Federica Furfaro

Thiopurine treatment in inflammatory bowel disease: Response predictors, safety, and withdrawal in follow-up

BACKGROUND AND AIMS Thiopurines represent the mainstay of immunosuppressive therapy in inflammatory bowel diseases. Since it is likely that response to therapy and adverse events depends on the genetic background of patients our study aimed to evaluate retrospectively response to therapy and safety in a mixed IBD population in Southern Europe. METHODS We evaluated demographic and clinical data of our patients treated with thiopurines. after 6 months in responders and non-responders to therapy. Moreover the likelihood to remain in thiopurine monotherapy was evaluated in responders, whereas adverse events were investigated in all patients. RESULTS Among disease- and patient-related parameters a shorter disease duration, female gender and ileal disease in Crohns patients were associated with better response. By ROC analysis, the best predictors of response were decreasing values of C-reactive protein and erythrocyte sedimentation rate. In the long-term more than half of IBD patients who responded at 6 months remained on monotherapy at 42 months. Flu-like syndrome represented the most frequent adverse event followed by abnormalities of liver function tests and myelotoxicity. Adverse events did occur at any time and were frequently impredictable. CONCLUSIONS In this retrospective study, thiopurines showed a good clinical efficacy, especially in patients with short duration of disease. Normalization of markers of systemic inflammation represents the most useful tool to assess response. Careful monitoring of patients is required during the whole duration of treatment although it may not prevent all severe complications.

Disease patterns in late-onset ulcerative colitis: Results from the IG-IBD “AGED study”

BACKGROUND Late-onset UC represents an important issue for the near future, but its outcomes and relative therapeutic strategies are yet poorly studied. AIM To better define the natural history of late-onset ulcerative colitis. METHODS In a multicenter retrospective study, we investigated the disease presentation and course in the first 3 years in 1091 UC patients divided into 3 age-groups: diagnosis ≥65years, 40-64 years, and <40years. Disease patterns, medical and surgical therapies, and risk factors for disease outcomes were analyzed. RESULTS Chronic active or relapsing disease accounts for 44% of patients with late-onset UC. Across all age-groups, these disease patterns require 3-6 times more steroids than remitting disease, but immunomodulators and, to a lesser extent, biologics are less frequently prescribed in the elderly. Advanced age, concomitant diseases and related therapies were found to be inversely associated with the use of immunomodulators or biologics, but not with surgery. CONCLUSIONS The conclusion that late-onset UC follows a mild course may apply only to a subset of patients. an important percentage of elderly patients present with more aggressive disease. Since steroid use and surgery rates did not differ in this subgroup, lower use of immunosuppressive therapy and biologics may reflect concerns in prescribing these therapies in the elderly.

The safety of biological pharmacotherapy for the treatment of ulcerative colitis

ABSTRACT Introduction: Biological agents are effective in ulcerative colitis (UC). Currently, 3 anti-TNF agents (infliximab, adalimumab, and golimumab) and 1 anti-integrin agent (vedolizumab) are approved for the treatment of UC. The mechanism of action of biologic agents can also give rise to several side effects, some even serious. It remains uncertain to what extent biologic treatments may be associated with an increased rate of infections, malignancies and other adverse events Areas covered: Our aim is to review the relevant data available in the literature and briefly summarize the safety profile of biological therapy in UC. We performed a literature search using the OVID, MEDLINE, PUBMED and EMBASE databases. Also other relevant sources of safety data were also used. Expert opinion: All biological agents currently used in UC are relatively safe. Accurate prevention measures and screening prior to start such therapies, and regular surveillance programs are strongly recommend to minimize any risk of infections, malignancy and other adverse events related to the use of monoclonal antibodies in UC patients.

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.

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

Efficacy of tumour necrosis factor antagonists in stricturing Crohn’s disease: A tertiary center real-life experience

BACKGROUND Stenosis is the most common complication of Crohns disease (CD). Long-term outcome of patients receiving tumour necrosis factor (TNF) antagonists for such disease complication is poorly understood. METHODS 51 CD patients (from July 2006 to November 2015) who had a diagnosis of small bowel or colonic stenosis, diagnosed by colonoscopy and/or MRI enterography, and were treated with TNF antagonists (adalimumab or infliximab) were enrolled. The primary outcome was to assess the rate of success of TNF antagonists on avoiding abdominal surgery for stricturing CD patients. RESULTS 20 patients (39.2%) underwent surgery during the follow-up period. The overall incidence of abdominal surgery was 1.8 per 100 person-months at risk, while the median time to surgery was 37.9 months. The univariable and multivariable Coxs proportional hazards analysis of baseline parameters indicated that disease location (colonic vs ileal, HR: 28.2, 95% CI: 2.45-324, p=0.007; ileocolonic vs ileal, HR: 3.38, 95% CI: 1.09-10.5, p=0.035), prestenotic dilatation (per 1-mm increase, HR: 1.08, 95% CI: 1.01-1.15, p=0.022) and the existence of non-perianal fistula (HR: 9.77, 95% CI: 2.99-31.9, p<0.001) are independent risk factors for abdominal surgery. CONCLUSIONS In stricturing CD, anti-TNFs are effective in up to about two-thirds of the patients.

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.

Targeting S1P in Inflammatory bowel disease: new avenues for modulating intestinal leukocyte migration

Sphingosine 1 phosphate [S1P] is a bioactive lipid mediator involved in the regulation of several cellular processes though the activation of a G protein-coupled receptor family known as the S1P receptors [S1PRs]. Advances in the understanding of the biological activities mediated by S1PRs have sparked great interest in the S1P/S1PRs axes as new therapeutic targets for the modulation of several cellular processes. In particular, the S1P/S1PR1 axis has been identified as key regulator for lymphocyte migration from lymph nodes. The blockade of this axis is emerging as a new therapeutic approach to control the aberrant leukocyte migration into the mucosa in inflammatory bowel disease [IBD]. This review briefly summarises the current evidence coming from clinical studies, and discusses the future prospects of S1P inhibitors for treatment of inflammatory bowel disease.

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.

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.