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.

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.

Ustekinumab en la artritis psoriásica y la enfermedad de Crohn / Ustekinumab in Psoriatic Arthritis and Crohn Disease

Aunque la indicación principal de ustekinumab (UST) en el momento actual es la psoriasis, su innovador mecanismo de acción aventura otras indicaciones en un futuro próximo, entre ellas, la artritis psoriásica (APs) y la enfermedad de Crohn (EC). La psoriasis y la APs son entidades donde la interacción de elementos de restricción genética, junto a factores ambientales e inmunológicos juegan un papel clave para dar lugar a las manifestaciones propias de ambas enfermedades. Una de las principales vías patogénicas en estas condiciones es el eje IL-23/Th17, y existen sobradas evidencias para apoyar intervenciones farmacológicas sobre el mismo. En el momento actual, sólo disponemos de un agente con capacidad de actuar sobre esta diana, UST, un anticuerpo monoclonal humano frente a la subunidad común p40 de la IL-12 e IL-23. Aunque disponemos de cierta información sobre su utilidad en el tratamiento de la APs, aún precisamos de más datos sobre su eficacia y seguridad en este campo. Por otra parte, la EC es una enfermedad inflamatoria crónica de etiología desconocida que afecta al tubo digestivo. El tratamiento consiste en el uso de corticoides, inmunosupresores y anticuerpos anti factor de necrosis tumoral. Algunos pacientes no responden, por lo que es necesario disponer de alternativas de tratamiento, entre las que se encuentra UST. Recientemente, dos estudios fase IIb apuntan a que UST induce y mantiene la respuesta clínica en la EC, principalmente en pacientes con fracaso previo a infliximab y proteína C reactiva elevada en el momento del tratamiento. Aún quedan interrogantes por resolver, como la dosis más eficaz o la vía de administración más adecuada, y se precisan más estudios para evaluar la eficacia y determinar el mejor esquema terapéutico en la EC. El presente trabajo revisa la información disponible hasta la fecha sobre la utilidad potencial de este nuevo agente en el tratamiento de la APs y la EC (AU)

Although ustekinumab is currently licensed for the treatment of psoriasis, in view of the innovative mechanism of action of this biologic agent, it is reasonable to hypothesize that it will, in the near future, be approved for other indications, such as the treatment of psoriatic arthritis and Crohn disease. Interactions between genetic, environmental, and immunological factors play a key role in the pathogenesis of both psoriasis and psoriatic arthritis. The IL-23/TH17 axis is one of the main pathogenic pathways in these diseases, and there is ample evidence to support the use of pharmacologic agents targeting this pathway. Ustekinumab, a human monoclonal antibody that binds to the p40 subunit shared by IL-12 and IL-23, is currently the only agent capable of modulating the IL-23/TH17 pathway. While there is some evidence supporting the use of ustekinumab in the treatment of psoriatic arthritis, more data on safety and efficacy are required. Crohn disease is a chronic inflammatory disease of unknown etiology that affects the digestive tract. It is treated with corticosteroids, immunosuppressants, and anti-TNF agents. Alternative treatments, such as ustekinumab, however, are needed for patients who do not respond to conventional therapy. The results of 2 recent phase IIb studies showed that ustekinumab induced and maintained clinical response in patients with Crohn disease; most of those who responded well had previously been unsuccessfully treated with infliximab and had elevated C reactive protein levels at the time of treatment. Many issues remain to be resolved, including the establishment of an optimal dose and administration route. Further studies are needed to evaluate the efficacy of ustekinumab in Crohn disease and to determine the best treatment regimen. The present chapter reviews the current evidence on the potential usefulness of ustekinumab in the treatment of psoriatic arthritis and Crohn disease (AU)

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.

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.

Liver dysfunction related to hepatitis B and C in patients with inflammatory bowel disease treated with immunosuppressive therapy.

BACKGROUND: There is no information about the frequency of liver dysfunction in patients with inflammatory bowel disease (IBD) treated with immunosuppressants and infected with hepatitis B (HBV) and/or C virus (HCV). AIM: To assess the influence of immunosuppressants on the course of HBV and HCV infection in IBD. METHODS: Patients with IBD with HBV and/or HCV infection from 19 Spanish hospitals were included. Clinical records were reviewed for the type of immunosuppressant used, treatment duration, liver function tests and viral markers before, during and after each immunosuppressant. Logistic and Cox regression analysis were used to identify predictors of outcome. RESULTS: 162 patients were included; 104 had HBV markers (25 HBsAg positive) and 74 had HCV markers (51 HCV-RNA positive), and 16 patients had markers of both infections. Liver dysfunction was observed in 9 of 25 HBsAg positive patients (36%), 6 of whom developed hepatic failure. Liver dysfunction in HCV was observed in 8 of 51 HCV-RNA positive patients (15.7%), and only one developed hepatic failure. The frequency and severity of liver dysfunction was significantly higher in HBV-infected patients than in HCV-infected patients (p=0.045 and p=0.049, respectively). Treatment with ≥2 immunosuppressants was an independent predictor of HBV reactivation (OR 8.75; 95% CI 1.16 to 65.66). The majority of patients without reactivation received only one immunosuppressant for a short period and/or prophylactic antiviral treatment. No definite HBV reactivations were found in anti-HBc positive patients lacking HBsAg. CONCLUSION: Liver dysfunction in patients with IBD treated with immunosuppressants is more frequent and severe in those with HBV than in HCV carriers and is associated with combined immunosuppression.

Clinical outcome of newly diagnosed Crohn's disease: a comparative, retrospective study before and after infliximab availability.

BACKGROUND: Infliximab (IFX) could change the course of Crohn's disease (CD) by reducing steroid use, surgery or prompting earlier introduction of immunomodulators (IMM). AIM: To evaluate the impact of IFX availability on the course of early CD. METHODS: Two cohorts of newly diagnosed CD patients were identified: The first cohort included patients diagnosed from January 1994 to December 1997 and the second from January 2000 to December 2003. All patients were diagnosed, treated and followed up in the same centre until December 1999 (first cohort) or December 2005 (second cohort). Development of disease-related complications, steroid, IMM or IFX requirements and intestinal resections during follow-up were registered. RESULTS: A total of 328 patients were included (146 first cohort, 182 second cohort). A similar proportion of patients in both cohorts received steroids, but steroid exposure resulted significantly more intense in the first cohort (P = 0.001). In the second cohort, 14% of patients received IFX. Thiopurines were used more (P = 0.001) and earlier (P = 0.012) in the second cohort. No differences in surgical requirements or the development of disease-related complications were found. CONCLUSIONS: Following a step-up therapeutic algorithm, IFX availability did not reduce surgical requirements or the development of disease-related complications.

Treatment cost of ulcerative colitis is apheresis with Adacolumn cost-effective?

BACKGROUND: Scarce data are available in Europe on the cost of treatment for ulcerative colitis (UC). AIM: To assess the cost of illness of moderate-to-severe UC in two scenarios: traditional treatment versus alternative treatment incorporating granulocyte, monocyte adsorption - apheresis (GMA-Apheresis; Adacolumn). To determine the relative cost-effectiveness of both options in steroid-dependent patients. METHODS: One-year cost-of-illness and cost-effectiveness analysis from the third-payer perspective using a decision tree model was carried out. Probabilities of each event were derived from the literature and an expert panel. Direct medical costs were obtained from official sources (euro2004). Effectiveness was measured by the proportion of patients achieving clinical remission. RESULTS: The average annual cost per patient treated with traditional treatment was estimated to be euro6740; with GMA-Apheresis, the cost was estimated to be euro6959. In steroid-dependent patients, the average annual cost was euro6059 and euro11,436, respectively. The proportion of patients achieving clinical remission with GMA-Apheresis was 22.5% higher. As second- and third-line therapy, a new course of corticosteroids and surgery was avoided in 18.5 and 4% of patients, respectively. CONCLUSIONS: Incorporating GMA-Apheresis (Adacolumn) in the therapeutic management of moderate-to-severe UC patients is cost-effective and implies savings related to the reduction of adverse effects derived from corticosteroid use and to the decreased number of surgical interventions.

[Implantation of a hospital registry of hereditary nonpolyposis colorectal cancer]. / Implantación de un registro hospitalario de cáncer colorrectal hereditario sin poliposis.

INTRODUCTION: Identification of patients with hereditary nonpolyposis colorectal cancer (HNPCC) can allow colorectal cancer (CRC) prevention through colonoscopy and polypectomies. The purpose of this study was to report the clinical characteristics of HNPCC families in our registry. PATIENTS AND METHOD: HNPCC was identified using the Amsterdam criteria. Familial clustering of CRC and extracolonic cancers were investigated in families. Individuals at risk were offered annual colonoscopy, starting from the age of 25 years. RESULTS: Twelve HNPCC families were identified. There were 46 cases of CRC in 38 patients. The mean age at diagnosis of CRC was 45.4 +/- 12.7 years (range 25-73 years). In patients with documented disease, right-sided tumors predominated. Eleven patients with extracolonic cancer were identified (six tumors located in the endometrium). Of 43 at-risk individuals, 29 accepted surveillance. CONCLUSIONS: Our data confirm the importance of the family history in identifying HNPCC. This study confirms previously described characteristics in HNPCC, namely, early age at onset of CRC, right-sided predominance, multiple synchronous and metachronous neoplasms, and increased extracolonic cancers. This is the first study of clinical data in a Spanish HNPCC registry.

Implantación de un registro hospitalario de cáncer colorrectal hereditario sin poliposis / Implantation of a hospital registry of hereditary nonpolyposis colorectal cancer

Introducción: La identificación de los pacientes afectados de cáncer colorrectal hereditario sin poliposis (CCRHSP) hace posible la prevención del cáncer colorrectal (CCR), mediante el cribado endoscópico y las polipectomías endoscópicas. La finalidad de nuestro estudio es presentar los datos clínicos de las familias incluidas en nuestro registro de CCRHSP. Pacientes y método: El CCRHSP se identifica mediante los criterios de Ámsterdam. Se analiza la historia familiar de CCR y de neoplasias extracolónicas. Entre las familias identificadas, a los familiares en situación de riesgo se les ofrece la realización de cribado mediante colonoscopia anual, a partir de los 25 años de edad. Resultados: Se identifica a 12 familias que cumplen los criterios de Ámsterdam. En total se presentan 46 casos de CCR en 38 pacientes. La edad media en el momento del diagnóstico es de 45,4 ± 12,7 años, con un rango de entre 25 y 73 años. Entre los pacientes con histología documentada, predominan las lesiones del colon derecho. Se identifica a 11 pacientes con neoplasias extracolónicas (6 localizadas en el endometrio). En total, 29 de 43 familiares de riesgo aceptaron el cribado endoscópico. Conclusiones: Los datos confirman la importancia de la historia familiar para la identificación del CCRHSP. Este estudio confirma las características previamente descritas para el CCRHSP, como la edad temprana de presentación del CCR, la localización preferente en el colon derecho, la presencia de múltiples lesiones sincrónicas o metacrónicas y el incremento de las neoplasias extracolónicas. Éste es el primer estudio con datos clínicos de un registro de CCRHSP en España

Introduction: Identification of patients with hereditary nonpolyposis colorectal cancer (HNPCC) can allow colorectal cancer (CRC) prevention through colonoscopy and polypectomies. The purpose of this study was to report the clinical characteristics of HNPCC families in our registry. Patients and method: HNPCC was identified using the Amsterdam criteria. Familial clustering of CRC and extracolonic cancers were investigated in families. Individuals at risk were offered annual colonoscopy, starting from the age of 25 years. Results: Twelve HNPCC families were identified. There were 46 cases of CRC in 38 patients. The mean age at diagnosis of CRC was 45.4 ± 12.7 years (range 25-73 years). In patients with documented disease, right-sided tumors predominated. Eleven patients with extracolonic cancer were identified (six tumors located in the endometrium). Of 43 at-risk individuals, 29 accepted surveillance. Conclusions: Our data confirm the importance of the family history in identifying HNPCC. This study confirms previously described characteristics in HNPCC, namely, early age at onset of CRC, right-sided predominance, multiple synchronous and metachronous neoplasms, and increased extracolonic cancers. This is the first study of clinical data in a Spanish HNPCC registry

Review article: colorectal cancer surveillance in ulcerative colitis - what should we be doing?

Different societies have published guidelines for colorectal cancer (CRC) surveillance in ulcerative colitis (UC). While it would seem that most gastroenterologists and endoscopists agree with these guidelines, different studies have shown that in clinical practice, the concept of dysplasia is not fully understood, and therefore, the guidelines are not always followed. According to some studies, the reason why gastroenterologists do not follow the recommendations is inadequate education. The main advance in recent years in this subject is in endoscopic diagnosis of dysplasia. The magnification and chromoendoscopy allow targeted biopsies to be taken. Some studies indicate that nontargeted biopsies are not useful in ruling out dysplasia. It is also important to realize that most dysplasia is visible in conventional colonoscopy. In colonoscopy, it is not only significant to detect dysplasia-associated lesions or masses; the endoscopist should also be trained to detect, in the course of conventional exploration, subtle changes in colour or in mucosal surfaces that imply dysplasia. Adherence to guidelines had been extensively assessed in other disease conditions (asthma, hypertension, etc.). According to our knowledge there are no such data regarding CRC surveillance in UC. Some barriers that may affect physicians include: (i) knowledge (lack of awareness or lack of familiarity); (ii) attitudes (lack of agreement, lack of self-efficacy, lack of outcome expectancy, or the inertia of previous practice) and (iii) behaviour (external barriers). In conclusion, we need new guidelines for CRC surveillance in UC, which must take into account the advances in risk factors of dysplasia and new technologies to study colon dysplasia.

[Lactose malabsorption in ulcerative colitis. A case-control study]. / Malabsorción de lactosa en la colitis ulcerosa. Estudio de casos y controles.

BACKGROUND: The role of lactose malabsorption in ulcerative colitis is controversial. The aim of this study was to compare the prevalence of lactose malabsorption in a group of ulcerative colitis patients and a control group and to modify lactose consumption in view of the results. METHODS: Lactose malabsorption was studied using the hydrogen breath test in 52 patients with ulcerative colitis and 34 controls after ingestion of 25 g of lactose. A questionnaire on ingestion of milk products was also administered. RESULTS: Of the 52 patients with ulcerative colitis, 13 (25%) presented lactose malabsorption compared with 11 of the 34 (32%) controls (p = 0.45). Twenty-four patients (46%) had been advised to completely eliminate lactose from their diets. Twenty-seven of the 39 patients without malabsorption had reduced or eliminated lactose consumption after being diagnosed with ulcerative colitis. CONCLUSIONS: No significant differences in the prevalence of lactose malabsorption was found between patients with ulcerative colitis and controls. We believe that systematic elimination of lactose from the diets of these patients is erroneous. In our environment, we recommend the hydrogen breath test only in patients with symptoms of lactose intolerance.

[Endoscopic management of foreign bodies in the esophagus. Results of a retrospective series of 501 cases]. / Abordaje endoscópico de los cuerpos extraños esofágicos. Resultados de una serie retrospectiva de 501 casos.

We present the results of a retrospective study of endoscopic management (with flexible endoscopy) in 501 patients admitted for suspected ingestion of a foreign body between 1977 and 1997. The mean age of the patients was 55.73 19.38. Foreign bodies were found in the esophagus in 322 patients (64.3%) and endoscopic removal was successful in 307 (95.35%). More experienced endoscopists, with more than 45 cases, had a higher success rate (98.1%) than did less experienced endoscopists (87.9%) (p < 0.01). The most frequent type of foreign body in our series was meat bolus (32.8%). Underlying disease was found in 38.9%, and peptic stenosis was the most frequent. The only severe complication found was esophageal perforation in one patient (0.3%). Emergency flexible endoscopy is the most effective method for managing patients admitted for suspected ingestion of a foreign body and for the removal of foreign bodies located in the esophagus.

[Tropical chronic pancreatitis in a young patient]. / Pancreatitis crónica tropical en una paciente joven.

Tropical chronic pancreatitis is a form of idiopathic chronic pancreatitis that has not previously been described in Spain. Typically it is related to dietary factors and malnutrition, although genetic factors may also play a significant role in the development of the disease. We report a case of chronic tropical pancreatitis in a 27-year-old woman from the Dominican Republic domiciled in Spain since 1992. The patient was admitted to our hospital for acute pancreatitis that fulfilled the diagnostic criteria (clinical and radiological) for chronic tropical pancreatitis. This case has led us to review this uncommon entity. Because of the increasing number of immigrants from tropical countries, chronic tropical pancreatitis will probably need to be taken into account in the differential diagnosis of chronic pancreatitis in our patients.

[Celiac disease of the adult following orthotopic liver transplantation. Description of a case]. / Enfermedad celíaca del adulto tras trasplante ortotópico de hígado. Descripción de un caso.

A case of celiac disease of the adult is herein described in a patient with a history of orthotopic liver transplantation because of cirrhosis due to hepatitis C virus. The patient presented with a decrease in the levels of cyclosporinemia, diarrhea and an increase in transaminases. This is an infrequent form of presentation leading to differential diagnosis with a complication related to the liver disease.

[Prevalence of monosymptomatic celiac disease in patients with iron deficiency anemia]. / Prevalencia de enfermedad celíaca monosintomática en pacientes con anemia ferropénica.

A prospective study of the prevalence of monosymptomatic celiac disease presented as ferropenic anemia in patients admitted for study such complication of was carried out. All the patients were evaluated by gastroscopy and biopsy of the distal duodenal segment, regardless of endoscopic appearance. Patients presenting an endoscopic lesion clearly suggestive as the origin of the chronic bleeding were excluded from the study. The prevalence of celiac disease, the only manifestation of which was ferropenic anemia, was 3.3% in this series. What is important to note in this study is the importance of duodenal biopsy in the study of ferropenic anemia, with the aim of avoiding diagnostic delay of a possible monosymptomatic celiac disease as the cause of the anemia.