Genetic biomarkers of methotrexate response and safety in Crohn's disease: Data from the Spanish ENEIDA registry.

AIMS: Methotrexate (MTX) is used to induce and maintain remission in patients with steroid-dependent Crohn's disease (CD). Despite its proven efficacy, its use is limited due to associated adverse events. Polymorphisms involving folate pathway genes might influence MTX efficacy and toxicity. We aimed to assess the impact of certain polymorphisms on the therapeutic outcomes of MTX in CD. METHODS: Patients with CD who exclusively followed MTX monotherapy and fulfilled inclusion criteria were identified from the GETECCU ENEIDA registry. Variants of ATIC, DHFR, MTHFR, SLC19A1, ABCB1 and ABCC3 genes were analysed and their association with efficacy and toxicity was assessed. RESULTS: A total of 129 patients were included in the analysis. MTX was used at a median weekly dose of 25 mg (interquartile range, 15-25 mg) and a median time of 14 months (interquartile range, 4-52 months). Thirty-seven percent of the patients achieved disease remission with MTX monotherapy, while 34% were nonresponders (MTX failure). MTX-related toxicity occurred in 40 patients (30%), leading to MTX discontinuation in 19%. DHFR rs408626 (odds ratio [OR] 3.12, 95% confidence interval [CI] 1.22-7.69; P = .017) and MTHFR rs1801133 (OR 2.86, 95% CI 1.23-6.68; P = .015) variants, and smoking (OR 2.61, 95% CI 1.12-6.05; P = .026) were associated with a higher risk of MTX failure. Additionally, the MTHFR rs1801131 variant was associated with a higher risk of MTX-related adverse effects (OR 2.78, 95% CI 1.26-6.13, P = .011). CONCLUSION: Our study shows that variants of MTHFR and DHFR genes may be associated with MTX efficacy and adverse events in patients with CD.

Economic impact of inflammatory bowel disease in Catalonia: a population-based analysis.

Background: Inflammatory bowel disease (IBD) has a major economic impact on healthcare costs. Objectives: The aim of this study was to evaluate the current healthcare expenditure associated with IBD in a population-wide study in Catalonia. Design: Retrospective observational study. Methods: All patients with IBD included in the Catalan Health Surveillance System (CHSS) were considered eligible. The CHSS compiles data on more than 7 million individuals in 2020 (34,823 with IBD). Data on the use of healthcare resources and its economic impact were extracted applying the International Classification of Diseases, 10th revision, Clinical Modification codes (ICD-10-CM codes). Health expenditure, comorbidities, and hospitalization were calculated according to the standard costs of each service provided by the Department of Health of the Catalan government. The data on the IBD population were compared with non-IBD population adjusted for age, sex, and income level. IBD costs were recorded separately for Crohn's disease (CD) and ulcerative colitis (UC). Results: Prevalence of comorbidities was higher in patients with IBD than in those without. The risk of hospitalization was twice as high in the IBD population. The overall healthcare expenditure on IBD patients amounted to 164M€. The pharmacy cost represents the 60%. The average annual per capita expenditure on IBD patients was more than 3.4-fold higher (IBD 4200€, non-IBD 1200€). Average costs of UC were 3400€ and 5700€ for CD. Conclusion: The risk of comorbidities was twice as high in patients with IBD and their use of healthcare resources was also higher than that of their non-IBD counterparts. Per capita healthcare expenditure was approximately 3.4 times higher in the population with IBD. Trial registration: The study was not previously registered.

Economic impact of inflammatory bowel disease in Catalonia The manuscript includes data of the most recent epidemiologic data about the high economic impact of IBD in Catalonia.

Incidence of Myelotoxicity and Other Adverse Effects Related to Thiopurine Starting in Patients with Inflammatory Bowel Disease: Retrospective Observational Study in a Third-Level Hospital.

BACKGROUND AND OBJECTIVES: Thiopurines are an effective treatment for the maintenance of remission in inflammatory bowel disease (IBD). They can present adverse effects (AEs), with myelotoxicity being the most relevant. This study aims to determine the incidence of AEs related to the starting of thiopurines in our centre. METHODOLOGY: Retrospective study. The AEs in patients that were started on thiopurines between January 2016 and June 2020 were registered, with a two-year follow-up. The mean and standard deviation were used to describe the quantitative variables, and percentages and confidence intervals were used for the qualitative variables. The statistical significance was set at a p-value < 0.05. RESULTS: 98 patients were included, with 64 AEs detected in 48 patients (49%). Most of the AEs appeared in the first 6 months. The most relevant were: 21 neutropenia (21.4%), 19 hypertransaminasemia (19.4%), 13 digestive intolerances (13.2%), 6 acute pancreatitis (6.12%), 3 phototoxicity (3%), and 2 unknown origin fevers (2%). In 29 patients (29.4%) the treatment had to be suspended due to AEs. In 11 cases (11.2%), azathioprine (AZA) was switched to 6-mercaptopurine (6 MP) as 5 showed tolerance and 6 patients needed suspension due to AEs. Eight patients required hospital admission, but none of them needed intensive care unit admission. There were no fatal adverse effects. CONCLUSIONS: Thiopurines are a safe drug with few AEs, especially after the first months of treatment. These results suggest that periodic analytic follow-up may not be necessary after the initial period of treatment.

Heterogeneity in pharmacological treatment and outcomes in Crohn's disease patients in Catalonia: a population-based observational study.

BACKGROUND: Heterogeneity in the treatment of a disease is a marker of suboptimal quality of care. The aim of this study is to evaluate the heterogeneity in the treatment used and the outcomes for Crohn's disease (CD) in Catalonia. METHODS: All patients with CD included in the Catalan Health Surveillance System (data on more than seven million individuals from 2011 to 2017) were identified. The different Catalonian health areas were grouped into 19 district groups (DG). Treatments used rates (systemic corticosteroids, non-biological and biological immunosuppressant) and outcomes rates (hospitalization and surgery) were calculated. RESULTS: The use of systemic corticosteroids presented a decreasing trend over the study period, with an average rate of use in the different territories between 11% and 17%. The use of non-biological immunosuppressant treatment has remained stable, with an average rate of use ranging from 22% to 40% per year depending on the DG. The use of biological immunosuppressant treatment increased with an average rate of use in the different territories ranging from 10 to 23%.Hospitalizations for any reason showed an increasing trend between 2011 and 2017 with an average rate of between 23% and 32% per year depending on the area. Hospitalizations for CD presented a decreasing trend, with an average rate of between 5% and 11% per year. Surgical treatment remained stable over time, rates per year were between 0.5% and 2%. CONCLUSION: A remarkable geographical heterogeneity in the use of different treatments and in outcomes of CD was observed between different geographical areas of Catalonia. KEY MESSAGEThere is a notable geographical heterogeneity in the administration of biological and immunosuppressive treatments to Crohn's disease patients in Catalonia.There is also a geographical heterogeneity in their rates of hospitalization and surgical intervention.

Effectiveness and Safety of Ustekinumab in Ulcerative Colitis: Real-world Evidence from the ENEIDA Registry.

BACKGROUND AND AIMS: The development programm UNIFI has shown promising results of ustekinumab in ulcerative colitis [UC] treatment which should be confirmed in clinical practice. We aimed to evaluate the durability, effectiveness, and safety of ustekinumab in UC in real life. METHODS: Patients included in the prospectively maintained ENEIDA registry, who received at least one intravenous dose of ustekinumab due to active UC [Partial Mayo Score [PMS]>2], were included. Clinical activity and effectiveness were defined based on PMS. Short-term response was assessed at Week 16. RESULTS: A total of 95 patients were included. At Week 16, 53% of patients had response [including 35% of patients in remission]. In the multivariate analysis, elevated serum C-reactive protein was the only variable significantly associated with lower likelihood of achieving remission. Remission was achieved in 39% and 33% of patients at Weeks 24 and 52, respectively; 36% of patients discontinued the treatment with ustekinumab during a median follow-up of 31 weeks. The probability of maintaining ustekinumab treatment was 87% at Week 16, 63% at Week 56, and 59% at Week 72; primary failure was the main reason for ustekinumab discontinuation. No variable was associated with risk of discontinuation. Three patients reported adverse events; one of them had a fatal severe SARS-CoV-2 infection. CONCLUSIONS: Ustekinumab is effective in both the short and the long term in real life, even in a highly refractory cohort. Higher inflammatory burden at baseline correlated with lower probability of achieving remission. Safety was consistent with the known profile of ustekinumab.

Analysis of the Association between Fatigue and the Plasma Lipidomic Profile of Inflammatory Bowel Disease Patients.

Inflammatory bowel disease (IBD) is a chronic, relapsing noninfectious inflammatory condition of the intestinal tract with two main phenotypes, ulcerative colitis (UC) and Crohn's disease (CD), and globally increasing incidence and prevalence. Nearly 80% of the IBD patients with active disease and 50% of those with inactive disease suffer fatigue with significant impairment of their quality of life. Fatigue has been associated with multiple factors in IBD patients but, in most cases, no direct cause can be identified, and risk factors in clinically quiescent IBD are contradictory. Furthermore, as the assessment of fatigue is subjective, there is an unmet clinical need for fatigue biomarkers. In this explorative study, we analyzed the plasma lipidomic profiles of 47 quiescent UC and CD patients (23 fatigued, 24 nonfatigued) using ultraperformance liquid chromatography-time-of-flight mass spectrometry (UPLC-TOFMS). The results showed changes in lipids associated with fatigue and IBD. Significantly decreased levels of phosphatidylcholines, plasmanyls, sphingomyelins, lysophosphatidylcholines, phosphatidylethanolamines, phosphatidylinositols, phosphatidylserines, and eicosanoids were observed in patients with fatigue. Network and metabolic pathway analysis indicated a dysregulation of the arachidonic acid and glycerophospholipid metabolisms and the sphingolipid pathway. The protein-metabolite interaction network showed interactions between functionally related metabolites and proteins, displaying 40 disease-associated hidden proteins including ABDH4, GLTP, and LCAT.

Fendrix vs Engerix-B for Primo-Vaccination Against Hepatitis B Infection in Patients With Inflammatory Bowel Disease: A Randomized Clinical Trial.

INTRODUCTION: To compare Engerix-B and Fendrix hepatitis B virus for primo vaccination in inflammatory bowel disease (IBD). METHODS: Patients with IBD were randomized 1:1 to receive Engerix-B double dose or Fendrix single dose at months 0, 1, 2, and 6. Anti-HBs titers were measured 2 months after the third and fourth doses. Response to vaccination was defined as anti-HBs ≥100 UI/L. Anti-HBs titers were measured 2 months after the third and fourth doses and again at 6 and 12 months after the fourth dose. RESULTS: A total of 173 patients were randomized (54% received Engerix-B and 46% Fendrix). Overall, 45% of patients responded (anti-HBs ≥100 IU/L) after 3 doses and 71% after the fourth dose. The response rate after the fourth dose was 75% with Fendrix vs 68% with Engerix-B (P = 0.3). Older age and treatment with steroids, immunomodulators, or anti-tumor necrosis factor were associated with a lower probability of response. However, the type of vaccine was not associated with the response. Anti-HBs titer negativization occurred in 13% of patients after 6 months and 20% after 12 months. Anti-HBs ≥100 IU/L after vaccination was the only factor associated with maintaining anti-HBs titers during follow-up. DISCUSSION: We could not demonstrate a higher response rate of Fendrix (single dose) over Engerix-B (double dose). A 4-dose schedule is more effective than a 3-dose regimen. Older age and treatment with immunomodulators or anti-tumor necrosis factors impaired the success. A high proportion of IBD patients with protective anti-HBs titers after vaccination loose them over time. The risk of losing protective anti-HBs titers is increased in patients achieving anti-HBs <100 IU/L after the vaccination.

Antitumor Necrosis Factor Agents to Treat Endoscopic Postoperative Recurrence of Crohn's Disease: A Nationwide Study With Propensity-Matched Score Analysis.

INTRODUCTION: Patients with Crohn's disease experiencing endoscopic postoperative recurrence (POR) may benefit from antitumor necrosis factor (TNF) agents but scarce data on this are available. Our aim was to assess the efficacy of anti-TNF in improving mucosal lesions in patients with endoscopic POR. METHODS: Multicenter, retrospective, study of patients with Crohn's disease who underwent therapy with anti-TNF agents for endoscopic POR (Rutgeerts score > i1). Treatment outcomes were assessed by the findings in the last ileocolonoscopy performed after anti-TNF therapy was initiated. Endoscopic improvement and remission were defined as any reduction in the baseline Rutgeerts score and by a Rutgeerts score < i2, respectively. RESULTS: A total of 179 patients were included, 83 were treated with infliximab and 96 with adalimumab. Median time on anti-TNF therapy at the last endoscopic assessment was 31 months (interquartile range, 13-54). Endoscopic improvement was observed in 61%, including 42% who achieved endoscopic remission. Concomitant use of thiopurines and treatment with infliximab were associated with endoscopic improvement (odds ratio [OR] 2.15, 95% confidence interval [CI] 1.04-4.46; P = 0.03, and OR 2.34, 95% CI 1.18-4.62; P < 0.01, respectively) and endoscopic remission (OR 3.16, 95% CI 1.65-6.05; P < 0.01, and OR 2.01, 95% CI 1.05-3.88; P = 0.04, respectively) in the multivariable logistic regression analysis. These results were confirmed in a propensity-matched score analysis. DISCUSSION: In patients with endoscopic POR, anti-TNF agents improve mucosal lesions in almost two-thirds of the patients. In this setting, concomitant use of thiopurines and use of infliximab seem to be more effective in improving mucosal lesions.

Time Trends of Crohn's Disease in Catalonia from 2011 to 2017. Increasing Use of Biologics Correlates with a Reduced Need for Surgery.

BACKGROUND AND AIMS: Data from clinical trials suggest that biological drugs may improve the outcomes in Crohn's disease (CD) by reducing the need for surgery or hospitalization. The aim of this study is to evaluate the time-trends of the use of biological drugs and other treatments for CD, and its relationship with outcomes in Catalonia. MATERIALS AND METHODS: All patients with CD included in the Catalan Health Surveillance System (containing data on a population of more than 7.5 million) from 2011 to 2017 were identified. The exposures to different treatments for inflammatory bowel disease were retrieved from electronic invoicing records. RESULTS: Between 2011 and 2017, the use of salicylates, corticosteroids and immunosuppressive treatment fell from 28.8% to 17.1%, 15.8% to 13.7%, and 32.9% to 29.6%, respectively (p < 0.001). Biological treatment use rose from 15.0% to 18.7% (p < 0.001). Ostomy rates per 1000 patients/year fell from 13.2 in 2011 to 9.8 in 2017 (p = 0.003), and surgical resection rates from 24.1 to 18.0 (p < 0.001). The rate of CD-related hospitalizations per 1000 patients/year also fell, from 92.7 to 72.2 (p < 0.001). CONCLUSIONS: Biological drug use rose from 15.0% to 18.7% between 2011 and 2017. During this period, we observed an improvement in the outcomes of CD patients.

A Prospective Pilot Randomized Study: Electroacupuncture vs. Sham Procedure for the Treatment of Fatigue in Patients With Quiescent Inflammatory Bowel Disease.

BACKGROUND: Fatigue is a common symptom in patients with inflammatory bowel disease (IBD), and it often persists despite clinical remission. Acupuncture has been shown to be effective for treating fatigue in patients with many chronic diseases. The main objective of the study was to assess the efficacy of electroacupuncture (EAc), compared with sham EAc (ShEAc) or being on a waitlist (WL), for treating fatigue in patients with quiescent IBD in a single-blind randomized trial. METHODS: Fifty-two patients with IBD in clinical remission and fatigue were randomly assigned to 1 of 3 groups: EAc, ShEAc, or WL. Patients in the EAc and ShEAc groups received 9 sessions over 8 weeks. Fatigue was evaluated with the IBD-validated Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-FS). RESULTS: Baseline characteristics were similar in the 3 groups. Both EAc and ShEAc presented improved Functional Assessment of Chronic Illness Therapy-Fatigue Scale scores compared with baseline: the respective improvements were 9.53 (95% confidence intervals, 6.75-12.3, P < 0.001) and 5.46 points (95% confidence intervals, 2.7-9.7, P = 0.015), respectively. No significant changes were observed in the WL group. In the comparison of treatment groups, EAc was nonsignificantly better than ShEAc (EAc, 33.27 and ShEAc, 28.13, P = 0.168); both EAc and ShEAc improved fatigue scores significantly compared to WL (24.5; P = 0.01 and 0.04, respectively). CONCLUSIONS: Both EAc and ShEAc reduced fatigue scores in IBD patients when compared to WL. No differences were observed between EAc and ShEAc, although the study was not powered to rule out a difference. Acupuncture may offer improvements to patients with few other treatment alternatives. Clinical Trials Org Id: NCT02733276.

Short and long-term effectiveness and safety of vedolizumab in inflammatory bowel disease: results from the ENEIDA registry.

BACKGROUND: Effectiveness of vedolizumab in real world clinical practice is unknown. AIM: To evaluate the short and long-term effectiveness of vedolizumab in patients with inflammatory bowel disease (IBD). METHODS: Patients who received at least 1 induction dose of vedolizumab were included. Effectiveness was defined based on Harvey-Bradshaw index (HBI) in Crohn's disease (CD) and Partial Mayo Score (PMS) in ulcerative colitis (UC). Short-term response was assessed at week 14. Variables associated with short-term remission were identified by logistic regression analysis. The Kaplan-Meier method was used to evaluate the long-term durability of vedolizumab treatment. Cox model was used to identify factors associated with discontinuation of treatment and loss of response. RESULTS: 521 patients were included (median follow-up 10 months [interquartile range 5-18 months]). At week 14, 46.8% had remission and 15.7% clinical response. CD (vs UC), previous surgery, higher CRP concentration and disease severity at baseline were significantly associated with impaired response. The rate of vedolizumab discontinuation was 37% per patient-year of follow-up (27.6% in UC and 45.3% in CD, P < 0.01). CD (vs UC), anaemia at baseline, steroids during induction and CRP concentration were associated with lower durability of treatment. Seven per cent of patients developed adverse events, infections being the most frequent. CONCLUSIONS: Over 60% of IBD patients respond to vedolizumab. Many patients discontinue treatment over time. CD and disease burden impair both short- and long-term response. Vedolizumab seems to be safe in clinical practice.

Prevalence, incidence and mortality of inflammatory bowel disease in Catalonia. A population-based analysis.

INTRODUCTION: Few recent data on the epidemiology of inflammatory bowel disease (IBD) are available, especially in Southern Europe. AIM: To evaluate the prevalence, incidence and mortality of IBD in Catalonia during the period 2011-2016. MATERIAL AND METHODS: Data on the prevalence, incidence and mortality of IBD were obtained from the Catalan Health Surveillance System (CHSS). Crude incidence and prevalence rates were calculated for all the Catalan population. Trends in age-sex-adjusted rates were also estimated, and logistic regression was used to calculate the adjusted mortality odds ratio (OR). Data for Crohn's disease (CD) and ulcerative colitis (UC) were analyzed separately. RESULTS: The prevalence per 100,000 inhabitants in 2016 was 353.9 for UC and 191.4 for CD. The total number of IBD patients rose from 29543 in 2011 to 40614 in 2016. IBD was associated with significantly elevated adjusted mortality ratios: 1.28 (95% CI: 1.6-1.4) for UC and 1.85 (95% CI: 1.62-2.12) for CD. CONCLUSIONS: IBD prevalence is very high and is increasing rapidly in Catalonia. Both CD and UC are associated with significantly higher mortality rates. Key message Crohn disease and ulcerative colitis present a small but significant increase in mortality compared to non-inflammatory bowel disease. The prevalence of inflammatory bowel disease is increasing rapidly in Catalonia. Data on prevalence and incidence suggest that the number of patients may double in approximately 10 years.

Prevalence of Malnutrition and Nutritional Characteristics of Patients With Inflammatory Bowel Disease.

BACKGROUND AND AIMS: This study sought to determine the prevalence of malnutrition in patients with inflammatory bowel disease, to analyse the dietary beliefs and behaviours of these patients, to study their body composition, to evaluate their muscular strength and to identify the factors associated with malnutrition in these patients. METHODS: This was a prospective, multicentre study. Crohn's disease and ulcerative colitis patients from 30 Spanish centres, from the outpatient clinics, were included. A questionnaire of 11 items was applied to obtain data from patients' dietary behaviour and beliefs. Patients who accepted were evaluated to assess their nutritional status using Subjective Global Assessment and body mass index. Body composition was evaluated through bioelectrical impedance. RESULTS: A total of 1271 patients were included [51% women, median age 45 years, 60% Crohn's disease]. Of these, 333 patients underwent the nutritional evaluation. A total of 77% of patients declared that they avoided some foods to prevent disease relapse. Eighty-six per cent of patients avoided some foods when they had disease activity because of fear of worsening the flare. Sixty-seven per cent of patients modified their dietary habits after disease diagnosis. The prevalence of malnutrition was 16% [95% confidence interval = 12-20%]. In the multivariate analysis, history of abdominal surgery, active disease and avoidance of some foods during flares were associated with higher risk of malnutrition. CONCLUSIONS: The prevalence of malnutrition in inflammatory bowel disease patients was high. We identified some predictive factors of malnutrition. Most of the patients had self-imposed food restrictions, based on their beliefs.

Fatigue in out-patients with inflammatory bowel disease: Prevalence and predictive factors.

BACKGROUND AND AIM: Fatigue is a common and bothersome symptom in inflammatory bowel disease (IBD) patients. The study was aimed to determine the relationship of biological and psychological factors with IBD-related fatigue. METHODS: Consecutive clinically inactive IBD outpatients receiving immunosuppressants or biological drugs were enrolled between January and December 2013. Patients completed a Fatigue score (FACIT-F), various psychological, quality of life (IBDQ-9), and IBD activity scores. Biological parameters were assessed, including levels of interleukins (IL-5, IL-8 and IL-12) and micronutrients. RESULTS: We prospectively recruited 202 patients (28% ulcerative colitis and 72% Crohn's disease) for the study. Fatigue measured by FACIT-F score was prevalent in the studied population (54%, 96/177) and higher than in the general population. In the univariate analysis no relation was found between IL levels or micronutrient deficiencies and fatigue. Fatigue was significantly related to female sex, Crohn's disease, joint disorders, body mass index (BMI), psychological tests, thiopurine use, and anti-TNF treatment. All these variables were included in the multivariate analysis. Female sex (OR: 4.8), high BMI (OR:1.2) and higher depression rates (OR:1.2) were predictors of increased fatigue. High IBDQ-9 score (OR: 0.82) was significantly related to lower degrees of fatigue. CONCLUSION: Fatigue was prevalent in quiescent IBD patients with moderate-to-severe disease. It was associated with high levels of depression, low quality of life, and female sex. No association was found with the other biological and psychological factors evaluated.

Effectiveness of adalimumab for the treatment of ulcerative colitis in clinical practice: comparison between anti-tumour necrosis factor-naïve and non-naïve patients.

BACKGROUND: Ulcerative colitis (UC) treatment is focused to achieve mucosal healing, avoiding disease progression. The study aimed to evaluate the real-world effectiveness of adalimumab (ADA) in UC and to identify predictors of remission to ADA. METHODS: This cohort study used data from the ENEIDA registry. Clinical response, clinical remission, endoscopic remission, adverse events (AE), colectomy, and hospitalisations were evaluated; baseline characteristics and biological parameters were compared to determine predictors of response. RESULTS: We included 263 patients (87 naïve and 176 previously exposed to anti-tumour necrosis factor alpha, TNF). After 12 weeks, clinical response, clinical remission, and endoscopic remission rates were 51, 26, and 14 %, respectively. The naïve group demonstrated better response to treatment than the anti-TNF-exposed group at short-term. Clinical and endoscopic remission within 1 year of treatment was better in the naïve group (65 vs. 49 and 50 vs. 35 %, respectively). The rates of AE, dose-escalation, hospitalisations, and colectomy during the first year were higher in anti-TNF-exposed patients (40, 43, and 27 % vs. 26, 21, and 11 %, respectively). Patients with primary failure and intolerance to the first anti-TNF and severe disease were associated with worse clinical response. Primary non-response to prior anti-TNF treatment and severe disease were predictive of poorer clinical remission. Low levels of C-reactive protein (CRP) and faecal calprotectin (FC) at baseline were predictors of clinical remission. CONCLUSIONS: In clinical practice, ADA was effective in UC, especially in anti-TNF naïve patients. FC and CRP could be predictors of treatment effectiveness.

Systematic review: third-line susceptibility-guided treatment for Helicobacter pylori infection.

BACKGROUND: Susceptibility-guided therapies (SGTs) have been proposed as preferable to empirical rescue treatments after two treatment failures. The aim of this study was to perform a systematic review and meta-analysis evaluating the effectiveness and efficacy of SGT as third-line therapy. METHODS: A systematic search was performed in multiple databases. Studies reporting cure rates of Helicobacter pylori with SGT in third-line therapy were selected. A qualitative analysis describing the current evidence and a pooled mean analysis summarizing the cure rates of SGT in third-line therapy was performed. RESULTS: No randomized controlled trials or comparative studies were found. Four observational studies reported cure rates with SGT in third-line treatment, and three studies which mixed patients with second- and third-line treatment also reported cure rates with SGT. The majority of the studies included the patients when culture had been already obtained, and so the effectiveness of SGT and empirical therapy has never been compared. A pooled mean analysis including four observational studies (283 patients) showed intention-to-treat and per-protocol eradication rates with SGT of 72% (95% confidence interval 56-87%; I(2) : 92%) and 80% (95% confidence interval 71-90%; I(2) : 80%), respectively. CONCLUSIONS: SGT may be an acceptable option as rescue treatment. However, cure rates are, at best, moderate and this approach has never been compared with a well-devised empirical therapy. The evidence in favor of SGT as rescue therapy is currently insufficient to recommend its use.

Ustekinumab for the Treatment of Refractory Crohn's Disease: The Spanish Experience in a Large Multicentre Open-label Cohort.

BACKGROUND: Ustekinumab is a fully human monoclonal antibody against IL-12/23. Ustekinumab induced clinical response and maintained higher rate of response than placebo in patients with Crohn's disease (CD). This study aims to assess the effectiveness and safety of ustekinumab in refractory patients with CD in real-life practice. METHODS: Consecutive patients with CD who were treated with subcutaneous ustekinumab between March 2010 and December 2014 were retrospectively included in a multicenter open-label study. Clinical response was defined by Harvey-Bradshaw index score and assessed after the loading doses, 6, 12 months, and last follow-up. RESULTS: One hundred sixteen patients were included, with a median follow-up of 10 months (interquartile range: 5-21). Clinical response after loading ustekinumab was achieved in 97/116 (84%) patients. The clinical benefit at 6, 12 months, and at the end of the follow-up was 76%, 64%, and 58%, respectively. Dose escalation was effective in 8 of 11 (73%) patients. Perianal disease also improved in 11 of 18 (61%) patients with active perianal fistulae. The initial response to ustekinumab and previous use of more than 2 immunosuppressant drugs were associated with a clinical response to ustekinumab maintenance therapy. In contrast, previous bowel resection predicted a long-term failure with ustekinumab. Adverse events were reported in 11 (9.5%) patients, but none required ustekinumab withdrawal. CONCLUSIONS: Subcutaneous ustekinumab is effective and safe in a high proportion of patients with CD that were resistant to conventional immunosuppressant and antitumor necrosis factor drugs.