Agents In Inflammatory Bowel Disease Research Articles

Positioning biologics-A case-based discussion: Anti-tumor necrosis factor biological agents/biosimilars.

The case presentations discussed in this session underscored the importance of developing treatment strategies that are both effective in maintaining disease control and that are tailored to individual patient needs. For each case, the role of anti-tumor necrosis factor (anti-TNF) treatments was advocated. In both cases, anti-TNF treatment was seen as the most appropriate option based on the patient's age, presentation and, in one case, desire for pregnancy. In both case presentations, treatment using an anti-TNF therapy was considered appropriate based on the evidence presented below. The role of biosimilars was discussed. The availability of biosimilars on the Pharmaceutical Benefits Scheme (PBS) immediately reduces the cost of the originator drug and allows for tendering for individual contracts on a state or hospital basis in an attempt to reduce pharmaceutical costs. Tumor necrosis factor has long been recognized as a pivotal inflammatory mediator in many chronic immune-mediated diseases. The development of monoclonal antibodies directed against TNF that induce and maintain remission have revolutionized targeted treatment for inflammatory bowel disease (IBD).1 These treatments commonly result in mucosal healing associated with improved clinical outcomes. Anti-TNF biological agents are the current mainstay biological treatments for Crohn's disease and ulcerative colitis in Australia.2 Even though this class of drug was first subsidized by the PBS in 2007, optimizing their use has only occurred in recent years. The benefit of thiopurine co-therapy is well-recognized for infliximab,3 and there is some evidence that thiopurine co-therapy may provide benefit when used with adalimumab.4 The therapeutic drug monitoring (TDM) revolution has provided clinicians with additional tools for this class of drug, and the recent Australian consensus statements on TDM in IBD5 illustrate the appropriate role of TDM in anti-TNF treatment optimization. Interventional strategies based on TDM-guidance include relevant, objective clinical outcomes that will further our knowledge on the optimal use of these drugs. The rapidity of action of anti-TNF agents make them ideal for hospitalized IBD patients, especially in the setting of acute severe ulcerative colitis where infliximab remains the only viable biological agent to date.6 All these advantages make anti-TNF a highly suitable biological agent treatment option in the setting of refractory IBD. Currently, in Australia, the persistence of anti-TNF therapies is low, with a median persistence of ~50% at 3 years.7 Persistence is significantly lower in elderly subjects, which might reflect the willingness for these subjects to undergo surgical resection or the concerns over systemic-immunosuppression leading to the development of opportunistic infections and skin or hematological malignancies. As such, anti-TNF biological agents are not uniformly embraced, and there is a need for alternative drugs with a lower potential for serious adverse effects. Alternative non-anti-TNF biological agents are now available and are more suitable in this subset of the IBD population. Primary non-response and secondary loss of response result in treatment failures and switch within- and out of class.5 The additional listing of golimumab, a subcutaneous anti-TNF agent for the treatment of ulcerative colitis, onto the PBS for reimbursement will further increase the access of anti-TNF agents for Australian IBD patients. The availability of biosimilars and incentives for their use will further modify the anti-TNF therapy treatment landscape. Anti-TNF therapies have by far the most patient years of usage, volume of publications, safety data, and experience in pregnancy of all biological therapies and are at present the most used class of biological agents in IBD. RL serves on advisory boards for Aspen, AbbVie, Celgene, Ferring, Hospira, Janssen-Cilag, MSD, Pfizer and Takeda. He has received educational grants from Shire, Janssen-Cilag and Takeda.

Donkey milk lysozyme ameliorates dextran sulfate sodium-induced colitis by improving intestinal barrier function and gut microbiota composition

Donkey milk lysozyme (DML) is a potential therapeutic agent for inflammatory bowel disease (IBD), while the mechanism remains obscure. Here, we reported that DML ameliorated weight loss, colon damage and mucosal inflammation in colitis mice. Additionally, DML increased the expression of occluding and zonula occludens-1, and reduced that of claudin-2, thus improving mechanical barrier function. It also inhibited the expression of tumour necrosis factor-α and interleukin-13, and reduced the myeloperoxidase level for strengthen of immune barrier function. DML increased gut microbiota composition diversity, promoting growth of probiotics and inhibiting pernicious bacteria, indicating that DML played an important role in microbial barrier function. The X-ray structure of DML was determined, which contained a core structure with conserved active site. The different conformation and residues of binding subsites may indicate diverse binding ability to substrates. These results suggested that oral administration of DML is a promising novel therapeutic for treatment of IBD.

Synthesis and biological evaluation of pyridine-linked indanone derivatives: Potential agents for inflammatory bowel disease

A series of pyridine-linked indanone derivatives were designed and synthesized to discover new small molecules for the treatment of inflammatory bowel disease (IBD). Compounds 5b and 5d exhibited strongest inhibitory activity against TNF-α-induced monocyte adhesion to colon epithelial cells (an in vitro model of colitis). In TNBS (2,4,6-trinitrobenzenesulfonic acid)-induced rat colitis model, oral administration of the compounds 5b and 5d ameliorated colitis with significant recovery in altered expressions of E-cadherin, TNF-α and IL-1β expressions, indicating 5b and 5d as potential agents for therapeutics development against IBD.

Oligonucleotide-Based Therapies for Inflammatory Bowel Disease.

The growing understanding of the immunopathogenesis of inflammatory bowel diseases (IBDs) has contributed to the identification of new targets whose expression/activity can be modulated for therapeutic purposes. Several approaches have been employed to develop selective pharmaceutical compounds; among these, antisense oligonucleotides (ASOs) or synthetic oligonucleotides represent a valid option for inhibiting or enhancing, respectively, the expression/function of molecules that have been implicated in the control of IBD-related inflammation. In this context, data have been accumulated for the following compounds: alicaforsen, an ASO targeting intercellular adhesion molecule-1, a transmembrane glycoprotein that regulates rolling and adhesion of leukocytes to inflamed intestine; DIMS0150 and BL-7040, two oligonucleotides that enhance Toll-like receptor-9 activity; Mongersen, an ASO that inhibits Smad7, thereby restoring transforming growth factor-β1/Smad-associated signaling; STNM01, a double-stranded RNA oligonucleotide silencing carbohydrate sulfotransferase, an enzyme involved in fibrogenic processes, and hgd40, a specific DNAzyme inhibiting expression of the transcription factor GATA3. In this article, we review the rationale and the available data relative to the use of these agents in IBD. Although pre-clinical and phase II trials in IBD support the use of oligonucleotide-based therapies for treating the pathogenic process occurring in the gut of patients with these disorders, further work is needed to establish whether and which patients can benefit from specific ASOs and identify biomarkers that could help optimize treatment.

Proactive Therapeutic Drug Monitoring of TNF Antagonists in Inflammatory Bowel Disease.

Proactive therapeutic drug monitoring (TDM) to titrate tumor necrosis factor (TNF) antagonists has emerged recently as a tool to routinely monitor drug concentration to achieve target levels in patients with quiescent inflammatory bowel disease (IBD). The purpose of the present review article was to present available data exploring the concept of proactive TDM. While several observational studies have identified an association between proactive TDM and better IBD outcomes, 2 randomized controlled studies did not confirm this advantage. Based on the evidence to date, proactive TDM cannot be recommended in daily practice. However, analysis is hampered by the low level of evidence for the cutoffs used and the need for point-of-care assays. Regarding economic issues and de-escalating strategies, proactive TDM may have several future indications in IBD. Exploratory studies on proactive TDM with newly available biologic agents in IBD are also awaited.

Efficacy and Safety of Anti–TNF-α Agents in Inflammatory Bowel Disease After Liver Transplant: A Case Series

BackgroundUlcerative colitis (UC) and Crohn disease (CD) can appear de novo or worsen after liver transplant. Our aim was to assess the efficacy and safety of anti–tumor necrosis-alpha (anti–TNF-α) agents after transplantation. MethodsWe reviewed the clinical database of our center searching for all liver transplant patients with inflammatory bowel disease who were treated with anti–TNF-α agents between 1997 and 2017. Clinical response was assessed from clinical activity indices 12 weeks after starting treatment. The median age of the 6 patients (3 women) was 37 years. Four patients were diagnosed before transplantation (2 UC and 2 CD), and in the other 2 the disease appeared de novo (1 UC and 1 CD). The indications for transplant were primary sclerosing cholangitis (n = 3), cryptogenic cirrhosis (n = 2), and hepatitis C virus cirrhosis (n = 1). ResultsClinical response was seen in 3 of the 6 patients and, in the 3 cases for whom endoscopic data were available, no mucous healing was seen. The only adverse effects noted over a mean follow-up of 15 months were 1 cytomegalovirus infection and 1 severe infusion reaction to infliximab. No patients had recurrence of primary sclerosing cholangitis in the graft, and none of the patients died. ConclusionUse of an anti–TNF-α agent in a liver transplant patient with inflammatory bowel disease may be an effective option, with an acceptable risk-benefit ratio. Further studies are required to confirm their use in this context.

Novel Therapies and Treatment Strategies for Patients with Inflammatory Bowel Disease.

This article reviews current treatment options and strategies and provides an update on the status of drug development programs of new therapeutic agents for inflammatory bowel diseases (IBD). In the past two decades, tumor necrosis factor antagonist therapy has given clinicians better treatment options. However, not all patients respond to induction therapy with these agents, and of those initially responding, up to 40% ultimately lose response due to suboptimal drug exposure (e.g., caused by immunogenicity), side effects, or other poorly characterized mechanisms. Recently, additional therapies, such as vedolizumab, an integrin blocker that prevents T cell trafficking to the gut, and ustekinumab, an antibody blocking the common p40 subunit of interleukin (IL)-12 and 23, were introduced to the market. In addition, other agents including novel anti-trafficking therapies (e.g., anti-β7 and sphingosine-1-phosphate receptor modulators), antibodies against p19 (unique to IL-23), and small molecules including Janus kinase inhibitors are under investigation in phase II and III trials. Furthermore, the management of IBD has evolved from targeting control of symptoms to suppression of mucosal inflammation. This shift in thinking has been accompanied by the early use of highly effective therapy in poor prognosis patients, accelerated treatment escalation and utilization of a treat to target paradigm approach, and adoption of therapeutic drug monitoring. The treatment landscape for IBD is rapidly evolving with the recent approval of novel biologics as well as several other agents in late phase of clinical development. Moreover, we have started to use agents more intelligently with a focus on risk stratification and early use of highly effective therapy in high-risk patients, treat to target using patient-reported outcomes (PROs), biomarkers, endoscopy, and therapeutic drug monitoring.

Anti-Tumor Necrosis Factor-α-Induced Dermatological Complications in a Large Cohort of Inflammatory Bowel Disease Patients.

The broader use of anti-tumor necrosis factor (TNF) agents in inflammatory bowel disease (IBD) has been associated with a high rate of adverse reactions. Dermatological complications are among the most common adverse events. We assessed the incidence, risk factors, management, and outcome of anti-TNF-induced dermatological complications in a large cohort of IBD patients. This was an observational retrospective study at a single tertiary referral center. All consecutive adult IBD patients treated with anti-TNF agents between 2005 and 2015 were identified. Patients who developed at least one dermatological complication while on anti-TNF therapy were included. From the 732 patients treated with anti-TNF agents, 211 (29%) developed at least one dermatological complication: 52% women (mean age of 42±13years), 85% with Crohn's disease, 67% were under infliximab. Median follow-up time under anti-TNF therapy was 53 (27-77) months. Dermatological complications recorded were: infections (13.5%), psoriasiform lesions (5.3%), injection/infusion reactions (3.8%), skin cancer (0.5%), and miscellaneous (5.6%). Overall, female gender (OR=1.658, p=0.029), smoking (OR=2.021, p=0.003), and treatment with an infliximab dose of 10mg/kg (OR=2.012, p=0.007) were independent risk factors for dermatological complications in multivariable analysis. Female gender (OR=3.63, p=0.017), smoking (OR=2.846, p=0.041), and treatment with adalimumab (OR=8.894, p<0.001) were independently associated with development of psoriasiform lesions. Three (3%) patients with infectious complications and 12 (31%) patients with psoriasiform lesions discontinued anti-TNF therapy definitively. Dermatological manifestations occurred in almost one-third of our population. Infections were the most common complication, but anti-TNF-induced psoriasiform lesions were the most common cause for anti-TNF therapy definitive discontinuation.

P748 Clinical outcomes and prognostic factors of methotrexate therapy in combination with anti-TNF agents in inflammatory bowel disease

Combination therapy with an immunomodulator and anti-tumour necrosis factor (TNF) is one of the crucial therapeutic strategies for inflammatory bowel disease (IBD) management. Methotrexate (MTX) is a second-line immunomodulator and has received much attention in recent years due to several advantages over thiopurine. We aimed to investigate clinical outcomes and prognostic factors of MTX therapy when combined with anti-TNF in IBD patients. We retrospectively reviewed 70 IBD patients (Crohn’s disease [n = 57], Ulcerative colitis [n = 13]) (age, 18–63 years) treated with MTX in combination with anti-TNF agents for induction or maintenance therapy at Severance and Gangnam Severance Hospital, Seoul, Korea. 22 (31.4%) were initially commenced on oral and 48 (68.6%) started subcutaneous route. Initial MTX dosage was 7.5–25.0 mg/week. Drug data for MTX therapy and outcomes data for clinical efficacy were analysed. Moreover, sustained clinical benefit of MTX therapy which was defined as ongoing use of MTX or intentional discontinuation of successful therapy before last follow-up was also evaluated. Recruitment algorithm. A total of 49 patients were selected for the analysis of induction therapy, and steroid free clinical remission was achieved in 22 (44.9%) of the 49 patients at 3 months, 13 (50.0%) of the 26 patients at 12 months, and 4 (44.4%) of the 9 patients at 24 months. Co-therapy with second line anti-TNF agent was associated with a failure of clinical remission at 3 months (odds ratio [OR]: 0.084, 95% confidence interval [CI]: 0.009–0.838). Meanwhile, 60 patients were selected for the analysis of maintenance therapy, and 17 (28.3%) patients experienced relapse during follow-up period of 3–26 months. Anaemia (Haemoglobin < 11 mg/l) at maintenance initiation was independent predictor of relapse (hazard ratio [HR]: 3.847, 95% CI: 1.153–12.829). Factors related with failure of sustained clinical benefit of MTX in combination therapy were obesity (≥23 kg/m2) (HR: 4.117, 95% CI: 1.380–12.296), concomitant adalimumab (vs. infliximab) therapy (HR: 3.872, 95% CI: 1.419–10.571), and female sex (HR: 3.271, 95% CI: 1.119–9.561). Adverse event related with MTX occurred in 24 (34.3%) patients, and 3 (4.3%) patients discontinued MTX due to adverse event. MTX therapy in combination with anti-TNF was relatively well tolerated. The type of combined anti-TNF agents and baseline patient characteristics rather than the MTX dosage and administration route were crucial factors in determining clinical outcome.

Killed Vaccines Are Effective in Infants of Mothers on Biologics for IBD

With the exception of certolizumab-pegol, biologic agents for inflammatory bowel disease (IBD) cross the placenta and are measurable in newborns' blood

Tauroursodeoxycholic acid protects bile acid homeostasis under inflammatory conditions and dampens Crohn's disease-like ileitis

Bile acids regulate the expression of intestinal bile acid transporters and are natural ligands for nuclear receptors controlling inflammation. Accumulating evidence suggests that signaling through these receptors is impaired in inflammatory bowel disease. We investigated whether tauroursodeoxycholic acid (TUDCA), a secondary bile acid with cytoprotective properties, regulates ileal nuclear receptor and bile acid transporter expression and assessed its therapeutic potential in an experimental model of Crohn's disease (CD). Gene expression of the nuclear receptors farnesoid X receptor, pregnane X receptor and vitamin D receptor and the bile acid transporters apical sodium-dependent bile acid transporter and organic solute transporter α and β was analyzed in Caco-2 cell monolayers exposed to tumor necrosis factor (TNF)α, in ileal tissue of TNFΔARE/WT mice and in inflamed ileal biopsies from CD patients by quantitative real-time polymerase chain reaction. TNFΔARE/WT mice and wild-type littermates were treated with TUDCA or placebo for 11 weeks and ileal histopathology and expression of the aforementioned genes were determined. Exposing Caco-2 cell monolayers to TNFα impaired the mRNA expression of nuclear receptors and bile acid transporters, whereas co-incubation with TUDCA antagonized their downregulation. TNFΔARE/WT mice displayed altered ileal bile acid homeostasis that mimicked the situation in human CD ileitis. Administration of TUDCA attenuated ileitis and alleviated the downregulation of nuclear receptors and bile acid transporters in these mice. These results show that TUDCA protects bile acid homeostasis under inflammatory conditions and suppresses CD-like ileitis. Together with previous observations showing similar efficacy in experimental colitis, we conclude that TUDCA could be a promising therapeutic agent for inflammatory bowel disease, warranting a clinical trial.

Corticosteroids and Thiopurines, But Not Tumor Necrosis Factor Antagonists, are Associated With Cytomegalovirus Reactivation in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis.

The association between cytomegalovirus (CMV) reactivation and individual immunosuppressive agents in inflammatory bowel disease (IBD) has not been clearly defined. Therefore, we performed a systematic review and meta-analysis to assess this association. Multiple electronic databases were searched systematically through July 2015 for observational studies reporting CMV reactivation (based on serum-based or tissue-based tests) in IBD patients stratified by medication exposure. We estimated summary odds ratios (ORs) and 95% confidence intervals (CI) using random-effects model. Study quality was assessed using the Newcastle-Ottawa scale. Sixteen observational studies were identified. As compared with nonexposed patients, exposure to corticosteroids (CS) (12 studies, 1180 patients, 52.3% exposed; OR, 2.05; 95% CI, 1.40-2.99) and thiopurines (14 studies, 1273 patients, 24.1% exposed; OR, 1.56; 95% CI, 1.01-2.39) was associated with increased risk of CMV reactivation. In contrast, as compared with patients not exposed to tumor necrosis factor (TNF) antagonists, exposure to TNF antagonists was not associated with an increased risk of CMV reactivation (7 studies, 818 patients, 18.5% exposed; OR, 1.44; 95% CI, 0.93-2.24). The results remained stable for CS and thiopurines when the analysis was limited to hospitalized patients, and by a tissue-based diagnosis. Studies were limited in the ability to assess the impact of concomitant immunosuppressive therapy, duration of medication exposure, and disease severity. On the basis of 16 observational studies, exposure to CS or thiopurines, but not TNF antagonists, was associated with an increased risk of CMV reactivation in IBD patients.

P.05.3: Limitations and Difficulties in using Anti-TNF Alpha Agents in Inflammatory Bowel Disease. A Survey of the Italian Group for Inflammatory Bowel Disease (IG-IBD)

P.05.3: Limitations and Difficulties in using Anti-TNF Alpha Agents in Inflammatory Bowel Disease. A Survey of the Italian Group for Inflammatory Bowel Disease (IG-IBD)

Vitamin D in pediatric gastrointestinal disease.

The purpose of this review is to examine the prevalence of vitamin D deficiency in pediatric gastrointestinal disease, specifically celiac disease and inflammatory bowel disease (IBD); to discuss the role of vitamin D and its deficiency in gastrointestinal disease pathophysiology; and to present current literature regarding diagnosis and treatment of vitamin D deficiency in these pediatric gastrointestinal diseases. Vitamin D deficiency is common in children with gastrointestinal symptoms and disease processes. In celiac disease, vitamin D status should be routinely assessed at the time of diagnosis and during subsequent follow up if deficient. There is growing evidence to suggest an inverse association between vitamin D and IBD activity; however, the therapeutic role of vitamin D in IBD patients requires further investigation. Suboptimal vitamin D status commonly occurs in children with gastrointestinal disease. It is advisable to check serum 25-hydroxy vitamin D levels in children with newly diagnosed celiac disease and IBD. In celiac disease, vitamin D status should be assessed during subsequent follow up if deficient. In IBD, 25-hydroxy vitamin D levels should be checked at least yearly. Therapy should be provided to maintain a level of greater than 30 ng/ml but less than 100 ng/ml; however, the ideal vitamin D dosing regimen to treat vitamin D deficiency and to maintain this optimum level remains unknown. The role of vitamin D as a therapeutic agent in IBD is still under investigation.

P574 Limitations and difficulties in using anti-TNF-alpha agents in inflammatory bowel disease. A survey of the Italian Group for Inflammatory Bowel Disease (IG-IBD)

P574 Limitations and difficulties in using anti-TNF-alpha agents in inflammatory bowel disease. A survey of the Italian Group for Inflammatory Bowel Disease (IG-IBD)

Effect of Immunomodulators and Biologic Agents on Malignancy in Patients with Inflammatory Bowel Disease

Immunosuppressive agents and biological agents are widely used for therapy in patients with inflammatory bowel disease (IBD). However, these therapies may be associated with an increased risk of malignancy. There is evidence that exposure of the therapeutic agents such as thiopurine and anti-tumor necrosis factor for IBD is associated with an increased risk of lymphoproliferative disorders, skin cancers, or uterine cervical cancers. This article reviews the malignancies associated with the use of immunosuppressive agents and biological agents in IBD.

The consequences of Campylobacter infection.

The purpose of this review is to provide an update on the clinical, public health and economic consequences of Campylobacter infection. Campylobacter is a leading bacterial cause of food-related illness. Its importance is enhanced by the chronic sequelae that can result from acute infection. Recent advances include a new clinical classification system for neurological sequelae with the aim of speeding accurate diagnosis and appropriate treatment, a better understanding of the mechanisms underlying postinfectious functional gastrointestinal disorders, the emergence of Campylobacter concisus and Campylobacter showae as potential aetiological agents in inflammatory bowel disease, a new mechanism for antimicrobial resistance in campylobacters and a better appreciation of the economic costs. Campylobacter infection is very common and can lead to serious chronic sequelae and considerable personal, healthcare and societal costs.

Serology of Viral Infections and Tuberculosis Screening in an IBD Population Referred to a Tertiary Centre of Southern Italy.

Background With the introduction of more potent immunosuppressive agents in inflammatory bowel disease, prevention of opportunistic infections has become necessary by introducing screening programs. Prevalence of the most important infectious agents may vary in different geographical areas. The aim of our study was to assess the immune status for hepatitis B, varicella, mononucleosis, and cytomegalovirus infection together with the determination of the hepatitis C and tuberculosis status in Southern Italy. Methods Prevalence of latent tuberculosis, together with serology of hepatitis B and C, Epstein-Barr virus, varicella zoster, and cytomegalovirus were collected by analysing retrospectively the clinical charts of IBD patients. Data were integrated with demographic and clinical features. Results Data from 509 IBD patients divided in two age groups showed a prevalence of HBV infection in nonvaccinated patients of 9%. Seroprotection (HBsAb) in vaccinated IBD patients was lower (p < 0.0001) compared with that in controls. Prevalences of herpesvirus infections fluctuate between 51% (CMV) and 85% (EBV) and 84% (VZV) in younger patients. Latent tuberculosis and hepatitis C infection were found only in patients > 37 years of age. Conclusions In younger patients, high susceptibility rates for primary herpesvirus infections should determine the choice of treatment. Loss of HBV seroprotection in already vaccinated patients should be considered for booster vaccination programs.

QseC inhibition as an antivirulence approach for colitis-associated bacteria

Hosts and their microbes have established a sophisticated communication system over many millennia. Within mammalian hosts, this dynamic cross-talk is essential for maintaining intestinal homeostasis. In a genetically susceptible host, dysbiosis of the gut microbiome and dysregulated immune responses are central to the development of inflammatory bowel disease (IBD). Previous surveys of stool from the T-bet-/-Rag2-/- IBD mouse model revealed microbial features that discriminate between health and disease states. Enterobacteriaceae expansion and increased gene abundances for benzoate degradation, two-component systems, and bacterial motility proteins pointed to the potential involvement of a catecholamine-mediated bacterial signaling axis in colitis pathogenesis. Enterobacteriaceae sense and respond to microbiota-generated signals and host-derived catecholamines through the two-component quorum-sensing Escherichia coli regulators B and C (QseBC) system. On signal detection, QseC activates a cascade to induce virulence gene expression. Although a single pathogen has not been identified as a causative agent in IBD, adherent-invasive Escherichia coli (AIEC) have been implicated. Flagellar expression is necessary for the IBD-associated AIEC strain LF82 to establish colonization. Thus, we hypothesized that qseC inactivation could reduce LF82's virulence, and found that an absence of qseC leads to down-regulated flagellar expression and motility in vitro and reduced colonization in vivo. We extend these findings on the potential of QseC-based IBD therapeutics to three preclinical IBD models, wherein we observe that QseC blockade can effectively modulate colitogenic microbiotas to reduce intestinal inflammation. Collectively, our data support a role for QseC-mediated bacterial signaling in IBD pathogenesis and indicate that QseC inhibition may be a useful microbiota-targeted approach for disease management.

Genetic Associations with Adverse Events from Anti-TNF Therapy in IBD Patients: 2016 ACG Presidential Poster Award

Introduction: Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract that includes Crohn's disease (CD) and ulcerative colitis (UC). Anti-TNF agents are effective therapies for IBD patients, but adverse events such as infusion reactions, allergic reactions, and infections limit the use of these medications. The objective of this study was to identify genetic associations with adverse events to anti-TNF agents in IBD subjects.Figure 1Methods: This study was a retrospective review of patients at Cedars-Sinai IBD Center. Patients included in the study were those that had given consent, had Immunochip data available and carried a diagnosis of IBD (Crohn's disease ulcerative colitis, or IBDU) and who had been treated with anti-TNF agents (infliximab, adalimumab, and certolizumab pegol for CD; infliximab, adalimumab, and golimumab for UC). Adverse events were identified by chart review. Standard and rigorous QC criteria were applied to the genetic data, which was generated using Immunochip. Genetic association was assessed by logistic regression after correcting for population structure. Results: Altogether we identified 1317 IBD subjects exposed to anti-TNF agents in whom Immunochip data were available. 65/1317 (4.94%) subjects developed infusion reactions; 88/1317 (6.68%) subjects developed an allergic reaction; 12/1317 (0.91%) subjects developed a lupus like reaction; and 10/1317 (0.76%) developed an infection attributed to an anti-TNF. The development of any reaction was identifi ed in 187/1317 (14.2%). rs1505992 which is the known IBD SNP tagging PTGER4 was associated with allergic reaction to anti-TNF (p= 0.0054; OR 0.53). Of the known IBD-associated SNPs: rs6740462 tagging SPRED2 (p = 0.0049, OR 0.42); rs13300483 tagging TNFSF15 (p = 0.0085, OR 0.51); and rs7702331 tagging FOXD1/TMEM174 (p = 0.0089, OR 0.50) were all associated with infusion reactions. Other genetic associations with adverse events are shown in the tables. Conclusion: Our data have implicated a number of IBD-associated SNPs in adverse reactions to anti-TNF therapy in IBD subjects. In addition our data have implicated genes involved in: response to viral infection (STAT2, KIF4B); IL6 regulation (PTPN2); cAMP production (ADCY8); and endoplasmic reticulum function (SEC61B). Additional studies will be needed to replicate and extend these findings and to see if these findings together with other modalities are able to identify patients at high-risk of anti-TNF associated adverse events.