Andrew Ippoliti

Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis

We present a genome-wide association study of ileal Crohn disease and two independent replication studies that identify several new regions of association to Crohn disease. Specifically, in addition to the previously established CARD15 and IL23R associations, we identified strong and significantly replicated associations (combined P < 10−10) with an intergenic region on 10q21.1 and a coding variant in ATG16L1, the latter of which was also recently reported by another group. We also report strong associations with independent replication to variation in the genomic regions encoding PHOX2B, NCF4 and a predicted gene on 16q24.1 (FAM92B). Finally, we demonstrate that ATG16L1 is expressed in intestinal epithelial cell lines and that functional knockdown of this gene abrogates autophagy of Salmonella typhimurium. Together, these findings suggest that autophagy and host cell responses to intracellular microbes are involved in the pathogenesis of Crohn disease.

Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study

Ulcerative colitis is a chronic inflammatory disease of the colon that presents as diarrhea and gastrointestinal bleeding. We performed a genome-wide association study using DNA samples from 1,052 individuals with ulcerative colitis and preexisting data from 2,571 controls, all of European ancestry. In an analysis that controlled for gender and population structure, ulcerative colitis loci attaining genome-wide significance and subsequent replication in two independent populations were identified on chromosomes 1p36 (rs6426833, combined P = 5.1 × 10−13, combined odds ratio OR = 0.73) and 12q15 (rs1558744, combined P = 2.5 × 10−12, combined OR = 1.35). In addition, combined genome-wide significant evidence for association was found in a region spanning BTNL2 to HLA-DQB1 on chromosome 6p21 (rs2395185, combined P = 1.0 × 10−16, combined OR = 0.66) and at the IL23R locus on chromosome 1p31 (rs11209026, combined P = 1.3 × 10−8, combined OR = 0.56; rs10889677, combined P = 1.3 × 10−8, combined OR = 1.29).

Patients with Inflammatory Bowel Disease are at Risk for Vaccine-Preventable Illnesses

BACKGROUND:Patients with chronic, immune-mediated conditions such as inflammatory bowel disease (IBD) are often treated with long-term immunosuppressive therapies, potentially increasing their risk of developing an infection. Empiric data suggest that vaccines are underutilized in immunocompromised patients, despite published guidelines recommending their use. We aimed to assess exposure risk and immunization status among patients receiving care in an IBD specialty clinic.METHODS:Patients completed a self-administered, pretested, structured questionnaire during a routine visit for the management of IBD. Survey questions related to medical and immunization histories, and exposures to known risk factors for influenza, pneumococcus, viral hepatitis, and varicella. Additionally, in a subgroup of patients who agreed to donate a sample of blood, immune status to hepatitis A (HAV), hepatitis B (HBV), and varicella was determined.RESULTS:Two hundred four patients were asked to participate in the study; 169 completed surveys and comprised the study population. Mean age was 35 yr (range 13–75 yr). One hundred forty-six respondents (86%) reported current or prior use of immunosuppressive medications. Only 45% of respondents recalled tetanus immunization within the past 10 yr, 41 (28%) reported regularly receiving flu shots, and 13 (9%) reported having received pneumococcal vaccine. The most common reasons for nonimmunization with influenza included lack of awareness (49%) and concern for side effects (18%). Responses indicated that 75 (44%) patients were at risk for HBV but only 47 (28%) had been vaccinated against the infection; of patients with previous HBV vaccination, only three of nine (33%) had measurable antibodies against hepatitis B surface antigen.CONCLUSIONS:Immunization against selected vaccine-preventable illnesses was uncommon in patients with IBD, despite the presence of significant risk factors. Efforts to improve immunization status among patients with IBD and other chronic, immune-mediated conditions are needed.

Safety and Efficacy of Adalimumab (D2E7) in Crohn's Disease Patients with an Attenuated Response to Infliximab

OBJECTIVES:Although infliximab is highly effective in the treatment of Crohns disease (CD), attenuated response to infliximab may develop over time in a subgroup of patients. The aim of our study was to examine the safety and efficacy of adalimumab (D2E7), a fully humanized anti-TNF-α Ab, in CD patients who had experienced an attenuated response to infliximab.METHODS:Fifteen patients with active CD who experienced an attenuated response to infliximab were treated with adalimumab over a 6-month period. Patients, received a loading dose of 80 mg subcutaneously followed by 40 mg every 2 wk. The clinical response to adalimumab was classified as complete response, partial response, or nonresponse.RESULTS:Two patients received the loading dose of adalimumab but did not have adequate follow-up evaluations. Of the remaining 13 patients, 7 (54%) had a complete response, 4 (31%) had a partial response, and 2 (15%) were nonresponders. In six patients, the maintenance dose was increased in order to maintain clinical response. Eight of 11 (73%) patients on concurrent corticosteroids were able to discontinue or significantly decrease the dose of the steroids. Adalimumab was well tolerated without signs or symptoms of allergic reaction except in two patients who developed an injection site reaction.CONCLUSIONS:Our preliminary data suggest that adalimumab may be a safe and effective therapy for patients with CD who have experienced an attenuated response to infliximab.

Two doses of omeprazole versus placebo in symptomatic erosive esophagitis: The U.S. multicenter study

Two hundred thirty patients with reflux symptoms and endoscopically proven erosive esophagitis were enrolled from 15 U.S. centers into a randomized, double-blind, dose-ranging study comparing placebo with omeprazole, 20 or 40 mg given once daily in the morning. Esophagitis grade 2 was present in 44% of patients, grade 3 in 37% of patients, and grade 4 in 19% of patients. Endpoints, defined as complete relief of heartburn and complete esophageal mucosal healing, were assessed after 4 and 8 weeks of treatment. Both omeprazole doses were significantly superior to placebo in complete endoscopic healing. After 8 weeks of treatment, 73.5% of patients in the 20-mg omeprazole group and 74.7% in the 40-mg omeprazole group, compared with 14.0% in the placebo group, had complete healing of the esophageal mucosa. At the end of the study, complete relief of daytime heartburn was obtained in 79.5% of patients in the 20-mg omeprazole group, 81.6% in the 40-mg omeprazole group, and 37.2% in the placebo group (P less than or equal to 0.05). Complete relief of nighttime heartburn was noted by 79.5% of patients in the 20-mg omeprazole group, 85.1% in the 40-mg omeprazole group, and 34.9% in the placebo group (P less than or equal to 0.05). The median time to complete relief of daytime and nighttime heartburn occurred earlier in the 40-mg group than in the 20-mg group (9 vs. 17 days and 9 vs. 20 days, respectively); however, these differences were not statistically significant. Relief of acid regurgitation and dysphagia also occurred earlier in the 40-mg group. Omeprazole was well tolerated in this group of patients. No unexpected adverse experiences occurred. The results of this study confirm those of six multicenter, international trials in which omeprazole in doses of 20-60 mg provided a degree of esophageal mucosal healing and complete relief of reflux symptoms superior to any other medical treatment.

Esophagitis in scleroderma: Prevalence and risk factors

Of 53 patients with scleroderma (43 women and 10 men) evaluated by esophagoscopy and biopsy, 32 (60%) had erosive esophagitis. Symptoms of heartburn and dysphagia were significantly more frequent in the patients who had erosive esophagitis but often were present in those without this condition. Abnormal motility characterized by loss of peristalsis in the distal esophagus was present in all patients with erosive esophagitis, including the 5 who were asymptomatic. No patient with normal esophageal motility had erosive esophagitis at endoscopy. The patients with erosive esophagitis also had significantly diminished lower esophageal sphincter pressures and increased frequency and duration of gastroesophageal reflux episodes. Stricture was present in 13 of 32 patients with erosive esophagitis and was absent in the other 21 patients. The duration of disease, rate of gastric emptying, and fungal smear and culture were not significantly different in those with or without esophagitis. Treatment of fungal infection for a month had little beneficial effect. The pattern of esophageal motility in scleroderma identifies high and low risk groups for esophagitis and stricture, and can be used to select those who require further investigation, irrespective of symptoms.

A pilot study of adalimumab in infliximab‐allergic patients

The anti-TNF-&agr; antibody infliximab (Remicade) is highly effective in the treatment of Crohns disease. A subset of patients experience allergic reactions as a result of antibodies to infliximab (ATIs). The purpose of the current study is to describe the safety and efficacy of adalimumab (Humira) in patients previously allergic or intolerant to infliximab. Adalimumab is an anti-TNF-&agr; agent containing only human peptide sequences. Seven patients have been treated with adalimumab who had experienced immediate- or delayed-hypersensitivity reactions to infliximab and one with infliximab-induced lupus. Except for injection site discomfort, adalimumab was well tolerated without signs or symptoms of allergic reactions. One patient who had previously received pooled human immunoglobulin developed a pruritic rash after each dose of adalimumab. Patients with active disease who had previously experienced a robust response to infliximab responded to adalimumab as reflected by an improvement in Harvey-Bradshaw index and inflammatory markers. Based on these preliminary data, adalimumab may be a safe and effective substitute for infliximab-allergic patients. Individuals who have been exposed to human antibodies may be sensitized to other human antibodies such as adalimumab.

Randomized trial of argon plasma coagulation vs. multipolar electrocoagulation for ablation of Barrett's esophagus

BACKGROUND Endoscopic ablation of Barretts esophagus has been described in which various thermocoagulation modalities are used in combination with a high dose of a proton pump inhibitor. No randomized comparison of ablation strategies has been published. METHODS Referred patients were screened to identify those with Barretts esophagus 2 to 7 cm in length, without high-grade dysplasia or cancer. Included patients received pantoprazole (40 mg twice a day), followed by randomization to treatment with argon plasma coagulation (APC) or multipolar electrocoagulation (MPEC). The primary outcome measure was the number of treatment sessions required for endoscopic ablation. RESULTS Of 235 patients screened, 52 were randomized. The mean length of Barretts esophagus was 3.1 cm in the MPEC group vs. 4.0 cm in the APC group (p = 0.03). Otherwise, the treatment groups were similar with regard to baseline characteristics. The mean number of treatment sessions required for endoscopic ablation was 2.9 for MPEC vs. 3.8 for APC (p = 0.04) in an intention-to-treat analysis (p = 0.249, after adjustment for the difference in length of Barretts esophagus). The proportion of patients in which ablation was endoscopically achieved proximal to the gastroesophageal junction was 88% for the MPEC group vs. 81% for the APC group (p = 0.68) and histologically achieved in 81% for MPEC vs. 65% for APC (p = 0.21). The mean time required for the first treatment session was 6 minutes with MPEC vs. 10 minutes with APC (p = 0.01) in per protocol analysis. There was no serious adverse event, but transient moderate to severe upper-GI symptoms occurred after MPEC in 8% vs. 13% after APC (p = 0.64). Conclusions Although there were no statistically significant differences, ablation of Barretts esophagus with pantoprazole and MPEC required numerically fewer treatment sessions, and endoscopic and histologic ablation was achieved in a greater proportion of patients compared with treatment with pantoprazole and APC.

Immunosuppression Impairs Response to Pneumococcal Polysaccharide Vaccination in Patients With Inflammatory Bowel Disease

OBJECTIVES:The treatment of inflammatory bowel disease (IBD) often includes immunosuppressive medications, which may increase the risk of vaccine-preventable illnesses. We aimed to assess the impact of immunosuppression on immune responses to pneumococcal vaccination in patients with IBD.METHODS:The study design consists of a prospective controlled clinical trial. This study was carried out at a tertiary-care IBD clinic. The subjects for the study belonged to one of the following three groups: adult patients with IBD on combination TNF-blockers and immunomodulators (Group A), those without immunosuppressive therapy (Group B), and age-matched healthy controls (Group C). The treatment consisted of immunization with 23-valent pneumococcal polysaccharide vaccines (PSVs). The main outcome was immune response for five serotypes defined as a twofold or greater increase from pre-vaccination titers and ⩾1 μg post-vaccination titer.RESULTS:Sixty-four subjects participated in the study: 20 in Group A, 25 in Group B, and 19 in Group C. Pre-vaccination titers were similar among the three groups. Vaccine responses were lower in Group A than in Group B (P⩽0.01 for four out of five antigens) and Group C (P<0.01 for all five antigens). Overall vaccine response was seen in 45, 80, and 85% of Groups A, B, and C (P=0.01), respectively.CONCLUSIONS:Immune response to PSV-23 is impaired in Crohns disease (CD) patients on combination immunosuppressive therapy but is normal among non-immunosuppressed patients. Given the unpredictable likelihood for immunosuppressive therapy, newly diagnosed patients with IBD should undergo vaccination before the initiation of immunosuppressive therapy.

Does Infliximab Influence Surgical Morbidity of Ileal Pouch-Anal Anastomosis in Patients with Ulcerative Colitis?

PurposeSince infliximab has been approved for treatment of patients with refractory ulcerative colitis, surgeons will be increasingly faced with operating on patients who have failed therapy with this potent immunosuppressant. This study was designed to compare short-term complications in patients with ulcerative colitis who were treated with and without infliximab before colectomy.MethodsThe charts of patients undergoing ileal pouch-anal anastomosis or subtotal colectomy for refractory ulcerative colitis during the five-year period ending October 2005 were reviewed. Postoperative medical and surgical complications were assessed.ResultsSeventeen patients had failed infliximab treatment and 134 patients were never treated with infliximab. Ileal pouch-anal anastomosis was performed in 112 patients (74 percent) and subtotal colectomy in 39 patients (36 percent). There were no deaths. Postoperative complications were observed in 43 patients (28 percent), with no significant difference observed between infliximab-treated (37 percent) and infliximab-untreated patients (27 percent). Of 61 patients (40 percent) treated with preoperative cyclosporine A, 5 patients also had been treated with infliximab. The infliximab and cyclosporine A-treated patient group had an 80 percent complication rate, significantly higher than the 29 percent complication rate noted in the cyclosporine A only-treated group (P--.04).ConclusionsAlthough preoperative treatment with infliximab alone does not significantly increase the incidence of postoperative complications, using both inflixiamb and cyclosporine A before colectomy in refractory ulcerative colitis is associated with high surgical morbidity.