treatment-resistant ADs, which became the basis for larger-scale phase II and III studies. In parallel, there has also been an era of immense progress in biological therapy in ADs. The aim of this document is to provide revised and updated guidelines for both the current application and future development of HSCT in ADs in relation to the benefits, risks and health economic considerations of other modern treatments. Patient safety considerations are central to guidance on patient selection and HSCT procedural aspects within appropriately experienced and Joint Accreditation Committee of International Society for Cellular Therapy and EBMT accredited centres. A need for prospective interventional and non-interventional studies, where feasible, along with systematic data reporting, in accordance with EBMT policies and procedures, is emphasized.

Randomised clinical trial: the efficacy and safety of propionyl-L-carnitine therapy in patients with ulcerative colitis receiving stable oral treatment.

BACKGROUND: Ulcerative colitis (UC) is characterised by impaired fatty-acid oxidation; l-carnitine has a key role in fatty-acid metabolism and short-chain fatty acids such as butyrate and propionate are important energy source for intestinal epithelial cells. AIM: To evaluate efficacy and safety of colon-release propionyl-L-carnitine (PLC) in patients with mild-to-moderate UC receiving stable oral aminosalicylate or thiopurine therapy. METHODS: In a multicentre, phase II, double-blind, parallel-group trial, patients were randomised to receive PLC 1 g/day, PLC 2 g/day or placebo. Main inclusion criteria were as follows: age 18-75; disease activity index (DAI) score 3-10 inclusive, be under oral stable treatment with aminosalicylate or thiopurine. The primary endpoint was clinical/endoscopic response, defined as a decrease in DAI score ≥ 3 points or remission, defined as a DAI score ≤ 2 with no individual sub-score > 1. RESULTS: Of 121 patients who were randomised, 57 of 79 (72%) patients receiving PLC (combined 1 g and 2 g cohort) had a clinical/endoscopic response vs. 20 of 40 (50%) receiving placebo (P = 0.02). Specifically, in PLC 1 g/day group, 30 of 40 (75%) patients had clinical/endoscopic response (P = 0.02 vs. placebo) and 27 of 39 (69%) in the PLC 2 g/day group (P = 0.08 vs. placebo). Rates of remission were 22/40 (55%), 19/39 (49%), 14/40 (35%) in the PLC 1 g, PLC 2 g, and placebo groups, respectively. PLC had a similar safety profile to placebo; the most common adverse events were gastrointestinal. CONCLUSION: Propionyl-L-carnitine 1 g/day should be investigated further as a co-treatment for mild-to-moderate ulcerative colitis (NCT-01026857).

Pregnancy outcome in inflammatory bowel disease: prospective European case-control ECCO-EpiCom study, 2003-2006.

BACKGROUND: Inflammatory bowel disease (IBD) frequently affects women during their reproductive years. Pregnancy outcome in women with IBD is well described, particularly in retrospective studies. AIM: To evaluate the pregnancy outcome in patients with IBD in a prospective European multicentre case-control study. METHODS: Inflammatory bowel disease pregnant women from 12 European countries were enrolled between January 2003 and December 2006 and matched (1:1) to non-IBD pregnant controls by age at conception and number of previous pregnancies. Data on pregnancy and newborn outcome, disease activity and therapy were prospectively collected every third month using a standard questionnaire. Logistic regression analysis with odds ratio was used for statistical analyses. P value<0.05 was considered significant. RESULTS: A total of 332 pregnant women with IBD were included: 145 with Crohn's disease (CD) and 187 with ulcerative colitis (UC). Median age (range) at conception was 31 years (15-40) in CD and 31 (19-42) in UC patients. No statistically significant differences in frequency of abortions, preterm deliveries, caesarean sections, congenital abnormalities and birth weight were observed comparing CD and UC women with their non-IBD controls. In CD, older age was associated with congenital abnormalities and preterm delivery; smoking increased the risk of preterm delivery. For UC, older age and active disease were associated with low birth weight; while older age and combination therapy were risk factors for preterm delivery. CONCLUSION: In this prospective case-control study, women with either Crohn's disease or ulcerative colitis have a similar pregnancy outcome when compared with a population of non-inflammatory bowel disease pregnant women.

Tailored TiO2 layers for the photocatalytic ozonation of cumylphenol, a refractory pollutant exerting hormonal activity.

Photocatalytic ozonation by Al-supported TiO(2) films is successfully applied to the mineralization of 4-cumylphenol, a recalcitrant endocrine disrupting compound. A possible reaction mechanism implying the intermediate formation of bisphenols is proposed on the grounds of HPLC-MS and FTIR analyses.

Bowel ultrasound and mucosal healing in ulcerative colitis.

BACKGROUND AND AIM: Mucosal healing (MH) after short-term medical treatment is being considered as an important step in the therapeutic work-up of inflammatory bowel disorder (IBD) patients due to the potential prognostic role of MH in predicting disease outcome. However, IBD patients are reluctant to be re-endoscoped during follow-up; therefore, there is a need for non-invasive alternative index of MH which can replace endoscopy in clinical practice. We evaluated bowel ultrasound (US) as a surrogate of colonoscopy in a series of consecutive patients with active ulcerative colitis (UC). PATIENTS AND METHODS: 83 patients with moderate to severe UC requiring high-dose steroids were initially recruited; endoscopic severity of UC was graded 0-3 according to Baron score, and US severity was also graded 0-3 according to the colonic wall thickening and the presence of vascular signal at power Doppler. 74 patients responsive to steroids and then maintained on 5-ASA compounds were followed up with repeated colonoscopy and bowel US at 3, 9 and 15 months from entry. Concordance between clinical, endoscopic and US scores at various visits was determined by kappa statistics. Multiple unconditional logistic regression models were used to assess the predictivity of Truelove, Baron and US scores measured at 3 and 9 months on the development of a UC relapse (Baron score 2-3) at 15 months. RESULTS: An inconsistent concordance was found over time between 0 and I Baron scores and Truelove score (weighted kappa between 0.38 and 0.94), with high and consistent concordance between 0 and I Baron scores and US scores (weighted kappa between 0.76 and 0.90). On logistic regression analysis, a moderate/severe Baron score, regardless of their Truelove score, at 3 months was associated with a high risk of endoscopic activity at 15 months (OR 5.2; 95% CI: 1.6-17.6); similarly, patients with severe US scores (2-3) at 3 months had a high risk of severe endoscopic activity at 15 months (OR 9.1; 95% CI: 2.5-33.5). DISCUSSION: In expert hands bowel US may be used as a surrogate of colonoscopy in evaluating the response to high-dose steroids in severe forms of UC. US score after 3 months of steroid therapy accurately predicts clinical outcome of disease at 15 months.

Role of small-bowel endoscopy in the management of patients with inflammatory bowel disease: an international OMED-ECCO consensus.

Crohn's disease and ulcerative colitis are lifelong diseases seen predominantly in the developed countries of the world. Whereas ulcerative colitis is a chronic inflammatory condition causing diffuse and continuous mucosal inflammation of the colon, Crohn's disease is a heterogeneous entity comprised of several different phenotypes, but can affect the entire gastrointestinal tract. A change in diagnosis from Crohn's disease to ulcerative colitis during the first year of illness occurs in about 10 % - 15 % of cases. Inflammatory bowel disease (IBD) restricted to the colon that cannot be characterized as either ulcerative colitis or Crohn's disease is termed IBD-unclassified (IBDU). The advent of capsule and both single- and double-balloon-assisted enteroscopy is revolutionizing small-bowel imaging and has major implications for diagnosis, classification, therapeutic decision making and outcomes in the management of IBD. The role of these investigations in the diagnosis and management of IBD, however, is unclear. This document sets out the current Consensus reached by a group of international experts in the fields of endoscopy and IBD at a meeting held in Brussels, 12-13th December 2008, organised jointly by the European Crohn's and Colitis Organisation (ECCO) and the Organisation Mondiale d'Endoscopie Digestive (OMED). The Consensus is grouped into seven sections: definitions and diagnosis; suspected Crohn's disease; established Crohn's disease; IBDU; ulcerative colitis (including ileal pouch-anal anastomosis [IPAA]); paediatric practice; and complications and unresolved questions. Consensus guideline statements are followed by comments on the evidence and opinion. Statements are intended to be read in context with qualifying comments and not read in isolation.

Immunomodulatory effects of 1,25-dihydroxyvitamin D3 on TH1/TH2 cytokines in inflammatory bowel disease: an in vitro study.

Crohn's disease (CD) is associated with a higher type-1-helper T cell (Th1) cytokine expression, whereas ulcerative colitis (UC) appears to express a modified Th2 response. In addition to its classic role in calcium homeostasis, calcitriol, the hormonal active form of vitamin D, exerts immunoregulatory effects such as modulation of Th1/Th2 cytokines. Therefore, calcitriol administration could modify immune dysfunction in CD and UC. Nine patients with UC (M/F: 5/4; mean age 47 years, remission(R)/active(A) disease: 7/2), 8 patients with CD (M/F: 2/6; mean age 36, R/A 5/3) and 6 healthy controls (HC) (M/F: 3/3, mean age 4) were enrolled. Peripheral blood was collected after a drug-washout of 15 days and peripheral blood mononuclear cells were stimulated with mitogens alone or in the presence of physiological concentrations of calcitriol (100 pg/ml). Type 1 (IL-2, TNF-alpha, IFN-gamma) and type 2 (IL-10) cytokine production was assayed on supernatants by ELISA. Compared to HC, TNF-alpha production was significantly higher both in UC (p=0.0002) and CD (p=0.0001) patients, at baseline and after incubation with calcitriol (UC p=0.0003, CD p=0.0009). The effects of calcitriol incubation were: 1) reduced IFN-gamma (p=0.024) and increased IL-10 (p=0.06) production in UC patients; 2) reduced TNF-alpha production in CD (p=0.032); 3) no significant effects in HC. Calcitriol increased, albeit not significantly, IL-10 production in UC compared to CD patients (p=0.09). These results suggest an important modulatory role of vitamin D in the Th1/Th2 immune response. The observation that the effect of this modulation was different in CD compared to UC patients provides an interesting area of research into the pathogenesis and treatment of these inflammatory conditions.

Use of colonoscopy in the management of patients with Crohn's disease: appropriateness and diagnostic yield.

INTRODUCTION: Colonoscopy is a necessary tool in the management of Crohn's disease, but the benefit achieved by the procedure is a matter of debate. In the present study we evaluate the clinical impact of performing colonoscopy in Crohn's disease patients. METHODS: Consecutive patients with Crohn's disease undergoing colonoscopy were considered. The following issues were considered: appropriateness of indications; relevant findings able to change the management of the patients; the endoscopist's management decisions based on patient's clinical picture, i.e. increased, maintained or decreased treatment, compared with those selected after performing endoscopy. RESULTS: 204 patients (116 male/88 female, mean age 41 years) were included. Colonoscopy was judged indicated in 52.9% cases, according to current guidelines. In 54% of patients, endoscopy revealed a significant lesion, and this rate was significantly lower for non-indicated procedures (25.9%, p<0.0001). The endoscopic findings were in disagreement with symptoms in about 25% of cases, but the impact of the endoscopic findings on the endoscopist's decision was likely to be very small without any differences between appropriate and inappropriate procedures. CONCLUSIONS: Endoscopy is a potent tool in the management of Crohn's disease, if correctly used, but in the majority of cases a correct therapeutic decision may be established simply on the basis of clinical picture and non-invasive markers, whilst relevant endoscopic findings have a relatively low impact on the medical treatment.

Photocatalytic degradation of toluene in the gas phase: relationship between surface species and catalyst features.

Photocatalytic activity of both commercial and homemade samples was tested for the degradation of toluene in the gas phase by using two different irradiation sources, UV and solar. The role played by humidity in affecting the final toluene degradation was discussed. Catalyst deactivation (due to the high toluene level, 1000 ppm) and subsequent regeneration, by washing with water, were analyzed. Highest degradations and corresponding kinetic constants were achieved in the case of the anatase/brookite composite samples, while the commercial ones (including P25 Degussa) showed lower efficiency. Various adsorbed aromatic species (benzoic acid, the major surface product hydroquinone, benzylic alcohol, benzaldehyde, and cresols) obtained by washing the exhaust catalysts were analyzed by HPLC. Parallel results were achieved by Fourier transform infrared attenuated total reflectance (FTIR-ATR) spectroscopy. The presence of different photodegradation surface species for the various photocatalysts suggests the occurrence of different reaction pathways, depending on the fine physicochemical features of the specific TiO2 adopted in the reaction.

Extraintestinal manifestations of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is associated with a variety of extraintestinal manifestations (EIMs) that may produce greater morbidity than the underlying intestinal disease and may even be the initial presenting symptoms of the IBD. As many as 36% of patients with IBD have at least one EIM. Some are more common related to active colitis (joint, skin, ocular, and oral manifestations). Others are especially seen with small bowel dysfunction (cholelithiasis, nephrolithiasis, and obstructive uropathy), and some are nonspecific disorders (osteoporosis, hepatobiliary disease, and amyloidosis). Patients with perianal Crohn's disease are at higher risk for developing EIMs than other IBD patients. Also the presence of one EIM appears to confer a higher likelihood of developing other manifestations than would be expected by chance alone. The identified pathogenetic autoimmune mechanisms include genetic susceptibility antigenic display of autoantigen, aberrant self-recognition, and immunopathogenetic autoantibodies against organ-specific cellular antigen(s) shared by colon and extra-colonic organs. Microbes may play an important role, probably by molecular mimicry. Early recognition of these extraintestinal manifestations should help guide therapy that will reduce overall morbidity in affected patients. This paper reviews the diagnosis, therapy and management of the more common EIMs.

Autologous haematopoietic stem cell transplantation without CD34+ cell selection in refractory Crohn's disease.

OBJECTIVES: Autologous haematopoietic stem cell transplantation (HSCT) with CD34(+) cell selection has recently been used in the treatment of refractory Crohn's disease, showing good safety and promising efficacy. We investigated the safety and efficacy of HSCT with unselected peripheral blood stem cells (PBSCs) in moderate-severe refractory Crohn's disease. PATIENTS: Four patients (three male, one female; age range 26-45 years) with active moderate-severe Crohn's disease (median Crohn's Disease Activity Index (CDAI) 319, range 272-345), refractory or intolerant to multiple drugs including infliximab, were enrolled. INTERVENTIONS: Unselected PBSCs were collected after mobilisation with cyclophosphamide (CTX) 1.5 g/m2 and granulocyte-colony stimulating factor (G-CSF) 10 microg/kg. The conditioning regimen included CTX 50 mg/kg on days -5 to -2 and rabbit anti-thymocyte globulin (ATG) 2.5 mg/kg on days -4 to -2. MAIN OUTCOME MEASURES: Primary endpoints were toxicity and clinical remission (CDAI<150) at 3 months. Secondary endpoints were clinical and endoscopic response at 3 months and toxicity, clinical and endoscopic remission at 12 months. RESULTS: No improvement or slight deterioration was observed following mobilisation (median CDAI 339, range 258-404). At the third month, the primary endpoint of clinical remission was achieved in all patients, with a median CDAI of 91 (range 56-102), and complete endoscopic remission was achieved in 2/3 patients. After a median follow-up of 16.5 months, 3/4 patients maintained both clinical and endoscopic remission, despite withdrawal of all drugs, and complete fistula closure was observed in all affected patients. No deaths or life-threatening infection occurred. Unexpected adverse events included a perianal abscess after mobilisation in one patient, pleural and pericardial effusions in another and BK virus-related macrohaematuria in another, all rapidly resolved with conservative treatment. CONCLUSION: Autologous HSCT with unselected PBSC appears to be safe and can induce and maintain remission in previously refractory Crohn's disease patients.