Daniela Gilardi

Complementary and alternative medicine in inflammatory bowel diseases: what is the future in the field of herbal medicine?

The use of complementary and alternative medicine is wide-spread not only in Eastern countries, but also in the Western world. Despite the increasing evidence on the harmful effects induced by several naturopathic/homeopathic products, patients seem to appreciate these remedies, in particular because they consider them to be absolutely safe. This same phenomenon is common among inflammatory bowel disease (IBD) patients. As a result there is a significant request for scientific data to evaluate both the efficacy and safety of these remedies, and to support the use of such medications as adjuvant treatments to biological and synthetic drugs. We aimed to review the current evidence on efficacy and safety of some natural products that are believed to be effective in inflammatory bowel disease. Further perspectives for the clinical use of herbal products and strategies for improving knowledge about herbal products in IBD are also discussed.

IL-23 Blockade for Crohn s disease: next generation of anti-cytokine therapy

ABSTRACT Introduction: Adaptive immunity in intestinal inflammation may play a key role in the pathogenesis of Crohn’s disease. In particular, interleukin (IL)-23 may be a key mediator in chronic intestinal inflammation by inducing the differentiation of naïve CD4 + T cells into Th17, with the production of several pro-inflammatory cytokines. Furthermore, IL-23 induces interferon-γ (IFN- γ) production from activated T cells, a critical cytokine in innate and adaptive immunity against infections. Areas covered: We aim to review the available data from literature regarding the role of IL-23, with a more specific focus on the recent progresses in the therapeutic modulation of this cytokine. Expert commentary: Increased knowledge regarding the role of IL-23 has allowed for the development of effective therapeutic progresses by blocking the IL-23 mediated pathways. Primary or secondary loss of response to anti-TNF therapies in Crohn’s disease patients during the first year is widely described in literature: the development of new drugs, with alternative mechanisms of action, is thus a key point to consider for the optimal management of these subjects. Drugs blocking the IL-12/23 pathway showed a good efficacy and safety profile in immune-mediated diseases Further studies are necessary regarding the role of the single blockade of IL-23.

The clinical potential of etrolizumab in ulcerative colitis: hypes and hopes.

Antiadhesion molecules are effective and safe in patients with ulcerative colitis (UC). Etrolizumab, a monoclonal antibody targeting both α4β7 and αEβ7, represents a promising therapy for patients with UC, since this novel mechanism of action may be effective in blocking leukocyte recruitment both at the vascular and at the mucosal level. Preliminary studies show that etrolizumab is effective in inducing clinical response and remission, and mucosal healing. Moreover, new predictors of response have recently been identified, opening the way to a tailored therapeutic approach. This review of the literature aims to present and discuss the most recent evidence on etrolizumab in UC, focusing on the clinical implications of the use of etrolizumab in UC.

Letter: immunogenicity of infliximab originator vs. CT-P13 in IBD patients

H. Yanai S. Ben-Shachar L. Mlynarsky L. Godny M. Leshno H. Tulchinsky I. Dotan Department of Gastroenterology and Liver Diseases, IBD Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Genetics Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel Division of Surgery, Tel Aviv Sourasky Medical Center, Colorectal unit, Tel Aviv, Israel Coller School of Management, Tel Aviv University, Tel Aviv, Israel Email: irisdo@clalit.org.il

Emerging therapeutic targets and strategies in Crohn's disease.

ABSTRACT Crohn’s disease (CD) is an immune-mediated inflammatory bowel disease, in which inflammation is driven by a complex interaction between the microbiota, immune cells, genes and mediators. New mechanisms of action and several cytokines have been identified as factors involved in the inflammatory process in CD, and many new molecules have been developed to treat this complex disease. New agents have been developed that target leukocyte trafficking, block or adhesion molecules for example, as well as the development of antibodies against classic inflammatory cytokines or therapies directed against IL-12/23 and Janus kinases. The development of selective mechanisms of action and targeting of different cytokines or inflammatory mediators for each patient presents the biggest challenge for the future in CD therapy. Such agents are currently at different phases of development. We aim to review the current literature data on a targeted approach in CD, which could be promising alternative approach for CD patients in the near future.

Golimumab: clinical update on its use for ulcerative colitis.

Monoclonal antibodies directed against tumor necrosis factor alpha (anti-TNF-α agents) have dramatically changed the therapeutical approach to inflammatory bowel diseases, such as Crohns disease and ulcerative colitis. A new anti-TNF drug, golimumab, has recently been approved for patients with moderate to severe ulcerative colitis. Its efficacy has been demonstrated by preclinical and clinical studies and the drug showed an efficacy and safety profile in line with the other anti-TNF agents, such as infliximab and adalimumab. This review gives an overview on golimumab in the treatment of moderate to severe ulcerative colitis.

Full Interchangeability in Regard to Immunogenicity Between the Infliximab Reference Biologic and Biosimilars CT-P13 and SB2 in Inflammatory Bowel Disease

Background Infliximab (IFX) biosimilars CT-P13 and SB2 have comparable efficacy, safety, and immunogenicity to the originator Remicade (RMC). However, concerns about cross-switching patients between the 3 brands were raised in the absence of cross reactivity data between them. We aimed to determine whether antibodies to infliximab (ATI) in inflammatory bowel disease (IBD) patients cross-react with RMC, CT-P13, and SB2. Methods Based on previous ATI status, samples from 34 patients participating in the BIOSIM01 study (13 RMC, 9 CT-P13, and 12 switchers) were selected. Patients were treated with either RMC only, or CT-P13 only, or with RMC switched to CT-P13. Additionally, 28 IFX-naïve patients were assayed as controls. In total, 180 samples were analyzed. ATI trough levels were measured in parallel with 3 different bridging Enzyme Linked Immunosorbent Assays constructed using the 3 drugs. Spearmans coefficient and percentages of agreement were used to study the correlation between each assay. Results In total, 76 samples out of 152 IFX-treated patient samples were ATI-positive (30 RMC, 14 CT-P13, and 32 switchers). All resulted ATI-positive when either CT-P13 or SB2 bridging assays were used. The overall percentage of agreement was 100% when compared either with CT-P13 or SB2 assays. No significant differences were found among ATI levels and coefficients (Spearmans 0.98 to 1.0, P < 0.0001). Conclusions ATI of RMC-treated, CT-P13-treated or RMC to CT-P13 switched patients show full cross-reactivity with CT-P13 and SB2. Findings suggest that immunodominant epitopes in the reference and CT-P13 drugs are equally present in SB2. Data support full interchangeability between biosimilars in regard to immunogenicity.

Safety and efficacy of sodium hyaluronate (IBD98E) in the induction of clinical and endoscopic remission in subjects with distal ulcerative colitis

BACKGROUND Sodium hyaluronate can contribute to the hydration and maintenance of the integrity of the intestinal mucosa. Restoration of the protective layer with sodium hyaluronate may contribute to the induction of remission of active ulcerative colitis. METHODS We investigated the safety and efficacy of sodium hyaluronate enema (IBD98E) in distal active ulcerative colitis, in a prospective, uncontrolled, open-label pilot trial. Subjects with active distal ulcerative colitis (UCDAI ≥ 4 and sigmoidoscopy score ≥ 1) received IBD98E 60 mL enema once a day. Primary endpoints were safety and clinical response rate at Day 28. Secondary endpoints included clinical remission, endoscopic remission, and tolerability of IBD98E. Paired Students t-test was performed to assess statistically significant differences in subjects between baseline and Day 28. RESULTS Twenty-one subjects were enrolled. The overall safety profile was good; no serious adverse events were recorded. At Day 28, 9 subjects (42.9%) were clinical responders, and 10 subjects (47.6%) had an endoscopic response. Eight subjects (38.1%) achieved clinical remission, and 10 subjects (47.6%) achieved endoscopic remission. The mean average UCDAI score decreased from 6.10 to 3.81 at Day 28 (p=0.001), and average endoscopic score decreased from 1.57 to 1.10 (p=0.004). CONCLUSION IBD98E seems to be safe and effective for the induction of clinical and endoscopic remission. Placebo-controlled studies are warranted.

Comparative Accuracy of Bowel Ultrasound Versus Magnetic Resonance Enterography in Combination With Colonoscopy in Assessing Crohn’s Disease and Guiding Clinical Decision-making

Background The comparative accuracy of bowel ultrasound [US] versus magnetic resonance enterography [MRE] in combination with colonoscopy [CS] in assessing Crohns disease [CD] and influencing the decision-making process is unknown. Methods Consecutive ileo-colonic CD patients seen in a tertiary referral centre were prospectively assessed by MRE, CS, and bowel US, within 1 week. Sensitivity, specificity, accuracy, positive predictive value [PPV], and negative predictive value [NPV] of bowel US in assessing localisation, enhancement [presence of vascularisation at Power Doppler], active disease [presence of ulcers at colonoscopy], strictures, fistulas, and abscesses were calculated using CS + MRE findings together as a reference standard. Two blinded inflammatory bowel disease [IBD] specialists reviewed MRE and bowel US findings and were asked to decide the therapeutic strategy [continue versus change therapy]. Kappa agreement with clinical decision was calculated. Results Sixty CD patients [36 with endoscopic disease activity, 28 with complications] were enrolled. For localisation, sensitivity, specificity, accuracy, PPV, and NPV of bowel US were 88%, 96%, 91%, 96%, and 85%, respectively; for enhancement, 87%, 92%, 89%, 93%, and 86%; for activity, 92%, 100%, 96%, 100%, and 94%; for strictures, 75%, 86%, 81%, 78%, and 83%; for fistulas, 100%, 98%, 98%, 66%, and 100%; for abscesses, 100%, 96%, 96%, 33%, and 100%. The concordance of management of CD patients based on bowel US or MRE findings, alone, compared with clinical decision, was 0.768 and 0.767, respectively [p <0.001]. The concordance between bowel US and MRE on management of CD patients was 0.800 [p <0.001]. Conclusions Bowel US is very accurate in assessing CD and is a non-invasive, easy-to-use tool to manage CD patients in clinical practice.

Accuracy of Humanitas Ultrasound Criteria in Assessing Disease Activity and Severity in Ulcerative Colitis: A Prospective Study

Abstract Background Colonoscopy [CS] is the standard for assessing disease activity in ulcerative colitis [UC], although invasive and poorly tolerated. Bowel ultrasound [BUS] may be a valid alternative in UC patients; however, the comparative accuracy between BUS and CS is unknown. Methods Consecutive patients with UC were prospectively assessed by CS and BUS. Colonic wall thickening [CWT >3 mm], colonic wall flow at power Doppler [CWF], colonic wall pattern [CWP], and presence of lymph nodes evaluated at BUS were compared with CS. The endoscopic activity was assessed according to the Mayo endoscopic sub-score [0–3]. All BUS investigations were performed by two independent gastroenterologists and the kappa statistic for agreement was calculated. Ultrasonography-based criteria (Humanitas Ultrasound Criteria [HUC]) were developed. Results A total of 53 UC patients [56% with left-sided colitis, 19% with pancolitis] were prospectively enrolled. Of these, 22 patients had mucosal healing [Mayo endoscopic sub-score 0–1] and 31 patients were in endoscopic activity. CWT, CWF, hypoechogenic CWP and the presence of lymph nodes significantly correlated with endoscopic activity [p < 0.05]. CWT [p = 0.01] and CWF [p = 0.09] were independent predictors for endoscopic activity. The HUC developed are: [i] the presence of a CWF and CWT > 3 mm; or [ii] the absence of a CWF and CWT > 4.43 mm. They showed high accuracy for the detection of disease activity [sensitivity 0.71, specificity 1.00]. The interobserver agreement for BUS was excellent [kappa 0.86]. Conclusions BUS is a non-invasive, easy-to-use tool to manage UC patients in clinical practice. HUC were very accurate in assessing disease activity in UC patients.