Anti-integrin Agents Research Articles

Old and New Biologics and Small Molecules in Inflammatory Bowel Disease: Anti Integrins

Recently, novel biologics or small molecular drugs have been introduced for overcoming the unmet needs associated with anti-tumor necrosis factor α agents for inflammtory bowel disease (IBD) treatment. Among these novel drugs, anti integrin agents block leukocyte trafficking to the intestine by blocking the interaction between integrin and cell adhesion molecules. Vedolizumab (anti-α4β7) is most widely used anti-integrin approved in both ulcerative colitis and Crohn's disease .It has been shown to be effective in both induction and maintenance therapy with a favorable safety profile due to gut selectivity. Several models incorporating clinical, genetic, immune and gut microbial markers to predict response to vedolizumab in IBD have been developed. Etrolizumab (anti-β7) blocks leukocyte trafficking via α4β7 and cell adhesion via αEβ7 integrins. In addition, the introduction of subcutaneous vedolizumab showed similar efficacy and safety with improved patients' convenience. Other investigational anti-integrin therapies include abrilumab (anti-α4β7 IgG2), PN-943 (orally administered and gut-restricted α4β7 antagonist peptide), AJM300 (orally active small molecule inhibitor of α4), and ontamalimab (anti-MAdCAM-1 IgG).

The Use of Immunomodulators, Biologic Therapies, and Small Molecules in Patients With Inflammatory Bowel Disease and Solid Organ Transplant.

Patients with inflammatory bowel diseases (IBDs) may require solid organ transplants (SOTs) for multiple reasons, making its prevalence slightly higher than the general population. Although immunosuppression used in SOT may help control IBD-related inflammation, many patients still require additional immunosuppressive medications. We aim to assess the effectiveness and safety of the combination of SOT-related immunosuppression and IBD medications in patients with liver, kidney, or heart transplantation. We conducted a clinical review using PubMed, Scopus, MEDLINE, Embase, and Google Scholar databases for our search. We included data from systematic reviews, meta-analyses, case series, and case reports to assess the safety, effectiveness, and side effect profile of immunomodulators, biologic therapies, and small molecules in patients with SOT. Our review encompassed 25 liver, 6 kidney, and 1 heart transplant studies involving patients with IBD. Common liver transplant immunosuppressants included tacrolimus, mycophenolate mofetil, cyclosporine, and steroids. Anti-TNF agents, widely used in all SOT types, showed no significant safety issues, though infections and malignancies were noted. Patients with liver transplant on tacrolimus responded well to anti-integrins and ustekinumab without major complications. For kidney transplants, cyclosporine and tacrolimus were prevalent, and their combination with anti-TNF or ustekinumab was generally safe, with rare reports of malignancy or infection. Hence, the use of anti-TNF, anti-integrin agents, and ustekinumab appears to be safe in patients with SOT, regardless of their transplant related immunosuppression. More studies are needed in patients with kidney and heart transplants and in patients treated with small molecules for their IBD.

Treatment of inflammatory bowel disease-Asian perspectives: the results of a multinational web-based survey in the 8th Asian Organization for Crohn's and Colitis meeting.

As the characteristics of inflammatory bowel disease (IBD) differ between Asians and Westerners, it is necessary to determine adequate therapeutic strategy for Asian IBD patients. We evaluated the current treatment of IBD in Asian countries/regions using a web-based survey. The Korean Association for the Study of Intestinal Diseases conducted a multinational web-based survey for current IBD care in Asia between September 16, 2020, and November 13, 2020. A total of 384 doctors treating IBD patients from 24 Asian countries/regions responded to the survey. Anti-tumor necrosis factor (TNF) agents, anti-integrins, and anti-interleukin-12/23 agents were available for use by 93.8%, 72.1%, and 70.1% of respondents in Asian countries/regions. Compared with a previous survey performed in 2014, an increased tendency for treatment with biologics, including anti-TNF agents, was observed. In the treatment of corticosteroid-refractory acute severe ulcerative colitis, 72.1% of respondents chose anti-TNF agents, followed by tacrolimus (11.7%). In the treatment of corticosteroid-refractory Crohn's disease, 90.4% chose anti-TNF agents, followed by thiopurines (53.1%), anti-interleukin-12/23 agents (39.3%), and anti-integrin agents (35.7%). In the treatment of Crohn's disease patients refractory to anti-TNF agents, the most preferred strategy was to measure serum levels of anti-TNF and anti-drug antibodies (40.9%), followed by empiric dose escalation or shortening of dosing intervals (25.3%). Although there were some differences, treatment strategies for patients with IBD were mostly similar among Asian doctors. Based on the therapeutic outcomes, it is necessary to identify the most appropriate therapeutic strategy for Asian IBD patients.

P704 The effect of antiTNFα and anti-integrin agents on liver steatosis in inlamatory bowel disease patients with non-alcoholic fatty liver disease

Abstract Background Non-alcoholic fatty liver disease (NAFLD) has been recognized as a common condition in inflammatory bowel disease (IBD) patients and could contribute to their overall morbidity. Anti-TNFα and anti-integrin agents have been the cornerstones of IBD therapy with proven clinical efficacy, but it΄s effect on liver steatosis is still unclear. Therefore this study aimed to evaluate the impact of anti-TNFα and anti-integrin agents on liver steatosis in IBD patients with proven NAFLD. Methods A total of 32 IBD patients with NAFLD, naive to biologic agents, 21 with an established diagnosis of ulcerative colitis, and 11 with Crohn’s disease were prospectively recruited for the study. NAFLD was defined by a baseline attenuation (ATT) coefficient measured by shear-wave (SW) elastometry of 0.63 dB/cm/MHz or higher and a baseline alanine aminotransferase (ALT) of more than 40 IU/L for males and 35 IU/L for females. The exclusion criteria were alcohol use (consuming > 40 g alcohol/day for men and > 20 g/day for women in the preceding 12 months), concomitant chronic viral hepatitis, the presence of hepatic carcinoma, biliary disease, drug use, and hypothyroidism. A total of 11 patients were treated with Adalimumab, 9 patients with Infliximab, and 12 patients with Vedolizumab. The SW elastometry and laboratory exams were performed at the moment of therapy induction and after the 6-month course of therapy. Results The anti-TNFα treatment significantly reduced liver steatosis according to the ATT coefficient dynamic (0.70±0.07 vs 0.66±0.03 dB/cm/MHz, p=0.021) and ALT level dynamic came on the verge of statistical significance (44±7 vs 40±6 IU/L, p=0.058). We did not observe a significant difference between the Infliximab- and Adalimumab-treated patients. The anti-integrin agent, Vedolizumab, had no impact on liver steatosis (0.66±0.03 vs 0.67±0.04 dB/cm/MHz) and ALT level dynamic (47±4 vs 45±5, p=0.29). Both groups of agents had no impact on patients’ lipid profile dynamic. We found no correlation between liver steatosis level and CRP and fecal calprotectin dynamic. Conclusion In the short term, we observed potential beneficial effects of anti-TNFα agents on liver steatosis of IBD patients with proven NAFLD.

THE USE OF IMMUNOMODULATORS, BIOLOGIC THERAPIES AND SMALL MOLECULES IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE AND SOLID ORGAN TRANSPLANTS

Abstract INTRODUCTION Over the past 20 years, the number of solid organ transplants (SOT) for a variety of indications has been on the rise. Consequently, more patients with inflammatory bowel diseases (IBD) are also receiving SOT. Although SOT related immunosuppression may at times control IBD related inflammation, many patients still require additional immunosuppressive medications for control of their IBD. With the growing therapeutic armamentarium for IBD, physicians are in search for guidance on the safety of using additional immunosuppressive medications in patients who are already receiving transplant related immunosuppressive medications. METHODS We performed a review of published literature that addressed the use of immunomodulators, biologic agents, and small molecules in patients with IBD who also had a SOT. We searched PubMed, Scopus, MEDLINE, and Google Scholar databases for studies published on the topic in English between January 1st, 1910, and August 1st, 2022. We have included data from systematic reviews, meta-analyses, case reports and case series to assess the safety, effectiveness, and side effects of immunomodulators, biologic therapies and small molecules in patients with liver, renal and/or heart transplantations. RESULTS We identified 25 publications on liver transplants, 6 on renal transplants, and 1 on heart transplants in patients with IBD. Among liver transplant patients, the most common immunosuppressive medications used were tacrolimus, mycophenolate mofetil, cyclosporine and steroids. In patients with IBD, anti-TNF agents (infliximab and adalimumab) were used in SOT with no major adverse safety concerns. The most common adverse events included infections (Clostridioides difficile and CMV) and malignancies (colon cancer). As for anti-integrin agents (vedolizumab and natalizumab) and ustekinumab, their efficacy and safety were mainly reported in patients with liver transplant on tacrolimus with no major adverse events reported. For patients with renal transplant, the main immunosuppression used were cyclosporine and tacrolimus. The combination of these immunosuppressive drugs with either anti-TNF therapy or ustekinumab had a good safety profile with rare malignancy occurrence. In one case report with heart transplant in a patient with IBD and on tacrolimus, no complications were reported. CONCLUSION SOT has become the mainstay for treating several common diseases. As such, gastroenterologists will care for more patients with IBD who have had a SOT. From this extensive review, the use of anti-TNF, anti-integrin agents and ustekinumab seem to be safe in patients with SOT, regardless of their transplant related immunosuppression which is usually comprised of tacrolimus, cyclosporine, and prednisone. More studies are needed in patients with renal and heart transplant and in patients treated with small molecules for their IBD.

Dietary Considerations for Inflammatory Bowel Disease Are Useful for Treatment of Checkpoint Inhibitor-Induced Colitis.

Checkpoint molecules are cell surface receptors on immune cells that mitigate excessive immune responses, but they have increased expression levels in cancer to facilitate immune escape. Checkpoint blockade therapies (e.g., anti-PD-1, anti-CTLA-4, and anti-LAG-3 therapy, among others) have been developed for multiple cancers. Colitis associated with checkpoint blockade therapy has pathophysiological similarities to inflammatory bowel disease (IBD), such as Crohn's disease and ulcerative colitis. Current therapeutic guidelines for checkpoint blockade-induced colitis include corticosteroids and, if the patient is refractory to steroids, immunomodulating antibodies, such as anti-TNF and anti-integrin agents. Interestingly, immunomodulatory molecules, such as TNFα, are upregulated in both IBD and checkpoint-mediated colitis. The inflammatory colitis toxicity symptoms from checkpoint blockade are similar to clinical symptoms experienced by patients with IBD. The pathophysiologic, dietary, and genetic factors associated with IBD will be reviewed. We will then explain how the principles developed for the treatment of IBD can be applied to patients experiencing inflammatory bowel toxicity secondary to checkpoint blockade.

Ustekinumab Is Associated with Real-World Long-Term Effectiveness and Improved Health-Related Quality of Life in Crohn's Disease

BackgroundProspectively and systematically collected long-term real-world clinical data on ustekinumab (anti-interleukin-12/23) are still scarce.AimsTo assess the long-term effectiveness of ustekinumab in patients with active Crohn’s disease (CD).MethodsThis is a prospective multicenter study of adult patients with CD initiating ustekinumab according to recommended doses at 20 Swedish hospitals. The primary outcome was clinical remission (Harvey–Bradshaw Index (HBI) ≤ 4 points) at weeks 52 and 104. Secondary outcomes included clinical response (≥ 3-point-decrease in HBI among patients with initial HBI ≥ 5 points), treatment retention, and biomarkers (C-reactive protein (CRP), hemoglobin, fecal-calprotectin) at weeks 52 and 104 compared to baseline. We also reported Health-related Quality of Life (HRQoL) measures.ResultsOf 114 included patients, 107 (94%) had previously failed ≥ 1 and 58 (51%) ≥ 2 anti-tumor necrosis factor agents. Forty (35%) had failed anti-integrin agents. Ustekinumab retention rates at weeks 52 and 104 were 70% (n = 80/114) and 61% (n = 69/114), respectively. Clinical response was seen in 36% (n = 25/69) and 29% (n = 20/69) of the patients, and remission was achieved in 32% (n = 31/96) and 29% (n = 28/96) at weeks 52 and 104, respectively. Median HBI and CRP levels decreased significantly at both timepoints as compared to baseline. Significant improvements were also observed in HRQoL. Adverse events were reported in 11% (n = 13/114) of the patients, including five cases of severe adverse events. No malignancies were observed.ConclusionsIn this nationwide prospective real-world 104-week-follow-up study of adult patients with active CD, ustekinumab was associated with long-term clinical effectiveness and improvement in HRQoL measures when used in routine clinical care.

Essential updates 2020/2021: Colorectal diseases (benign)-Current topics in the surgical and medical treatment of benign colorectal diseases.

The development of new drugs for inflammatory bowel disease (IBD) is remarkable, and treatment strategies using multiple agents and various techniques are required; however, the treatment strategy is likely to be complex. Therefore, appropriate evaluation of traditional surgical treatment strategies and accurate knowledge of the efficacy and limitations of novel treatments are required. Total infectious complications were found to be associated with the use of corticosteroids and anti‐tumor necrosis factor‐α agents, but not with immunomodulators, anti‐integrin agents, and 5‐aminosalicylic acid. Regarding surgical procedures for IBD, conceived anastomosis methods, including Kono‐S for Crohn's disease stenosis, are associated with better outcomes than conventional techniques. Autologous cell transplantation for Crohn's fistulae has been shown to have a favorable outcome. Diverticulitis is increasing and will be treated more frequently in the future. Risk factors for the incidence of diverticulitis and differences in pathogenesis according to right or left side diverticulitis have been reported. Antibiotic therapy may be omitted for uncomplicated diverticulitis. Moreover, regarding surgical procedures, both bowel resection and anastomosis are associated with favorable short‐term outcomes, higher stoma closure rate, and superior medical economy compared to Hartmann's procedure. Risk factors for recurrence after diverticulitis surgery may provide better postoperative follow‐up. In this review, we explore the current topics of colorectal benign diseases, focusing on IBD and diverticulitis, based on clinical trials and meta‐analyses from 2020‐2021. This review consolidates the available knowledge and improves the quality of surgical procedures and perioperative management for IBD and diverticulitis.

Anti-integrin drugs in clinical trials for inflammatory bowel disease (IBD): Insights into promising agents

Introduction Despite huge and increasing developments in the treatment of inflammatory bowel disease (IBD), a significant percentage of patients with Crohn’s disease (CD) and ulcerative colitis (UC) is still in need of an effective and safe therapeutic option. Tackling the trafficking of leukocytes specifically within or directed to the inflamed gut appears to be a particularly promising strategy, and several new anti-integrin agents are currently under investigation in clinical trials. Areas covered This review summarizes efficacy and safety data from phase 1, 2 and 3 clinical trials on investigational drugs, including monoclonal antibodies (etrolizumab, abrilumab, ontamalimab) and oral small molecules (AJM300, PTG-100). It also discusses the future perspectives for the treatment of IBD patients with this class of agents. Expert opinion The pipeline of anti-integrin agents is well assorted, and it is reasonable to expect that some will be introduced in the market soon. Among the most exciting features of this class are the gut selectivity, the convenient subcutaneous and oral administrations and the reassuring safety profiles. Most of the new anti-integrins seem to improve outcomes in UC but not in CD, however these data are far from definitive and several pivotal trials are still under way.

Risk of postoperative infectious complications from medical therapies in inflammatory bowel disease.

Medications used to treat inflammatory bowel disease (IBD) have significantly improved patient outcomes and delayed time to surgery. However, some of these therapies are recognized to increase the general risk of infection and have an unclear impact on postoperative infection risk. To assess the impact of perioperative IBD medications on the risk of postoperative infections within 30 days of surgery. We searched the Cochrane IBD Group's Specialized Register (29 October 2019), MEDLINE (January 1966 to October 2019), Embase (January 1985 to October 2019), the Cochrane Library, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform from inception up to October 2019, and reference lists of articles. Randomized controlled trials, quasi-randomized controlled trials, non-randomized controlled trials, prospective cohort studies, retrospective cohort studies, case-control studies and cross-sectional studies comparing participants treated with an IBD medication preoperatively or within 30 days postoperatively to those who were not taking that medication (either another active medication, placebo, or no treatment). We included published study reports and abstracts. Two review authors independently screened titles and abstracts and extracted data. The primary outcome was postoperative infection within 30 days of surgery. Secondary outcomes included incisional infections and wound dehiscence, intra-abdominal infectious complications and extra-abdominal infections. Three review authors assessed risks of bias using the Newcastle-Ottawa Scale. We contacted authors for additional information when data were missing. For the primary and secondary outcomes, we calculated odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs) using the generic inverse variance method. When applicable, we analyzed adjusted and unadjusted data separately. We evaluated the certainty of the evidence using GRADE. We included 68 observational cohort studies (total number of participants unknown because some studies did not report the number of participants). Of these, 48 studies reported including participants with Crohn's disease, 36 reported including participants with ulcerative colitis and five reported including participants with indeterminate colitis. All 42 studies that reported urgency of surgery included elective surgeries, with 31 (74%) of those also including emergency surgeries. Twenty-four studies had low risk of bias while the rest had very high risk. Based on pooling of adjusted data, we calculated ORs for postoperative total infection rates in participants who received corticosteroids (OR 1.70, 95% CI 1.38 to 2.09; low-certainty evidence), immunomodulators (OR 1.29, 95% CI 0.95 to 1.76; low-certainty evidence), anti-TNF agents (OR 1.60, 95% CI 1.20 to 2.13; very low-certainty evidence) and anti-integrin agents (OR 1.04, 95% CI 0.79 to 1.36; low-certainty evidence). We pooled unadjusted data to assess postoperative total infection rates for the use of aminosalicylates (5-ASA) (OR 0.76, 95% CI 0.51 to 1.14; very low-certainty evidence). One secondary outcome examined was wound-related complications in participants using: corticosteroids (OR 1.41, 95% CI 0.72 to 2.74; very low-certainty evidence), immunomodulators (OR 1.35, 95% CI 0.96 to 1.89; very low-certainty evidence), anti-TNF agents (OR 1.18, 95% CI 0.83 to 1.68; very low-certainty evidence) and anti-integrin agents (OR 1.64, 95% CI 0.77 to 3.50; very low-certainty evidence) compared to controls. Another secondary outcome examined the odds of postoperative intra-abdominal infections in participants using: corticosteroids (OR 1.53, 95% CI 1.28 to 1.84; very low-certainty evidence), 5-ASA (OR 0.77, 95% CI 0.45 to 1.33; very low-certainty evidence), immunomodulators (OR 0.86, 95% CI 0.66 to 1.12; very low-certainty evidence), anti-TNF agents (OR 1.38, 95% CI 1.04 to 1.82; very low-certainty evidence) and anti-integrin agents (OR 0.40, 95% CI 0.14 to 1.20; very low-certainty evidence) compared to controls. Lastly we checked the odds for extra-abdominal infections in participants using: corticosteroids (OR 1.23, 95% CI 0.97 to 1.55; very low-certainty evidence), immunomodulators (OR 1.17, 95% CI 0.80 to 1.71; very low-certainty evidence), anti-TNF agents (OR 1.34, 95% CI 0.96 to 1.87; very low-certainty evidence) and anti-integrin agents (OR 1.15, 95% CI 0.43 to 3.08; very low-certainty evidence) compared to controls. The evidence for corticosteroids, 5-ASA, immunomodulators, anti-TNF medications and anti-integrin medications was of low or very low certainty. The impact of these medications on postoperative infectious complications is uncertain and we can draw no firm conclusions about their safety in the perioperative period. Decisions on preoperative IBD medications should be tailored to each person's unique circumstances. Future studies should focus on controlling for potential confounding factors to generate higher-quality evidence.

Current Role of Anti-Integrin Therapy in Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a chronic inflammatory intestinal disorder with multifactorial etiology. Management of IBD is divided into conventional treatment and new treatment with biologic agents. The first biologic agents used for IBD was tumor necrosis factor (TNF)-inhibitor. However, TNF-inhibitor as a biologic agent has several limitations such as low rate of clinical response and systemic immunosuppressive side effects. Anti-integrin is a recently developed biologic agent which selectively inhibits leukocyte trafficking towards site of inflammation. The inhibition is caused by blocking the actions of integrin, a cell adhesion molecules (CAMs) that is necessary for leukocyte trafficking and leukocytes express specific integrin receptors for specific organs. Therefore, use of gut-specific anti-integrin agents in IBD can selectively prevent influx of leukocytes into the intestine to reduce inflammation without reducing immune function in other locations. As a result, gut-specific anti-integrin is hypothesized to have lower risk of infections and lower risk of malignancy than TNF-inhibitor while maintaining high therapeutic benefits, making anti-integrin a promising therapy for IBD in the future.

Approach to Latent Tuberculosis Infection Screening Before Biologic Therapy in IBD Patients: PPD or IGRA?

The use of biological agents for the treatment of chronic inflammatory conditions such as inflammatory bowel diseases (IBD) has been on the rise.1,2 Current biological therapies include antitumor necrosis factor-α (anti-TNF-α), anti-interleukin-12/23, and anti-integrin agents. Before initiation of biological drugs, screening for Mycobacterium tuberculosis infection is required to avoid reactivation or worsening of disease after immunosuppression. It has been shown that anti-TNF-α treated patients have a 14-fold increased risk of tuberculosis (TB) infection/reactivation compared with healthy controls.3 The methods for screening for TB have evolved over time and vary from region to region.

Safety of Immune Checkpoint Inhibitors in Patients With Pre-Existing Inflammatory Bowel Disease and Microscopic Colitis.

Enterocolitis is among the leading adverse events associated with immune checkpoint inhibitors (ICIs). There are limited retrospective data regarding the safety of ICIs in patients with inflammatory bowel disease (IBD; ulcerative colitis, Crohn's disease) because they have been generally excluded from clinical trials testing ICIs. Furthermore, there are no outcome data available in patients with microscopic colitis, a leading cause of chronic diarrhea. We aimed to study the safety of ICIs in patients with cancer with pre-existing IBD or microscopic colitis. We retrospectively reviewed the records of patients with cancer treated at our institution who received at least 1 dose of either a programmed cell death-1 (PD-1)/ PD-1 ligand inhibitor, cytotoxic T-lymphocyte-associated antigen 4 inhibitor, or both between 2011 and 2018. We identified patients with pre-existing IBD or microscopic colitis. Of 548 patients with solid tumor treated with an ICI, we identified 25 with pre-existing colitis (21 IBD; 4 microscopic colitis). An enterocolitis flare occurred in 7 patients (28%): 3 of 4 patients (75%) with microscopic colitis and 4 of 21 (19%) with IBD. All were treated with systemic corticosteroids, 2 required an anti-tumor necrosis factor agent, and one required an anti-integrin agent and colectomy for treatment of refractory colitis. ICI therapy was discontinued in all patients who experienced an enterocolitis flare. In our cohort, exacerbation of enterocolitis occurred in a notable percentage of patients with IBD and a majority of patients with microscopic colitis, leading to discontinuation of ICIs. Although these data suggest that patients with cancer with pre-existing IBD/microscopic colitis may be treated with ICIs, additional studies are needed to validate our results.

Optimizing Immunization Strategies in Patients with IBD.

Recent advances in the treatment of inflammatory bowel disease (IBD) include the use of immune modifiers and monoclonal antibodies, such as tumor necrosis factor (TNF) alpha inhibitors, anti-integrin agents, janus kinase inhibitors, and interleukin-12/23 inhibitors. These agents achieve higher rates of clinical remission and mucosal healing than conventional therapy. However, these therapies increase the risk of infections, including some vaccine-preventable diseases. Infections are one of the most common adverse event of immunosuppressive therapy. Thus, providers should optimize immunization strategies to reduce the risk of vaccine-preventable infections in patients with IBD. There are several newly licensed vaccines recommended for adults by the US Advisory Committee on Immunization Practices. This review will focus on how gastroenterology providers can implement the adult immunization schedule approved by ACIP for patients with IBD.

Risk of Postoperative Infectious Complications From Medical Therapies in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis.

To assess the impact of inflammatory bowel disease (IBD) medications on postoperative infection risk within 30 days of surgery. We searched multiple electronic databases and reference lists of articles dating up to August 2018 for prospective and retrospective studies comparing postoperative infection risk in patients treated with an IBD medication perioperatively with the risk in patients who were not taking that medication. Outcomes were overall infectious complications and intra-abdominal infections within 30 days of surgery. Sixty-three studies were included. Overall infectious complications were increased in patients who received anti-tumor necrosis factor (TNF) agents (odds ratio [OR] 1.26; 95% confidence interval [CI], 1.07-1.50) and corticosteroids (OR 1.34; 95% CI, 1.25-1.44) and decreased in those who received 5-aminosalicylic acid (OR 0.63; 95% CI, 0.46-0.87). No difference was observed in those treated with immunomodulators (OR 1.08; 95% CI, 0.94-1.25) or anti-integrin agents (OR 1.06; 95% CI, 0.67-1.69). Both corticosteroids and anti-TNF agents were associated with increased intra-abdominal infection risk (OR 1.63; 95% CI, 1.33-2.00 and OR 1.46; 95% CI, 1.08-1.97, respectively), whereas no impact was observed with 5-aminosalicylates, immunomodulators, or anti-integrin therapy. Twenty-two studies had low risk of bias while the remaining studies had very high risk. Corticosteroids and anti-TNF agents were associated with increased overall postoperative infection risk as well as intra-abdominal infection in IBD patients, whereas no increased risk was observed for immunomodulators or anti-integrin therapy. Although these results may result from residual confounding rather than from a true biological effect, prospective studies that control for potential confounding factors are required to generate higher-quality evidence.

P527 A review of adverse events associated with immunosuppressive treatments in inflammatory bowel disease patients

Abstract Background Medical therapies that suppress various pathways involved in inflammation comprise the mainstay of inflammatory bowel disease (IBD) treatment. Adverse events, including the development of serious infection and malignancy, have been associated with these therapies. This study evaluates the current evidence regarding serious adverse events associated with immunosuppressive agents in the IBD patient population. Methods A systematic search was conducted in September 2019 by combining three key research themes: inflammatory bowel disease, immunosuppression, and adverse events. For this systematic review, adverse events are defined as either the development or recurrence of malignancy or the development of serious infection necessitating hospital admission. Results There is a demonstrated association between thiopurine use and increased risk of both nonmelanoma skin cancer (NMSC) or lymphoma. The length of thiopurine exposure required to increase NMSC risk is, however, unclear. Of the papers reporting on exposure length and NMSC risk, the thiopurine exposure duration required to result in a statistically significant increase in NMSC risk varied from 6 months to 5 years. Among the studies retrieved, there is a lack of consensus on malignancy risk associated with the use of anti-TNF agents. From 5 studies on malignancy risk associated with the use of anti-TNF agents, one concluded that malignancy risk is increased while three concluded that risk is unchanged from baseline. The fifth study is inconclusive on any possible association. Confounding by past or concurrent thiopurine exposure remains an issue. There is a clear association between combination therapy with both thiopurines and anti-TNF agents and increased malignancy risk when compared with exposure to either thiopurine or anti-TNF therapy alone. Anti-integrin agents were not found to be associated with an increase in adverse effects when compared with placebo, while nil studies on ustekinumab were retrieved. Individual studies on infection risk do not consistently stratify infections according to severity, limiting any analysis. Conclusion An established association between thiopurine use and increased risk of both lymphoma or NMSC exists. However, the duration of thiopurine exposure necessary to increase NMSC risk is uncertain. There is a lack of consensus on whether anti-TNF agents increase malignancy risk due to confounding from past or concurrent thiopurine exposure. Combination therapy increases malignancy risk when compared with exposure to either thiopurine or anti-TNF therapy alone. Limited studies on the newer biologic therapies were retrieved. Finally, evidence which stratifies infections according to severity is lacking.

P010 Measurement of colonic mucosal content of biologics with the use of magnetic resonance imaging (MRI): A pilot study in patients with ulcerative colitis

Abstract Background Anti-tumour necrosis factor antagonists (infliximab) as well as other molecules with different modes of action, including anti-integrin agents (vedolizumab), are currently used in patients with ulcerative colitis (UC Numerous studies have demonstrated a positive correlation between serum biologic drug concentrations and favourable therapeutic outcomes, whereas low or undetectable drug concentrations can lead to treatment failure. However, despite immunological issues, lack of and or loss of response may also be attributed to drug pharmacokinetics, of which penetration to the target tissue (colon wall) may play a crucial role Methods We used MRI to perform biochemical analyses of infliximab, adalimumab and vedolizumab concentrations testing the hypothesis that MRI relaxation time can be used to track antibodies in both mucosal biopsy samples and serum. All MR scans were performed with an Optima MR360 from General Electric Healthcare. To determine spin–lattice (T1) and spin–spin (T2) relaxation times, the Fast Spin Echo (FSE) sequence was used. Results The measured values of T1 relaxation times for infliximab, adalimumab, and vedolizumab were 2227 ± 35 ms, 2000 ± 22 ms and 1288 ± 15 ms, respectively. The obtained T2 relaxation times were 130 ± 11 ms, 90 ± 5, and 75 ± 10 ms, respectively. A decrease of both T1 and T2 values of 15 ± 3% are observed in serum from patients with ulcerative colitis. The values of infliximab and adalimumab were similar; the values of vedolizumab measurements in serum were about 50% lower. We find primary evidence that in T1 and T2 decreased in serum samples with ulcerative colitis and increase with the administration of infliximab, adalimumab and vedolizumab drugs. Samples of healthy tissue have T1 and T2 in the range of 2700 ± 5 ms and 150 ms ± 5 ms, respectively. A 30% decrease in T1 and T2 are observed for samples with ulcerative colitis. In this pilot study, we observed that values of T1 and T2 for tissues and serum that contain infliximab and adalimumab are similar, but vedolizumab shows a difference of about 30% when compared with infliximab and adalimumab. Conclusion MRI is an excellent method for quantitative and qualitative measurements of drug content in tissues and biological fluids. This is an innovative use of magnetic resonance imaging to develop a methodology for imaging of drugs that act as contrast agents via interaction with water in serum and tissue.

Natural Products: Experimental Efficient Agents for Inflammatory Bowel Disease Therapy

Inflammatory bowel disease (IBD) is a chronic, elusive disorder resulting in relapsing inflammation of intestine with incompletely elucidated etiology, whose two representative forms are ulcerative colitis (UC) and Crohn's disease (CD). Accumulating researches have revealed that the individual genetic susceptibility, environmental risk elements, intestinal microbial flora, as well as innate and adaptive immune system are implicated in the pathogenesis and development of IBD. Despite remarkable progression of IBD therapy has been achieved by chemical drugs and biological therapies such as aminosalicylates, corticosteroids, antibiotics, anti-tumor necrosis factor (TNF)-α, anti-integrin agents, etc., healing outcome still cannot be obtained, along with inevitable side effects. Consequently, a variety of researches have focused on exploring new therapies, and found that natural products (NPs) isolated from herbs or plants may serve as promising therapeutic agents for IBD through antiinflammatory, anti-oxidant, anti-fibrotic and anti-apoptotic effects, which implicates the modulation on nucleotide- binding domain (NOD) like receptor protein (NLRP) 3 inflammasome, gut microbiota, intestinal microvascular endothelial cells, intestinal epithelia, immune system, etc. In the present review, we will summarize the research development of IBD pathogenesis and current mainstream therapy, as well as the therapeutic potential and intrinsic mechanisms of NPs in IBD.

ANTIINTEGRIN AVG3 SAV-RGD AS COMBINANT FOR DTIC WITH HUMAN AMELANOTIC SKIN MELANOMA

Introduction. The avB3 integrin (cell adhesion molecule) plays the role of the receptor, including, metalloproteinase matrix 2, involved in melanoma metastasis. We have been characterized as an antimelanoma original anti-integrin agent SAV-RGD (lyo-SAV-RGD), specifically binding to melanoma cells by means of the Arg-Gly-Asp tripeptide. More significant inhibited effect was obtained on amelanotic human skin melanoma MeWo. Accordingly, the experimental evaluation of the effectiveness of lyo-SAV-RGD in combination with the «gold» standard of antimelanoma chemotherapy dacarbazine (DTIC) is relevant. Objective: a comparative study of the combination of DTIC+lyo-SAV-RGD on the model of pigmented melanoma of human skin MeWo. Material and methods. The model of human skin melanoma MeWo in vivo/in vitro: s.c. xenografts in Balb/c nude mice, sensitive to DTIC cell line MeWo and obtained prospectively stable subline MeWo/DTIC was used. In vitro experiments the time of cell doubling in both models was determined and the individual range of agent concentrations was studied. Therapy with DTIC+lyo-SAV-RGD were administered in simultaneously sequentially, first the single 150 mg/kg DTIC, then lyo-SAV-RGD 9-fold course in the total dose of 900 mg/kg (the first dose is doubled). To control of the group with single dose 250 mg/kg of DTIC close to the maximum tolerated dose (MTD). All experiments were performed by standard methods using significant evaluation criteria and adequate statistical processing of the results (p<0.05). Results. For MeWo and MeWo/DTIC cells with a certain prospectively identical doubling time of the doubling time of tumor cells (Tpot) at the level of 23.0±2.3 h and 23.1±1.8 h, DTIC was practically non-cytotoxic, IC50=410±4 g/ml and IC50=860±27 g/ml (IC50<1o0 g/ml). However, the absolute value of the active concentrations of DTIC was significantly less known for murine pigmented melanoma, 1200-1400 g/ ml. Lyo-SAV-RGD, on the contrary, was cytotoxic for both melanoma variants at the same level, IC50=100±3.1 g/ml, and in the range from 1,0 to 100 g/kg caused cell death in direct dependence on the concentration. On s.c. MeWo xenografts DTIC at the dose of 250 mg/kg was effective at T/ C<30% (criterion T/C<42%) with partial death of mice from toxicity. The combination of DTIC+lyo-SAV-RGD showed an identical effect regardless of dose reduction by 40%, T/C=38% (p=0.001). Conclusion. A comparative study on the model of human skin melanoma MeWo revealed in vitro the absence of significant cytotoxicity of DTIC and at the same time cytotoxicity of anti-integrin avB3 lyo-SAV-RGD for MeWo and MeWo/DTIC cells. On xenografts MeWo combined therapy DTIC+lyo-SAV-RGD with dose reduction cytostatic 40% made it possible to obtain the maximum antitumor effect (T/C=38% vs 30%) with improved tolerability. The obtained data suggest that the introduction of anti-integrin avB3 into the scheme with DTIC is advisable to increase the selectivity of cytotoxic action of cytostatics.

Outcomes of Vedolizumab Treatment in Patients With Immune Checkpoint Inhibitor-Induced Diarrhea and Colitis: A Multi-Center Study

Introduction: Immune mediated diarrhea and colitis (IMDC) can limit immune checkpoint inhibitor (ICPI) treatment, which is an efficacious treatment for advanced malignancies. Given the immune mediated mechanism of this toxicity, steroids and infliximab are commonly used. These agents induce systemic immunosuppression with its associated morbidity. We aimed to assess clinical outcomes of vedolizumab (a gut-targeted anti-integrin agent) as an alternative treatment for IMDC. Methods: This is a retrospective case series of adults who had IMDC and received vedolizumab from 12/2016 to 4/2018 from MD Anderson Cancer Center and Medstar-Georgetown University Center. All patients had IMDC that is refractory to steroids and/or infliximab. Results: Total of 28 patients were included; 20 males (71%), 25 Caucasians (89%) with mean age of 63 years. The most common malignancy was melanoma in 7 patients (25%). According to ICPI regimen, 8 patients (29%) received anti-cytotoxic T lymphocyte associated antigen-4 (CTLA-4), 12 (43%) programmed death protein-1 or its ligand (PD-1/L-1) and 8 (29%) combination therapy. Median time from ICPI to IMDC onset was 10 weeks (IQR 1-70). Fifteen patients (54%) had grade 2 and 13 (46%) had grade 3 or 4 IMDC. Diagnostic evaluations for IMDCare shown in Table 1. Mucosal ulceration was present in 8 patients (29%), whereas non-ulcerative inflammation was present 13 (46%). All of our patients had features of active histological inflammation; 14 (50%) had features of chronicity, and 10 (36%) had features of microscopic colitis. The treatment and outcomes of IMDC are shown in Table 2. Mean duration of steroid treatment was 96 days (SD 74). Seven patients received infliximab in addition to steroids and were refractory to it. Median number of vedolizumab infusions was 3 (IQR 1-4) with a dose of 300 mg. Mean duration of follow-up in our study was 15 months. Twenty four patients (86%) achieved and sustained clinical remission. Repeat endoscopic evaluation was performed in 17 patients. Endoscopic remission was attained in 7 (54%) of the 13 patients who had abnormal endoscopic findings initially with 5/17 (29) patients reaching histological remission as well. Table 3 lists the characteristics of patients who had clinical remission. In our cohort, only 1 patient developed skin rash and 1 had joint pain. Conclusion: Vedolizumab can be appropriate for the treatment of steroid refractory IMDC, with favorable outcomes and good safety profile.110_A Figure 1 No Caption available.110_B Figure 2 No Caption available.110_C Figure 3 No Caption available.