Carlos Taxonera

Fecal Calprotectin and Lactoferrin for the Prediction of Inflammatory Bowel Disease Relapse

Background: The purpose of the study was to determine the role of fecal calprotectin and lactoferrin in the prediction of inflammatory bowel disease relapses, both in patients with ulcerative colitis (UC) and Crohns disease (CD), in a large, long‐term, follow‐up study. Methods: The prospective multicenter study included CD and UC patients who had been in clinical remission for 6 months. At baseline, patients provided a single stool sample for calprotectin and lactoferrin determination. Follow‐up was 12 months in patients showing no relapse and until activity flare in relapsing patients. Results: In all, 163 patients (89 CD, 74 UC) were included. Twenty‐six patients (16%) relapsed during follow‐up. Calprotectin concentrations in patients who suffered a relapse were higher than in nonrelapsing patients (239 ± 150 versus 136 ± 158 μg/g; P < 0.001). Relapse risk was higher in patients having high (>150 μg/g) calprotectin concentrations (30% versus 7.8%; P < 0.001) or positive lactoferrin (25% versus 10%; P < 0.05). Fecal calprotectin (>150 μg/g) sensitivity and specificity to predict relapse were 69% and 69%, respectively. Corresponding values for lactoferrin were 62% and 65%, respectively. The area under the receiver operating characteristic curve to predict relapse using calprotectin determination was 0.73 (0.69 for UC and 0.77 for CD). Better results were obtained when only colonic CD disease or only relapses during the first 3 months were considered (100% sensitivity). High fecal calprotectin levels or lactoferrin positivity was associated with clinical relapse in Kaplan–Meier survival analysis, and both fecal tests were associated with relapse in the multivariate analysis. Conclusions: Fecal calprotectin and lactoferrin determination may be useful in predicting impending clinical relapse—especially during the following 3 months—in both CD and UC patients. (Inflamm Bowel Dis 2009)

Early Azathioprine Therapy Is No More Effective Than Placebo for Newly Diagnosed Crohn's Disease

BACKGROUND & AIMS A small placebo-controlled trial reported the efficacy of mercaptopurine therapy for children newly diagnosed with Crohns disease, yet little is known about the efficacy of early thiopurine therapy in adults. METHODS We performed a prospective double-blind trial of adult patients with a recent (<8 weeks) diagnosis of Crohns disease. Patients were randomly assigned to groups given azathioprine (2.5 mg · kg(-1) · day(-1), n = 68) or placebo (n = 63) at 31 hospitals from February 2006 to September 2009. Corticosteroids but no other concomitant medications were allowed for control of disease activity. The primary measure of efficacy was sustained corticosteroid-free remission. RESULTS After 76 weeks of treatment, 30 patients treated with azathioprine (44.1%) and 23 given placebo (36.5%) were in sustained corticosteroid-free remission (difference of 7.6%; 95% confidence interval, -9.2 to 24.4%; P = .48). The rates of relapse (defined as Crohns Disease Activity Index score >175) and corticosteroid requirements were similar between groups. A post hoc analysis of relapse, defined as a Crohns Disease Activity Index score >220, showed lower relapse rates in the azathioprine group than in the placebo group (11.8% vs 30.2%; P = .01). Serious adverse events occurred in 14 patients in the azathioprine group (20.6%) and 7 in the placebo group (11.1%) (P = .16). A larger percentage of patients in the azathioprine group had adverse events that led to study drug discontinuation (20.6%) than in the placebo group (6.35%) (P = .02). CONCLUSIONS In a study of adults with Crohns disease, early azathioprine therapy was no more effective than placebo to achieve sustained corticosteroid-free remission but was more effective in preventing moderate to severe relapse in a post hoc analysis. EudraCT 2005-001186-34.

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.

Genetic predisposition to acute gastrointestinal bleeding after NSAIDs use

Impaired drug metabolism is a major cause of adverse drug reactions, and it is often caused by mutations at genes coding for drug‐metabolising enzymes. Two amino‐acid polymorphisms of cytochrome P4502C9 (CYP2C9), an enzyme involved in the metabolism of several nonsteroidal anti‐inflammatory drugs (NSAIDs), were studied in 94 individuals with acute bleeding after NSAIDs use and 124 individuals receiving NSAIDs with no adverse effects. The frequency of CYP2C9 variant alleles was increased in overall bleeding patients, with a significant trend to higher risk with increasing number of variant alleles (P=0.02). The odds ratio for bleeding patients receiving CYP2C9 substrates (n=33) was 2.5 for heterozygous and 3.7 for homozygous carriers of mutations (P<0.015), suggesting that the inherited impairment of CYP2C9 activity increases the risk for severe adverse drug reactions after NSAIDs use.

Manifestaciones extraintestinales en la enfermedad inflamatoria intestinal: diferencias entre la enfermedad de Crohn y la colitis ulcerosa

Fundamento y objetivo: La prevalencia de las manifestaciones extraintestinales (MEI) en la enfermedad inflamatoria intestinal (EII) varia en funcion de las areas geograficas, el tipo de EII, la localizacion, la duracion de la enfermedad y el tratamiento y la rapidez en el diagnostico. El objetivo de este trabajo ha sido determinar la prevalencia de las principales MEI en la EII y las diferencias existentes entre la enfermedad de Crohn (EC) y la colitis ulcerosa (CU). Pacientes y metodo: Estudio prospectivo en el que se incluyo a 566 pacientes con EII (295 con EC y seguimiento medio de 11,6 anos [extremos: 2-32 anos] y 271 con CU y seguimiento medio de 10,4 anos [extremos: 2-36 anos]. Los datos referidos a las MEI y tests de laboratorio se obtuvieron en el momento del diagnostico y durante las visitas posteriores. Resultados: La aparicion de al menos una MEI se observo en el 46,6% de los pacientes. Las MEI fueron frecuentes tanto en la CU (51,5%) como en la EC (42,2%). Las manifestaciones hepatobiliares (odds ratio [OR] = 1,91; intervalo de confianza [IC] del 95%, 1,15-3,16), la enfermedad tromboembolica venosa (OR = 4,26; IC del 95%, 1,3-15,4) y las artralgias (OR = 1,59; IC del 95%, 1,01-2,5) fueron mas frecuentes en la CU que en la EC. El eritema nodoso (OR = 2,35; IC del 95%, 1,13-5,0) y las artritis perifericas (OR = 1,95; IC del 95%, 1,02-3,74) fueron mas frecuentes en la EC. La prevalencia de las manifestaciones oculares y del resto de manifestaciones articulares no difirio entre la CU y la EC. Conclusiones: La prevalencia de las MEI en los pacientes con EII espanoles es una de las mas altas publicadas. La frecuencia del tipo de MEI es diferente entre los pacientes con EC y CU, un aspecto que es importante conocer para realizar un diagnostico adecuado de la EII y de sus complicaciones.

Acute pancreatitis in inflammatory bowel disease, with special reference to azathioprine-induced pancreatitis

Background  Pancreatitis is a potentially severe condition. Patients with inflammatory bowel disease (IBD) seem to be at increased risk for acute pancreatitis.

Adalimumab induction and maintenance therapy for patients with ulcerative colitis previously treated with infliximab

Aliment Pharmacol Ther 2011; 33: 340–348

Crohn's disease: a review of current treatment with a focus on biologics.

Crohn’s disease is a debilitating and expensive disease that is growing in incidence in both developing and developed countries. While conventional therapies, such as corticosteroids and immunosuppressants, continue to play a vital role in treating this condition, it is evident that many affected individuals do not respond to therapy or develop intolerable adverse effects. The addition of modern biological therapies to the Crohn’s disease armamentarium is providing a change in expectations for disease outcome. Infliximab and adalimumab are currently the only biological agents approved for induction and maintenance treatment in adults (infliximab and adalimumab) and children (infliximab) with Crohn’s disease. Furthermore, infliximab has a beneficial effect on perianal fistulas. Other tumour necrosis factor (TNF)-α inhibitors, such as certolizumab pegol, also demonstrate promising results in adults with moderate to severe active disease. In addition, adalimumab and certolizumab pegol have shown clinical efficacy in patients who are intolerant to or lose response to infliximab, suggesting that switching between agents may allow response to be maintained over time. The primary safety concerns with TNFα inhibitors include increased risk of serious infection (including reactivation of tuberculosis), malignancy (particularly lymphoma) and demyelinating disease. Other agents in development include recombinant human anti-inflammatory cytokines, agents that target pro-inflammatory cytokines and granulocyte-macrophage colony-stimulating factors. Further prospective studies will provide interesting insight into different mechanisms by which factors involved in the pathophysiology of Crohn’s disease can be modulated.

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.

Induction of psoriasis with anti-TNF agents in patients with inflammatory bowel disease: A report of 21 cases

AIM Anti-tumor necrosis factor (TNF)-alpha agents are widely used for the treatment of both inflammatory bowel disease (IBD) and psoriasis. Psoriatic skin lesions induced by anti-TNF have been described in patients with IBD. We report a case series of psoriasis induced by anti-TNF agents in IBD patients. METHODS Systematic analysis of cases of psoriasis induced by anti-TNF in an IBD patient cohort in tertiary hospitals of Madrid. RESULTS A total of 21 of 1294 patients with IBD treated with anti-TNF-alpha agents developed drug-induced psoriasis (cumulative incidence 1.62%; 95% CI 1.06%-2.47%): 14 patients with infliximab and 7 with adalimumab; seventeen with Crohns disease, 4 with ulcerative colitis. The onset of skin lesions varied in a wide range of time (after a mean 13±8 doses). The most frequent site of skin lesions was the limbs (62%) followed by the trunk (48%) and the scalp (43%). The psoriasis phenotypes were plaque psoriasis (57%), scalp (14%), palmoplantar pustulosis (14%), pustular generalized psoriasis (5%), guttate (5%) and inverse (5%). Four patients interrupted the anti-TNF treatment, and that led to the complete regression of lesions in 1 of them. The other 17 patients were maintained on anti-TNF therapy and managed with topical steroids. CONCLUSION Psoriatic lesions can be induced by anti-TNF drugs. Plaque psoriasis on the extremities and trunk were the most frequent presentations in our series. Topical steroid treatment is effective in most patients. Anti-TNF discontinuance may be reserved for patients with severe psoriasis or patients without response to topical therapy.