Antonio López San Román

Serum lipopolysaccharide-binding protein in endotoxemic patients with inflammatory bowel disease.

Background In inflammatory bowel disease (IBD), enhanced inflammatory activity in the gut is thought to increase the risk of bacterial translocation and endotoxemia. By searching for signs of endotoxin‐signaling cascade activation, including augmented levels of endotoxin, lipopolysaccharide‐binding protein (LBP), and soluble CD14 receptor (sCD14), this prospective study sought to establish whether endotoxemia could contribute to greater clinical activity of disease. Methods Concentrations of plasma endotoxin, LBP, sCD14, several cytokines, acute phase proteins and clinical activity indices were determined in 104 patients with Crohns disease (CD) and 52 patients with ulcerative colitis (UC). Results Endotoxemia was present in 48% of the patients with CD and in 28% of the patients with UC. The mean LBP was higher in patients with active CD (23.1 ± 13.7 &mgr;g/mL) and UC (21.4 ± 10.9 &mgr;g/mL) than in healthy controls (7.2 ± 1.8 &mgr;g/mL; P < 0.01). Elevated serum concentrations of endotoxin and LBP were even detected in patients with inactive CD. Among the patients with active IBD, those with higher endotoxin levels had the worst clinical activity scores and the highest LBP levels. Treatment normalized LBP concentrations, from 29.1 ± 13.0 to 15.2 ± 7.3 &mgr;g/mL; (P < 0.05) in active CD and from 21.7 ± 9.8 to 13.6 ± 5.7 &mgr;g/mL; (P < 0.01) in active UC, along with normalizing endotoxin and sCD14 plasma concentrations. Conclusions Patients with IBD show increased serum levels of endotoxin, LBP and sCD14. This alteration correlates with disease activity, with normal levels recovered after treatment, although less completely in Crohns disease, and parallels a rise in proinflammatory cytokines, suggesting a contribution of bacterial products to the inflammatory cascade in these patients. (Inflamm Bowel Dis 2007)

Outcomes of Pregnancies Fathered by Inflammatory Bowel Disease Patients Exposed to Thiopurines

OBJECTIVES:Immunomodulators are used as maintenance treatment of inflammatory bowel disease (IBD). Data regarding their possible effects in the course of pregnancy when the father is exposed at the time of conception are limited.METHODS:To evaluate the outcomes of pregnancies of which the fathers were exposed to thiopurines at the time of conception. A series of male patients followed in seven IBD clinics in Madrid, Spain, was studied. Any exposure to thiopurines during the 3 months preceding conception was considered significant. Controls were pregnancies fathered by patients who either had never been treated with thiopurines or had interrupted them >3 months before conception. Statistical comparisons and multivariate analysis were carried out with the generalized estimating equations model.RESULTS:There were 46 conceptions in the exposed group (mercaptopurine 9, azathioprine 37) and 84 in the control group. In the exposed group, there were more Crohns patients (82.6% vs. 53.6%), the duration of the disease was longer (median: 8 vs. 5 years), fathers were slightly older (mean: 34.2 vs. 32.7 years), and there were fewer patients on mesalamine (15.2% vs. 47.6%). Otherwise, baseline characteristics were similar in both groups. There were no significant differences regarding unsuccessful pregnancies—namely, spontaneous abortions, ectopic pregnancies, anembryonic pregnancies, or fetal deaths (10.9% exposed group vs. 13.1% control group; odds ratio (OR): 0.79, confidence interval (CI): 0.22–2.85), preterm births (4.3% vs. 2.4%; OR: 1.3, CI: 0.22–7.61), low birth weight (6.5% vs. 6%; OR: 1.06, CI: 0.25–4.54), or congenital malformations (2.2% vs. 2.4%; OR: 0.82, CI: 0.08–9). No infant neoplasms were detected. The proportion of conceptions that needed >1 year to be achieved was higher in the exposed group, but this was not statistically significant (15.2% vs. 8.3%; OR: 1.92, CI: 0.54–6.88). Multivariate analysis was carried out for unsuccessful pregnancies and fertility impairment, and it showed that, although mesalamine exposure confounded the effect of the exposure to thiopurines on these outcomes, this effect was still nonsignificant (respectively, OR: 0.49, CI: 0.17–1.44; OR: 2.82, CI: 0.7–11.38).CONCLUSIONS:Our data do not support the practice of routinely recommending to male patients that they interrupt thiopurines when wanting to conceive.

6-Mercaptopurine in patients with inflammatory bowel disease and previous digestive intolerance of azathioprine

Objective Azathioprine and 6-mercaptopurine are useful therapies in inflammatory bowel diseases. Despite their efficacy, their use is limited owing to treatment intolerance or toxicity in 10–15% of patients. It has been suggested that both drugs could be interchangeable. Material and methods All patients treated with 6-mercaptopurine because of previous digestive intolerance of azathioprine in four Spanish hospitals were reviewed. Tolerance of 6-mercaptopurine therapy was assessed. Results Fifteen patients (11 Crohns disease, 4 ulcerative colitis) were included. Immunosuppressant therapy was prescribed for steroid-dependent disease in 13 cases, and for perianal disease in 2. Main symptoms of digestive intolerance were epigastric pain, nausea and vomiting, which developed within the first weeks of treatment. Acute pancreatitis was ruled out in all the cases. Five patients commenced 6-mercaptopurine immediately after azathioprine discontinuation and 7 patients within the first month. Eleven patients (73.3%) tolerated 6-mercaptopurine and reached the therapeutic goals; only two patients had to discontinue 6-mercaptopurine because of adverse effects. Conclusions Treatment with 6-mercaptopurine is a safe alternative in patients with inflammatory bowel diseases and previous digestive intolerance of azathioprine.

Tuberculous Chemoprophylaxis Requirements and Safety in Inflammatory Bowel Disease Patients Prior to Anti-TNF Therapy

Background: Preventive actions are advised since the use of anti‐tumor necrosis factor (TNF) agents is known to increase the risk of tuberculosis (TB). No data related to the effectiveness and safety of the preventive chemoprophylaxis (ChP) for TB in inflammatory bowel disease (IBD) patients are available. The goal was to evaluate the requirements, effectiveness, and safety profile of ChP in IBD patient candidates for anti‐TNF therapy. Methods: All IBD patients diagnosed with latent TB while evaluated for anti‐TNF therapy from the IBD database of 9 Spanish centers were included. Epidemiological and clinical data, risk factors for hepatotoxicity, ChP regimens, and side effects were registered. Results: Sixty‐three out of 497 IBD evaluated patients (12.5%) had latent TB. Sixty‐eight percent were on immunomodulators and 42% on systemic corticosteroids when a TB skin test (TST) was performed. The detection of a positive TST was done in 86% after a single exposure, but 14% needed a booster. All but 1 were treated with isoniazid alone for 6 or 9 months, and only 1 case required ChP discontinuation because of hepatotoxicity. No risk factors for hepatotoxicity were found. No cases of active TB were noticed in the 67 patients further treated with anti‐TNF therapy. Conclusions: More than 10% of Spanish IBD patients who are candidates for anti‐TNF therapy have latent TB. TST retest is required to identify at least 14% of such patients; therefore, it should be considered if the initial TST is negative. ChP is safe in IBD patients even in those taking concomitant, potentially hepatotoxic drugs.

Infliximab maintenance therapy is associated with decreases in direct resource use in patients with luminal or fistulizing Crohn's disease.

Goals To estimate the impact of infliximab (IFX) maintenance therapy on the use of hospital resources in patients with Crohns disease (CD). Study Medical records of patients treated with IFX maintenance therapy (5 mg/kg body weight; intravenous infusion) for luminal (L) or fistulizing (F) CD at 13 hospitals were retrospectively reviewed. Patients were assessed as their own controls. Use of CD-related healthcare resources was recorded comparing 1-year periods before and after first IFX infusion (pre-IFX and post-IFX). Results One hundred fifty-three CD patients (n=84 L; 69 F) fulfilled the inclusion criteria. Mean number of IFX infusions was 7/y with an average of 335 mg/infusion dose/patient. During the pre-IFX period, 55% of patients needed hospitalization versus 31% in the post-IFX period (P<0.001). Mean inpatient stay was 11.3 d/y [11.2 (L), 11.5 (F)] for the pre-IFX period, and 6.3 d/y [6.2 (L), 6.3 (F)] in the post-IFX period (P<0.001). Surgery was required in 24% patients in the pre-IFX period and in 11% post-IFX (P<0.001). There were no significant changes in the incidence of outpatient visits although emergency room visits fell significantly. Conclusions Maintenance IFX in CD patients is associated with decreases in the use and length of hospitalizations and the need for surgery in clinical practice.

Adalimumab is effective in long-term real life clinical practice in both luminal and perianal Crohn's disease. The Madrid experience

OBJECTIVE To evaluate effectiveness and safety of adalimumab in CD patients of the Madrid area and identify predictors of response. METHODS Multicenter retrospective survey of all CD patients treated with adalimumab in 9 hospitals of the Madrid area (Spain). Univariate and multivariate analysis of predictors of response was performed. RESULTS 174 patients included (50% males) with a median follow-up of 40 weeks. 30% had active perianal fistulizing disease at the beginning of the therapy with adalimumab. 59% had been previously treated with infliximab, being the lost of response (42.2%) the most frequent cause of withdrawal of the drug. 33% of patients needed dose escalation from every-other week to every week. The median time for this dose escalation was 33 weeks (range 2-120). The percentages of complete response at 4 weeks, 6 months and end of follow-up were 63, 70 and 63% in luminal disease and 49, 50 and 41% in perianal disease respectively. The prevalence of adverse events was 18% (most frequent was: 5 abscesses) causing the withdrawal of the drug in 21% of them. CONCLUSIONS Adalimumab is effective and safe for the management of CD, even in refractory cases to infliximab.

Idiopathic pancreatitis in inflammatory bowel disease

BACKGROUND AND AIMS The incidence of pancreatitis is increased in inflammatory bowel disease. However, pancreatitis as an extraintestinal manifestation of the intestinal disease is exceedingly rare. We have retrospectively analyzed the prevalence of pancreatitis in a combined hospital cohort, and specifically studied cases in which no other cause than the intestinal disease itself could be found. METHODS The prevalence of pancreatitis in 1057 inflammatory bowel disease patients from two hospitals in the Community of Madrid, Spain, was determined by means of database examination. RESULTS The prevalence of pancreatitis was 2.74% (29 cases); only in four patients (0.38%) it was considered idiopathic and thus a possible extraintestinal manifestation. Underlying chronic pancreatitis was identified in three of these four patients. CONCLUSIONS In inflammatory bowel disease patients, pancreatitis is more often due to a nonrelated cause, and cases that can be adscribed to extraintestinal manifestation of the intestinal disease are comparatively rare.

Filgrastim en la enfermedad de Crohn refractaria con absceso intraabdominal

Resumen El tratamiento con factor recombinante estimulante de progenitores granulociticos (filgrastim) parece ser una alternativa terapeutica segura, bien tolerada y potencialmente efectiva en pacientes con una enfermedad de Crohn activa. Presentamos el caso de un varon adolescente con enfermedad de Crohn y absceso intraabdominal asociado, en el que los tratamientos convencionales habian fracasado, que experimento una importante respuesta al tratamiento con factor recombinante estimulante de progenitores granulociticos.