Seema A. Patil

Mucosal-Associated Invariant T Cells in the Human Gastric Mucosa and Blood: Role in Helicobacter pylori Infection

Mucosal-associated invariant T (MAIT) cells represent a class of antimicrobial innate-like T cells that have been characterized in human blood, liver, lungs, and intestine. Here, we investigated, for the first time, the presence of MAIT cells in the stomach of children, adults, and the elderly undergoing routine endoscopy and assessed their reactivity to Helicobacter pylori (H. pyloriu2009–u2009Hp), a major gastric pathogen. We observed that MAIT cells are present in the lamina propria compartment of the stomach and display a similar memory phenotype to blood MAIT cells. We then demonstrated that gastric and blood MAIT cells are able to recognize H. pylori. We found that CD8+ and CD4−CD8− (double negative) MAIT cell subsets respond to H. pylori-infected macrophages stimulation in a MR-1 restrictive manner by producing cytokines (IFN-γ, TNF-α, IL-17A) and exhibiting cytotoxic activity. Interestingly, we observed that blood MAIT cell frequency in Hp+ve individuals was significantly lower than in Hp−ve individuals. However, gastric MAIT cell frequency was not significantly different between Hp+ve and Hp−ve individuals, demonstrating a dichotomy between blood and gastric tissues. Further, we observed that the majority of gastric MAIT cells (>80%) expressed tissue-resident markers (CD69+ CD103+), which were only marginally present on PBMC MAIT cells (<3%), suggesting that gastric MAIT cells are readily available to respond quickly to pathogens. These results contribute important new information to the understanding of MAIT cells function on peripheral and mucosal tissues and its possible implications in the host response to H. pylori.

Characterization and Functional Properties of Gastric Tissue-Resident Memory T Cells from Children, Adults, and the Elderly

T cells are the main orchestrators of protective immunity in the stomach; however, limited information on the presence and function of the gastric T subsets is available mainly due to the difficulty in recovering high numbers of viable cells from human gastric biopsies. To overcome this shortcoming we optimized a cell isolation method that yielded high numbers of viable lamina propria mononuclear cells (LPMC) from gastric biopsies. Classic memory T subsets were identified in gastric LPMC and compared to peripheral blood mononuclear cells (PBMC) obtained from children, adults, and the elderly using an optimized 14 color flow cytometry panel. A dominant effector memory T (TEM) phenotype was observed in gastric LPMC CD4+ and CD8+ T cells in all age groups. We then evaluated whether these cells represented a population of gastric tissue-resident memory T (TRM) cells by assessing expression of CD103 and CD69. The vast majority of gastric LPMC CD8+ T cells either co-expressed CD103/CD69 (>70%) or expressed CD103 alone (~20%). Gastric LPMC CD4+ T cells also either co-expressed CD103/CD69 (>35%) or expressed at least one of these markers. Thus, gastric LPMC CD8+ and CD4+ T cells had the characteristics of TRM cells. Gastric CD8+ and CD4+ TRM cells produced multiple cytokines (IFN-γ, IL-2, TNF-α, IL-17A, MIP-1β) and up-regulated CD107a upon stimulation. However, marked differences were observed in their cytokine and multi-cytokine profiles when compared to their PBMC TEM counterparts. Furthermore, gastric CD8+ TRM and CD4+ TRM cells demonstrated differences in the frequency, susceptibility to activation, and cytokine/multi-cytokine production profiles among the age groups. Most notably, children’s gastric TRM cells responded differently to stimuli than gastric TRM cells from adults or the elderly. In conclusion, we demonstrate the presence of gastric TRM, which exhibit diverse functional characteristics in children, adults, and the elderly.

Comparative Effectiveness of Anti-TNF Agents for Crohn’s Disease in a Tertiary Referral IBD Practice

BackgroundThe three Food and Drug Administration (FDA)-approved anti-tumor necrosis factor drugs (anti-TNFs) for Crohn’s disease (CD) have not been directly compared.AimTo compare the efficacy of the three anti-TNFs for CD in clinical practice.MethodsRetrospective review of patients initiated on anti-TNF between 2004 and 2008. Disease activity, quality of life, and remission rates were compared between groups over 1xa0year.ResultsSixty patients with CD were initiated on anti-TNF from 2004 to 2008: 31 on infliximab (IFX) and 29 on adalimumab (ADA) or certolizumab pegol (CTZ). More patients in the ADA/CTZ scores group had prior exposure to anti-TNF (76 versus 10xa0%, pxa0<xa00.01). Mean Harvey–Bradshaw Index (HBI) scores in the IFX group were lower than in the ADA/CTZ group at 12xa0months (2.72xa0±xa03.34 versus 5.63xa0±xa05.33, pxa0=xa00.03). At 12xa0months, more IFX patients were in remission compared with those on ADA/CTZ (88 versus 53xa0%, pxa0≤xa00.01). Mean Short Inflammatory Bowel Disease Questionnaire (SIBDQ) scores were not different between the IFX and ADA/CTZ groups at 12xa0months. Stratified analyses and logistic regression based on prior anti-TNF use did not show differences in remission rates at any time point post-baseline between groups.ConclusionsAfter adjustment for prior anti-TNF there was no difference in remission rates between the IFX and ADA/CTZ groups at any time point post-baseline. This suggests that differences between groups were accounted for by a higher rate of prior anti-TNF in the ADA/CTZ group. Our results should be reviewed with caution given the small sample size.

Update in the Management of Extraintestinal Manifestations of Inflammatory Bowel Disease

Inflammatory bowel disease, comprised of Crohn’s disease and ulcerative colitis, are chronic inflammatory disorders of the gastrointestinal tract. Up to 40xa0% of patients with inflammatory bowel disease can develop inflammation in other organ systems of the body. These extraintestinal manifestations (EIM) can affect the musculoskeletal, ocular, mucocutaneous, and hepatobiliary systems. Symptoms related to EIM can result in impaired quality of life, and complications of EIM can lead to disfigurement, functional deficits, and even life-threatening organ dysfunction. Some EIM parallel the activity of IBD, and respond to treatment of the underlying disease. Others, however, follow an independent course and require targeted treatment.

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.

Racial Differences in Disease Activity and Quality of Life in Patients with Crohn’s Disease

BackgroundThe existing literature on racial differences in Crohn’s disease (CD) activity and quality of life (QOL) is limited and extrapolated from surrogate measures.AimThe aim of our study was to compare objective markers of disease activity and QOL over time by race.StudyA clinical data repository of inflammatory bowel disease (IBD) patients at University of Maryland, Baltimore IBD Program, was used. CD patients from 2004 to 2009 were included if they had greater than or equal to two clinic visits with disease activity and QOL scores during the study period. Differences in disease activity and QOL were compared by race over time.ResultsA total of 296 patients with CD met inclusion criteria; of these, 19xa0% (56/296) were African Americans (AA) and 81xa0% (240/296) were Caucasian. Baseline disease activity and QOL scores did not differ by race (pxa0>xa00.05). Caucasians had a steady decline in disease activity and increase in QOL. AA experienced a similar pattern of change in disease activity and QOL scores over time; however, the declines were not statistically significant between groups. At each time point post-baseline, disease activity and QOL scores were similar between races.ConclusionWe found that Caucasian and AA patients with CD had similar disease activity and QOL scores at initial presentation and over time. Thus, AA do not represent a more severe subgroup of CD patients to treat. These findings have important implications for clinicians that care for patients with CD.

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.

Anti-TNF therapy is associated with decreased imaging and radiation exposure in patients with Crohn's disease.

Background:Diagnostic imaging is frequently used in Crohns disease (CD) for diagnosis, evaluation of complications, and determination of response to treatment. Patients with CD are at risk for high radiation exposure in their lifetime. The aim of our study was to compare the effective dose of radiation in CD patients the year prior to and the year after initiation of anti-tumor necrosis factor (anti-TNF) agents or corticosteroids. Methods:We conducted a retrospective review of 99 CD patients initiated on anti-TNF therapy or corticosteroids between 2004 and 2009 in a tertiary care center. Results:Sixty-five patients were initiated on anti-TNF agents and 34 were initiated on corticosteroids. The anti-TNF cohort was significantly younger at diagnosis and at the time of initiation of anti-TNF or steroid therapy. The anti-TNF group had significantly more stricturing, penetrating, and perianal disease than the corticosteroid group. The anti-TNF cohort had a significant reduction in number of radiologic exams (5.5 vs. 3.7, P < 0.01) as well as a significant reduction in the cumulative radiation dose (28.1 vs. 15.0 mSv, P < 0.01) the year after initiation of therapy. This reduction was largely attributable to decreased use of computed tomography (CT) scans. In contrast, there was no significant change in radiation exposure in the corticosteroid cohort. Logistic regression analysis showed a strong trend toward higher exposure in patients with complicated disease behavior (stricturing or penetrating phenotype) (odds ratio [OR] 2.87, 95% confidence interval [CI] 0.98–8.38). Conclusions:Initiation of anti-TNF therapy for treatment of CD is associated with a significant reduction in diagnostic radiation exposure. Conversely, steroid treatment does not reduce diagnostic radiation exposure.

Can you hear me now? Frequent telephone encounters for management of patients with inflammatory bowel disease.

Inflammatory bowel diseases (IBDs), including Crohn’s disease (CD) and ulcerative colitis, are chronic inflammatory conditions of the gastrointestinal tract that can result in debilitating symptoms, poor quality of life, and use of immunosuppressant medication, hospitalization, and surgery. The optimal management of IBD requires effective patient-provider communication. IBD is characterized by periodic exacerbations, the potential for adverse effects of therapy, and sometimes emergent complications; therefore, communication often occurs outside of scheduled office visits. A physician extender such as a nurse coordinator often is employed in busy IBD practices to enhance patient-provider communication during and between office visits. Ramos-Rivers et al conducted a prospective study to quantify and examine patterns of telephone encounters in a tertiary IBD center. A nurse coordinator was assigned to each IBD provider to handle telephone calls from the provider’s patients. All ingoing and outgoing calls from 2009 to 2010 were analyzed. In 2009, there were 21,979 calls made to and from 2475 patients (mean, 8.9 calls/patient). In 2010, there were 32,667 calls made to and from 3118 patients (mean, 10.5 calls/patient). Telephone encounters outnumbered office visits 2-fold. Approximately half of the calls were generated by the patient and an additional quarter of the calls were generated by the nurse for clinical reasons. Of the remaining calls, 12% were for prescription refills, 10% were for insurance authorization, and 1% were for form completion and record requests. Therefore, three fourths of calls were generated by patients or coordinators for clinical issues or care coordination. A subgroup of patients from an IBD registry were identified to analyze demographic and clinical characteristics associated with telephone encounters (n 1⁄4 764 in 2009, and n 1⁄4 801 in 2010). Patients were stratified into 4 categories by annual call volume: 0 to 1 telephone encounters per year (low telephone encounters [LTE]), 2 to 5 telephone encounters per year, 6 to 10 telephone encounters per year, and more than 10 telephone encounters per year (high telephone encounters [HTE]). Approximately 15% of patients were in the HTE category each year; however, these patients accounted for half of all calls to the referral center each year. Interestingly, HTE IBD patients changed over time because only 32% of HTE patients remained in this category the following year. Factors associated with HTE included female sex, a diagnosis of CD, a greater number of previous IBD surgeries, prednisone use, increased C-reactive protein level and sedimentation rate, narcotic use, psychiatric comorbidities, and chronic abdominal pain. Anti–tumor necrosis factor use was associated with HTE for CD but not for ulcerative colitis. HTE patients were more likely to have a diminished quality of life, as defined by a Short Inflammatory Bowel Disease Questionnaire score of less than 50, than those with LTE. HTE patients were more likely to use health care resources and HTE patients underwent more clinic visits, emergency room (ER) visits, and hospitalizations than LTE IBD patients. Thirty-six percent of HTE patients were seen in the ER compared with 6% of LTE patients (P < .001); similarly, 40% of HTE patients were admitted compared with 4% of LTE patients (P < .001). When the investigators analyzed clusters of telephone calls and subsequent ER visits or hospitalizations, they found that IBD patients with 8 or more telephone encounters over 30 days were 4 times more likely to visit the ER or to be hospitalized than patients with only 1 encounter. The authors of this study should be complimented for evaluating the burden of telephone encounters among patients with IBD at a tertiary IBD center. IBD providers are keenly aware of the volume of calls that this patient group generates as well as the value of a physician extender such as a nurse coordinator to assist with the call volume; however, few studies have documented the magnitude of the call burden, factors associated with increased telephone encounters, or the impact of a physician extender in handling calls in patients with IBD. A Cochrane review reported a trend toward improved mental health scores in IBD patients receiving nurse support; however, health care use among these patients was not reported. In an Australian study, IBD nurse intervention led to a significant reduction of outpatient assessments, ER visits, and hospitalizations. Similarly, a study from Cambridge compared use of health care resources the year before and the year after implementation of an IBD nurse. Hospital visits were reduced 38%, length of stay was reduced 19%, and patient satisfaction improved with use of an IBD nurse. During these tumultuous financial times in medicine, providers often are being asked to domorewith fewer resources. Based on the results of this study, approximately 125 ingoing or outgoing calls per day occur at large referral IBD centers. The vast majority of these calls are related to complex clinical care issues as opposed to simple medication refill requests. What is not known is the time spent on each telephone call as well as additional coordination time that stems from each call. We speculate that the time spent is significant. We anticipate that IBD providers will cite the study by Ramos-Rivers et al to both hospital and departmental administrators to garner support for additional resources tomanage this complex group of patients. In addition, Ramos-Rivers et al identify a subgroup of “at risk” IBD patients (HTE patients) who are more likely to experience poor outcomes and thus increased health care use. Previous studies also have reported an

Medical versus surgical management of penetrating Crohn’s disease: the current situation and future perspectives

ABSTRACT Introduction: The development of penetrating Crohn’s disease (CD) occurs in up to 50% of patients over the course of their lifetime. While the presentation of these complications, including free perforation, intra-abdominal abscess, and enteric fistula, are usually obvious, the management can require a nuanced approach, with distinct short and long-term approaches. Areas covered: This review discusses medical and surgical methods of treating these complications, including the role of percutaneous drainage of abscesses, the implications of a stricture associated with a fistula, and the efficacy of postoperative anti-TNF therapy in preventing recurrence after surgical treatment. Expert commentary: An approach to the management of these complications that begins with control of sepsis, including broad-spectrum antibiotics, bowel rest, and nutritional support is proposed. The next appropriate step is a diagnostic evaluation to determine the utility of medical versus surgical therapy, considering the presence of a stricture and prior immunosuppressive therapy. Postoperative anti-TNF therapy, a highly effective method to prevent recurrence, should be considered in many cases.