Alon Lang

Curcumin in Combination With Mesalamine Induces Remission in Patients With Mild-to-Moderate Ulcerative Colitis in a Randomized Controlled Trial

BACKGROUND & AIMS The phytochemical compound curcumin was reported to be effective in maintaining remission in patients with ulcerative colitis (UC). We investigated curcumins efficacy in inducing remission in patients with active mild-to-moderate UC. METHODS We performed a multicenter randomized, placebo-controlled, double-blind study of 50 mesalamine-treated patients with active mild-to-moderate UC (defined by the Simple Clinical Colitis Activity Index [SCCAI]) who did not respond to an additional 2 weeks of the maximum dose of mesalamine oral and topical therapy. Patients were randomly assigned to groups who were given curcumin capsules (3 g/day, n = 26) or an identical placebo (n = 24) for 1 month, with continued mesalamine. The primary outcome was the rate of clinical remission (SCCAI ≤2) at week 4. Clinical and endoscopic responses were also recorded. RESULTS In the intention-to-treat analysis, 14 patients (53.8%) receiving curcumin achieved clinical remission at week 4, compared with none of the patients receiving placebo (P = .01; odds ratio [OR], 42; 95% confidence interval [CI], 2.3-760). Clinical response (reduction of ≥3 points in SCCAI) was achieved by 17 patients (65.3%) in the curcumin group vs. 3 patients (12.5%) in the placebo group (P < .001; OR, 13.2; 95% CI, 3.1-56.6). Endoscopic remission (partial Mayo score ≤1) was observed in 8 of the 22 patients evaluated in the curcumin group (38%), compared with none of 16 patients evaluated in the placebo group (P = .043; OR, 20.7; 95% CI, 1.1-393). Adverse events were rare and comparable between the 2 groups. CONCLUSIONS Addition of curcumin to mesalamine therapy was superior to the combination of placebo and mesalamine in inducing clinical and endoscopic remission in patients with mild-to-moderate active UC, producing no apparent adverse effects. Curcumin may be a safe and promising agent for treatment of UC. Clinicaltrials.gov number: NCT01320436.

Risk Factors Regarding the Need for a Second Operation in Patients with Crohn’s Disease

Background/Aims: The majority of Crohn’s disease patients undergo surgery. However, the factors that predict post-operative recurrence remain controversial. The aim of the present study was to shed light on the potential predictors of such recurrence. Methods: 86 patients who underwent operative procedures for Crohn’s disease were retrospectively studied. Recurrence was defined as the need for a second operation. Life table and multivariate analysis were performed to find the predictors of recurrence. Results: In 26/86 (30%) of the patients, post-operative recurrence was diagnosed within a mean of 42 months of the follow-up. Logistic regression analysis revealed that smoking (OR 3.69, 95% CI 2.06–11.52) and perforating disease (OR 4.09, 95% CI 1.31–12.65) were associated with a risk of recurrence. However, survival analysis showed that only perforating disease was associated with an early post-operative recurrence (log-rank test, p < 0.001). Neither resected surgical specimen characteristics, nor the duration and the location of the disease were found to predict the need for a second operation. Conclusion: The risk for Crohn’s disease patients who undergo surgery is related to the presence of perforating disease and smoking, which predict the need for a second operation. The former is associated with an even earlier recurrence.

Lidocaine inhibits secretion of IL-8 and IL-1β and stimulates secretion of IL-1 receptor antagonist by epithelial cells

Lidocaine and related local anaesthetics have been shown to be effective in the treatment of ulcerative colitis (UC). However, the mechanisms underlying their therapeutic effect are poorly defined. Intestinal epithelial cells play an important role in the mucosal inflammatory response that leads to tissue damage in UC via the secretion of pro‐inflammatory cytokines and chemokines. The aim of this study was to evaluate the direct immunoregulatory effect of lidocaine on pro‐inflammatory cytokine and chemokine secretion from intestinal epithelial cells. HT‐29 and Caco‐2 cell lines were used as a model system and treated with lidocaine and related drugs. The expression of IL‐8, IL‐1β and the IL‐1 receptor antagonist (RA) were assessed by ELISA and quantification of mRNA. In further experiments, the effect of lidocaine on the secretion of IL‐8 from freshly isolated epithelial cells stimulated with TNFα was tested. Lidocaine, in therapeutic concentrations, inhibited the spontaneous and TNFα‐stimulated secretion of IL‐8 and IL‐1β from HT‐29 and Caco‐2 cell lines in a dose‐dependent manner. Similarly, suppression of IL‐8 secretion was noted in the freshly isolated epithelial cells. Other local anaesthetics, bupivacaine and amethocaine, had comparable effects. Lidocaine stimulated the secretion of the anti‐inflammatory molecule IL‐1 RA. Both the inhibitory and the stimulatory effects of lidocaine involved regulation of transcription. The results imply that the therapeutic effect of lidocaine may be mediated, at least in part, by its direct effects on epithelial cells to inhibit the secretion of proinflammatory molecules on one hand while triggering the secretion of anti‐inflammatory mediators on the other.

Impact of Cannabis Treatment on the Quality of Life, Weight and Clinical Disease Activity in Inflammatory Bowel Disease Patients: A Pilot Prospective Study

Background and Aims: Inflammatory bowel disease (IBD) patients suffer from significant morbidity and diminished life quality. The plant cannabis is beneficial in various gastrointestinal diseases, stimulating appetite and causing weight gain. Our aims were to assess whether treatment with inhaled cannabis improves quality of life, disease activity and promotes weight gain in these patients. Methods: Patients with long-standing IBD who were prescribed cannabis treatment were included. Two quality of life questionnaires and disease activity indexes were performed, and patient’s body weight was measured before cannabis initiation and after 3 months’ treatment. Results: Thirteen patients were included. After 3 months’ treatment, patients reported improvement in general health perception (p = 0.001), social functioning (p = 0.0002), ability to work (p = 0.0005), physical pain (p = 0.004) and depression (p = 0.007). A schematic scale of health perception showed an improved score from 4.1 ± 1.43 to 7 ± 1.42 (p = 0.0002). Patients had a weight gain of 4.3 ± 2 kg during treatment (range 2–8; p = 0.0002) and an average rise in BMI of 1.4 ± 0.61 (range 0.8–2.7; p = 0.002). The average Harvey-Bradshaw index was reduced from 11.36 ± 3.17 to 5.72 ± 2.68 (p = 0.001). Conclusions: Three months’ treatment with inhaled cannabis improves quality of life measurements, disease activity index, and causes weight gain and rise in BMI in long-standing IBD patients.

Follow-Up of Exocrine Pancreatic Function in Type-1 Diabetes mellitus

In a previous study, mild to moderate exocrine pancreatic insufficiency, as measured by the secretin-pancreozymin test, was found in 23 (43%) of 53 patients with type-1 diabetes mellitus. Of these 53 patients, 20 (7 of whom initially had an abnormal secretin-pancreozymin test) were available for a follow-up examination 11 years later. Of the 7 patients with abnormal exocrine pancreatic function at the first test, 5 remained abnormal and 2 became normal, whereas of the 13 patients with initially normal pancreatic function the test result remained normal in 11 patients and became abnormal in 2. In these 2 groups the test result did not differ significantly between both tests. However, exocrine pancreatic function had returned to normal or had become abnormal in 2 patients, respectively, at the second test. In the 3 patients with exocrine pancreatic insufficiency at the first and second tests, the lipase level had not fallen below 10% or less than the normal level at which steatorrhea occurs and therapy is required. There was no significant correlation between the duration of the diabetes and the test results for both time points of investigation. The data suggest that mild to moderate exocrine pancreatic insufficiency found in type-1 diabetes is due to an early event in the course of the diabetes and does not progress. Therefore, this finding is of minor clinical importance and expensive pancreatic enzyme substitution will not be required.

Lidocaine down-regulates nuclear factor-κB signalling and inhibits cytokine production and T cell proliferation

Lidocaine is a commonly used local anaesthetic agent which has also been found to possess anti‐inflammatory activity in several disorders. However, the mechanism of this effect has been little explored. The aim of this study was to investigate the effect of lidocaine on stimulated human T cells. The effect of lidocaine on Jurkat T cells was examined by enzyme‐linked immunosorbent assay (ELISA) to determine secretion of interleukin (IL)‐2, and by the [3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide] viability assay. Tumour necrosis factor (TNF)‐α and IL‐2 mRNA expression was determined by reverse transcription–polymerase chain reaction. In addition, the effect of lidocaine on the proliferation of freshly isolated peripheral blood (PB) CD3+ T cells was examined by carboxyfluorescein succinimidyl ester dilution. Apoptosis induction and cytokine production and secretion were determined by annexin V/PI assay, intracellular immunostaining and ELISA respectively. The results showed that lidocaine exerts a dose‐dependent inhibition of IL‐2 and TNF‐α secretion by Jurkat T cells at the protein and mRNA levels. Moreover, lidocaine reduced nuclear factor‐κB (NF‐κB) signalling in clinically relevant concentrations. Similarly, proliferation of anti‐CD3 stimulated PB T cells was abrogated significantly by lidocaine, and the percentage of interferon‐γ‐ and TNF‐α‐producing T cells was diminished after culture with this agent. In both experimental systems, lidocaines effect was not mediated by cytotoxic mechanism, as no significant apoptosis or necrosis was demonstrated following co‐culture of T cells with this drug. In conclusion, lidocaines anti‐inflammatory effect may be mediated by a drug‐induced abrogation of T cell proliferation and cytokine secretion independent of cell death. These effects are mediated at least partly by inhibition of NF‐κB signalling.

Association between mutations in the CARD15 (NOD2) gene and Crohn's disease in Israeli Jewish patients

Ulcerative colitis (UC) and Crohns disease (CD) are heterogeneous disorders characterized by chronic intestinal inflammation. Genetic predisposition is a major risk factor in both diseases. The CARD15 (NOD2) gene has been implied as a candidate gene in the pathogenesis CD. Our aim was to delineate the frequency of three missense and one frameshift variant of CARD15 in Israeli Jewish CD and UC patients. DNA was extracted from blood samples from 238 unrelated inflammatory bowel disease (IBD) patients, 68 with UC and 170 with CD. The DNA was genotyped for two missense mutations, R675W and G881R, and one frameshift mutation, 980FS981X. Mutations in CARD15 were observed with significantly greater frequency in CD patients (46/170, 27%) than in UC patients (7/68, 10%) (P = 0.005). Homozygous and compound heterozygous carriers were restricted to seven (4%) patients with CD as compared to none of the UC patients (P = 0.01). Similar rates in Ashkenazi and non‐Ashkenazi Jewish patients were observed. Age‐of‐onset of disease was lower in Ashkenazi mutation carriers as compared to non‐carriers of Ashkenazi origin (18.7 ± 8.6 years vs. 25.8 ± 13.4 years, respectively, P = 0.03). No other phenotypic characteristics could distinguish mutation carriers from non‐carriers. We conclude that germline mutations in the CARD15 gene are more frequently found in CD than UC patients and appear to predict an earlier age‐of‐onset in Ashkenazi Jewish patients. No association could be demonstrated between CARD15 mutations and specific disease course or behavior.

Familial clustering of Crohn's disease in Israel: Prevalence and association with disease severity

Background: There is limited data addressing the severity of Crohns disease (CD) in patients with a family history of inflammatory bowel disease (IBD) compared to sporadic cases. Methods: We investigated the familial occurrence of IBD and its correlation with disease behavior in CD patients attending the Israeli IBD Foundation meeting using a structured questionnaire. Results: The study group consisted of 181 CD patients with a total of 825 1st degree relatives. Positive family history for IBD in a 1st degree relative was reported in 30 patients (16%). Nine out of the 360 parents (2.5%) had IBD (4 CD, 5 UC). There were 17 siblings with IBD (15 CD, 2 UC) out of 351 (4.8%). Ten out of 114 (8.8%) offsprings had IBD (6 CD, 4 UC). When two siblings were affected, their respective age of disease onset was strikingly concordant (r = 0.76, p = 0.008). There was no difference between sporadic and familial CD patients in the age of disease onset, the location of disease, proportion of smokers or percentage of Ashkenazi origin. Furthermore, similar proportions of sporadic and familial patients underwent intestinal surgery, had penetrating or obstructive complications or were treated by immunomodulators and/or biologics. There was also no difference in the reported percentage of time with active disease or the number of flare‐ups. Conclusions: The prevalence of familial disease among Jewish CD patients in Israel is at the high range of the rate found in other ethnicities. Having a positive family history of IBD has no impact on the severity of the disease.

Somatostatin inhibits pro-inflammatory cytokine secretion from rat hepatic stellate cells.

Abstract: Background/aims: Activated hepatic stellate cells (HSCs) have been implicated in hepatic fibrosis. Somatostatin (SOM) has an immunomodulatory role. The aim of this study was to assess the secretion of pro‐inflammatory cytokines by HSCs and to determine the effect of SOM on the secretion of these mediators.

Travel-Associated Health Risks for Patients With Inflammatory Bowel Disease

BACKGROUND & AIMS There are few data on risk of travel for patients with inflammatory bowel disease (IBD). We assessed rates of illness while traveling among patients with IBD. METHODS We performed a retrospective, case-controlled study of illnesses among 222 patients with IBD and 224 healthy individuals (controls) during 1099 total trips. Data were retrieved by structured questionnaires, personal interviews, and chart review. RESULTS Participants had 142 episodes of illness during the trips; 92% were enteric disease. An episode of illness occurred during 79/523 (15.1%) trips made by patients with IBD compared with 63/576 (10.9%) trips made by controls (odds ratio [OR], 1.44; 95% confidence interval [CI], 1.01-2.0; P = .04). However, this difference was mostly attributable to the increased incidence of illness among IBD patients traveling in industrialized countries. In contrast, the rate of illness among travelers to developing countries was similar among patients with IBD and controls (34/200, 17% vs 52/243, 21% of trips, respectively; P = .24). Moreover, numerically more controls that traveled to the tropics developed illness than travelers with IBD (43/135 vs 23/97, respectively; P = .18). In multivariate analysis, factors that increased risk for travel illness included frequent flares of IBD (OR, 1.9; 95% CI, 1.1-3.4; P = .02) and prior IBD-related hospitalizations (OR, 3.5; 95% CI, 1.3-9.3; P = .01); remission within 3 months before traveling reduced the risk for illness (OR, 0.3; 95% CI, 0.16-0.5; P < .001). Use of immunomodulatory drugs was not independently associated with risk of illness during travel. CONCLUSIONS Patients with IBD have a higher rate of illness compared with controls during trips to industrialized countries, but not to developing or tropical regions. These findings indicate that most travel-associated illnesses stem from sporadic IBD flares rather than increased susceptibility to enteric infections.