Long-term outcome of patients with steroid-refractory acute severe UC treated with ciclosporin or infliximab.

OBJECTIVE: Ciclosporin and infliximab have demonstrated short-term similar efficacy as second-line therapies in patients with acute severe UC (ASUC) refractory to intravenous steroids. The aim of this study was to assess long-term outcome of patients included in a randomised trial comparing ciclosporin and infliximab. DESIGN: Between 2007 and 2010, 115 patients with steroid-refractory ASUC were randomised in 29 European centres to receive ciclosporin or infliximab in association with azathioprine. Patients were followed until death or last news up to January 2015. Colectomy-free survival rates at 1 and 5 years and changes in therapy were estimated through Kaplan-Meier method and compared between initial treatment groups through log-rank test. RESULTS: After a median follow-up of 5.4 years, colectomy-free survival rates (95% CI) at 1 and 5 years were, respectively, 70.9% (59.2% to 82.6%) and 61.5% (48.7% to 74.2%) in patients who received ciclosporin and 69.1% (56.9% to 81.3%) and 65.1% (52.4% to 77.8%) in those who received infliximab (p=0.97). Cumulative incidence of first infliximab use at 1 and 5 years in patients initially treated with ciclosporin was, respectively, 45.7% (32.6% to 57.9%) and 57.1% (43.0% to 69.0%). Only four patients from the infliximab group were subsequently switched to ciclosporin. Three patients died during the follow-up, none directly related to UC or its treatment. CONCLUSIONS: In this cohort of patients with steroid-refractory ASUC initially treated by ciclosporin or infliximab, long-term colectomy-free survival was independent from initial treatment. These long-term results further confirm a similar efficacy and good safety profiles of both drugs and do not favour one drug over the other. TRIAL REGISTRATION NUMBER: EudraCT: 2006-005299-42; ClinicalTrials.gouv number: NCT00542152; post-results.

Role of TNFRSF1B polymorphisms in the response of Crohn's disease patients to infliximab.

Infliximab (IFX) is a valid treatment for Crohn's disease (CD), but a relevant percentage of patients do not benefit from this therapy. In the Japanese population, the response to IFX was associated with markers in the TNF receptor superfamily 1A (TNFRSF1A) and 1B (TNFRSF1B) genes. We aimed to replicate the association previously described in the Japanese population and to ascertain the role of TNF receptors as modulators of the response to IFX. We studied 297 white Spanish CD patients with a known response to IFX: 238 responders and 59 primary nonresponders. Four single nucleotide polymorphisms (SNPs) were analyzed: rs767455 in TNFRSF1A and rs1061622, rs1061624, and rs3397 in TNFRSF1B. Comparisons between groups were performed with chi-square tests or the Fisher's exact test. Different features (sex, age, disease duration, smoking among others) were evaluated as possible confounding factors. No significant association was found between the studied TNFRSF1A polymorphisms and response to IFX. In the TNFRSF1B gene, the haplotype rs1061624_A-rs3397_T was significantly increased in nonresponders: p = 0.015, OR = 1.78, 95% CI 1.09-2.90; and an increased frequency of rs1061622_G carriers was observed in patients with remission: p = 0.033 vs nonresponders and p = 0.023 vs patients with a partial response. Our results support a role of TNFRSF1B gene variants in the response to IFX in CD patients.

The course of inflammatory bowel disease during pregnancy and postpartum: a prospective European ECCO-EpiCom Study of 209 pregnant women.

BACKGROUND: The impact of pregnancy on the course of IBD is still controversial. AIM: To investigate the impact of pregnancy on IBD and to search for factors with potential impact on remission. METHODS: Pregnant IBD women from 12 European countries were enrolled between January 2003 and December 2006 and compared at conception (1:1) with nonpregnant IBD women. Data on disease course were prospectively collected at each trimester during pregnancy and in the postpartum (6 months) using a standardised questionnaire. RESULTS: A total of 209 pregnant IBD women were included: 92 with Crohn's disease (CD; median age 31 years, range 17-40) and 117 with ulcerative colitis (UC; median age 32 years, range 19-42). No statistically significant difference in disease course during pregnancy and postpartum was observed between pregnant and nonpregnant CD women. Longer disease duration in CD and immunosuppressive therapy were found to be risk factors for activity during pregnancy. Pregnant UC women were more likely than nonpregnant UC women to relapse both during pregnancy (RR 2.19; 95% CI: 1.25-3.97, 0.004) and postpartum (RR 6.22; 95% CI: 2.05-79.3, P = 0.0004). During pregnancy, relapse was mainly observed in the first (RR 8.80; 95% CI 2.05-79.3, P < 0.0004) and the second trimester (RR 2.84, 95% CI 1.2-7.45, P = 0.0098). CONCLUSIONS: Pregnant women with Crohn's disease had a similar disease course both during pregnancy and after delivery as the nonpregnant women. In contrast, pregnant women with ulcerative colitis were at higher risk of relapse during pregnancy and in the postpartum than nonpregnant ulcerative colitis women.

Evaluation of liver fibrosis by transient elastography (Fibroscan®) in patients with inflammatory bowel disease treated with methotrexate: a multicentric trial.

BACKGROUND: Methotrexate is an effective treatment for inflammatory bowel disease (IBD). However, long-term treatments have been associated with the development of liver fibrosis. FibroScan® is a noninvasive, safe, and effective technique to evaluate liver fibrosis. AIM: To evaluate the presence of significant liver fibrosis by transient elastography (FibroScan®) in IBD patients treated with methotrexate. METHODS: Cross-sectional study including IBD patients treated with methotrexate from different hospitals. Clinical and analytical data, duration of treatment, and cumulative dose of methotrexate were obtained. Liver stiffness was assessed by FibroScan®. The cutoff value for significant liver fibrosis (according to METAVIR) was F ≥ 2: 7.1 kPa. Results. In the study, 46 patients were included, 30 women (65%), with a mean age of 43 ± 10 years. 31 patients had Crohn's disease (67.4%), 13 ulcerative colitis (28.3%), and 2 indeterminate colitis (4.3%). The mean cumulative dose of methotrexate was 1242 ± 1349 mg, with a mean treatment duration of 21 ± 24 months. The mean value of liver stiffness was 4.7 ± 6.9 kPa. There were 35 patients (76.1%) with F01, 8 patients (17.4%) with F = 2, and 3 patients with F ≥ 3 (6.5%). There were no differences in liver stiffness depending on sex, age, type of IBD, or cumulative dose of methotrexate. CONCLUSIONS: (1) Development of advanced liver fibrosis in IBD patients treated with methotrexate is exceptional. (2) There were no differences in liver stiffness depending on the type of IBD or the cumulative dose of methotrexate. (3) FibroScan® may be potentially useful for evaluation and follow-up of liver fibrosis in methotrexate-treated patients.

Thiopurine methyl-transferase activity and azathioprine metabolite concentrations do not predict clinical outcome in thiopurine-treated inflammatory bowel disease patients.

BACKGROUND: Low thiopurine-methyl-transferase (TPMT) activity and high 6-thioguanine-nucleotide (6TGN) concentrations have been linked to therapeutic success in inflammatory bowel disease patients treated with thiopurines; however, this has not been implemented in clinical practice. AIM: To identify a therapeutic threshold value for TPMT or 6TGN concentrations, and their capability to predict treatment safety and efficacy. METHODS: Prospective multicentre study including steroid-resistant/dependent patients starting thiopurines. The TPMT activity was determined at inclusion (>5 U/mL required). Azathioprine metabolites [6TGN, 6-methyl-mercaptopurine ribonucleotides (6MMP), and 6TGN/6MMP and 6TGN/TPMT ratios] were periodically monitored during steroid tapering and after withdrawal for 6 months or until a new flare occurred. RESULTS: A total of 113 patients were analysed (62% clinical response). Areas under the receiver operating characteristic (ROC) curve (AUC) relating clinical response and metabolite levels at 2, 4 and 6 months after steroid withdrawal were less than 0.7. The AUCs relating final response and initial TPMT activity or metabolite concentrations at 2, 4, 8 and 16 weeks after starting thiopurines were less than 0.7. No cut-off point with worthwhile sensitivity/specificity was found. Eight (7%) patients developed thiopurine-related toxicity that could not be linked to TPMT activity or 6TGN levels. CONCLUSIONS: Our results do not support determination of TPMT activity or 6TGN concentrations to predict treatment outcome, and no useful serum metabolites threshold value to adjust the drug's dose was identified.

Mercaptopurine rescue after azathioprine-induced liver injury in inflammatory bowel disease.

BACKGROUND: Azathioprine (AZA) liver toxicity arises in approximately 3% of inflammatory bowel disease patients and may result in treatment discontinuation. AIM: To describe the tolerance to mercaptopurine (MP) in patients with previous AZA-related liver injury. METHODS: Retrospective description of 31 patients (14 Crohn's, 17 ulcerative colitis), in which AZA therapy was interrupted because of liver injury, with MP started as alternative therapy. RESULTS: Mean AZA dose was 2.2 +/- 0.4 mg x kg/day. Median (interquartile range) of AZA exposure when liver injury was detected was 2 months (1-5.2). The type of AZA-related injury was cytolitic in 32%, cholestatic in 39% and mixed in 29%. After a median of 2.5 months (0.7-5.2), the therapy was switched to MP at a mean dose of 1.3 +/- 0.2 mg x kg/day. Median of follow-up of MP therapy was 32 months (8-54). In 87.1% of patients (95%CI: 70-96%), MP was tolerated without further liver injury; of these, 77.4% tolerated full MP doses and 9.7% tolerated lower doses. In a further cohort of 12.9% of patients, (95%CI: 3-29%), liver injury reappeared (two cholestasis, two mixed), 1-3 months after the onset of MP exposure. CONCLUSION: The administration of MP is a good alternative in patients with AZA-related liver injury, before thiopurines are definitely discarded.

Acute pancreatitis in inflammatory bowel disease, with special reference to azathioprine-induced pancreatitis.

BACKGROUND: Pancreatitis is a potentially severe condition. Patients with inflammatory bowel disease (IBD) seem to be at increased risk for acute pancreatitis. AIM: To describe the incidence, main causes and possible predictive factors of acute pancreatitis in inflammatory bowel disease. METHODS: Information was retrospectively extracted from the clinical records of patients followed in the IBD Units of nine hospitals in Madrid (n = 5073). RESULTS: A total of 82 acute pancreatitis episodes were diagnosed (cumulative incidence, 1.6%); 98% of them were mild. Recurrent acute pancreatitis developed in 13% of patients. Most cases of acute pancreatitis (63.4%) were attributed to drug exposure [azathioprine/mercaptopurine (AZA/MP) n = 46, mesalazine (mesalamine) n = 6]; 20.7% were idiopathic, and 12.2% were biliary. Incidence of acute pancreatitis in patients treated with AZA/MP was 3.1%. In patients with acute pancreatitis, female gender (OR 3.4 95% CI: 1.3-9.3; P = 0.012) and Crohn's disease (CD) (OR 5.8 95% CI: 1.6-20.6; P = 0.007) were risk factors for AZA/MP-associated acute pancreatitis, the latter also when analysed only in patients treated with AZA/MP (n = 1477) (OR 5.2 95% CI: 1.8-14; P = 0.002). CONCLUSIONS: The incidence of acute pancreatitis in our IBD patients (1.6%) is similar to that previously described. Drugs, mainly AZA/MP, are the leading cause. AZA-induced acute pancreatitis is always mild. Patients with CD are at a higher risk for AZA/MP-associated acute pancreatitis. The frequency of idiopathic acute pancreatitis is higher than expected, suggesting that part of these cases could be extraintestinal manifestations of IBD.

Review article: how to control and improve adherence to therapy in inflammatory bowel disease.

Any chronic disease is a risk situation for non-adherence to treatment. This results in suboptimal medication, and poor disease control. Adherence and compliance are directly related to therapeutic success, which is further complicated in inflammatory bowel disease patients. There is a wide array of circumstances that increase the likelihood of non-compliance in a given patient: difficult-to-follow treatment schedules (multiple doses and multiple drugs), insufficient patient information, longer evolution of the disease and inactive disease. Depression, male gender, active employment and living alone are also associated with poorer adherence to therapy. Monitoring drug intake is possible in many circumstances, directly or indirectly (urinary salicylate levels; erythrocyte metabolites and increased mean corpuscular volume and bilirubin in patients under azathioprine; blood levels of ciclosporin or tacrolimus). However, such measures are probably better utilized for dose adjustment and not for the identification of non-compliant patients. High-risk patients are a target group in which pre-emptive intervention could ensure better compliance. If the question of non-adherence arises, for instance, as a possible cause of therapy failure, the patient should be carefully approached. This should take into consideration factors that may be corrected and, most importantly, should aim at building a better patient-doctor relationship.

Infliximab induces clinical, endoscopic and histological responses in refractory ulcerative colitis.

BACKGROUND: infliximab is a monoclonal antiTNF-ct antibody that has repeatedly shown to be effective in the management of Crohn's disease. However, data are scarce about its efficacy in ulcerative colitis. AIM: to describe the joint experience of three Spanish hospitals in the use of infliximab in patients with active refractory ulcerative colitis. PATIENTS AND METHODS: we present seven cases of ulcerative colitis (6 with chronic active disease despite immunosuppressive therapy, and one with acute steroid-refractory ulcerative colitis) treated with infliximab 5 mg/kg of body weight. Clinical response was evaluated by means of the Clinical Activity Index at 2, 4 and 8 weeks after initial infusion. Biochemical (erythrocyte sedimentation rate and C-reactive protein), endoscopic, and histological changes were also assessed. RESULTS: mean age of patients was 45.8 +/- 17 years (range 23-77); 4 were female. No adverse effects were recorded. Inflammatory activity diminished significantly in 6 of 7 patients (85.7%; CI 95%: 42-99%) both from a clinical (p = 0.01) and biochemical (p <0.05) point of view. Five out of six patients (83.3%; 36-99%) with corticosteroid-dependent disease could be successfully weaned off these drugs. Five patients were endoscopicly controlled both before and after therapy, and a positive endoscopic and histological response could be recorded in all of them. CONCLUSION: infliximab may be an effective and safe therapy for some patients with ulcerative colitis refractory to other forms of therapy, although controlled studies are needed to assess its role in the general management of this disease.

Efficacy and safety of thiopurinic immunomodulators (azathioprine and mercaptopurine) in steroid-dependent ulcerative colitis.

BACKGROUND: The efficacy of azathioprine in the management of steroid-dependent ulcerative colitis is taken for granted. However, study populations frequently include together steroid-dependent and refractory patients. AIM: To assess the efficacy and safety of thiopurinic immunomodulators in strictly defined steroid-dependent ulcerative colitis. METHODS: Survey of 34 patients with steroid-dependent ulcerative colitis, treated with azathioprine according to protocol. Therapeutical success: glucocorticoid withdrawal within 12 months, without steroid requirements during another year. RESULTS: Mean age was 39.1 +/- 17 years. Pancolitis and extensive colitis accounted for 50% of cases. Therapeutic success of immunomodulator treatment reached 70.6%, intention to treat analysis (confidence interval 95%: 52-84%) and 72.7%, as per protocol (confidence interval 95%: 54-86%). Mean time to steroid withdrawal was 4.6 months. In therapy successes, mean corpuscular volume and total serum bilirubin increased with treatment time (P = 0.0001). Fifteen adverse effects were observed in 13 patients (38%). Azathioprine was withdrawn in seven cases (20.6%); in four of them (with liver toxicity), treatment with mercaptopurine was indicated. CONCLUSIONS: Therapy with thiopurinic immunomodulators (azathioprine) represents the first option in the management of steroid-dependent ulcerative colitis. Its efficacy (70%) and its acceptable safety support this view. Increasing mean corpuscular volume and serum bilirubin values may be a surrogate marker of a beneficial effect.

Seven-day proton pump inhibitor, amoxicillin and clarithromycin triple therapy. factors that influence Helicobacter pylori eradications success.

AIM: To evaluate which factors influence eradication success with standard triple therapy for Helicobacter pylori. PATIENTS AND METHODS: A prospective study was made of 891 patients infected by H. pylori and diagnosed with duodenal ulcer (n=422), gastric ulcer (n=221), or functional dyspepsia (n=248). Initially, an endoscopy with biopsies of antrum and body (haematoxylin-eosin stain), and a 13C-urea breath test were performed. All patients were treated for seven days with either omeprazole 20 mg twice daily in 442 patients (OCA) or pantoprazole 40 mg twice daily in 449 patients (PCA), associated to clarithromycin (500 mg twice a day) and amoxicillin (1 g twice a day). Two months after completing therapy urea breath test was repeated to confirm eradication. RESULTS: Mean age +/- SD was 51.6 +/- 15 years, 61% were male. Overall eradication rate was 73.7% (95% CI 69-77%) and 80.8% (77-84%) with OCA and PCA therapy, respectively, showing significant difference between treatment regimens (chi 2 =6.3; p= 0.01). As refers to underlying diseases, H. pylori eradication was achieved in 77.4% (74-80%) of peptic ulcers and 77% (71-82%) of functional dyspepsia (p=n.s.). With our two treatment regimens (OCA/PCA) eradication success was 74/81% in peptic ulcer (p=0.03), and 72/80% in functional dyspepsia (p=0.1). In the multivariate analysis, type of therapy was the only variable that correlated with eradication success (odds ratio 1.5; 95% CI: 1.1-2.1) (chi2 model: 6,4; p=0.01). CONCLUSIONS: Standard triple therapy containing a proton pump inhibitor, clarithromycin and amoxicillin for seven days achieves in our community a moderate eradication success; this result could improve by using pantoprazole instead of omeprazole. This therapy is equally effective in patients with peptic ulcer and functional dyspepsia.

Efficacy of quadruple therapy with pantoprazole, bismuth, tetracycline and metronidazole as rescue treatment for Helicobacter pylori infection.

AIM: To study the efficacy of a 7-day quadruple regimen combining pantoprazole, bismuth, tetracycline and metronidazole as rescue treatment for Helicobacter pylori infection after failure of standard triple therapy. METHODS: A prospective study was made of 140 patients infected with H. pylori and diagnosed with peptic ulcer or non-ulcer dyspepsia in whom triple therapy with proton pump inhibitor, clarithromycin and amoxicillin had failed. The patients were treated with quadruple therapy including pantoprazole, 40 mg twice daily, colloidal bismuth subcitrate, 120 mg four times daily, tetracycline, 500 mg four times daily, and metronidazole, 500 mg three times daily, for 7 days. Two months after completion of therapy, a 13C-urea breath test was performed to confirm eradication. RESULTS: With quadruple therapy, the H. pylori eradication rates were 82% (95% confidence interval (CI), 75-88%) by 'intention-to-treat' and 85% (95% CI, 79-91%) by 'per protocol'. No major side-effects were observed. No differences in eradication success were observed in relation to underlying disease (peptic ulcer: 85% (95% CI, 76-91%) vs. non-ulcer dyspepsia: 83% (95% CI, 68-93%)) or smoking habits (smokers: 86% (95% CI, 75-93%) vs. non-smokers: 83% (95% CI, 71-91%)). CONCLUSION: Quadruple therapy with pantoprazole, bismuth, tetracycline and metronidazole for 7 days is an effective H. pylori eradication treatment for patients in whom standard triple therapy has failed.

[Evolution and treatment response in microscopic colitis]. / Curso evolutivo y respuesta al tratamiento de las colitis microscópicas.

AIM: To study the clinical characteristics, treatment response and evolution in patients with microscopic colitis. MATERIAL AND METHODS: We performed a retrospective analysis of 24 patients (15 with collagenous colitis and 9 with lymphocytic colitis). Clinical and diagnostic features, treatment response and evolution according to the presence of maintenance therapy were evaluated. RESULTS: The mean age of the patients was 59.7 years and most were male. Nine patients took non-steroidal anti-inflammatory drugs (NSAID). No significant association was found with other drugs. Four patients presented associated rheumatological disease. Most patients presented insidious-onset diarrhea without pathological products, which was frequently associated with other symptoms (abdominal pain, bloating, weight loss, asthenia, tenesmus, and incontinence). Seven patients showed a slight increase in globular sedimentation rate. Fat in stools and radiological investigations (transit and opaque enema) were normal in patients who underwent these tests. Endoscopy revealed non-specific alterations in 42% of the patients while results were normal in the remaining patients. One patient showed clinical improvement on withdrawal of NSAIDs and 4 patients improved spontaneously. Clinical response was achieved in 7 of 13 patients treated with antimotility drugs, in 8 of 9 patients treated with salicylates, in 3 treated with oral corticoids, in 1 treated with cholestyramine and in 1 treated with topical budesonide. Nineteen patients required no maintenance therapy, 4 were administered salicylates and 1 was administered cholestyramine. After a mean follow-up of 42 months, evolution was chronic and intermittent in 14 patients and chronic and continuous in 1; 9 patients presented a single episode. No significant differences were found between patients administered maintenance therapy and those who were not or between collagenous colitis and lymphocytic colitis in the parameters analyzed. CONCLUSIONS: Microscopic colitis constitutes a group of diseases characterized by chronic diarrhea, few systemic effects and minimal radiological and/or endoscopic alterations. Evolution is characterized by recurrent episodes, with good response to treatment with cholestyramine, salicylates or corticoids when required.

Liver transplantation for type Ib glycogenosis with reversal of cyclic neutropenia.

We describe a case of glycogen storage disease type Ib in 32-year old male patient with poor metabolic control in spite of medical and nutritional management and the use of recombinant granulocyte stimulating factor. Because of this, liver transplantation was considered as a definitive treatment. We comment on the metabolic results of liver transplantation performed, with reversal of hypoglycemia, hyperuricemia, hypertriglyceridemia and cyclic neutropenia, all of which persist 4 years post-transplant. In view of this case, we believe that liver transplantation is a feasible option to consider in patients with type Ib glycogenosis as a definitive therapeutic procedure.

Vaccination against hepatitis B virus in cirrhotic patients on liver transplant waiting list.

Patients with cirrhosis may fail to respond to anti-hepatitis B vaccine. An adequate response would be especially interesting when patients are on a liver transplant waiting list. Posttransplantation de novo hepatitis B has been well documented. One possible source is the grafting of organs from hepatitis B surface antigen (HBsAg)-negative, antibody to HBsAg (anti-HBs)-positive, antibody to hepatitis B core antigen-positive donors. The achievement of high titers of anti-HBs could be protective in this setting. We studied prospectively the response rate to recombinant hepatitis B vaccine (3 40-microg doses administered at 0, 1, and 2 months) in 62 patients with end-stage liver disease awaiting liver transplantation. Twenty-two patients showed antibody response (44%). A further 3 doses were administered in 15 of 28 nonresponders and were effective in 9 patients. Thus, the response rate reached 62% (31 of 50 patients completing 1 or 2 vaccination schedules before liver transplantation). Classic hepatitis B vaccination studies of patients with cirrhosis yield lower response rates. Vaccination with this double-dose schedule should be considered in such patients before liver transplantation.