Novel Orally Administered Recombinant Anti-TNF Alpha Fusion Protein for the Treatment of Ulcerative Colitis: Results From a Phase 2a Clinical Trial.

BACKGROUND AND OBJECTIVE: OPRX-106 is an orally administered BY2 plant cell-expressing recombinant TNF fusion protein (TNFR). Oral administration of OPRX-106 was shown to be safe and effective in inducing favorable anti-inflammatory immune modulation in humans. The current study was aimed at determining the safety and efficacy of OPRX-106 in patients with ulcerative colitis (UC). METHODS: Twenty-five patients with active mild-to-moderate UC were enrolled in an open-label trial. Patients were randomized to receive 2 or 8 mg of OPRX-106 administered orally once daily, for 8 weeks. Patients were monitored for safety and efficacy including clinical response or clinical remission, based on the Mayo score. The histopathological improvement in Geboes score, calprotectin level and hs-CRP, and exploratory immune parameters by means of fluorescence-activated cell sorting and cytokine levels were monitored. RESULTS: Oral administration of OPRX-106 was found to be safe and well tolerated without absorption into the circulation. Out of 24 patients, 18 completed the trial. The analysis of the patients completing treatment demonstrated clinical efficacy as measured by clinical response or remission in 67% and 28%, respectively. Reduction in calprotectin levels and improved Geboes score were noted in the majority of the treated patients. The beneficial clinical effect was associated with an increase in a CD4+CD25+FoxP3 subset of suppressor lymphocytes and a reduction in interleukin 6 and interferon gamma serum levels. CONCLUSIONS: Oral administration of the nonabsorbable OPRX-106 is safe and effective in mild-to-moderate UC, and not associated with immune suppression, while inducing favorable anti-inflammatory immune modulation.

ASCA and ANCA among Bedouin Arabs with inflammatory bowel disease, the frequency and phenotype correlation.

BACKGROUND: Serological markers used for diagnostic purposes and disease stratification in inflammatory bowel disease. We aimed to investigate the frequency of ASCA and ANCA among Arab Bedouin IBD patients and its relationship to disease phenotype and course. METHODS: From cohort of 68, 25 Crohn's disease (CD) and 25 Ulcerative colitis (UC) patients were recruited (72%). ASCA IgG was determined by ELISA assay. Immunofluorescence analysis of ANCA was performed. RESULTS: The IgG ASCA was detected in 13 (52%) of the CD patients and in three (12%) UC patients. The prevalence of ANCA among UC patients was positive with 76%, sub-grouped, atypical ANCA in 9 patients (36%), pANCA in six patients (24%) and cANCA in 4 patients (16%). The detection of ASCA among CD patients was found not to be a reliable predictor of young age at diagnosis, gender, ileal involvement, anti-TNF treatment or surgery. UC patients with positive ANCA were younger, mean age 40.2 ± 11.9 compared with 57.3 ± 21.2 (p = 0.03), and diagnosed at a younger age, 29.2 ± 11.8 compared with 43.5 ± 15.3 (p = 0.05). CONCLUSION: The frequency of ASCA among Bedouin CD patients and ANCA among UC patients was high, however ASCA was not found to have a predictive value for disease phenotype or course. Positive ANCA in UC patients was predictive for younger age and age at diagnosis.

NOD2/CARD15 Mutations among Bedouin Arabs with Inflammatory Bowel Disease: Frequency and Phenotype Correlation.

BACKGROUND: Inflammatory bowel disease (IBD) prevalence is increasing among Bedouin Arabs in Israel. This population is known to have a high rate of consanguinity. NOD2/CARD15 mutations are well-studied in IBD. OBJECTIVES: To investigate the frequency of NOD2/CARD15 mutations in IBD Bedouin patients and their relevance to disease phenotype. METHODS: The IBD-Arab cohort in southern Israel included 68 patients, of which 25 Crohn's disease (CD) patients and 25 ulcerative colitis (UC) patients consented to participate (72%). Blood samples were obtained from all participants who were genotyped for NOD2/CARD15 variants Arg702Trp, Gly908Arg, and Leu1007fsinsC. RESULTS: The NOD2/CARD15 mutation frequency was higher in Crohn's disease than in ulcerative colitis patients. Carrier frequency for the Gly908Arg mutation in CD and UC patients was 8/25 (32%) and 3/25 (12%), respectively (P = 0.08). Neither the Arg702Trp nor Leu1007fsinsC mutation was found in our cohort. No homozygous/compound heterozygote mutations were found. Genotype-phenotype analysis revealed that CD patients carrying the Gly908Arg mutation were younger at diagnosis, 22.8 ± 4.5 vs. 28.82 ± 9.1 years (P = 0.04). All carriers were males, compared with 41.2% in non-carriers (P = 0.005). NOD2/CARD15 mutation carriers with UC were older, 67.0 ± 24.5 years compared with 41.2 ± 12.3 years (P = 0.006). No other associations regarding disease localization or other clinical parameter were found. CONCLUSIONS: The frequency of NOD2/CARD15 gene mutations is high in CD and UC among Bedouin Arab IBD patients and is associated with younger age at onset in CD and male gender.

Comparison of the Long-Term Oncological Outcomes of Stent as a Bridge to Surgery and Surgery Alone in Malignant Colonic Obstruction.

BACKGROUND: Self-expanding metallic stents (SEMS) insertion is an alternative to emergency surgery in malignant colonic obstruction. However, the long-term oncological outcome of stents as a bridge to surgery is limited and controversial. OBJECTIVES: To determine the long-term oncological outcome of stents as a bridge to surgery. METHODS: Data of patients who underwent emergency surgery and endoscopic stent insertion as a bridge to surgery due to obstructing colon cancer at Soroka Medical Center during a 14 year period were collected retrospectively. Preoperative data, tumor staging, and oncological outcomes in terms of local recurrence, metastatic spread, and overall survival of the patients were compared. RESULTS: Sixty-four patients (56% female, mean age 72 years) were included in the study: 43 (67%) following emergency surgery, 21 stent inserted prior to surgery. A stent was inserted within 24-48 hours of hospital admission. The mean time between SEMS insertion and surgery was 15 days (range 0-30). Most of the patients had stage II (41%) and stage III (34%) colonic cancer. There was no difference in tumor staging and localization between groups. There was no significant difference in disease recurrence between SEMS and surgery groups, 24% and 32%, respectively. Disease-free survival rates were similar between the SEMS group (23.8%) and surgery group (22%). Four year and overall survival rates were 52.4% vs. 47.6%, 33.3% vs. 39.5%, respectively. CONCLUSIONS: SEMS as a bridge to surgery in patients with obstructing colon cancer provide an equivalent long-term oncological outcome to surgery alone.

A comparative reappraisal of the Rome II and Rome III diagnostic criteria: are we getting closer to the 'true' prevalence of irritable bowel syndrome?

OBJECTIVES: Revisions of the diagnostic criteria for irritable bowel syndrome have led to varying prevalence estimates. The Rome III criteria require a lower symptom frequency than Rome II (at least 10% of the time for Rome III, compared with at least 25% of the time for Rome II). In an epidemiological survey of a representative sample of Israeli adults using Rome II, we reported the prevalence for irritable bowel syndrome as 2.9%. The official Rome II integrative questionnaire, used for that study, enables a close approximation of Rome III rates, facilitating a retrospective comparison of these criteria. METHODS: A representative sample of 1000 adults was interviewed with a validated Hebrew version of the official Rome II integrative questionnaire. The data were re-evaluated retrospectively to compare the Rome II results with a close approximation of the new Rome III criteria. RESULTS: The prevalence rates for irritable bowel syndrome were 2.9 and 11.4%, respectively, for Rome II and Rome III. The corresponding consultation rates were 57.1 and 41.7%, indicating that the more strict Rome II criteria may select out a group of patients with more severe disease or greater psychosocial problems. Women made up 71.4% of irritable bowel syndrome by Rome II and 62.5% by Rome III. CONCLUSIONS: In the present retrospective study, the prevalence rate for irritable bowel syndrome in our population is significantly higher by Rome III compared with Rome II. Rome III may more closely reflect the socioeconomic burden of irritable bowel syndrome compared with the overly strict Rome II. Prospective comparative studies should be conducted to confirm these results.

Sci-B-VacTM Vs ENGERIX-B Vaccines for Hepatitis B Virus in Patients with Inflammatory Bowel Diseases: A Randomised Controlled Trial.

BACKGROUND AND AIMS: Response rate to second-generation hepatitis B virus vaccines is relatively low in patients with inflammatory bowel diseases compared with the general healthy population. We compared the efficacy and safety of a third- vs a second-generation hepatitis B virus vaccine in a group of patients with inflammatory bowel diseases treated with immunosuppressive medications. METHODS: Prospective, randomised, single-blind, controlled study. Eligible patients were randomly assigned to receive one of two vaccines, ENGERIX-B or Sci-B-Vac. The vaccines were administered in three doses at 0, 1, and 6 months. The primary endpoint was defined as the titre of anti-hepatitis B S [HBs] antibodies following the standard three-dose hepatitis B virus vaccination schedule. RESULTS: A total of 72 patients complied with study protocol [37 and 35 patients in the ENGERIX-B and Sci-B-Vac groups, respectively]. Overall, 75% of the cohort seroconverted. The primary endpoint was met in 81.1% in the ENGERIX-B group and 68.6% in the Sci-B-Vac group [p = 0.22]. Patients in the Sci-B-Vac group showed a statistically significant decreased seroconversion rate compared with the ENGERIX-B group, with use of tumour necrosis factor [TNF] alpha inhibitors [p = 0.03], and higher degree of disease activity [p = 0.03]. CONCLUSIONS: Overall seroconversion rate in our cohort was higher than in previous reports in the literature, possibly due to a low disease activity state in the majority of participants. Third-generation hepatitis B virus vaccines showed no apparent advantage over standard of care vaccine in this patient group.

Inflammatory bowel disease and preterm delivery.

OBJECTIVE: The present study investigates pregnancy outcome in women with IBD and examines the effect of pregnancy on the severity of IBD. METHOD: A case-control study comparing deliveries by mothers with IBD between January 1988 and January 2005 was performed. For every birth by a mother with IBD, four births by non-IBD mothers were randomly selected and adjusted for ethnicity and year of delivery. RESULT: During the study period there were 48 deliveries to patients with Crohn's disease and 79 deliveries to patients with ulcerative colitis. Higher rates of preterm delivery (<37 weeks) were found among patients with IBD as compared to the controls (odds ratios (OR)=2.2; 95% confidence interval (CI)=1.3-3.8). This association remained significant after adjustment for labor induction and multiple gestations, using the Mantel-Haenszel technique (weighted OR=2.1; 95% CI 1.3-3.5 and weighted OR=2.0; 95% CI 1.2-3.5; P=0.012; respectively). In addition, these patients had higher rates of fertility treatments (OR=2.2; 95% CI=1.1-4.4). Using a multivariate analysis, controlling for maternal age and fertility treatments, preterm delivery was seen to be significantly associated with IBD (adjusted OR=2.0; 95% CI=1.2-3.5). Perinatal outcomes, such as perinatal mortality, low Apgar scores, and congenital malformations, were comparable to the outcomes in the control group. CONCLUSION: Maternal IBD is an independent risk factor for preterm delivery. IBD is not associated with adverse perinatal outcome.

The epidemiology of primary biliary cirrhosis in southern Israel.

BACKGROUND: The epidemiology of primary biliary cirrhosis has changed significantly over the last decade, with a trend towards increasing prevalence in many places around the world. OBJECTIVES: To determine the overall prevalence of PBC in southern Israel and the specific rates for different immigrant groups between January 1993 and October 2004. METHODS: Multiple case-finding methods were used to identify all cases of PBC in the study region. Age-adjusted prevalence rates were compared among the different immigrant groups. RESULTS: A total of 47 cases of PBC were identified with an overall prevalence of 55 cases per million. All patients were women, and all except for a Bedouin Arab were Jewish. Foreign-born patients comprised 70% of our PBC cohort even though they represent only 45.4% of the regional population. This predominance of immigrants did not change when the rates were adjusted for age (P < 0.001). The prevalence rates were 40, 177, and 58 cases per million for those born in Israel, North Africa or Asia, and Eastern Europe, respectively. The age-specific prevalence rate for women older than 40 years varied from 135 cases per million among those born in Israel to 450 among immigrants from Eastern Europe and the former USSR to 700 cases per million among immigrants from North Africa and Asia. CONCLUSIONS: The prevalence of PBC in southern Israel is similar to that reported from some European countries. The rate is much higher among Jews than Arabs and among immigrants to Israel compared to native Israelis.

"Bread madness" revisited: screening for specific celiac antibodies among schizophrenia patients.

PURPOSE: A possible association between gluten consumption and schizophrenia has been reported. The objective was to compare patients with chronic schizophrenia and matched controls for sociodemographic variables, prevalence of celiac-specific anti-endomysial antibodies and disease-related variables. SUBJECTS AND METHODS: The study group was comprised of 50 consecutive patients diagnosed with schizophrenia, 18 years of age and older attending the out-patient clinic of the Mental Health Center in Beer-Sheva, Israel. The control group was comprised of mentally normal volunteers who came to primary care clinics for blood tests unrelated to gastrointestinal tract complaints and who were not diagnosed with celiac disease. Known celiac patients and those who refused to participate, did non-speak Hebrew or were incoherent were excluded from the study. All participants in both groups underwent a blood test for anti-endomysial IgA antibody and completed a questionnaire. RESULTS: Each group was comprised of 50 participants. There were no significant differences between the groups in gender, BMI or country of birth. The mean age of the study group was significantly higher than the controls. All tests for anti-endomysial antibody in both groups were negative. DISCUSSION AND CONCLUSIONS: In contrast to previous reports, we found no evidence for celiac disease in patients with chronic schizophrenia as manifested by the presence of serum IgA anti-endomysial antibodies. It is unlikely that there is an association between gluten sensitivity and schizophrenia.

Microscopic colitis.

Microscopic colitis is an idiopathic chronic inflammatory bowel disease presenting with watery diarrhea. While colonoscopy and radiology findings are normal, the colon shows striking pathologic findings, including lymphocytic colitis and collagenous colitis. The clinical course is usually benign with sustained remission. Recent medical evidence shows that bismuth and budesonide are effective treatments.

Endoscopic self-expanding metal stents for acute colonic obstruction.

The current study presents our experience with the introduction of self-expanding metal stents (SEMS) and assesses success rate, clinical outcomes, and complications. We conducted a historical cohort study reviewing endoscopic SEMS insertions between 2000 and 2010. Overall, 51 patients underwent stent insertion: 38 with an emergent procedure and 13 with a semielective procedure. SEMS was inserted in 27 men and 24 women with a mean age of 68.9 years. Colonic malignancy was the cause of obstruction in all patients. The tumors were localized in the rectosigmoid in 33 (64.7%), in the left colon in 16 (31.4%), and in the right colon in two cases (3.9%). Endoscopic SEMS insertion was technically successful in 68.4 per cent of patients in an emergency and in 84.6 per cent of patients in a semielective setting. Successful stent insertion allowed a "bridge to surgery" in 23 and palliative care in 14 patients. Stent migration occurred in three, obstruction in two, and bowel perforation in three cases. Nineteen patients in the emergent group underwent a subsequent successful semielective colonic resection within 8.1 days (range, 2 to 30 days) of stent insertion. There were two cases (11.1%) of major and four cases (22.2%) of minor postoperative complications in this series. No anastomotic leaks were observed. Mean postoperative hospitalization was 10.1 days (range, 5 to 45 days). Endoscopic stent insertion is a relatively simple procedure providing an effective first-line treatment for relief of symptoms of acute malignant colorectal obstruction, preventing acute perforation, and serving either as a preoperative procedure (allowing lower morbidity semielective surgery) or as palliative care.

Prevalence of GERD symptoms in a representative Israeli adult population.

The prevalence of gastroesophageal reflux disease (GERD) symptoms in the general population is lower in Asian than Western countries. Data are lacking for countries in the Middle East. The aim of the study was to determine the prevalence and severity of GERD symptoms among Israeli Jews. A questionnaire including 8 specific questions for GERD symptoms was administered by telephone interview to a representative sample of the population. One thousand two hundred twenty-one of 1839 individuals were successfully contacted and 981 had valid, complete data. The mean age was 45.0 years and 55% were females. Over the previous year 34.8% of the respondents reported suffering any GERD symptom. Of these 11.6% reported retrosternal burning, 11.7% retrosternal pain, 19.0% an acid taste in the mouth, and 17.5% reflux of gastric content. In all, 6.5%, 5.2%, 10.4%, and 7.9%, respectively, suffered these symptoms at least once a week, and 2.0%, 1.8%, 2.4%, and 2.3%, respectively, defined their symptoms as frequent and severe. Male sex (P=0.01) and a functional lower gastrointestinal (GI) disorder (P<0.0001) contributed significantly to the severity of upper GI reflux-like symptoms. In conclusion, GERD symptoms are common among Israeli Jews. The symptoms are generally of mild-to-moderate severity and are significantly associated with lower functional GI disorders.

Rates of functional bowel disorders among Israeli Bedouins in rural areas compared with those who moved to permanent towns.

BACKGROUND & AIMS: Half of Israeli Bedouin society has undergone a transition from nomadic existence to permanent towns, causing cultural and social upheaval. The aim was to compare rates of irritable bowel syndrome (IBS) and functional bowel disorders (FBDs) between Israeli Bedouins still living under rural conditions with those in permanent towns. METHODS: Interviews were conducted in Arabic by trained Bedouin interviewers at 8 Bedouin clinics. The same interviewers surveyed the 2 sectors under identical sampling and interviewing conditions at the same time. FBDs were diagnosed by Rome II criteria. RESULTS: One thousand seven hundred fifty-five Bedouins participated, 1018 from permanent towns and 737 from rural areas. Sixty percent were female (58.2% for rural and 62.0% for towns). The mean age was 39.1 +/- 14.1 years (39.0 +/- 14.3 years for towns, 39.2 +/- 13.9 years for rural; P = NS). The mean level of education was 4.3 +/- 5.4 years (4.6 +/- 5.6 years for towns, 3.7 +/- 5.2 years for rural; P < .0001). IBS was diagnosed in 9.4% of town and 5.8% of rural Bedouins ( P < .01). In contrast, rural Bedouins had significantly higher rates of functional abdominal bloating (7.9% vs 2.8%, P < .0001) and a marginally higher rate of functional constipation. Bedouins living in towns attributed their gastrointestinal symptoms to stress more than rural Bedouins did ( P < .05). Stress and poor global feeling of well-being were significant contributors for IBS in logistic regression models for both sectors. CONCLUSIONS: Bedouins living in permanent towns have significantly higher rates of IBS than rural Bedouins. Although these findings might be associated with the stressful social upheaval that they have undergone, further study is needed to substantiate this point.

Successful surgical treatment of a primary liver gastrinoma during pregnancy: a case report.

Primary neuroendocrine tumors of the liver, particularly gastrinomas, are exceptionally rare. We present a case of a sporadic primary liver gastrinoma in a young woman in whom the definitive diagnosis was reached, and surgical therapy was performed during pregnancy.

Does insertion of a rectal tube after colonoscopy reduce patient discomfort and improve satisfaction?

BACKGROUND: Distention of the colon is a major contributor to patient discomfort after colonoscopy. Some physicians and nurses believe insertion of a rectal tube relieves this discomfort and improves patient satisfaction with the procedure. This prospective, randomized, controlled trial assessed rectal tube insertion for reduction or prevention of abdominal bloating and discomfort after colonoscopy. METHODS: One hundred fifty-seven patients were prospectively randomized to groups with (n = 68) and without (n = 89) rectal tube insertion after colonoscopy. Patients were evaluated for bloating, discomfort, and pain before the procedure, at its conclusion, at discharge, and 24 hours later (by telephone). Satisfaction was also assessed at discharge and 24 hours later. RESULTS: There were no differences between groups with respect to age, gender, hospitalization status, comorbidity, or socioeconomic status. In both groups the cecum was reached in 90% of patients and procedure time was similar. There were no differences between the groups in abdominal bloating (patient and nurse assessment), abdominal discomfort, or satisfaction at any time point. There were no serious complications. The subgroup of patients who experienced more severe pain and discomfort, regardless of whether a rectal tube was inserted, was characterized by more complaints of bloating, more incomplete procedures, and a higher rate of previous abdominal operations. CONCLUSIONS: Insertion of a rectal tube after colonoscopy does not affect abdominal bloating, pain, or discomfort during recovery from the procedure or over the subsequent 24 hours, nor does it affect overall patient satisfaction.