Refractory Colitis Research Articles

S726 Fecal Transplantation Improved Patients’ Reported Outcome After Immune Checkpoint Inhibitor Colitis

Introduction: Immune checkpoint inhibitors (ICIs) have become standard treatment for cancers poorly responsive to traditional chemotherapy. The most common GI toxicity of this class of drugs is ICIs colitis (IMC) associated with difficulty to treat chronic diarrhea and risk of fatality. We have previously demonstrated that fecal microbiota transplantation (FMT) was effective in the treatment of a small number of refractory cases suggesting the gut microbiome is involved in the pathogenesis of ICIs colitis. Further large studies are needed to determine its efficacy. Methods: The present study summarizes our experience with FMT treatment of 37 patients with refractory ICIs colitis. We measured the efficacy of FMT and patients’ reported outcome (PRO) via established MD Anderson Symptom Inventory (MDASI). Among them, 9 patients had concurrent CDI as well at the time of diagnosis. (Table) Results: Thirty-seven patients included in our study, with a median age of 59 years and mostly had genitourinary cancers (35.1%) followed by melanoma (27.0%). Most patients had a peak CTCAE diarrhea grade ≥ 3 (91.9%) and colitis grade ≥ 2 (89.1%). Ulcerous (18, 48.6%) and non-ulcerous (12, 32.4%) inflammation was predominant endoscopic findings. 36 (97.3%) patients received corticosteroids, and 33 (89.1%) received add-on infliximab or vedolizumab. IMC symptom response was 83.7% after FMT with median time to response of 5 days. The rate of complications is 16.2% at 7 days and 5.4% at 30 days, and mostly were transient and mild. Response rate among 28 patients without concurrent CDI was 85.7%. Thirty-five (94.6%) patients demonstrated colitis remission at the last follow up. On the PRO analysis, we observed a favorable trend of significant patient-reported symptom reduction on diarrhea during 12 weeks after FMT, along with improved daily physical functioning on working. (Figure) Conclusion: Evidence is accumulating to suggest that efficacy and prevention of ICI related toxicities is dependent upon a healthy diverse microbiome. In the present study, we have shown that FMT achieved 83.7% success rate in patients with IMC with a favorable safety profile. FMT could become a preferred treatment option for the IMC in the future practice.Figure 1.: Patients Reported Outcome Summary Table 1. - Characteristic before FMT No. (%) (n=37) Concurrent CDI# 9 (24.3%) Highest grade of diarrhea of initial IMC onset – no. (%) 1 or 2 3 (8.1%) 3 or 4 34 (91.9%) Highest grade of colitis of initial IMC onset – no. (%) 1 4 (10.8%) 2- 4 33 (89.2%) Initial endoscopic findings – no (%), n=36 Ulcers 18 (48.6%) Non-ulcer inflammation 12 (32.4%) Normal 6 (16.2%) Hospitalizations – no. (%) 29 (78.3%) Median duration of hospitalization – days (IQR) 8 (5-13) Treatment of GI adverse events – no. (%) Steroid 36 (97.3%) Infliximab/vedolizumab added 33 (89.1%) FMT characteristic and outcome Symptom improvement after FMT, all patients – no (%) 31 (83.7%) Symptom improvement after FMT (no concurrent CDI, n=28) – no (%) 24 (85.7%) Median time from FMT to symptom improvement– days (IQR), n=37 5 (2-10) FMT-related complications within 7 days –no (%) 6 (16.2%) FMT-related complications within 30 days –no (%) 2 (5.4%) Colitis status at the end of the study period Clinical remission – no (%) 35 (94.6%) Persistent symptoms – no (%) 2 (5.4%)

Considerations when starting patients on multiple biologics and small molecules.

Inflammatory bowel disease (IBD) is complex disease that poses significant economic, and psychological burden on patients. Despite advent of newer biologics and small molecules targeting different aspects of immunopathogenesis, there appears to be a plateau in clinical outcomes. In this review we discuss the role of multiple biologics, existing evidence and various considerations when prescribing multiple biologics. Recent scientific advances helped to unravel the pathophysiology of inflammatory bowel disease and newer cytokines have been identified which can be potential targets in the management of IBD. Targeting more than one cytokine appears to be logical solution to break the therapeutic ceiling to improve clinical outcomes in IBD. The combination biologics appear safe and effective; however, the available evidence is limited. Refractory IBD, presence of other immune mediated inflammatory diseases and extra intestinal manifestations are currently the common considerations of combination biologics in IBD. Inflammatory bowel disease is a complex immune mediated disease with diverse clinical presentation and often has a complicated clinical course requiring multidisciplinary management. As the number of targeted therapies increases so does the concern on their safety and efficacy. Combination biologics though may appear to be safe, we need well designed prospective studies for firm conclusions.

Biologic Therapy for Refractory Immune Checkpoint Inhibitor Colitis.

Immune checkpoint inhibitors (ICI) are treatments for several cancer types. Pathogenesis of ICI-induced colitis is not yet clearly explained as it can be disguised as another form such as inflammatory bowel disease or IBD. Recent studies revealed that ICI-induced colitis is a unique form of colitis wherein the synergy of regulatory T cells with the gut microbiome is involved. Diagnosis of colitis can be done via endoscopic lesions and histopathological methods. A patient with colitis can be compared with someone who has IBD. Initial treatment is a corticosteroid. Cooperation between gastroenterologists and oncologists is required to understand further the complete diagnosis and management of different behaviors of ICI-induced colitis. Although immunotherapy provides breakthroughs in treating cancer, adverse effects cannot be prevented and have to be carefully addressed. This study aimed to discuss different biologic therapeutic perspectives in treating refractory immune checkpoint inhibitor-induced colitis. This review provided guidelines, challenges, and suggested protocols for drug immunosuppression.

Tofacitinib to Treat Severe Acute Refractory Colitis in a Teenager: Case Report and Review of the Literature.

We report a challenging case of a teenage boy with ASC at diagnosis and conduct a discussion after a review of the literature regarding the use of tofacitinib in inflammatory bowel disease, especially in pediatric patients and in ASC. The patient was hospitalized for 10 weeks and was refractory to conventional therapies: intravenous corticosteroids, infliximab, methotrexate, and vedolizumab. He received 7 blood transfusions and also presented with a severe malnutrition requiring a total parenteral nutrition. Tofacitinib was considered as a medical last resort before colectomy and was started at week 8. Thirteen days after starting tofacitinib, he was asymptomatic and was discharged on tofacitinib as sole treatment. By week 9 of tofacitinib, a colonoscopy showed both endoscopic and histological remission. He has remained in clinical remission at 6-month follow-up. Tofacitinib may be an alternative medical treatment to avoid colectomy in ASC. It is a small molecule with a rapid onset and few severe adverse events. It has been used for ASC in adult patients, allowing to avoid colectomy in more than 60%. To our knowledge, this is one of the few pediatric patients with refractory ASC at initial diagnosis who responded to tofacitinib.

Stem Cell-Based Therapies for Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a chronic, relapsing disease that severely affects patients’ quality of life. The exact cause of IBD is uncertain, but current studies suggest that abnormal activation of the immune system, genetic susceptibility, and altered intestinal flora due to mucosal barrier defects may play an essential role in the pathogenesis of IBD. Unfortunately, IBD is currently difficult to be wholly cured. Thus, more treatment options are needed for different patients. Stem cell therapy, mainly including hematopoietic stem cell therapy and mesenchymal stem cell therapy, has shown the potential to improve the clinical disease activity of patients when conventional treatments are not effective. Stem cell therapy, an emerging therapy for IBD, can alleviate mucosal inflammation through mechanisms such as immunomodulation and colonization repair. Clinical studies have confirmed the effectiveness of stem cell transplantation in refractory IBD and the ability to maintain long-term remission in some patients. However, stem cell therapy is still in the research stage, and its safety and long-term efficacy remain to be further evaluated. This article reviews the upcoming stem cell transplantation methods for clinical application and the results of ongoing clinical trials to provide ideas for the clinical use of stem cell transplantation as a potential treatment for IBD.

Management of refractory inflammatory bowel disease.

Nearly one-third of patients with inflammatory bowel disease (IBD) do not achieve remission despite our best therapies. When this happens, it is critical to understand the reason for treatment failure. Once nonresponse is confirmed, these patients should be referred to an IBD centre for multidisciplinary care. This review will discuss the remaining treatment options, including escalation of biologics to unlicensed doses, combination biologics, nonvalidated therapies and surgical options. It will additionally provide updates in the management of acute severe ulcerative colitis (ASUC). There is an increasing interest in combination biologics to treat refractory IBD, although data supporting its safety and effectiveness are limited. The use of hyperbaric oxygen, mesenchymal stem cell therapy and dietary interventions also show early promise in this area. Studies have additionally focused on personalized therapy to identify aggressive phenotypes and predict treatment response in these challenging patients. In ASUC, infliximab and cyclosporine remain mainstays of treatment, and tofacitinib shows promise as a salvage therapy. Refractory IBD is common, yet large knowledge gaps remain. Recent and ongoing studies have focused on medical, surgical and dietary approaches with mixed success. Larger prospective studies are desperately needed to address this complex issue.

The diagnosis and management of CMV colitis in IBD patients shows high practice variation: a national survey among gastroenterologists

Background Clinical guidelines on cytomegalovirus (CMV) colitis in inflammatory bowel disease (IBD) are hampered by the low quality of evidence. In this study, we aim to explore the attitude and management of CMV colitis in IBD among gastroenterologists. Methods A web-based survey was distributed to adult and pediatric gastroenterologists and trainees in academic and general hospitals in the Netherlands. The survey comprised data collection on respondents’ demographics, attitudes towards the importance of CMV infection in IBD on a visual analogue scale (from 0 to 100), and diagnostic and therapeutic strategies. Results A total of 73/131 invited respondents from 32 hospitals completed the survey (response rate of 56%). The importance of CMV infection was scored at a median 74/100. Respondents indicated CMV testing as appropriate in the clinical setting of steroid-refractory colitis (69% of respondents), hospitalized patients with active colitis (64%), immunomodulator or biological refractory colitis (55%) and active colitis irrespective of medication use (14%). CMV diagnostics include histology of colonic biopsies (88% of respondents), tissue CMV PCR (43%), serum CMV PCR (60%), CMV serology (25%) and fecal CMV PCR (4%). 82% of respondents start antiviral therapy after a positive CMV test on colonic biopsies (histology or PCR). Conclusions Most Dutch gastroenterologists acknowledge the importance of CMV colitis in IBD. Strategies vary greatly with regard to the indication for testing and diagnostic method, as well as indication for the start of antiviral therapy. These findings underline the need for pragmatic clinical studies on different management strategies, in order to reduce practice variation and improve the quality of care. Summary of the established knowledge on this subject: The clinical significance of CMV-associated colitis in IBD remains a matter of debate Recommendations regarding CMV colitis in current international guidelines are based on low to moderate evidence levels and different diagnostic strategies are proposed What are the significant and/or new findings of this study? We show that there is a high practice variation of diagnosis and management of CMV colitis in IBD amongst adult and pediatric gastroenterologists This study underlined the need for pragmatic studies and guidelines on different management strategies including cut-off values to start therapy

Refractory Immune Checkpoint Inhibitor Colitis successfully managed with Tacrolimus

Immune Checkpoint Inhibitor related colitis (“irColitis”) can range in severity from mild symptoms that may self resole with supportive therapy, to life-threatening disease. More severe cases require immunosuppression with corticosteroids or biologic therapies, but there is little evidence about what to do when these agents fail. In this article we present a case of irColitis that was refractory to established pharmacological treatments, but then resolved after introduction of Tacrolimus. Successful treatment of irColitis with Tacrolimus has not previously been reported and so this finding will be significant for future research studies and guidelines.

Interleukin 21‐induced Mitochondrial Dysfunction Drives Regulatory T Cell Inflammatory Response during Intestinal Inflammation

BackgroundSignificant proportion of inflammatory bowel disease (IBD) patients continue to respond inconsistently to therapies, underscoring disease complexity and the need for efficacious treatment. Interleukin 21 (IL‐21), which is known to support T helper (Th) cell function, is highly expressed within inflamed intestinal tissues of IBD patients compared to healthy controls. In addition, inflammatory regulatory T cells (Tregs) have been linked to refractory human IBD. Given that healthy Tregs are critical for self‐tolerance and prevention of IBD, we investigated the metabolic role of IL‐21 in instigating Treg dysfunction and the therapeutic ramifications of targeting metabolism pathways during IBD pathogenesis.MethodsHuman Tregs as well as relevant control effector Th cells were generated from naïve CD4+ T cells isolated from healthy blood donors. Microarray analysis was utilized for targeted metabolic transcriptional profiling. Immune phenotyping was assessed by fluorescence‐activated cell sorting. Metabolic phenotyping of cells was assessed by Seahorse flux analysis and mass spectrometry‐based metabolomics. Ultrastructural analysis of mitochondria was performed by confocal and transmission electron microscopy. Intestinal inflammation was induced in Rag1‐/‐ (T and B cell deficient) mice by the adoptive transfer of pathogenic naïve CD4+ T cells.ResultsAcute IL‐21 stimulation of human Tregs induced glycolysis and fluctuations in mitochondrial respiration (i.e. oxidative phosphorylation – OXPHOS), as assessed by Seahorse flux analysis. In agreement, microarray analysis, validated by qPCR, revealed an IL‐21‐mediated increase in the expression of genes associated with glycolysis and pathways known to support anabolic and OXPHOS metabolism, thus resembling a hypermetabolic state. Furthermore, IL‐21 stimulation rendered Tregs susceptible to inflammatory response, as evidenced by the production of effector Th cell‐associated cytokines such as interferon γ, tumor necrosis factor, IL‐17A, and IL‐17F. Exploring the mechanisms underlying IL‐21‐induced effects, we found significant disruption of mitochondrial integrity with concomitant activation of glycogen synthase kinase 3 (GSK3) β, a kinase known to prevent pyruvate entry into the mitochondria. IL‐21‐induced GSK3β activation was accompanied by a marked increase in intracellular and extracellular metabolites such as pyruvate and lactate, as assessed by metabolomics. Importantly, GSK3 inhibition or supplementation with mitochondrial membrane‐permeable methyl pyruvate broadly abrogated metabolic wiring of and inflammatory responses by IL‐21‐stimulated Tregs and effector Th cells. Collectively, these results suggest that impaired mitochondrial pyruvate metabolism is a feature of inflammatory CD4+ T cells. Lastly, GSK3 inhibition prevented pathogenic CD4+ T cell‐induced colitis in mice as evidenced by reduced Disease Activity Index, Mouse Colon Histology Index, and serum inflammatory cytokines.ConclusionsIL‐21 potently engages human Tregs in a hypermetabolic state that augments inflammatory cytokine production via induction of mitochondrial dysfunction. Therefore desensitizing CD4+ T cells to detrimental cues, such as IL‐21, may also augment Treg function during human IBD.

Metabolic Dysfunction Governs Regulatory T Cell Inflammatory Response during Inflammatory Bowel Disease

Abstract Background Significant proportion of inflammatory bowel disease (IBD) patients respond inconsistently to therapies, underscoring disease complexity. Interleukin 21 (IL21) is highly expressed during IBD. In addition to T helper (Th) cells, inflammatory regulatory T cells (Tregs) have been linked to refractory IBD. Thus, we explored the metabolic role of IL21 in inducing Treg dysfunction and IBD. Methods Human Tregs and Th cells were subjected to transcriptional profiling and metabolic phenotyping. Colitis was induced in Rag1−/− mice by naïve CD4 T cell adoptive transfer. Results IL21 stimulation of human Tregs induced glycolysis and OXPHOS. In agreement, IL21 enhanced the expression of genes associated with glycolysis, anabolism, and OXPHOS, leading to inflammatory cytokine production. Mechanistically, we found disruption to mitochondrial integrity with concomitant activation of glycogen synthase kinase 3 (GSK3) β, a kinase known to prevent mitochondrial pyruvate metabolism. IL21-induced GSK3β activation was accompanied by pyruvate and lactate buildup. Notably, GSK3 inhibition or supplementation with membrane-permeable methyl pyruvate abrogated metabolic wiring of and inflammatory responses by IL21-stimulated Tregs and effector Th cells. These results suggest that impaired mitochondrial pyruvate metabolism is a feature of inflammatory CD4 T cells. Lastly, GSK3 inhibition prevented pathogenic CD4 T cell-induced colitis in mice, as evidenced by reduced Mouse Colon Histology Index and serum inflammatory cytokines. Conclusions IL21 engages Tregs in a hypermetabolic state that augments inflammatory cytokine production. Therefore, desensitizing CD4 T cells to IL21 may also augment Treg function during IBD. Supported by NIDDK award K01DK124358, the Center for Cell Signaling in Gastroenterology (P30DK084567), and the Mayo Clinic Center for Biomedical Discovery.

Overexpression of programmed death ligand 1 in refractory inflammatory bowel disease

Programmed death ligand 1 (PD-L1) dysregulation has been implicated in chronic inflammatory diseases, but its role in regulating intestinal mucosa inflammation is still unclear. The aim of this study was to assess PD-L1 expression in the intestinal mucosa of patients with refractory inflammatory bowel disease (IBD) compared to controls. We evaluated PD-L1 expression by immunohistochemistry in colectomy specimens of patients with ulcerative colitis (UC) and Crohn disease (CD) compared to controls. PD-L1 expression was assessed in colonic epithelium and inflammatory cells, along with the location of the inflammatory cells expressing PD-L1. All cases were stained with CD3, CD4, CD8, FOXP3, CD20, CD68, and CD90 immunostains to determine the types of cells expressing PD-L1. The UC group showed significantly higher PD-L1 expression in the colonic epithelium than both CD and control groups (both P<0.001), and CD was also significantly higher than the control group (P=0.004). Both UC and CD groups showed similar PD-L1 expression in the inflammatory infiltrate but significantly higher than the control group (both P<0.001). Among both IBD groups, higher IBD activity was associated with higher levels of PD-L1 expression in the colonic epithelium (P<0.05) and inflammatory infiltrate (P<0.001). When comparing PD-L1 expression to lineage-specific markers, CD3+, CD4+ T cells, CD68+ macrophages, and CD90+ colonic stromal cells appeared to be expressing PD-L1. These findings implicate a role for PD-L1 in the dysregulation of the immune response in refractory IBD. Further studies are warranted to better understand the role of the immune regulatory pathways in intestinal mucosa.

The role of Parenteral Nutrition in the treatment of children with refractory Inflammatory Bowel Disease – an old hat newly discovered

Inflammatory Bowel Disease (IBD) presenting in childhood is associated with more extensive and aggressive disease compared to adults. Achievement of sustained mucosal healing whilst maintaining adequate growth and emotional wellbeing are key strategies in the management of children with IBD (1). Since immunomodulators and biological therapy have become available treatment options have improved dramatically over the last 20 years (2). However, there is still a group of children with severe IBD refractory to medication.

Efficacy of Infliximab Dose Escalation in Patients with Refractory Immunotherapy-Related Colitis: A Case Series.

Immune checkpoint inhibitor-related colitis is a common complication of immunotherapy use in patients with cancer. Current guidelines recommend treatment with standard dose infliximab (IFX) for corticosteroid-refractory colitis; however, this case series suggests IFX dose escalation may be a viable treatment option for refractory cases.

Combining biological therapies in patients with inflammatory bowel disease: a Finnish multi-centre study

Background and aims Therapy with two concomitant biologicals targeting different inflammatory pathways has emerged as a new therapy option for treatment refractory inflammatory bowel disease (IBD). Data on the efficacy and safety of dual biological therapy (DBT) are scarce and are investigated in this study. Materials and methods Data on all patients treated with a combination of two biologicals in four Finnish tertiary centres were collected and analysed. Remission was assessed by a physician on the basis of biomarkers, endoscopic evaluation and alleviation of symptoms. Results A total of 16 patients with 22 trials of DBT were included. Fifteen patients had Crohn’s disease. The most common combination of DBT was adalimumab (ADA) and ustekinumab (USTE; 36%) with median follow-up of nine months (range 2–31). Altogether seven (32%) patients were in remission at the end of follow-up and in two trials response to DBT was assessed to be partial with the relief of patient symptoms. In a total of four trials DBT reduced the need for corticosteroids. The majority of patients achieving a response to DBT were treated with the combination of ADA and USTE (56%). At the end of follow-up all nine (41%) patients responding to DBT continued treatment. Infection complications occurred in three patients (19%). Conclusion DBT is a promising alternative treatment for refractory IBD, and half of our patients benefitted from it. More data on the efficacy and safety of DBT are needed especially in long-term follow up.

Surgery for ulcerative colitis complicated with colorectal cancer: when ileal pouch\u2013anal anastomosis is the right choice

Patients with ulcerative colitis (UC) are at risk of developing a colorectal cancer. The aim of this study was to examine our experience in the treatment of ulcerative Colitis Cancer (CC), the role of the ileal pouch–anal anastomosis (IPAA), and the clinical outcome of the operated patients. Data from 417 patients operated on for ulcerative colitis were reviewed. Fifty-two (12%) were found to have carcinoma of the colon (n = 43) or the rectum (n = 9). The indication to surgery, the histopathological type, the cancer stage, the type of surgery, the oncologic outcome, and the functional result of IPAA were examined. The majority of the patients had a mucinous or signet-ring carcinoma. An advanced stage (III or IV) was present in 28% of the patients. Early (stage I or II) CC was found in all except one patient submitted to surgery for high-grade dysplasia, low-grade dysplasia, or refractory colitis. Thirty-nine (75%) of the 52 patients underwent IPAA, 10 patients were treated with a total abdominal proctocolectomy with terminal ileostomy. IPAA was possible in 6/9 rectal CC. Cumulative survival rate 5 and 10 years after surgery was 61% and 53%, respectively. The survival rate was significantly lower for mucinous or signet-ring carcinomas than for other adenocarcinoma. No significant differences of the functional results and quality of life were observed between IPAA patients aged less than or more than 65 years. Failure of the pouch occurred in 5 of 39 (12.8%) patients for cancer of the pouch (2 pts) or for tumoral recurrence at the pelvic or peritoneal level. Early surgery must be considered every time dysplasia is discovered in patients affected by UC. The advanced tumoral stage and the mucous or signet-ring hystotype influence negatively the response to therapy and the survival after surgery. IPAA can be proposed in the majority of the patients with a functional result similar to that of UC patients not affected by CC. Failures of IPAA for peritoneal recurrence or metachronous cancer of the pouch can be observed when CC is advanced, moucinous, localized in the distal rectum, or is associated with primary sclerosing cholangitis.

A201 A CASE OF SYPHILIS MASQUARADING AS CROHN’S DISEASE

BackgroundIt is important for gastroenterologists to keep syphilis on their differential. We present a case of rectal syphilis initially misdiagnosed as Crohn’s disease with commensal intestinal spirochetosis.AimsThis case highlights how rectal syphilis can present with endoscopic and clinical findings consistent with refractory inflammatory bowel disease.MethodsCase report and literature review.ResultsA 58 healthy male was referred for flexible sigmoidoscopy after having increased frequency of bowel movements, up to 10 per day, with mucous secretions at times mixed with blood and a 35lbs weight loss. He complained of urgency, tenesmus and intermittent incontinence. Endoscopy showed evidence of proctitis in the distal 10cm of the rectum with ulceration, edema and friability with biopsies showing moderately active colitis, compatible with ulcerative colitis.5-ASA suppositories and subseqent oral prednisone had no effect. A colonoscopy 3 months later again showed proctitis and ulceration. Biopsies at this time showed moderately active proctitis with chronic architectural distortion and intestinal spirochetosis identified on Warthin-Starry stain in the right colon and rectum. Given the patient was immunocompetent he was diagnosed with inflammatory bowel disease and trialed on oral and rectal 5-ASA.Four months later flexible sigmoidoscopy showed extensive distal rectal ulceration, biopsies positive for chronic proctitis and intestinal spirochetosis. Given no response to 5-ASA the patient was started on infliximab with a slight improvement but incomplete resolution of his symptoms. Repeat endoscopy showed continued rectal ulceration.Incidentally, the patient had a same sex sexual encounter and subsequently tested positive for syphilis with positive T. pallidum EIA and an RPR of 1:8. He received benzathine penicillin G 2.4 million units intramuscularly.After treatment with penicillin, the patient’s symptoms improved with no further hematochezia and decreased frequency. Flexible sigmoidoscopy showed normal mucosa with no evidence of ulceration indicating the initial proctitis and ulceration was secondary to infection by T. pallidum.ConclusionsSyphilis, known as the “Great imitator,” is on the rise in Canada, with cases of infectious syphilis increasing more than 259.5% over the past decade. Rectal syphilis is often misdiagnosed as it can present with variable symptoms including puritis, tenesmus, urgency of defecation and anal discharge that may be purulent, mucoid or bloody. Endoscopic findings include non-specific proctitis, masses, ulceration and pseudotumors. Diagnosis is made with serology as pathology cannot differentiate between commensal intestinal spirochetosis and T. pallidum.Given the diversity of presentations and rise in incidence, gastroenterologists need to ensure they take a thorough sexual history and keep syphilis on their differential when encountering this common clinical scenario.Funding AgenciesNone

Selecting the Best Combined Biological Therapy for Refractory Inflammatory Bowel Disease Patients.

Current medical treatment for inflammatory bowel disease (IBD) does not achieve 100% response rates, and a subset of refractory and severely ill patients have persistent active disease after being treated with all possible drug alternatives. The combination of two biological therapies (CoT) seems a reasonable alternative, and has been increasingly tested in very difficult cases. The present review suggests that CoT seems to be safe and effective for refractory and severely ill IBD patients. Ustekinumab plus vedolizumab and vedolizumab plus anti-TNF were the most used CoTs for Crohn’s disease. For ulcerative colitis, the most used CoTs were vedolizumab plus anti-TNF and vedolizumab plus tofacitinib. The aforesaid CoTs have shown good efficacy and few adverse events have been reported.

PRKAR2A-derived circular RNAs promote the malignant transformation of colitis and distinguish patients with colitis-associated colorectal cancer.

BackgroundEmerging studies have proved that colonic inflammation caused by refractory inflammatory bowel disease (IBD) can initiate the colitis‐associated cancer (CAC), but the transition from inflammation to carcinoma is still largely unknown.MethodsIn this study, mouse colitis and CAC models were established, and the RNA‐seq by circRNA microarray was employed to identify the differentially expressed circRNAs and mRNAs in different comparisons (DSS vs. NC and AOM/DSS vs. DSS). The bioinformatics analyses were used to search the common characteristics in mouse colitis and CAC.ResultsThe K‐means clustering algorithm packaged these differential expressed circRNAs into subgroup analysis, and the data strongly implied that mmu_circ_0001109 closely correlated to the pro‐inflammatory signals, while mmu_circ_0001845 was significantly associated with the Wnt signalling pathway. Our subsequent data in vivo and in vitro confirmed that mmu_circ_0001109 could exacerbate the colitis by up‐regulating the Jak‐STAT3 and NF‐kappa B signalling pathways, and mmu_circ_0001845 promoted the CAC transformation through the Wnt signalling pathway. By RNA blasting between mice and humans, the human RTEL1‐ and PRKAR2A‐derived circRNAs, which might be considered as homeotic circRNAs of mmu_circ_0001109 and mmu_circ_0001845, respectively, were identified. The clinical data revealed that RTEL1‐derived circRNAs had no clinical significance in human IBD and CAC. However, three PRKAR2A‐derived circRNAs, which had the high RNA similarities to mmu_circ_0001845, were remarkably up‐regulated in CAC tissue samples and promoted the transition from colitis to CAC.ConclusionsOur results suggested that these human PRKAR2A‐derived circRNAs could be novel candidates for distinguishing CAC patients and predicted the prognosis of CAC.

COMBINATION USTEKINUMAB AND VEDOLIZUMAB THERAPY FOR REFRACTORY INFLAMMATORY BOWEL DISEASE: A SINGLE INSTITUTION CASE SERIES

Abstract INTRODUCTION Over the past 20 years, there have been great strides in the medical management of Inflammatory Bowel Disease (IBD). The advent of anti-TNF mAb therapy was transformative in the management of IBD and the positive effects are well documented1,2,3. While anti-TNF mAb biologics induce and maintain remission in IBD, a substantial portion of patients are refractory4. Newer biologic agents such as ustekinumab (UST) and vedolizumab (VDZ) have expanded therapeutic options for patients; however, obtaining deep remission in a subset of IBD patients remains challenging. We previously reported a successful case of deep remission in a patient with refractory stricturing Crohn’s Disease (CD) treated with maximum dosage UST + VDZ therapy5. Since this report, we have expanded our use of this combination in refractory IBD with encouraging results. METHODS Fifteen refractory IBD patients (12 CD, 3 UC) at the University of Kentucky were selected to initiate dual biologic therapy (DBT) with UST and VDZ. All patients previously failed other therapies, but demonstrated partial response to escalated dosing (Q4 week) of either VDZ or UST monotherapy. To determine DBT response, we analyzed fecal calprotectin (FC), C-reactive protein (CRP), albumin, BMI, hemoglobin, Harvey Bradshaw Index (HBI)/Mayo scores, endoscopic and histologic appearance. Steroid-free remission was defined by one or more of the following: 1) endoscopic and histologic remission, 2) normalization of biomarkers (FC and CRP) or 3) clinical remission defined by normalization of clinical scores AND normalization of albumin, hemoglobin, and BMI. Clinical remission was only used when endoscopic or biomarker data was not available. RESULTS Among the 12 CD patients receiving dual biologic therapy, 11 met criteria for remission (91.6%). Six of these CD patients had complete endoscopic and histologic remission. Three CD patients did not have follow-up endoscopic or FC data, but did have normalization of albumin, CRP, hemoglobin, and HBI scores. Two CD patients were initiated on DBT for spikes in biomarkers (FC and CRP) despite clinical remission. These biomarkers normalized after initiation of DBT. One of the CD patients did not achieve response, and no one with UC (3 patients) responded. Among the successful cases, the average time to remission was 14.9 weeks. There were no adverse events or safety concerns. CONCLUSION Dual biologic therapy with combination ustekinumab and vedolizumab is a promising and safe option for patients with refractory CD, particularly in those who demonstrate a partial response to monotherapy of either agent. This combination was not successful in our UC patients. This case series adds further support for the effectiveness of VDZ+ UST combination therapy in CD. Continued investigation is merited to support routine clinical use and improve access to this combination therapy.

VEDOLIZUMAB FOR REFRACTORY MICROSCOPIC COLITIS: A CASE SERIES

Abstract INTRODUCTION Microscopic colitis (MC) is a chronic inflammatory disease of the colon that causes non-bloody, watery diarrhea occurs up to 15 times daily in the presence of normal-appearing mucosa in the colon. There are two main subtypes of MC based on histopathologic features, collagenous colitis (CC) and lymphocytic colitis (LC)1. Treatment of each subtype is similar and should be determined by the severity of symptoms. Some patients suffer severe symptoms despite maximum dosage of budesonide, in these cases biologic therapies should be considered. Vedolizumab, a monoclonal antibody that targets α4β7-integrin, is a gut-specific biologic with an exceptional safety profile. Here, we report our experience with vedolizumab for severe, refractory MC. METHODS Eleven patients presenting to the University of Kentucky with severe microscopic colitis refractory to maximum budesonide and Imodium therapy were treated with vedolizumab. Vedolizumab was given at standard induction dosing (300mg IV at week 0, 2 and 6, and then every 8 weeks). RESULTS Of the eleven patients included in this study, seven reported subjective symptomatic improvement on vedolizumab monotherapy, with four patients attaining less than 3 stools per day. Of the remaining four patients, one continues to do well on vedolizumab and budesonide combination therapy while another developed a rash after vedolizumab induction and treatment was stopped. The third patient was transitioned from vedolizumab to adalimumab and is now well controlled symptomatically and the final patient has not reached symptomatic remission of her disease. Interestingly, of the seven patients who displayed symptomatic improvement with vedolizumab monotherapy, 5/7 patients also showed improvement in albumin levels. DISCUSSION Vedolizumab use in refractory microscopic colitis is increasingly recognized as a conceivable therapy for symptomatic improvement and disease remission. Our case series corroborates these findings, as the majority of our patients reported overall improved quality of life. Vedolizumab binds to the α4β7-integrin and prevent adhesion to its ligand, MAdCAM-1, which causes downstream prevention of T-cell adhesion. Although the exact pathophysiology of microscopic colitis remains largely unidentified, it has been postulated that exposure to a luminal antigen may trigger an inflammatory cascade, leading to activation of CD8 T suppressor cells that attack and cause luminal damage to enterocytes2. This hypothesis is supported by vedolizumab’s mechanism of action and proposed efficacy in MC. Due to low volume studies, the data supporting vedolizumab use in refractory microscopic colitis remains limited, and further studies are needed to elucidate the its potential as a first-line therapy. However, based on our experience, we recommend considering vedolizumab for patients suffering from refractory MC.