Efficacy and safety of short-term adalimumab treatment in patients with active Crohn's disease who lost response or showed intolerance to infliximab: a prospective, open-label, multicentre trial.

BACKGROUND: The use of tumour necrosis factor antagonists has changed the therapeutic approach to Crohn's disease. AIM: To determine response and remission rates associated with the 4-week induction phase of adalimumab treatment in patients with luminal and/or fistulizing Crohn's disease, who have lost response to or become intolerant of infliximab. METHODS: In this multicentre, prospective, open-label, observational, 52-week study, 50 adults received an induction dose of adalimumab (160 mg at baseline followed by 80 mg at week 2). RESULTS: Of the 36 patients with luminal Crohn's disease, 83% achieved clinical response [> or =70-point reduction in the Crohn's Disease Activity Index (CDAI) score] and 42% achieved clinical remission (CDAI score <150) at week 4. Of the 22 patients with fistulizing disease, five (23%) experienced fistula remission (complete closure of all fistulas that were draining at baseline), and nine (41%) experienced fistula improvement (> or =50% decrease in the number of fistulas that were draining at baseline) at week 4. Of the 19 adverse events, most [13 (68%)] were mild, and no serious or infectious adverse events occurred. CONCLUSIONS: Adalimumab may be an effective alternative in patients with luminal and/or fistulizing Crohn's disease who have lost response to or become intolerant of infliximab.

Standardization of the homogeneous mobility shift assay protocol for evaluation of anti-infliximab antibodies. Application of the method to Crohn's disease patients treated with infliximab.

BACKGROUND: The availability of a quantitative method to measure anti-infliximab (IFX) antibodies (ATI) would facilitate the implementation of therapeutic drug monitoring in clinical decision-making. Our aim was to standardize the homogeneous mobility shift assay (HMSA) used in the measure of ATI levels. METHODS: In this prospective longitudinal multicenter study, 50 IFX-treated Crohn's disease (CD) patients were followed up for 54weeks. During this period 360 human serum samples were analysed. Monomeric ATI levels were measured by a quantitative HMSA-method using an anti-IFX calibrator. IFX trough levels measured by ELISA were correlated with ATI levels. RESULTS: Using HMSA and a pure anti-idiotypic monoclonal antibody specific for IFX (anti-IFX calibrator), we measured the levels of monomeric ATI generated in Crohn's disease patients treated with IFX. Anti-IFX calibrator allowed to quantify monomeric antibodies against IFX with a low limit of quantification (3nM). The threshold level of ATI in order to classify the immunogenicity of the patients was 10nM. We observed that 24% (12/50) of IFX-treated patients developed ATI (>10nM) during the observation period (54weeks). Serum concentration of ATI higher than 10nM dramatically increased the probability (OR=51.1; 95% CI: 20.4-128.0; p<0.0001) of presenting low levels of IFX (⩽1.5nM) in serum, as observed in some CD patients treated with standard doses of the drug. CONCLUSIONS: The HMSA-method described here allows an accurate quantification of ATI concentration in international units (IU) and therefore it could be useful in the study of the relationship between ATI concentration, infliximab level and the clinical response to the drug.

A randomized controlled trial of a 10 week group psychotherapeutic treatment added to standard medical treatment in patients with functional dyspepsia.

OBJECTIVE: Epidemiological evidence suggests an association between psychological factors and functional dyspepsia (FD). Yet few randomized controlled trials (RCTs) of psychological interventions have been conducted for FD. We conducted an RCT to evaluate the efficacy of psychotherapy among chronic FD. METHODS: One hundred fifty-eight consecutive patients with FD were randomized to medical therapy plus psychotherapy consisted in 8 group and 2 individual sessions focused on teaching techniques for coping with FD (intensive treatment (IT); n=76) or medical therapy alone (conventional treatment (CT); n=82). Patients completed validated self-reported questionnaires before and after the 10-week treatment and 6 months later. Linear mixed-effects models were used, in intention-to-treat analysis. RESULTS: At the end of treatment period, statistically significant improvements were observed for IT compared with CT for dyspepsia-related quality of life (DRQoL). DRQoL mean changes of 6.09 and 3.54 were obtained in IT and CT patients, respectively (p=<0.0001); and SS mean changes of 11.55 and 4.57 were obtained in IT and CT patients, respectively (p=0.0013). Those improvements, measured by minimum clinically important difference (MCID), were clinically significant (DRQoL: 77% of the IT patients exceeded the MCID vs. the 45% of the CT; SS: 75% vs. 48%). Six months after treatment, those statistically significant improvements persisted for DRQoL (p=0.0067) and for SS (p=0.0405). Clinical improvements persisted for SS (63% vs. 41%). CONCLUSIONS: These findings suggest that adding psychotherapy to standard medical therapy improves short-term outcomes in patients with FD and may have long-term effects as well. The cost-effectiveness of intensive therapy needs to be evaluated. Registration number and name of trial registry: NCT01802710.

Development of explicit criteria for cholecystectomy.

OBJECTIVE: Consensus development techniques were used in the late 1980s to create explicit criteria for the appropriateness of cholecystectomy. New diagnostic and treatment techniques have been developed in the last decade, so an updated appropriateness of indications tool was developed for cholecystectomy in patients with non-malignant diseases. The validity and reliability of panel results using this tool were tested. METHODS: Criteria were developed using a modified Delphi panel judgement process. The level of agreement between the panelists (six gastroenterologists and six surgeons) was analysed and the ratings were compared with those of a second different panel using weighted kappa statistics. RESULTS: The results of the main panel were presented as a decision tree. Of the 210 scenarios evaluated by the main panel in the second round, 51% were found appropriate, 26% uncertain, and 23% inappropriate. Agreement was achieved in 54% of the scenarios and disagreement in 3%. Although the gastroenterologists tended to score fewer scenarios as appropriate, as a group they did not differ from the surgeons. Comparison of the ratings of the main panel with those of a second panel resulted in a weighted kappa statistic of 0.75. CONCLUSIONS: The parameters tested showed acceptable validity and reliability results for an evaluation tool. These results support the use of this algorithm as a screening tool for assessing the appropriateness of cholecystectomy.

Quality-of-life outcomes with laparoscopic vs open cholecystectomy.

BACKGROUND: Few studies have assessed the health outcomes of patients who underwent cholecystectomy. The goal of this study was to evaluate the health-related quality-of-life (HRQoL) improvement of patients undergoing laparoscopic versus open cholecystectomy. METHODS: A prospective observational study was performed of consecutive patients on waiting lists to undergo cholecystectomy for nonmalignant disease in six hospitals. Patients were asked to complete two questionnaires that measure (HRQoL)-the SF-36 and the Gastrointestinal Quality of Life Index (GIQLI)-before the intervention and 3 months later. RESULTS: Improvement after surgery, measured by the SF-36 and GIQLI, was similar for both surgical techniques. The SF-health transition item showed a perception of worse health, compared to 1 year previously, for those who underwent open surgery and complications were also higher. CONCLUSIONS: HRQoL improvement at 3 months was relevant and similar for both surgical techniques, although the health transition perception was worse for those who underwent open surgery.

[Response to recombinant DNA antihepatitis B vaccine in mentally retarded patients with Down's syndrome. A controlled study]. / Respuesta a la vacuna DNA recombinada antihepatitis B en los deficientes mentales con síndrome de Down. Estudio controlado.

To investigate the response of mentally retarded individuals (MR) with Down's syndrome (Down-MR) to recombinant hepatitis B vaccine, three doses (20 micrograms per dose) were administered on the usual schedule (months 0, 1 and 6) to two groups of MR with mean age of 14.6 years. The first group consisted of 32 MR-Down. The second group consisted of 35 MR other etiologies (non Down-MR). Both had the same sex distribution and similar ages and weight/height index. The post vaccination anti-HBs titers were measured on months 1, 2, 6 and 8. The results could be analysed in 63 MR. Eight months after vaccination, 100% of Down-MR and 91% of non Down-MR developed a response to the vaccine (anti-HBs greater than 10 IU/l). Both groups achieved high antibody titers (geometric mean 4.298 and 6.424, respectively). A significant inverse correlation of anti-HBs with age was found, but not with sex of with the weight-height index. It was concluded that Down-MR in young age have a normal response to recombinant hepatitis B vaccine at the usual dose and schedule. Therefore, the goal to suppress the reservoir of hepatitis B in Down-MR both in institutions for MR and in normal schools should be achieved.

[Hyperplastic gastropathy with acid hypersecretion. A case report]. / Gastropatía hiperplásica con hipersecreción ácida. Consideraciones a propósito de un caso.

The case of a 60-year-old male patient with hyperplastic hypersecretory gastropathy. The diagnosis was reached by means of the histologic study of a sample obtained by endoscopic macrobiopsy. Examination of the gastric secretions showed stimulate and basal hypersecretion; gastrinemia was normal and albumin levels were at the lower limit. Several observations are made concerning the acid secretion clinical aspects and treatment of this rare disorder.

Magnetic resonance study of the pancreatic duct.

AIM: to prospectively determine the diagnostic accuracy of magnetic resonance cholangiopancreatography (MRCP) in the evaluation of the normal and diseased pancreatic duct. METHODS: patients seen during a 6-month period with a diagnosis of biliary tract or pancreatic disease underwent endoscopic retrograde cholangiopancreatography (ERCP) after a previous MRCP. The pancreatic duct was evaluated with both techniques in 37 patients. RESULTS: the pancreatic duct appeared normal in ERCP in 27 patients, and also appeared normal in MRCP in 25 of these patients (specificity 93%). ERCP showed moderate-severe pancreatic duct dilation in 8 patients, in whom the same diagnosis was reached with MRCP (sensitivity 100%). The causes of dilation were chronic pancreatitis (2 patients), pancreatic cancer (3 patients) and ampullary tumor (2 patients); in 1 patient the findings with both techniques were suggestive of neoplasm of the head of the pancreas or focal chronic pancreatitis. Pancreas divisum was diagnosed in 2 patients by both methods, and the predominant dorsal duct as well as the ventral duct were visualized by MRCP. CONCLUSIONS: MRCP is an accurate technique for evaluating the normal or diseased pancreatic duct, and for determining the underlying disease.

[Percutaneous endoscopic feeding gastrostomy. Initial experience with 6 cases]. / Gastrostomía endoscópica percutánea de alimentación. Experiencia inicial en seis casos.

Over the past two years we have performed percutaneous endoscopic feeding gastrostomy (PEFG) in 5 patients, 4 males and 1 female, aged 42 to 89. All of them suffered from either incurable or severe illness which prevented their oral feeding. PEFG was performed following the method described by Gauderer and Ponsky or traction method. Only in one case it was difficult to perform and in another case a second PEFG was needed because of unintentional catheter extraction. PEFG allowed an adequate feeding in all of the patients until their death due to underlying disorder or to other causes during the follow-up period. The complications found included ascites infection in a patient with cirrhosis and pneumoperitoneum which resolved spontaneously in another case. No mortality was observed related to the procedure.

Translation and validation of the gastrointestinal Quality of Life Index (GIQLI).

OBJECTIVE: To translate into Spanish and validate the GIQLI, a health related quality of life questionnaire for gastrointestinal diseases. PATIENTS AND METHODS: All patients with a diagnosis of cholelithiasis, on waiting list to undergo a cholecystectomy, from three public hospitals, were included in this study. All patients were requested to fulfill the GIQLI and the SF-36 before and three months after the intervention. The validity, reliability and responsiveness of the GIQLI were studied. RESULTS: 353 patients completed both questionnaires before and after the intervention. The GIQLI was able to discriminate among levels of severity, measured by the number of previous biliary colics, between those with less (total GIQLI score: 102.7) or more than 6 colics (89.2). GIQLI domains correlated with those of the SF-36 (Pearson correlation coefficient from 0.58 to 0.79). Internal consistency of its domains was good (Cronbach alpha from 0.70 to 0.86). Responsiveness, measured by the standardized response mean, of the GIQLI ranged between 0.45 to 0.82, better than the generic questionnaire SF-36 (0.20 a 0.56). CONCLUSIONS: GIQLI translation into Spanish provides with a new tool to measure quality of life on gastrointestinal diseases. Our results support the validity, reliability and responsiveness of the GIQLI Spanish version.

Disease severity in familial cases of IBD.

BACKGROUND: Phenotypic traits of familial IBD relative to sporadic cases are controversial, probably related to limited statistical power of published evidence. AIM: To know if there are phenotype differences between familial and sporadic IBD, evaluating the prospective Spanish registry (ENEIDA) with 11,983 cases. METHODS: 5783 patients (48.3%) had ulcerative colitis (UC) and 6200 (51.7%) Crohn's disease (CD). Cases with one or more 1st, 2nd or 3rd degree relatives affected by UC/CD were defined as familial case. RESULTS: In UC and CD, familial cases compared with sporadic cases had an earlier disease onset (UC: 33 years [IQR 25-44] vs 37 years [IQR 27-49]; p<0.0001); (CD: 27 years [IQR 21-35] vs 29 years [IQR 22-40]; p<0.0001), higher prevalence of extraintestinal immune-related manifestations (EIMs) (UC: 17.2% vs 14%; p=0.04); (CD: 30.1% vs 23.6%; p<0.0001). Familial CD had higher percentage of ileocolic location (42.7% vs 51.8%; p=0.0001), penetrating behavior (21% vs 17.6%; p=0.01) and perianal disease (32% vs 27.1%; p=0.003). Differences are not influenced by degree of consanguinity. CONCLUSION: When a sufficiently powered cohort is evaluated, familial aggregation in IBD is associated to an earlier disease onset, more EIMs and more severe phenotype in CD. This feature should be taken into account at establishing predictors of disease course.

[Recomendations of vaccination in patients with inflammatory bowel disease (IBD)]. / Recomendaciones de vacunación en pacientes con enfermedad inflamatoria intestinal (EII).

The concept of inflammatory bowel disease (IBD) covers three entities: ulcerative colitis (UC), Crohn's disease (CD) and indeterminate colitis (IC). These diseases have in common a chronic and relapsing course, alternating periods marked by inflammatory activity with other quiescent periods, in which the patient is asymptomatic. For many years treatment of the disease, especially in acute phases, was based on the use of corticoids. However, in recent decades we have witnessed significant advances from the therapeutic point of view. It is estimated that during the course of the disease's evolution 80% of patients will need corticoids, 40% immunomodulators (IMM), and as many as 20% will require a biological medicine to control their disease. While all of this is accompanied by an improvement in quality of life, less hospital admissions or surgical interventions, their use also involves an increase in the risk of suffering infections, either due to germs normally found in the community or opportunistic infections. Moreover, infections are a cause of morbidity and mortality associated with IBD and some of them can be prevented with vaccinations, hence the importance that vaccination programs are acquiring in this groups of patients. We present a review of the relevant literature and propose a vaccination protocol for patients diagnosed with IBD.

Smoking does influence disease behaviour and impacts the need for therapy in Crohn's disease in the biologic era.

BACKGROUND: Recently, the notion that smoking may adversely affect Crohn's disease (CD) outcomes has been challenged by the suggestion that the widespread use of immunosuppressants and anti-TNF drugs might offset the adverse effects of tobacco. AIM: To reassess the influence of tobacco smoking on disease phenotype and complications on a time-dependent analysis, taking into account the different therapeutic interventions. METHODS: We designed a retrospective cohort study of 3224 patients with Crohn's disease. The data were collected from the Spanish national inflammatory bowel disease registry (ENEIDA), including information regarding demographics, clinical characteristics, disease complications, therapeutic interventions and smoking status. Patients were classified as nonsmokers, smokers and former smokers, according to their present and past smoking habits. RESULTS: In the univariate analysis, smokers had more strictures (22.6% vs. 19.3%, P < 0.05) and less colonic involvement (7.2% vs. 10.9%, P < 0.05), and were more frequently under treatment with steroids (91.6% vs. 85.8%, P < 0.05), immunosuppressants (73.5% vs. 63.6% P < 0.05) or anti-TNF drugs (31.4% vs. 25.1%, P < 0.05) than nonsmokers. In the time-dependent multivariate analysis, smokers were found to have a significantly decreased survival free of stricturing disease (HR: 1.5, CI 95% 1.18-1.90) or perianal complications (HR: 1.50, CI 95% 1.01-1.46), and had a higher risk for requiring thiopurine therapy (HR: 1.20, CI 95% 1.05-1.30). CONCLUSION: These results suggest that, despite the widespread use of immunosuppressants and anti-TNF drugs, smokers with Crohn's disease still have a more severe disease course, with increased therapeutic requirements when compared with nonsmokers.

Leukocytapheresis for steroid-dependent ulcerative colitis in clinical practice: results of a nationwide Spanish registry.

BACKGROUND: Several small, prospective, open studies suggest that leukocytapheresis might be efficient in patients with steroid-dependent ulcerative colitis (UC). AIM: To evaluate the short- and long-term effectiveness of leukocytapheresis for the management of steroid-dependent UC in clinical practice. METHODS: A Web-based, nationwide database specifically designed to record the efficacy and safety data of leukocytapheresis therapy in UC was available from September 2007 in Spain. Clinical data were collected at treatment baseline, 1 month after the last apheresis session (initial efficacy), and 6 and 12 months thereafter (long-term efficacy). Remission was defined as a Mayo Clinic index ≤2 together with complete steroid withdrawal and response as a decrease of ≥3 from the baseline score. RESULTS: A total of 142 steroid-dependent UC patients were included in the registry, most of them treated with the Adacolumn™ system. In 69% of patients thiopurine therapy failed to achieve steroid-free clinical remission. Initial clinical remission was obtained in 37% of cases. The initial corticosteroid dose, the number and frequency of apheresis sessions, or the previous failure of thiopurines and/or infliximab did not influence the initial remission rate, but a greater decrease in CRP levels was associated with a higher probability to obtain initial remission. At 6 and 12 months, 41 and 36% of patients were in clinical remission, respectively. Only one serious adverse effect was recorded. CONCLUSIONS: In clinical practice, apheresis allows long-term steroid-free clinical remission in up to one third of steroid-dependent UC patients, even in those with prior failure of thiopurines.

Fourth-line rescue therapy with rifabutin in patients with three Helicobacter pylori eradication failures.

BACKGROUND: In some cases, Helicobacter pylori infection persists even after three eradication treatments. AIM: To evaluate the efficacy of an empirical fourth-line rescue regimen with rifabutin in patients with three eradication failures. DESIGN: Multicentre, prospective study. PATIENTS: In whom the following three treatments had consecutively failed: first (PPI + clarithromycin + amoxicillin); second (PPI + bismuth + tetracycline + metronidazole); third (PPI + amoxicillin + levofloxacin). INTERVENTION: A fourth regimen with rifabutin (150 mg b.d.), amoxicillin (1 g b.d.) and a PPI (standard dose b.d.) was prescribed for 10 days. OUTCOME: Eradication was confirmed by (13) C-urea breath test 4-8 weeks after therapy. Compliance and tolerance: Compliance was determined through questioning and recovery of empty medication envelopes. Adverse effects were evaluated using a questionnaire. RESULTS: One-hundred patients (mean age 50 years, 39% men, 31% peptic ulcer/69% functional dyspepsia) were included. Eight patients did not take the medication correctly (in six cases due to adverse effects). Per-protocol and intention-to-treat eradication rates were 52% (95% CI = 41-63%) and 50% (40-60%). Adverse effects were reported in 30 (30%) patients: nausea/vomiting (13 patients), asthenia/anorexia (8), abdominal pain (7), diarrhoea (5), fever (4), metallic taste (4), myalgia (4), hypertransaminasemia (2), leucopenia (<1,500 neutrophils) (2), thrombopenia (<150,000 platelets) (2), headache (1) and aphthous stomatitis (1). Myelotoxicity resolved spontaneously in all cases. CONCLUSIONS: Even after three previous H. pylori eradication failures, an empirical fourth-line rescue treatment with rifabutin may be effective in approximately 50% of the cases. Therefore, rifabutin-based rescue therapy constitutes a valid strategy after multiple previous eradication failures with key antibiotics, such as clarithromycin, metronidazole, tetracycline and levofloxacin.

Long-term durability of response to adalimumab in Crohn's disease.

BACKGROUND: Adalimumab is an effective treatment for Crohn's disease (CD), but may also be associated with loss of response. Few reports provide insight into the durability of treatment of CD with adalimumab for periods longer than 12 months in clinical practice. AIMS: To evaluate the long-term durability of adalimumab maintenance treatment and to identify predictive factors associated with loss of response. METHODS: CD patients who initially responded to adalimumab were evaluated in a historical cohort study. Maintenance of long-term response was estimated using Kaplan-Meier analysis. Cox regression analysis was performed to identify potential predictive factors for loss of efficacy. RESULTS: In all, 380 CD patients were included (mean age, 38 years; 52% female). Of these, 43% had ileocolic CD, 50% inflammatory CD, and 41% perianal CD. Median follow-up with adalimumab was 8 months (range, 4-75 months). The annual risk of loss of response to adalimumab was 18% per patient-year of follow-up. Twenty-eight percent of patients were anti-TNF-naïve and 72% anti-TNF-experienced. The loss of efficacy was 8% per patient-year of follow-up in the anti-TNF-naïve patients and 22% in the anti-TNF-experienced group (P < 0.01). In the multivariate analysis, the presence of extraintestinal manifestations (hazard ratio [HR] = 1.7; 95% confidence interval [CI] = 1.02-2.9) and previous experience with other anti-TNF agents (HR = 2.5,95% CI = 1.2-5.3) were associated with higher risk of loss of efficacy. CONCLUSIONS: A relevant proportion of CD patients on long-term adalimumab lost response. The risk of loss of response was higher (more than 2-fold) in anti-TNF-experienced than in anti-TNF-naïve patients (22% vs. 8% per patient-year of treatment). Having extraintestinal manifestations seems to increase the risk of loss of efficacy.

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.