Evolution After Anti-TNF Discontinuation in Patients With Inflammatory Bowel Disease: A Multicenter Long-Term Follow-Up Study.

OBJECTIVES: The aims of this study were to assess the risk of relapse after discontinuation of anti-tumor necrosis factor (anti-TNF) drugs in patients with inflammatory bowel disease (IBD), to identify the factors associated with relapse, and to evaluate the overcome after retreatment with the same anti-TNF in those who relapsed. METHODS: This was a retrospective, observational, multicenter study. IBD patients who had been treated with anti-TNFs and in whom these drugs were discontinued after clinical remission was achieved were included. RESULTS: A total of 1,055 patients were included. The incidence rate of relapse was 19% and 17% per patient-year in Crohn's disease and ulcerative colitis patients, respectively. In both Crohn's disease and ulcerative colitis patients in deep remission, the incidence rate of relapse was 19% per patient-year. The treatment with adalimumab vs. infliximab (hazard ratio (HR)=1.29; 95% confidence interval (CI)=1.01-1.66), elective discontinuation of anti-TNFs (HR=1.90; 95% CI=1.07-3.37) or discontinuation because of adverse events (HR=2.33; 95% CI=1.27-2.02) vs. a top-down strategy, colonic localization (HR=1.51; 95% CI=1.13-2.02) vs. ileal, and stricturing behavior (HR=1.5; 95% CI=1.09-2.05) vs. inflammatory were associated with a higher risk of relapse in Crohn's disease patients, whereas treatment with immunomodulators after discontinuation (HR=0.67; 95% CI=0.51-0.87) and age (HR=0.98; 95% CI=0.97-0.99) were protective factors. None of the factors were predictive in ulcerative colitis patients. Retreatment of relapse with the same anti-TNF was effective (80% responded) and safe. CONCLUSIONS: The incidence rate of inflammatory bowel disease relapse after anti-TNF discontinuation is relevant. Some predictive factors of relapse after anti-TNF withdrawal have been identified. Retreatment with the same anti-TNF drug was effective and safe.

Safety of thiopurines and anti-TNF-α drugs during pregnancy in patients with inflammatory bowel disease.

OBJECTIVES: The safety of thiopurines and anti-tumor necrosis factor-α (TNF-α) drugs during pregnancy remains controversial, as the experience with these drugs in this situation is limited. Our aim is to assess the safety of thiopurines and anti-TNF-α drugs for the treatment of inflammatory bowel disease (IBD) during pregnancy. METHODS: Retrospective, multicenter study in IBD patients. Pregnancies were classified according to the therapeutic regimens during pregnancy or during the 3 months before the conception: non-exposed group, pregnancies exposed to thiopurines alone (group A), and pregnancies exposed to anti-TNF-α drugs (group B). An unfavorable Global Pregnancy Outcome (GPO) was considered if pregnancy developed with obstetric complications in the mother and in the newborn. RESULTS: A total of 187 pregnancies in the group A, 66 pregnancies in the group B, and 318 pregnancies in the non-exposed group were included. The rate of unfavorable GPO was different among the three groups (31.8% in non-exposed group, 21.9% in group A, and 34.8% in group B), being lower in pregnancies under thiopurines than among non-exposed (P = 0.01). The rate of pregnancy complications was similar among the three groups (27.7% in non-exposed, 20.9% in group A, and 30.3% in group B). The rate of neonatal complications was different among the three groups (23.3% in non-exposed group, 13.9% in group A, and 21.2% in group B), being lower in pregnancies under thiopurines than among non-exposed (P = 0.01). In the multivariate analysis, the treatment with thiopurines (odds ratio = 0.6; 95% confidence interval = 0.4-0.9, P = 0.02) was the only predictor of favorable GPO, whereas maternal age >35 years at conception was the only predictor of unfavorable GPO. The treatment with anti-TNF-α drugs was not associated with an unfavorable GPO. CONCLUSION: The treatment with thiopurines and anti-TNF-α drugs does not seem to increase the risk of complications during pregnancy and does seem to be safe for the newborn.

Characteristics and treatment of pyoderma gangrenosum in inflammatory bowel disease.

BACKGROUND: Pyoderma gangrenosum is a serious cutaneous complication seen in approximately 1 % of patients with inflammatory bowel disease (IBD). Oral corticosteroids are the mainstay treatment, although the evidence supporting their use is weak. AIMS: The purpose of this study was to investigate the characteristics of pyoderma gangrenosum associated with Crohn's disease or ulcerative colitis and which treatments are prescribed in Spanish clinical practice. METHODS: In this retrospective, observational study, the medical records from all patients with IBD and a diagnosis of pyoderma gangrenosum attended by the gastroenterology departments of 12 Spanish hospitals were reviewed. Data on patient demographics and characteristics, underlying IBD and treatment, and pyoderma gangrenosum characteristics, treatment, and outcome were collected and analyzed. RESULTS: The data from 67 patients were analyzed (41 [61.2 %] women, 41 [61.2 %] with Crohn's disease, 25 [37.3 %] with ulcerative colitis, and 1 [1.5 %] with indeterminate disease). The underlying disease was in remission in approximately one-third of patients at the time of presentation of pyoderma gangrenosum. Healing was achieved in all patients (in 3 without any systemic therapy). Oral corticosteroids were taken by 51 patients (76.1 %), almost always as first-line treatment, although definitive healing was attained in 19 (28.4 %). Biologic agents such as infliximab and adalimumab were taken by 31 patients (46.3 %) at some point (first-line in 6 patients [9.0 %]), with definitive healing in 29 patients (93.5 %). CONCLUSIONS: Oral corticosteroid therapy remains the most common treatment for pyoderma gangrenosum associated with inflammatory bowel disease. Biologic therapies such as infliximab and adalimumab should also be considered.

Enterocutaneous fistulas and Crohn´s disease: clinical characteristics and response to treatment.

INTRODUCTION: the low prevalence of enterocutaneous fistulas (ECF) in patients with Crohn´s disease (CD) justifies the scarcity of studies that analyze the effect of medical treatment and the need for surgery in these patients. The objective of this study was to evaluate the clinical characteristics of patients with CD who have ECF and the response to different treatments. MATERIALS AND METHODS: patients with CD who presented ECF fistula between 1970 and 2009 in three tertiary centers in Spain were analyzed retrospectively for their clinical characteristics, response to treatment as well as the correlation between the response to biological therapies for ECF and perianal disease. The inflammatory activity of the disease was measured using the Harvey-Bradshaw index. The definitions of partial or complete response were based on the treating physician´s judgment. RESULTS: twenty six patients were included (18 women); in more than half of cases (67%), anti-TNF treatment improved fistula drainage. Postoperative fistulas responded better to anti-TNF treatment than did spontaneous fistulas (80 versus 57%). One hundred percent and 60% of spontaneous and postoperative fistulas closed after surgery, respectively. CONCLUSIONS: although the majority of patients required surgery as the ultimate treatment, anti-TNF drugs improved fistula output in an acceptable percentage of patients who were treated. Therefore, this may be a treatment strategy prior to surgery in a select group of patients.

Maximizing the effect of biologics in inflammatory bowel disease.

The chronic course of inflammatory bowel disease (IBD) leads to recurrent episodes of active clinical symptoms, as well as long term complications, including hospitalizations, surgeries, and a decreased quality of life. Biologic agents have been shown to be effective for the induction and maintenance of remission in patients with moderate to severe IBD, and may alter the natural history of disease. Loss of response to biologic therapy is a common problem in clinical practice, the reasons for which are likely multifactorial; antibody development, alterations in drug clearance, and possibly a change to a non-TNF-driven inflammatory mechanism. Several studies have evaluated interventions that may lead to an increased rate of response and an increase in the durability. In this review, we evaluate ways to maximize anti-TNF treatment by administering scheduled therapy, using concomitant immunomodulator therapy, escalating dosage, and switching between biologic agents and classes. Finally, the role of antibody to infliximab (ATI) and infliximab serum trough levels are discussed in the context of optimizing biologic therapy for inflammatory bowel disease.

Latin American consensus on the quality indicators for comprehensive care clinics for patients with inflammatory bowel disease: PANCCO-GETECCU.

INTRODUCTION: Inflammatory bowel disease (IBD) is a chronic and incurable entity. The aim of the Pan American Crohn's and Colitis Organisation (PANCCO) is to create awareness of IBD, with special emphasis on Latin America, and the primary objective of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis (GETECCU, the Spanish acronym) is to obtain the accreditation of the clinical and therapeutic criteria for the diagnosis and treatment of IBD. AIM: To carry out a consensus for evaluating the approval criteria that a Comprehensive Care Clinic for Latin American IBD patients must meet, to be considered a center of excellence. MATERIALS AND METHODS: Fourteen clinical experts participated in the consensus. They were made up of specialists in gastroenterology, with broad clinical experience, spanning several years, in managing the care of a large number of patients with IBD, as well as advanced specialists in IBD. Thirteen of the participants came from 11 Latin American countries (Argentina, Brazil, Colombia, Dominican Republic, Ecuador, Guatemala, Mexico, Peru, Puerto Rico, Uruguay, and Venezuela) that have IBD clinics. An expert from Spain, representing the GETECCU, provided the methodologic support. The consensus consisted of 52 statements divided into three sections: 1) Structure indicators, 2) Process indicators, and 3) Result indicators. The Delphi panel method was applied. RESULTS: The present Latin American consensus describes the quality indicators that a Comprehensive Care Clinic for IBD patients must meet, to be considered a center of excellence, taking into account the needs of our region. CONCLUSIONS: This is the first Latin American consensus, jointly carried out by the PANCCO and GETECCU, to present accreditation standards for centers of excellence in the care of patients with IBD.

Treatment patterns and intensification within 5 year of follow-up of the first-line anti-TNFα used for the treatment of IBD: Results from the VERNE study.

BACKGROUND: Anti-TNFα represent one of the main treatment approaches for the management of inflammatory bowel diseases (IBD). Therefore,the evaluation of their treatment patterns over time provides valuable insights about the clinical value of therapies and associated costs. AIMS: To assess the treatment patterns with the first anti-TNFα in IBD. METHODS: Retrospective, observational study. RESULTS: 310 IBD patients were analyzed along a 5-year follow-up period. 56.2% of Crohn's disease (CD) patients started with adalimumab (ADA), while 43.8% started with infliximab (IFX). 12.9% of ulcerative colitis (UC) patients initiated with ADA, while 87.1% initiated with IFX. Treatment intensification was required in 28.9% of CD and 37.1% of UC patients. Median time to treatment intensification was shorter in UC than in CD (5.3 vs. 14.3 months; p = 0.028). Treatment discontinuation due to reasons other than remission were observed in 40.7% of CD and 40.5% of UC patients, although, in UC patients there was a trend to lower discontinuation rates with IFX (36.6%) than with ADA (66.7%). Loss of response accounted for approximately one-third of discontinuations, in both CD and UC. CONCLUSIONS: Around one-third of IBD biologic-naive patients treated with an anti-TNFα required treatment intensification (earlier in UC) and around 40% discontinued the anti-TNFα due to inappropriate disease control.

NOD2/CARD15: geographic differences in the Spanish population and clinical applications in Crohn's disease.

Crohn's disease (CD) is a genetically complex disease in which both genetic susceptibility and environmental factors play key roles in the development of the disorder. NOD2/CARD15 mutations are associated with CD. NOD2 encodes for a protein that is an intracellular receptor for a bacterial product (muramyl dipeptide), though the exact functional consequences of these mutations remain the subject of debate. NOD2/CARD15 mutations are associated with ileal CD, with stricturing behavior, and possibly with a more complicated course of CD. NOD2/CARD15 mutations associated with CD have demonstrated heterogeneity across ethnicities and populations throughout the world, with regional variations across Europe and Spain. However, "NOD2/CARD15 testing" is not yet ready for use in the clinical setting. One of the reasons is that we know that these genetic variants increase the risk of disease only marginally, and many healthy individuals carry the risk alleles, at present it is not recommended to screen first-degree relatives, because we do not have the ability to prevent the disease at the present time.

Health related quality of life in patients with Cohn´s disease in remission.

BACKGROUND: Crohn's disease (CD) affects Health Related Quality of Life (HRQoL) especially in patients with clinical activity but their impact over the disease during periods of remission has not been sufficiently studied. OBJECTIVE: To evaluate HRQoL in CD patients in remission and to identify socio-demographic and clinical factors related. METHODS: We included patients with CD in remission for at least 6 months, defined as a CDAI < 150 and a CRP < 5 mg/L. Socio-demographic and clinical parameters were recorded. HRQoL was evaluated with Short Form 36 Questionnaire (SF-36) and the Inflammatory Bowel Disease Questionnaire (IBDQ). Results were analyzed using multiple regressions with a confidence interval of 95%. RESULTS: Nine two patients (X = 37 +- 11.4 years, 52.2% men) were consecutively included. Two patients failed to fill correctly the questionnaire and were excluded. Scores on the SF-36 were lower than in the general population of similar age and sex. The most affected dimension in the SF-36 was General Health (47.98 +- 19.58) and the IBDQ Systemic Symptoms (5.15 +- 1.27). Age, colonic location and previous surgery was related with worse HRQoL, while higher educational status, more time since diagnosis, steroid-resistance and inflammatory behavior, was associated with better HRQoL. CONCLUSIONS: Despite being in remission, CD patients had affected their HRQoL, so we must continue working to achieve improvement in HRQL of these patients during these periods of the disease.

NOD2, CD14 and TLR4 mutations do not influence response to adalimumab in patients with Crohn's disease: a preliminary report.

INTRODUCTION: Adalimumab is a recombinant fully-human monoclonal immunoglobulin (IgG1) antibody utilized in the treatment of Crohn's disease. Unfortunately no clinical or genetic markers exist to predict response to anti-tumor necrosis factor-alpha (TNF) therapy. The aim of this study was to evaluate the association between selected genes involved in cytokine regulation and response to adalimumab treatment in Crohn's disease. METHODS: twenty-four patients with Crohn's disease either naïve (n = 8) or had lost response or were unable to tolerate the chimeric anti-TNF antibody infliximab (n=16) were enrolled in the study. Patients were genotyped for main polymorphisms in NOD2, CD14 and TLR4 genes. Response to adalimumab treatment was defined as a decrease of Crohn's disease activity index of at least 100 points or a closure of at least 50% of fistulas in case of fistulizing Crohn's disease. RESULTS: overall, 75% of patients did respond to treatment. However, no statistically significant association was found between any of the genotypes and the response to adalimumab. CONCLUSIONS: In our small study group no association between the studied polymorphisms and response to adalimumab was apparent. Systematic studies to search for genetic markers of response to anti-TNF therapy are necessary.

Psychological impact of Crohn's disease on patients in remission: anxiety and depression risks.

BACKGROUND: the role of anxiety and depression in CD patients in remission has been poorly investigated. OBJECTIVE: the aim of the study was to evaluate the frequency of anxiety and depression symptoms in CD patients in remission, and potential factors influencing the development of these symptoms. METHODS: CD patients older than 18 years in remission for at least 6 months before study entry were included. CD remission was defined as a Crohn s Disease Activity Index (CDAI) < 150 points together with C-reactive protein < 5 mg/L. A demographic questionnaire was filled in, and all patients were clinically classified. The therapy maintaining remission was also recorded. A Hospital Anxiety and Depression scale (HAD) was administered to all patients. Results are shown as OR and 95% CI, and analyzed by logistic regression. RESULTS: 92 consecutive patients were included (48 male, mean age 37 years, range from 18 to 71 years). One patient failed to correctly fill in the questionnaire. Anxiety and depression symptoms were present in 36 (39%) and 22 (24%) patients, respectively. Infliximab therapy was the only factor associated with anxiety (OR = 3.11; 95% CI: 1.03-9.43; p < 0.05). In contrast, the presence of depressive symptoms is less frequent in patients under infliximab therapy (OR = 0.16; 95% CI: 0.02-0.97; p < 0.05). CONCLUSIONS: despite clinical remission, an important number of CD patients present with anxiety or depressive symptoms. Infliximab therapy in CD patients is associated to more anxiety but fewer depressive symptoms. CD patients in remission would probably benefit from psychological support.

Effectiveness and Safety of the Switch from Remicade® to CT-P13 in Patients with Inflammatory Bowel Disease.

BACKGROUND AND AIMS: To evaluate the clinical outcomes in patients with IBD after switching from Remicade® to CT-P13 in comparison with patients who maintain Remicade®. METHODS: Patients under Remicade® who were in clinical remission with standard dosage at study entry were included. The 'switch cohort' [SC] comprised patients who made the switch from Remicade® to CT-P13, and the 'non-switch' cohort [NC] patients remained under Remicade®. RESULTS: A total of 476 patients were included: 199 [42%] in the SC and 277 [58%] in the NC. The median follow-up was 18 months in the SC and 23 months in the NC [p < 0.01]. Twenty-four out of 277 patients relapsed in the NC; the incidence of relapse was 5% per patient-year. The cumulative incidence of relapse was 2% at 6 months and 10% at 24 months in this group. Thirty-eight out of 199 patients relapsed in the SC; the incidence rate of relapse was 14% per patient-year. The cumulative incidence of relapse was 5% at 6 months and 28% at 24 months. In the multivariate analysis, the switch to CT-P13 was associated with a higher risk of relapse (HR = 3.5, 95% confidence interval [CI] = 2-6). Thirteen percent of patients had adverse events in the NC, compared with 6% in the SC [p < 0.05]. CONCLUSIONS: Switching from Remicade® to CT-P13 might be associated with a higher risk of clinical relapse, although this fact was not supported in our study by an increase in objective markers of inflammation. The nocebo effect might have influenced this result. Switching from Remicade® to CT-P13 was safe.

Prevalence and Factors Associated With Fatigue in Patients With Inflammatory Bowel Disease: A Multicentre Study.

BACKGROUND AND AIMS: The aims of this study were to determine the prevalence of fatigue in patients with inflammatory bowel disease [IBD], to identify the factors associated with fatigue and its severity, to assess the impact of fatigue on quality of life [QoL], and to evaluate the relationship between fatigue and sleep disorders. METHODS: This was a prospective multicentre study conducted at 22 Spanish centres. Consecutive patients followed at IBD Units were included. Fatigue was evaluated with the Fatigue Severity Scale [FSS] and the Fatigue Impact Scale [FIS]. Quality of life and sleep quality were assessed using the IBD Questionnaire-Short Form [IBDQ-9] and the Pittsburgh Sleep Quality Index [PSQI], respectively. RESULTS: A total of 544 consecutive adult IBD patients were included [50% women, mean age 44 years, 61% Crohn's disease]. The prevalence of fatigue was 41% (95% confidence interval [CI] = 37-45%). The variables associated with an increased risk of fatigue were: anxiety [OR = 2.5, 95% CI = 1.6-3.7], depression [OR = 2.4, 95% CI = 1.4-3.8], presence of extraintestinal manifestations [EIMs] [OR = 1.7, 95% CI = 1.1-2.6], and treatment with systemic steroids [OR = 2.8, 95% CI = 1.4-5.7]. The presence of EIMs [regression coefficient, RC = 8.2, 95% CI = 2.3-14.2], anxiety [RC = 25.8, 95% CI = 20.0-31.5], depression [RC = 30.6, 95% CI = 24.3-37.0], and sleep disturbances [RC = 15.0, 95% CI = 9.3-20.8] were associated with severity of fatigue. Patients with fatigue had a significantly decreased IBDQ-9 score [p < 0.001]. CONCLUSIONS: The prevalence of fatigue in IBD patients is remarkably high and has a negative impact on QoL. Therapy with systemic steroids is associated with an increased risk of fatigue. The severity of fatigue is associated with anxiety, depression, sleep disorders, and the presence of EIMs. Fatigue was not associated with anaemia, disease activity or anti-TNF therapy.

[Secondary amyloidosis in Crohn's disease]. / Amiloidosis secundaria en la enfermedad inflamatoria intestinal.

Amyloidosis is a clinical entity that results from the deposition of an extracellular protein material that causes disruption in the normal architecture of multiple organs and tissues, and impairs their function. Secondary amyloidosis is a rare but serious complication that may worsen the prognosis of patients with cancer, infection or chronic inflammatory disease, including inflammatory bowel disease, particularly Crohn's disease. We report two cases of Crohn's disease associated with secondary amyloidosis.

Phenotype and natural history of elderly onset inflammatory bowel disease: a multicentre, case-control study.

BACKGROUND: Onset during old age has been reported in upto 10% of total cases of inflammatory bowel disease (IBD). AIM: To evaluate phenotypic characteristics and the use of therapeutic resources in patients with elderly onset IBD. METHODS: Case-control study including all those patients diagnosed with IBD over the age of 60 years since 2000 who were followed-up for >12 months, identified from the IBD databases. Elderly onset cases were compared with IBD patients aged 18 to 40 years at diagnosis, matched by year of diagnosis, gender and type of IBD (adult-onset). RESULTS: One thousand three hundred and seventy-four elderly onset and 1374 adult-onset cases were included (62% ulcerative colitis (UC), 38% Crohn's disease (CD)). Among UC patients, elderly onset cases had a lower proportion of extensive disease (33% vs 39%; P < 0.0001). In CD, elderly onset cases showed an increased rate of stenosing pattern (24% vs 13%; P < 0.0001) and exclusive colonic location (28% vs 16%; P < 0.0001), whereas penetrating pattern (12% vs 19%; P < 0.0001) was significantly less frequent. Regarding the use of therapeutic resources, there was a significantly lower use of corticosteroids (P < 0.0001), immunosuppressants (P < 0.0001) and anti-TNFs agents (P < 0.0001) in elderly onset cases. Regarding surgery, we found a significantly higher surgery rate among elderly onset UC cases (8.3% vs 5.1%; P < 0.009). Finally, elderly onset cases were characterised by a higher rate of hospitalisations (66% vs 49%; P < 0.0001) and neoplasms (14% vs 0.5%; P < 0.0001). CONCLUSIONS: Elderly onset IBD shows specific characteristics and they are managed differently, with a lower use of immunosuppressants and a higher rate of surgery in UC.

[Life-threatening acute lower gastrointestinal bleeding in patients with Crohn's disease]. / Hemorragia digestiva baja masiva en pacientes con enfemedad de Crohn.

OBJECTIVE: We aimed at evaluating the frequency of acute severe bleeding in CD and its potential association to some risk factors, including clinical features of CD, environmental factors, and genetic alterations. MATERIAL AND METHODS: 174 consecutive patients with CD (103 female (59%) and 71 men (41%), with a mean age of 37 years) were included. We analyzed all major acute lower gastrointestinal (GI) hemorrhage related to CD. Potential risk factors like smoking, site of disease, and presence of gene mutations in CARD15, TLR-4, and CD14 were also analyzed. RESULTS: Three patients (1.7%) suffered from severe acute lower GI bleeding. All patients required surgery to resolve their hemorrhage, and this indication represented 3.4% of all surgical procedures related to CD. All three patients were young ( < 25 years) and suffered ileal CD with inflammatory pattern (L1-B1 in the Vienna Classification). No relationship was found between acute bleeding and any of the potential risk factors evaluated. CONCLUSIONS: Acute severe GI bleeding is a rare, but severe complication in CD patients, and presents mainly in patients with inflammatory ileal disease. An association of endoscopy and arteriography is necessary for diagnosis. Urgent surgery is usually required in these patients.

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.

Tuberculosis in Anti-Tumour Necrosis Factor-treated Inflammatory Bowel Disease Patients After the Implementation of Preventive Measures: Compliance With Recommendations and Safety of Retreatment.

BACKGROUND AND AIMS: Despite having adopted preventive measures, tuberculosis (TB) may still occur in patients with inflammatory bowel disease (IBD) treated with anti-tumour necrosis factor (anti-TNF). Data on the causes and characteristics of TB cases in this scenario are lacking. Our aim was to describe the characteristics of TB in anti-TNF-treated IBD patients after the publication of the Spanish TB prevention guidelines in IBD patients and to evaluate the safety of restarting anti-TNF after a TB diagnosis. METHODS: In this multicentre, retrospective, descriptive study, TB cases from Spanish hospitals were collected. Continuous variables were reported as mean and standard deviation or median and interquartile range. Categorical variables were described as absolute and relative frequencies and their confidence intervals when necessary. RESULTS: We collected 50 TB cases in anti-TNF-treated IBD patients, 60% male, median age 37.3 years (interquartile range [IQR] 30.4-47). Median latency between anti-TNF initiation and first TB symptoms was 155.5 days (IQR 88-301); 34% of TB cases were disseminated and 26% extrapulmonary. In 30 patients (60%), TB cases developed despite compliance with recommended preventive measures; *not performing 2-step TST (tuberculin skin test) was the main failure in compliance with recommendations. In 17 patients (34%) anti-TNF was restarted after a median of 13 months (IQR 7.1-17.3) and there were no cases of TB reactivation. CONCLUSIONS: Tuberculosis could still occur in anti-TNF-treated IBD patients despite compliance with recommended preventive measures. A significant number of cases developed when these recommendations were not followed. Restarting anti-TNF treatment in these patients seems to be safe.

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.

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.