Hyperbaric oxygen therapy is well tolerated and effective for ulcerative colitis patients hospitalized for moderate-severe flares: a phase 2A pilot multi-center, randomized, double-blind, sham-controlled trial.

BACKGROUND: Hyperbaric oxygen therapy (HBOT) markedly increases tissue oxygen delivery. Case series suggest it may have a potential therapeutic benefit in ulcerative colitis (UC). We investigated the therapeutic potential of HBOT as an adjunct to steroids for UC flares requiring hospitalization. METHODS: The study was terminated early due to poor recruitment with 18 of the planned 70 patients enrolled. UC patients hospitalized for moderate-severe flares (Mayo score ≥6, endoscopic sub-score ≥2) were block randomized to steroids + daily HBOT (n = 10) or steroids + daily sham hyperbaric air (n = 8). Patients were blinded to study assignment, and assessments were performed by a blinded gastroenterologist. Primary outcome was the clinical remission rate at study day 5 (partial Mayo score ≤2 with no sub-score >1). Key secondary outcomes were: clinical response (reduction in partial Mayo score ≥2, rectal bleeding sub-score of 0-1) and progression to second-line therapy (colectomy or biologic therapy) during the hospitalization. RESULTS: A significantly higher proportion of HBOT-treated patients achieved clinical remission at study day 5 and 10 (50 vs. 0%, p = 0.04). HBOT-treated patients less often required progression to second-line therapy during the hospitalization (10 vs. 63%, p = 0.04). The proportion requiring in-hospital colectomy specifically as second-line therapy for medically refractory UC was lower in the HBOT group compared to sham (0 vs. 38%, p = 0.07). There were no serious adverse events. CONCLUSION: In this small, proof-of-concept, phase 2A trial, the use of HBOT as an adjunctive therapy to steroids for UC patients hospitalized for moderate-severe flares resulted in higher rates of clinical remission, and a reduction in rates of progression to second-line therapy during the hospitalization. Larger well-powered trials are needed, however, to provided definitive evidence of therapeutic benefit.

Risk Factors for Hidradenitis Suppurativa in Patients with Inflammatory Bowel Disease.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disorder characterized by recurrent nodules, abscesses, and sinus tracts that can be debilitating and significantly impair quality of life. Small studies and case reports have suggested a possible association between HS and inflammatory bowel disease (IBD). AIMS: We performed a case-control study to further characterize IBD patients with HS in terms of smoking status, BMI, sites affected by HS, IBD type and features, and IBD medication history. METHODS: A total of 38 patients with HS and IBD were identified and matched on age, gender, and IBD type to 136 controls with IBD but not HS. Clinical characteristics of interest were obtained through extensive review of the electronic health record. RESULTS: Among patients with HS and IBD, the most common sites affected by HS were the inguinal, perianal, and axillary regions. Relative to patients with IBD alone, patients with HS and IBD were nearly six times more likely to be current smokers (p < 0.01) and nearly 11 times more likely to be obese (p < 0.01). Patients with HS and Crohn's were significantly more likely to have ileocolonic and perianal disease than patients with CD only (OR 8.31, 95% CI 2.90-23.80 and OR 2.85, 95% CI 1.19-6.81, respectively; p < 0.01 for both). CONCLUSIONS: Relative to patients with IBD who do not develop HS, patients with IBD and HS are more likely to be overweight or obese, to be former or current smokers, and to have ileocolonic and/or perianal disease.

Validation of a tool predicting important findings on computed tomography among Crohn's disease patients.

BACKGROUND: Patients with Crohn's disease (CD) are frequently subjected to computed tomography (CT) in the emergency department (ED). This young population is at higher risk of malignancy from radiation exposure. OBJECTIVES: We aimed to validate a decision tool predicting complications (perforation, abscess or other serious finding) on imaging at two sites. METHODS: We conducted a retrospective review of CT outcomes among patients with CD with ED visits at two tertiary care centers. Inclusion criteria were a CT of the abdomen/pelvis with contrast and complete lab data (erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)) within 24 hours of arrival at the University of Michigan (UM) (2012-2013) and the University of Pittsburgh (UPMC) (2009-2012). Sensitivity, negative predictive value (NPV), miss rate and CT avoidance rate were calculated. RESULTS: At UPMC (n = 210), the tool had a sensitivity of 88.9% and NPV of 98.0%, potentially saving 47.1% from CT with a miss rate of 1.0%. At UM (n = 248), the tool had a sensitivity of 90.9% and NPV of 96.0%, saving 40.3% from CT with a miss rate of 1.6%. CONCLUSION: A decision tool using CRP and ESR predicting CT outcomes among CD patients performed well in an external validation, allowing providers to forgo CT use with a low miss rate.

Silent Crohn's Disease Predicts Increased Bowel Damage During Multiyear Follow-up: The Consequences of Under-reporting Active Inflammation.

BACKGROUND: Patients with Crohn's disease (CD) in clinical remission with elevated C-reactive protein (CRP) have been labeled "silent CD" and have increased 2-year hospitalization rates when compared with asymptomatic patients with no biochemical evidence of inflammation. The risk of cumulative bowel damage in patients with silent CD is unknown. METHODS: Observational study of patients with CD prospectively followed in a tertiary referral natural history registry. Consecutive patients with CD in clinical remission (Harvey-Bradshaw Index ≤ 4) with good quality of life (short inflammatory bowel disease questionnaire score ≥ 50), and same day CRP measurement at first encounter, followed for a minimum of 4 years formed the study population. Disease trajectory was determined using change in Lémann Index as a measure of bowel damage. RESULTS: A total of 185 patients with CD (median age 42 years; 51.4% men) were included in the study. CRP elevation was observed in 43 (23%) patients (Silent CD cohort). Majority of them showed worsening disease trajectories based on change in Lémann Index when compared with asymptomatic patients with normal CRP (65% versus 36%, P < 0.0001). Multinomial logistic regression analysis demonstrated that elevated CRP was independently associated with 7-fold higher odds (odds ratio = 6.93, P < 0.0001) of having worse disease trajectories when compared with stable disease trajectories. CONCLUSIONS: Two-thirds of patients with CD in clinical remission, while demonstrating elevated CRP, will develop bowel damage over the ensuing years, despite feeling well. These patients with silent CD are an "at-risk" group who warrant further investigation to prevent development of disease-related complications.

Patterns of Antibiotic Exposure and Clinical Disease Activity in Inflammatory Bowel Disease: A 4-year Prospective Study.

BACKGROUND: Antimicrobial treatment is known to cause short- and long-term changes in the composition of normal human microbiota. The relationship between antibiotic use and overall clinical behavior in inflammatory bowel disease (IBD) has not been explored. We aim to prospectively characterize patterns of antibiotic use and clinical IBD activity in a large IBD cohort. METHODS: Prospective observational study from a longitudinal IBD natural history registry between 2009 and 2012. Antibiotic prescriptions were identified and categorized using electronic medical record data. Cumulative rates over the 4-year study period were compared. Demographic, clinical, laboratory, health care utilization, and treatment data of the patients with IBD were collected and analyzed. Quality of life was measured by Short IBD Questionnaire data. Primary outcomes were markers of disease activity including Short IBD Questionnaire scores, C-reactive protein levels, health care utilization, and medication use. RESULTS: Seven hundred eighteen patients followed over 4 years were included (47.6% male; mean age, 46.7 ± 15.2 yr), 59.9% had Crohn's disease, whereas 38.6% had ulcerative colitis. Most patients (66.3%) were exposed to antibiotics during the study period. Antibiotic-exposed patients were more likely to have Crohn's disease (63% versus 53.7%; P = 0.05), require narcotics (43.7% versus 14.9%; P < 0.0001), receive antidepressants (43.1% versus 18.6%; P < 0.001), prednisone (52.7% versus 31%; P < 0.0001), or biological therapy (52% versus 36.5%; P < 0.0001). Antibiotic-exposed patients had a lower mean Short IBD Questionnaire (50.2 ± 11.5 versus 56.4 ± 9.5; P < 0.0001), higher rates of C-reactive protein elevation (49.2% versus 31.8%; P < 0.0001), and higher health care utilization compared with nonantibiotic-exposed patients. CONCLUSIONS: The majority of patients with IBD receive antibiotic treatment, and these individuals demonstrate a more severe clinical course.

Cutaneous Manifestations of Crohn Disease.

Awareness of the extraintestinal manifestations of Crohn disease is increasing in dermatology and gastroenterology, with enhanced identification of entities that range from granulomatous diseases recapitulating the underlying inflammatory bowel disease to reactive conditions and associated dermatoses. In this review, the underlying etiopathology of Crohn disease is discussed, and how this mirrors certain skin manifestations that present in a subset of patients is explored. The array of extraintestinal manifestations that do not share a similar pathology, but which are often seen in association with inflammatory bowel disease, is also discussed. Treatment and pathogenetic mechanisms, where available, are discussed.

Stopping, continuing, or restarting immunomodulators and biologics when an infection or malignancy develops.

Thiopurines and biologics are being used earlier and more frequently for the treatment of Crohn's disease and ulcerative colitis. These medications are generally well tolerated and usually do not require cessation due to a side effect. Rare but serious infections and cancers may develop in patients on these immunosuppressants. Evidence-based data are lacking to guide physicians on whether continuing or stopping thiopurines and biologics is necessary and, when a side effect does occur, if and when restarting these medications is feasible. The aim of this review was to outline the infectious and malignant complications that may develop on these treatments and to provide recommendations for continuing, stopping, and restarting thiopurines and biologics once a patient develops a treatment-related complication. These are not formal guidelines and should not replace individualized care by the treating physician.

Postoperative therapy with infliximab prevents long-term Crohn's disease recurrence.

BACKGROUND & AIMS: A previous randomized, placebo-controlled study showed that infliximab maintenance therapy prevented recurrence of Crohn's disease 1 year after an ileocolonic resection. We evaluated recurrence of Crohn's disease, on the basis of endoscopic examination and/or the need for additional surgical resection, beyond the first postoperative year. METHODS: In a prospective, open-label, long-term follow-up study, 24 patients previously randomly assigned to receive infliximab for 1 year after an ileocolonic resection were given the option to continue, stop, or start infliximab therapy. The primary end point was the time to recurrence of Crohn's disease, on the basis of endoscopic evidence (endoscopic recurrence), from the initial assignment to postoperative infliximab or placebo. Secondary end points were rate of endoscopic recurrence, time to reoperation, and rate of surgical recurrence in relation to the total time on infliximab. RESULTS: All patients were followed for at least 5 years after surgery. Patients assigned to the infliximab group in the first year after surgery had a longer mean time to first endoscopic recurrence (1231 ± 747 days) than patients originally assigned to the placebo group (460 ± 121 days, P = .003). Colonoscopies identified Crohn's disease recurrence in 22.2% of patients who received long-term infliximab and in 93.9% of those not on infliximab (P < .0001). Compared with no infliximab, the adjusted rate ratio for being in endoscopic remission while on infliximab was 13.47 (95% confidence interval, 3.52-61.53; P = .0001). Patients originally assigned to the infliximab group had a mean longer time to surgery (1798 ± 359 days) than patients originally assigned to the placebo group (1058 ± 529 days, P = .04). The rate of surgical recurrence (required additional surgical resection) was significantly lower among patients who received infliximab for most of the follow-up period than patients who received it for shorter periods (20.0% vs 64.3%, P = .047). CONCLUSIONS: Postoperative infliximab maintenance beyond 1 year prevents recurrence of Crohn's disease.

Tumor necrosis factor α antagonist-associated psoriasis in inflammatory diseases: an analysis of the FDA adverse event reporting system.

BACKGROUND: Crohn's disease (CD) is a chronic inflammatory, relapsing, and progressive condition that leads to bowel damage and subsequent stricturing or penetrating complications. Tumor necrosis factor (TNF) α antagonists (e.g., infliximab) can achieve sustained remission in CD. However, a paradox exists as to whether use of these medications, which effectively treat psoriasis, also confer risk of developing psoriasiform lesions. METHODS: Data from the Food and Drug Administration Adverse Event Reporting System (2004-2011) were analyzed. Adverse event reports for the TNF-α antagonists infliximab, adalimumab, and certolizumab were reviewed. Primary "control" drugs examined included the non-CD drugs propranolol and lithium because of their recognized association with risk of psoriasis and the nonbiological CD drug mesalamine. Proportional reporting ratios for psoriasis adverse events were calculated for TNF-α antagonists versus control drugs. RESULTS: From more than 13 million reports in Adverse Event Reporting System, the biological group included 5432 reports with psoriasis listed (infliximab = 1789; adalimumab = 3475; and certolizumab = 168) compared with just 88 psoriasis reports for the control group (propranolol = 24; mesalamine = 24; and lithium = 40). Compared with control drugs, the psoriasis proportional reporting ratios for TNF-α antagonists were as follows: infliximab (6.61), adalimumab (12.13), and certolizumab (5.43) (P < 0.0001). The aggregate "class" proportional reporting ratio for all TNF-α antagonists versus control drugs was 9.24 (P < 0.0001). Similar results were observed when psoriasis reports were compared between TNF-α antagonists and other drugs used to treat CD, including azathioprine, 6-mercaptopurine, methotrexate, corticosteroids, ciprofloxacin, and the antimalarial drug, hydroxychloroquine. CONCLUSIONS: Data from the Food and Drug Administration Adverse Event Reporting System suggest that TNF-α antagonists used in the treatment of CD confer an increased risk of psoriasiform adverse events.

Evaluation for postoperative recurrence of Crohn disease.

Disease recurrence following resective surgery for Crohn disease remains a challenging clinical problem, and more studies are needed to better define risk stratification and treatment recommendations in the postoperative setting. Endoscopy remains the gold standard for the assessment of postoperative disease recurrence, and all Crohn disease patients who undergo surgery should undergo ileocolonoscopy within 6 to 12 months of surgery. The degree of endoscopic recurrence in the neoterminal ileum during this procedure provides prognostic information regarding the severity of the future disease course. WCE, MRE, and SICUS are all promising noninvasive modalities to assess for postoperative Crohn disease activity. However, further studies are needed to better define scoring systems, operating characteristics and variability, and prognostic data for each of these modalities. In patients at risk for early disease recurrence, more aggressive prophylactic therapy should be considered, in hopes of delivering true "top-down" therapy that may offer maximum impact in altering the natural history of Crohn disease.

Clinical course of Crohn's disease following treatment of lymphoma.

BACKGROUND: Crohn's disease (CD) patients may be at increased risk for the development of Hodgkin's lymphoma (HL) or non-Hodgkin's lymphoma (NHL), either through exposure to immunosuppressive medications or due to their underlying chronic inflammatory illness. There are limited data regarding the natural history of CD following treatment of lymphoma. We present a series of CD patients who were treated for lymphoma and describe the natural history of their CD following lymphoma treatment. METHODS: Retrospective case series from three academic referral centers was used. All CD patients with a history of lymphoma were identified. Demographic data, CD medication exposure, and surgical procedures before and after lymphoma treatment were recorded. RESULTS: Nine CD patients with a history of lymphoma were identified. Eight individuals received chemotherapy, while one patient was observed without treatment. Eight patients remained free of lymphoma for a mean of 72.8 months (range 1-276 months). The ninth patient had recurrence of his HL 3 years after lymphoma diagnosis. Following lymphoma treatment, two patients had quiescent CD with no specific therapy. Three patients demonstrated significant clinical relapse of their CD and a fourth patient developed CD after treatment of her lymphoma, which ultimately required long-term immunomodulator therapy with 6-mercaptopurine or methotrexate in the first three patients, and azathioprine in the fourth. Four patients required CD surgery after lymphoma treatment. CONCLUSION: We report on the clinical course of CD in patients who develop lymphoma. Significant clinical relapse of CD following successful medical treatment of lymphoma occurred frequently in patients with a history of this neoplasm.

Supportive therapy in IBD: what additional diagnoses and conditions must be treated?

Despite advances in our understanding of inflammatory bowel disease (IBD) pathogenesis and increased ability to treat patients with severe and refractory disease, patients continue to suffer from disease complications, and increasing numbers of both Crohn's disease (CD) and ulcerative colitis (UC) patients are admitted annually in the USA. The rapid evolution in IBD medications and treatment paradigms has contributed to a disparity in clinical care which may vary between expert centers routinely treating large numbers of IBD patients and hospitals with low annual IBD admissions. High-volume centers handling in excess of 150 IBD annual admissions have improved operative and inpatient outcomes compared with hospitals caring for IBD patients less frequently. Although the precise reason for this disparity in clinical outcomes is not known, we hypothesize that expert centers provide superior IBD supportive therapy. This supportive care includes additional diagnostic and therapeutic approaches to help patients achieve optimal outcomes. We review information regarding disparities in the quality of IBD clinical care then focus on supportive therapy for IBD patients, including diagnostic approaches to identify confounding factors contributing to poor IBD outcome, supportive therapeutic approaches to optimize the outcome in hospitalized IBD patients, and future directions exploring brain-body interaction in the treatment of pain, stress and sleep deprivation in patients suffering from IBD.

Adalimumab for Crohn's disease in clinical practice at Mayo clinic: the first 118 patients.

BACKGROUND: We sought to assess the effectiveness and safety of adalimumab for the treatment of Crohn's disease (CD) in clinical practice. METHODS: Demographic, clinical, and treatment data were abstracted from the medical record. The primary outcome was clinical response to induction therapy with adalimumab for CD (complete, partial, or nonresponse). RESULTS: In all, 118 patients were prescribed adalimumab for CD between January 2003 and June 2007. All but five subjects (96%) had received prior infliximab and 50 were on systemic corticosteroids at the time of initial adalimumab dose (44%). A complete response was achieved in 53 patients and 20 patients had no response. The cumulative probability of any response (complete or partial) was 81.3% at 1 year. Dose escalation was required in 59 patients (1-year cumulative probability, 54.0%). Among patients with complete response, 18 lost response during follow-up (1-year cumulative probability, 21.4%). Among 50 patients on corticosteroids at baseline the median daily dose was 20 mg, which decreased to a median of 0 mg during treatment. Sixty-four patients (54%) experienced a total of 117 adverse events. Thirteen patients (11%) experienced 15 serious adverse events. Sixteen patients (14%) discontinued adalimumab due to an adverse event. CONCLUSIONS: Adalimumab was both effective and well tolerated for the treatment of CD in this tertiary practice with a high prevalence of past infliximab exposure. This experience largely predates FDA approval of adalimumab for CD.

Preventive therapy in postoperative Crohn's disease.

PURPOSE OF REVIEW: Recurrence of Crohn's disease following surgical resection is common, but the optimal strategy to assess, prevent, and treat postoperative recurrence remains unclear. Recent developments in the prevention and management of postoperative recurrence have provided additional information. RECENT FINDINGS: Predictors of Crohn's disease recurrence after surgery include cigarette smoking, disease behavior, number of prior resections, family history, anastomotic type, and time to first surgery. Only penetrating disease behavior and continued cigarette smoking after surgery remain clear predictors of postoperative Crohn's disease recurrence. Ileocolonoscopy is the only modality to detect mucosal recurrence after surgery; however, surrogate markers of inflammation, specifically stool lactoferrin and calprotectin as well as small intestine contrast ultrasound, are promising. Due to the high rate of surgery for the treatment of complications of Crohn's disease, prevention of postoperative disease has received considerable attention. Recent studies of azathioprine/6-mercaptopurine, nitroimidazole antibiotics, and infliximab have broadened the spectrum of medication options postoperatively. SUMMARY: Smoking cessation and ileocolonoscopy for early detection of Crohn's disease recurrence should be part of any postoperative management strategy. The selection of medication and optimal time to initiate treatment after surgery is less certain. Postoperative immunomodulators and antitumor necrosis factor agents may prevent Crohn's disease in those at high risk for recurrence. Treatment of patients by predictors of recurrence and personalization of management based on genotypes/phenotypes will be the focus of future study.

Eosinophilic esophagitis: is it all allergies?

Eosinophilic esophagitis (EE) is an increasingly recognized disorder in the adult population, most often manifested by symptoms of dysphagia and food impaction. Mechanisms involving eotaxin-3, interleukin 5, and signal transducer and activator of transcription 6 have been studied and may represent future therapeutic targets. Patients commonly have a personal and family history of atopy, and both food allergies and aeroallergens have also been investigated as triggers of EE. Traditional allergy-testing methods, including skin prick testing and specific IgE testing, have been used to identify food and environmental allergies. However, new studies suggest that patch testing could add to diagnostic accuracy in EE because the disorder might not be a classic type I allergic response. Although studies of treatment of adults with EE have thus far focused on swallowed fluticasone proprionate, many trials in children have assessed the efficacy of food elimination and elemental diets. These diets, which have been extremely successful in reducing symptoms, have also been shown to induce histological improvement and remission. No similar studies have been conducted in adults; the tolerability of such an intervention may prove more difficult in this population. This article reviews the underlying pathophysiology of EE and describes evolving options for more accurately identifying food and environmental allergies. We also discuss the pediatric trials using food elimination and avoidance diets and suggest that this type of intervention may be an important area of future research in the adult population.