Review article: novel oral-targeted therapies in inflammatory bowel disease.

BACKGROUND: There is a great unmet clinical need for efficacious, tolerable, economical and orally administrated drugs for the treatment of inflammatory bowel disease (IBD). New therapeutic avenues have become possible including the development of medications that target specific genetic pathways found to be relevant in other immune mediated diseases. AIMS: To provide an overview of recent clinical trials for new generation oral targeted medications that may have a future role in IBD management. METHODS: Pubmed and Medline searches were performed up to 1 March 2018 using keywords: "IBD", "UC", "CD", "inflammatory bowel disease" "ulcerative colitis", "Crohn's disease" in combination with "phase", "study", "trial" and "oral". A manual search of the clinical trial register, article reference lists, abstracts from meetings of Digestive Disease Week, United European Gastroenterology Week and ECCO congress were also conducted. RESULTS: In randomised controlled trials primary efficacy endpoints were met for tofacitinib (JAK 1/3 inhibitor-phase III), upadacitinib (JAK 1 inhibitor-phase II) and AJM300 (α4-integrin antagonist-phase II) in ulcerative colitis. Ozanimod (S1P receptor agonist-phase II) also demonstrated clinical remission. For Crohn's disease, filgotinib (JAK1 inhibitor-phase II) met primary endpoints and laquinimod (quinolone-3-carboxide small molecule-phase II) was also efficacious. Trials using mongersen (SMAD7 inhibitor) and vidofludimus (dihydroorotate dehydrogenase inhibitor) have been halted. CONCLUSIONS: This is potentially the start of an exciting new era in which multiple therapeutic options are at the disposal of physicians to treat IBD on an individualised basis. Head-to-head studies with existing treatments and longer term safety data are needed for this to be possible.

MRI assessment of the postprandial gastrointestinal motility and peptide response in healthy humans.

BACKGROUND: Feeding triggers inter-related gastrointestinal (GI) motor, peptide and appetite responses. These are rarely studied together due to methodological limitations. Recent MRI advances allow pan-intestinal, non-invasive assessment of motility in the undisturbed gut. This study aimed to develop a methodology to assess pan-intestinal motility and transit in a single session using MRI and compare imaging findings to GI peptide responses to a test meal and symptoms in a healthy volunteer cohort. METHODS: Fifteen healthy volunteers (29.3±2.7 years and BMI 20.1±1.2 kg m-2 ) underwent baseline and postprandial MRI scans, symptom questionnaires, and blood sampling (for subsequent GI peptide analysis, Glucagon-like peptide-1 [GLP-1], Polypeptide YY [PYY], Cholecystokinin [CCK]) at intervals for 270 minutes following a 400 g soup meal (204 kcal, Heinz, UK). Gastric volume, gall bladder volume, small bowel water content, small bowel motility, and whole gut transit were measured from the MRI scans. KEY RESULTS: (mean±SEM) Small bowel motility index increased from fasting 39±3 arbitrary units (a.u.) to a maximum of 87±7 a.u. immediately after feeding. PYY increased from fasting 98±10 pg mL-1 to 149±14 pg mL-1 at 30 minutes and GLP-1 from fasting 15±3 µg mL-1 to 22±4 µg mL-1 . CCK increased from fasting 0.40±0.06 pmol mL-1 to 0.94±0.1 pmol mL-1 . Gastric volumes declined with a T1/2 of 46±5 minute and the gallbladder contracted from a fasting volume of 19±2 mL-1 to 12±2 mL-1 . Small bowel water content increased from 39±2 mL-1 to 51±2 mL-1 postprandial. Fullness VAS score increased from 9±5 mm to 41±6 mm at 30 minutes postprandial. CONCLUSIONS AND INFERENCES: The test meal challenge was effective in inducing a change in MRI motility end-points which will improve understanding of the pathophysiological postprandial GI response.

Ustekinumab: a novel therapeutic option in Crohn's disease.

INTRODUCTION: Although anti-tumour necrosis factor (TNF) agents have caused a paradigm shift in the management of moderate-to-severe Crohn's, they are sometimes associated with diminished or absent response in a considerable proportion of patients. Hence agents targeting pathways other than TNF are needed. Ustekinumab is a monoclonal antibody directed against the p40 subunit of IL-12 and 23. AREAS COVERED: This manuscript summarises the available evidence on the efficacy and safety of Ustekinumab in Crohn's disease through data available from randomised controlled trials and compassionate use programs across the world. EXPERT OPINION: Current literature strongly supports the fact that ustekinumab is clinically efficacious and reasonably safe for induction and maintenance of remission in moderate-to-severe Crohn's disease.

Novel concepts in inflammatory bowel disease.

INTRODUCTION: Clinical management in inflammatory bowel disease (IBD) is constantly changing. Although improvement in symptoms is of paramount importance, using this as the only surrogate marker of disease activity might underestimate disease burden. SOURCES OF DATA: New data from randomized clinical trials are now available. Treatment paradigms are constantly changing leading to an evolution in the therapeutic approach in routine IBD practice. AREAS OF AGREEMENT: Patients with an aggressive disease phenotype should be identified at the onset and treated more intensely in order to achieve long-lasting mucosal remission. AREAS OF CONTROVERSY: Patients who have mild and indolent disease need to be identified and not over treated. GROWING POINTS: The primary endpoint in IBD management should ideally be mucosal healing. Ample data are now available that correlates mucosal healing with surgical-free outcomes with minimal intestinal damage and patient disability. However, the exact degree of mucosal healing that will lead to improved long-term remission, decreased hospital and surgical rates remains unknown. AREAS TIMELY FOR DEVELOPING RESEARCH: Clinical translational work is needed to identify novel pathways in IBD pathogenesis that sub-select patients who would benefit by specific-cytokine pathway modulation.

Review article: dermatological complications of immunosuppressive and anti-TNF therapy in inflammatory bowel disease.

BACKGROUND: With the expanding list of medications available to treat patients with inflammatory bowel disease (IBD), it is important to recognise adverse events, including those involving the skin. Dermatological adverse events may be confused with extra-intestinal manifestations of IBD. AIM: To review drug-related dermatological manifestations associated with immunosuppressive and anti-tumour necrosis factor (anti-TNF) therapy. METHODS: The literature was searched on PubMed for dermatological adverse events in IBD. RESULTS: Present thiopurine exposure was associated with a 5.9-fold [95% confidence interval (CI), 2.1-16.4] increased risk of developing non-melanoma skin cancer (NMSC). The peak incidence is highest in Caucasians over the age of 65 years with crude incidence rates of 4.0 and 5.7/1000 patient-years for present and previous use. In anti-TNF-exposed subjects, drug-induced lupus was reported in 1% of the cases and a psoriatic rash in up to 3% of the cases. Anti-TNF monotherapy increases the risk of NMSC ~2-fold to a rate of 0.5 cases per 1000 person-years. Cutaneous lymphomas have been rarely reported in subjects on thiopurine or anti-TNF drug monotherapy. Combination therapy seems to have an additive effect on the risk of developing NMSC and lymphoma. CONCLUSIONS: Physicians need to be aware of the wide spectrum of dermatological complications of immunosuppressive and anti-TNF therapy in IBD, especially psoriasis and non-melanoma skin cancer. Vigilance and regular screening for non-melanoma skin cancer is recommended. Case discussions between gastroenterologists and dermatologists should be undertaken to best manage dermatological adverse events.

GLP-2 enhances barrier formation and attenuates TNFα-induced changes in a Caco-2 cell model of the intestinal barrier.

INTRODUCTION: Tight junctions are intercellular permeability seals that regulate paracellular transport across epithelia. Tight junction function, expression and localisation of constituent proteins are significantly altered by cytokines such as TNFα. Glucagon-like peptide-2 (GLP-2) is an intestinotrophic enteroendocrine peptide. It is not known whether GLP-2 regulates the barrier or tight junctions. The aim of this study was to investigate whether GLP-2 has an effect on tight junction function or protein expression, alone or in response to TNFα exposure. METHODS: Caco-2 cells were grown to confluence on filters in the presence or absence of GLP-2. The time course of transepithelial electrical resistance developing across the monolayer was measured; tight junction protein expression was quantified by immunoblotting. At day 20, TNFα in the presence or absence of GLP-2 was added. Changes in TEER and tight junction proteins expression were quantified. Both TNFα and GLP-2 were added on the basolateral side. RESULTS: GLP-2 exposed Caco-2 cell monolayers showed a significant increase in transepithelial electrical resistance compared to that in untreated control cells. At the same time, expression of the tight junction proteins occludin and zona occludens-1 (ZO-1) was increased at day 17 post-seeding (1.6-fold; p=0.037 and 4.7 fold; p=0.039 respectively). Subsequent TNFα exposure induced a significant 9.3-fold (p<0.001) decrease in transepithelial electrical resistance and a corresponding reduction in the expression of ZO-1 (5.3 fold; p<0.01). However, the TNFα-induced reduction in transepithelial electrical resistance in GLP-2-exposed cells was highly attenuated to 1.8-fold (p<0.01). No change in tight junction protein expression was noted in GLP-2 exposed cells after cytokine exposure. CONCLUSION: GLP-2 enhances formation of the epithelial barrier and its constituent proteins in Caco-2 cells, and diminishes the effects of TNFα. If these effects are replicated in vivo the GLP-2 receptor may present a therapeutic target in intestinal inflammation.

Dipeptidyl peptidase-4 expression is reduced in Crohn's disease.

BACKGROUND: Dipeptidyl peptidase 4 (DP4) is a serine protease that preferentially cleaves N-terminal dipeptides from polypeptides containing proline or alanine as the penultimate amino acid. DP4 inactivates glucagon like peptide-2 (GLP-2), a trophic peptide with cytoprotective and reparative properties in the injured gut; therefore DP4 potentially inhibits repair processes. DP4 also modulates the activity of GLP-1 and polypeptide YY (PYY) which regulate appetite and motility. No data are yet available on the tissue and plasma expression of DP4 in inflammatory bowel disease (IBD). METHODS: Tissue and plasma were studied from active CD and healthy controls for DP4 quantification. Experiments were also carried out in a reductionist Caco-2 cell line model of intestinal inflammation with TNFα incubation. DP4 expression was studied by tissue Western blotting and plasma enzymelinked immunosorbent assay (ELISA), in addition to quantitative polymerase chain reaction (qPCR). RESULTS: There was a ~2.7-fold decrease in DP4 protein in CD tissue (p=0.05). Plasma DP4 in CD was also significantly lower than the control group. A negative correlation between plasma DP4 levels and inflammatory activity as measured by C-reactive protein was observed. In Caco-2 cells an ~18-fold increase (p<0.0001) in DP4 protein expression was seen after incubation with TNFα at a concentration of 25 ng/µl for 48 hours paralleled by a 2-fold increase in DP4 mRNA. DISCUSSION: DP4 is reduced in tissue and plasma in active Crohn's disease. This is unlikely to represent simple downregulation induced by inflammation since the key proinflammatory cytokine strongly upregulated DP4 expression in Caco-2 cells. Clearly a more complex situation exists in vivo. We propose that reduced DP4 activity limits the cleavage of regulatory peptides, for example potentiating the trophic signal from GLP-2. Pharmacological DP4 inhibition may present an additional therapeutic target in IBD.

Direct Percutaneous Endoscopic Jejunostomy: High Completion Rates with Selective Use of a Long Drainage Access Needle.

Background. Direct percutaneous endoscopic jejunostomy (DPEJ) insertion is a useful technique for artificial nutritional support in selected patients. However, it is technically difficult and most case series report significant procedural failure rates. Methods. We reviewed our case series of DPEJ insertions, done in a tertiary care referral centre from 2002 to 2008. Patients were selected for DPEJ if they required artificial enteric nutritional support but were unsuitable for endoscopic gastrostomy. Our technique includes selective usage of a long drainage access needle for gut luminal puncture, selective fluoroscopic guidance and selective usage of general anaesthesia. Results. Of 40 consecutive patients undergoing attempted DPEJ insertion, 39/40 (97.5%) had a successful procedure. Sixteen cases (40%) required the drainage access needle for completion, nineteen cases (47.5%) were done with fluoroscopy, and five cases (12.5%) were done under general anaesthesia. There were no procedural complications. Conclusions. This technique led to a high completion rate and low complication rate. With appropriate care and expertise, DPEJ insertion is reliable and safe.

The preoperative electrocardiogram as an indicator of risk in major noncardiac surgery.

In this series of 198 patients studied prospectively before major noncardiac surgery, we previously reported that an abnormal preoperative electrocardiogram was a statistically significant independent predictor of an increased risk of postoperative complications, i.e., death, myocardial infarction, or myocardial ischemia. We therefore carried out a detailed analysis of the preoperative electrocardiographic (ECG) findings using Minnesota code criteria. Both ST-T abnormalities and intraventricular conduction delays showed a statistical trend toward a higher frequency in patients with a complicated vs. an uncomplicated postoperative course (82% vs. 59% and 24% vs. 7%, respectively). Although only a minority of patients with either ECG finding actually developed a complication (22% and 40% respectively), the preoperative ECG appears to be a useful screening method, with ST-T abnormalities and intraventricular conduction delays identifying patients at increased risk for postoperative complications.

Technetium-99m-pyrophosphate scintigraphy in patients with suspected acute myocardial infarction: impact of interobserver variability.

Technetium-99m-pyrophosphate (TcPYP) scintigraphy may have great value in patients with suspected acute myocardial infarction (AMI), but interobserver variability undoubtedly has adverse impact on predictive value. TcPYP scintigrams for 133 (80%) of 166 consecutive patients admitted for suspected AMI were interpreted independently by three experienced readers. Although there was complete agreement for 87 interpretations (65%), major discrepancies (i.e., at least one positive and one negative reading on the same scan) occurred for 28 scans (21%). To assess predictive accuracy, patients were categorized as follows: 36 had definite AMI manifest by new ECG Q waves and/or CK-MB evidence of AMI (group I), 56 were classified as possible AMI (group II), and 41 had AMI excluded (group III). Using only the definitive diagnostic categories (groups I and III), accuracy for each reader approximated 0.68, with no single reader being correct more often than any other.

Routine preoperative exercise testing in patients undergoing major noncardiac surgery.

A prospective study of preoperative exercise testing was carried out in 200 patients older than 40 years scheduled for elective major noncardiac surgery under general anesthesia. The exercise test response was electrocardiographically positive in 32 patients (16%) (2 patients had a markedly positive test), equivocal in 11 patients (5.5%) and negative in 157 patients (78.5%). The patients were followed with serial pre- and postoperative electrocardiograms (ECGs) and determinations of serum creatine kinase (CK) and CK-MB. Six patients (3%) had primary endpoints: 3 (1.5%) died postoperatively and 3 (1.5%) had definite postoperative myocardial infarction. Secondary endpoints of suspected postoperative myocardial ischemia/injury diagnosed by ECG or elevation in CK-MB levels occurred in 27 patients (14%). Endpoint events were more common in patients aged 70 years or older. Endpoint events were also more common in patients with an abnormal (positive or equivocal) preoperative exercise test response than in those with a negative response (27% vs 14%); however, preoperative exercise results were not statistically significant independent predictors of cardiac risk. Using multivariate analysis, the only statistically significant independent predictor of risk was the preoperative ECG. Endpoint events were more common in patients with an abnormal than in those with a normal ECG (23% vs 7%, p less than 0.002). Because the results of exercise testing do not appear to add substantially to the risk separation provided by the ECG at rest, exercise testing is not recommended as a routine preoperative method for assessing perioperative risk in older patients who are being evaluated before major elective noncardiac surgery under general anesthesia.

Routine serum enzyme tests in the diagnosis of acute myocardial infarction. Cost-effectiveness.

To determine the cost-effectiveness of routine use of serial SGOT, lactic dehydrogenase (LDH), and LDH isoenzyme determinations in patients with suspected acute myocardial infarction (AMI), 166 consecutive patients admitted to a coronary care unit were prospectively identified and clinical findings analyzed independently using predetermined criteria. Based on chest pain characteristics, ECG, and creatine kinase--MB (CK-MB) results, patients were placed in categories of definite AMI (31%), possible AMI (34%), or AMI excluded (36%). The SGOT and/or LDH patterns were considered positive (ie, suggestive of AMI) in 82% of the patients with definite AMI but only confirmed CK-MB results. Positive SGOT/LDH results yielded new clinically relevant information in only 14 patients (8%). Total charges for SGOT/LDH determinations in these 166 patients totaled $10,938 or approximately $780 for each additional clinically important positive result. When serial ECG and CK-MB results are available, routine serial SGOT/LDH determinations are not justified.