Leyla J. Ghazi

Practice of gastroenterologists in treating flaring inflammatory bowel disease patients with clostridium difficile: antibiotics alone or combined antibiotics/immunomodulators?

Background: The optimal management of Clostridium difficile infection (CDI) in flaring inflammatory bowel disease (IBD) patients has not been defined. Limited data suggest that coadministration of immunomodulators (IM) with antibiotics (AB) results in a worse outcome. We investigated the prevalent practice among North American gastroenterologists in this scenario. Methods: A structured questionnaire presented the clinical cases of two hospitalized patients with ulcerative colitis and concomitant CDI, either with or without prior IM treatment. The questionnaire was distributed to a sample of gastroenterologists at medical centers across North America. Respondents were requested to denote their therapeutic choices for these patients. Results: The survey included 169 gastroenterologists, 122 from the US and 47 from Canada, with an average of 12 ± 10 years of experience in gastroenterology. Forty‐two (25%) of the respondents were IBD experts. Seventy‐seven (46%) respondents elected to add an IM in combination with AB, whereas 82/169 (54%) treated the flare with AB alone (P = NS). The rate of administering combined AB+IM was similar for the IBD experts and the non‐IBD experts. Only 11% of respondents withdrew maintenance azathioprine upon the diagnosis of CDI. More IBD experts stopped azathioprine treatment compared to the non‐IBD experts (12/42 versus 6/127, P < 0.001). Overall, 65% of surveyed gastroenterologists stated they believe these patients are afflicted by two simultaneous but separate disease processes. Conclusions: There is significant disagreement among gastroenterologists on whether combination AB+IM or AB alone should be given to IBD patients with CDI‐associated flares. Controlled trials are needed to investigate the optimal management approach to this clinical dilemma. (Inflamm Bowel Dis 2010;)

Patients with Refractory Crohn's Disease Successfully Treated with Ustekinumab.

Background:Ustekinumab is a new biologic therapy targeting interleukin-12 and interleukin -23. It is currently approved for the treatment of psoriasis, but clinical trials have shown that it can induce and maintain remission in Crohns disease (CD). We aim to evaluate effectiveness of ustekinumab in the treatment of CD. Methods:A retrospective chart review was performed including patients (pts) from 2 academic medical centers with complicated, refractory CD started on ustekinumab between June 2011 and June 2014. Pts were treated based on a novel subcutaneous dosing schedule designed to simulate the intravenous load used in clinical trials. Results:Forty-five pts were treated with ustekinumab during this study period. Of the pts who had clinical parameters available before and after medication start, 46% achieved clinical response (Harvey–Bradshaw index decrease ≥3) and 35% achieved clinical remission (Harvey–Bradshaw index ⩽3). Short inflammatory bowel disease questionnaire scores increased significantly (46 [20, 68] to 55 [32, 70], P < 0.05). Erythrocyte sedimentation rate decreased significantly (20 [3, 54] to 12 [0, 42] mm/h, P < 0.05). C-reactive protein decreased significantly (4.9 [0.3, 111] to 3.3 [0.2, 226] mg/L, P < 0.05). Seventy-six percent of patients demonstrated an endoscopic response and 24% achieved complete endoscopic remission. Twelve patients (26%) were hospitalized for IBD-related issues. Four pts had infection-related complications. Six pts (13%) underwent surgery for IBD-related issues. Three pts stopped ustekinumab, 1 for pt preference and 2 for the lack of response. Conclusions:Using a novel subcutaneous dosing schedule, ustekinumab was successful in improving clinical, laboratory, and endoscopic markers of disease activity in patients with severe, refractory CD.

Guidelines for the Multidisciplinary Management of Crohn's Perianal Fistulas: Summary Statement

P erianal fistulas are common manifestations of Crohn’s disease that can result in tremendous morbidity, including scarring, persistent drainage, and fecal incontinence. The typical course for patients with perianal Crohn’s disease includes long time periods of actively draining fistulas and frequent relapses. The risk of developing Crohn’s perianal fistulas increases the more distal the disease involvement. Only 12% of patients with isolated ileal disease develop a perianal fistula compared with 92% of patients with rectal involvement. The frequency of perianal fistulas in patients with Crohn’s disease range from 17% to 43% in reports from referral centers. Three population-based studies have shown similar rates of perianal fistulas between 21% and 23% in patients with Crohn’s disease. Approximately, 5% of individuals will have isolated perianal disease without any evidence of luminal inflammation. In Olmsted County, Minnesota population, perianal disease was present at or before time of diagnosis in 45% of cases; 55% were found at median of 4.8 years (8 d–18.7 yr) after diagnosis. This underscores the difficulty in making the diagnosis of Crohn’s disease in patients who present with only perianal pathology. Natural history studies done before the widespread use of anti-tumor necrosis alpha antibodies (anti-TNF) found that 71% of patients with Crohn’s perianal fistulas required at least 1 operation for their perianal disease. Nearly, one-third of the patients required a major operation such as a proctectomy, proctocolectomy or diverting ileostomy because of refractory disease. It is unclear if the use of anti-TNF agents has decreased these surgical rates. ANATOMY A working knowledge of the perianal anatomy is needed to better understand the etiology and classification schemes for Crohn’s perianal fistulas. The anal canal comprised 2 muscular cylinders (Fig. 1). The internal anal (IAS) sphincter is formed from the continuation of the circular smooth muscle layer of the muscularis propria of the rectum. The external anal sphincter (EAS) is formed from the downward extension of skeletal muscle from the puborectalis muscle. The skeletal muscle above the puborectalis fans out to form the levator ani muscles. This serves to divide the perineum from the abdominal cavity. A potential space called the intersphincteric plane lies between the 2 sphincters. It contains fat and the longitudinal muscle. The dentate line separates the transitional and columnar epithelium of the rectum from the squamous epithelium of the anus. The dentate line is usually located at the middle portion of the IAS. Anal crypts are present at the dentate line. Anal glands exist at the base of many of these crypts and occasionally penetrate into the intersphincteric space and may be one of the sources for the development of perianal fistulas.

Guidelines for Medical Treatment of Crohn's Perianal Fistulas: Critical Evaluation of Therapeutic Trials

C rohn’s perianal fistulas are a common and debilitating complication of Crohn’s disease (CD). Patient’s who develop perianal fistulas often suffer from persistent drainage, pain, and incontinence. Understandably, this frequently leads to a poor quality of life. The damage caused by Crohn’s perianal fistulas can be worsened by improper treatment such as over aggressive surgical intervention or failure to recognize the manifestations of the disease process itself. Perianal fistulizing disease is a common manifestation of CD with approximately 21% to 23% of patients developing at least 1 perianal fistula during their lifetime. The risk of developing a perianal fistula is higher if there is active disease in the rectum. The treatment paradigm for treating Crohn’s perianal fistulas has changed rapidly since the development of anti-tumor necrosis alpha antibodies. The role of imaging and multispecialty care involving the gastroenterologist and the surgeon for these patients also continues to evolve. The accompanying articles “Guidelines for Imaging of Crohn’s Perianal Fistulizing Disease,” “Guidelines for the Surgical Treatment of Crohn’s Perianal Fistulas,” and “Guidelines for the Multidisciplinary Management of Crohn’s Perianal Fistulas: Summary Statement” propose clinical treatment guidelines for Crohn’s perianal fistulas based on the existing clinical data. The quality and efficacy of the data supporting or rejecting the use of a specific imaging modality, surgical intervention, or medical therapy are detailed in this technical review.

Step up versus early biologic therapy for Crohn's disease in clinical practice.

Background:Recent studies have demonstrated superior outcomes of early biologic therapy. Our purpose was to evaluate differences in disease course among patients in clinical practice treated with early biologic therapy compared with those receiving conventional Step Up therapy. Methods:Patients with Crohns disease evaluated from July 2004 to November 2010 at a tertiary referral center were included. Demographic data were obtained from a prospectively maintained database. Patients were categorized into 1 of 2 groups: Early Bio group (with or without concomitant immune suppressants) or Step Up group (initial immune suppressants with or without escalation to biologic). Disease activity, quality of life, use of steroids, and number of hospitalizations, and surgeries were assessed. Results:Ninety-three patients with Crohns disease met inclusion criteria: 39 (45%) in the Step Up group and 54 (58%) in the Early Bio group. There was no significant difference in demographic and clinical variables between groups. Mean Harvey–Bradshaw index and Short Inflammatory Bowel Disease Questionnaire scores at 3, 6, and 12 months were not different between groups. Response rates were higher in the Step Up group compared with the Early Bio group only at 3 months. Early Bio patients had a greater number of hospitalizations at 1 year (P = 0.04). Conclusions:In clinical practice, early biologic therapy did not improve disease activity or quality of life and did not decrease the need for steroids or surgeries 1 year after therapy. Our results suggest that clinical outcomes are not worsened using the conventional approach. Therefore, an accelerated Step Up approach for most patients seems reasonable.

Guidelines for Imaging of Crohn's Perianal Fistulizing Disease

P erianal fistulizing disease is very common in patients with Crohn’s disease and has been reported in up to 38% of these patients. Moreover, the presence of complex or multiple fistulas is seen in up to 23% of this group of patients. Perianal fistulizing disease is traditionally diagnosed and assessed with clinical evaluation and EUA. Imaging, however, has been used increasingly in patients with Crohn’s disease and perianal fistulas to confirm the diagnosis and exclude other underlying causes of pelvic sepsis, to classify the fistula for surgical planning, to predict surgical outcome, to assess for recurrent disease, and to monitor medical therapy. In this article, we discuss the practical indications of imaging in patients with Crohn’s disease and perianal fistulas. We also address the inherent advantages and disadvantages of the vast array of imaging tests currently available and address the role of imaging in monitoring treatment options.

Magnetic resonance enterography: state of the art.

Abstract:Crohns disease is a chronic inflammatory bowel disease of the gastrointestinal tract manifested by frequent periods of relapses and remissions of symptoms. The small bowel is most frequently affected. Progression of transmural inflammation can lead to stricturing or penetrating complications. At the time of diagnosis, approximately 10% of patients have disease beyond the reach of the colonoscope. Imaging can aid in clinical evaluation by depicting small bowel involvement and extraenteric disease. Magnetic resonance enterography (MRE) has emerged as a valuable tool and is being used with increasing frequency for the diagnosis and management of Crohns disease. This article will discuss the current state of the art in MRE. In addition to reviewing the literature reporting its utility, we will present case examples illustrating how MRE best depicts the various findings of Crohns disease within 4 imaging categories of disease: active inflammatory, fibrostenotic, fistulizing/perforating, and reparative or regenerative. We will present additional important clinical considerations in routine use of MRE, including implications for monitoring disease activity and response to treatment, cost-effectiveness, and appropriate use in the context of the American College of Radiology Appropriateness Criteria.

Sexual dysfunction in inflammatory bowel disease.

Abstract:Sexual health is a broad term that encompasses a variety of functions including sexual thoughts, desire, arousal, intercourse, orgasm, and the impact of body image. Sexual dysfunction in individuals with inflammatory bowel disease is multifactorial including the impact of psychosocial factors, disease activity, medical therapies, surgical interventions, body image perceptions and changes, hypogonadism, and pelvic floor disorders. Providers caring for patients with inflammatory bowel disease should be cognizant of these concerns and develop management plans and techniques for earlier diagnosis and treatment.

Telemedicine for Patients with Inflammatory Bowel Disease (Tele-IBD)

Background: Depression is common in patients with inflammatory bowel disease (IBD) and contributes to poor quality of life (QoL). The use of information technology for the remote management of patients with IBD is growing, but little is known about its impact on depressive symptoms (DS) and QoL. We aimed to evaluate the impact of telemedicine on DS and generic QoL in IBD patients. Methods: We analyzed data from the Telemedicine for Patients with IBD (TELE-IBD) study. During this 12-month clinical trial, patients were randomized to receive text message-based telemedicine weekly (TELE-IBD W), every other week (TELE-IBD EOW), or to standard care. Depressive symptoms and QoL were assessed over time with the Mental Health Inventory 5 (MHI-5) and the Short Form 12 (SF-12), respectively. We compared the change in MHI-5 and SF-12 (with separate physical (PCS) and mental component summary (MCS) scores) between the study arms. Results: A total of 217 participants were included in this analysis. After 1 year, there was no significant difference in the change in MHI-5 (TELE-IBD W +3.0 vs TELE-IBD EOW +0.7 vs standard care +3.4; P = 0.70), MCS (TELE-IBD W +1.4 vs TELE-IBD EOW +1.0 vs standard care +2.5; P = 0.89), and PCS scores (TELE-IBD W +0.4 vs TELE-IBD EOW +0.6 vs standard care +3.7; P = 0.06) between the groups. Conclusions: Text message-based telemedicine does not improve DS or QoL when compared with standard care in IBD patients treated at tertiary referral centers. Further studies are needed to determine whether telemedicine improves DS or QoL in settings with few resources.

Systemic and Terminal Ileum Mucosal Immunity Elicited by Oral Immunization With the Ty21a Typhoid Vaccine in Humans

Background & Aims Systemic cellular immunity elicited by the Ty21a oral typhoid vaccine has been extensively characterized. However, very limited data are available in humans regarding mucosal immunity at the site of infection (terminal ileum [TI]). Here we investigated the host immunity elicited by Ty21a immunization on terminal ileum–lamina propria mononuclear cells (LPMC) and peripheral blood in volunteers undergoing routine colonoscopy. Methods We characterized LPMC-T memory (TM) subsets and assessed Salmonella enterica serovar Typhi (S Typhi)–specific responses by multichromatic flow cytometry. Results No differences were observed in cell yields and phenotypes in LPMC CD8+-TM subsets following Ty21a immunization. However, Ty21a immunization elicited LPMC CD8+ T cells exhibiting significant S Typhi–specific responses (interferon-γ, tumor necrosis factor-α, interleukin-17A, and/or CD107a) in all major TM subsets (T-effector/memory [TEM], T-central/memory, and TEM-CD45RA+), although each TM subset exhibited unique characteristics. We also investigated whether Ty21a immunization elicited S Typhi–specific multifunctional effectors in LPMC CD8+ TEM. We observed that LPMC CD8+ TEM responses were mostly multifunctional, except for those cells exhibiting the characteristics associated with cytotoxic responses. Finally, we compared mucosal with systemic responses and made the important observation that LPMC CD8+S Typhi–specific responses were unique and distinct from their systemic counterparts. Conclusions This study provides the first demonstration of S Typhi–specific responses in the human terminal ileum mucosa and provides novel insights into the generation of mucosal immune responses following oral Ty21a immunization.