[Experience of patients with immune-mediated inflammatory diseases seen in a multidisciplinary integrated care unit]. / Experiencia de los pacientes con enfermedades inflamatorias inmunomediadas atendidos en una unidad de atención integral multidisciplinar.

OBJECTIVE: To describe the aspects with the greatest impact on the satisfaction of patients treated in a multidisciplinary unit specialising in immune-mediated inflammatory diseases (IMIDs) and to identify areas for improvement in the care model. METHODS: Cross-sectional descriptive study using a satisfaction survey structured in three blocks: sociodemographic variables, functional aspects of the unit and satisfaction with the professionals. Immediate satisfaction was measured on aspects related to the care received, the physical structure and the likelihood of recommending the unit. RESULTS: A total of 168 patients completed the surveys, the mean score of overall satisfaction with the unit was 4.75 (SD:0.4). The regression model showed the relationship between overall satisfaction and unit signage (OR:3.558, p=0.045, 95% CI: 1.027-12.33), coordination between professionals (OR:9.043, p=0.000, 95% CI: 2.79-29.28) and participation in decision making (OR: 44.836, p=0.000, 95% CI: 5.49-365.97). In terms of immediate satisfaction, the overall Net Promoter Score (NPS) was 87 (excellent). The mean score for coordination with Primary Care was 4.54 (SD:0.8) and they scored waiting time to be seen with 4.49 (SD:0.8), so they have been considered an area for improvement The mean score for coordination with Primary Care was 4.54 (SD:0.8) and they scored waiting time to be seen with 4.49 (SD:0.8), so both were considered areas for improvement. CONCLUSIONS: Coordination between intra-centre professionals and patient participation in decision-making explain the excellent level of patient satisfaction. The monitoring of satisfaction has made it possible to implement immediate improvement actions.

Single nucleotide polymorphisms in ADAM17, IL23R and SLCO1C1 genes protect against infliximab failure in adults with Crohn's disease.

BACKGROUND: To predict primary failure of infliximab (IFX) therapy in Crohn's disease (CD) and to identify patients who maintain long-term effectiveness to IFX is currently not feasible. Some genetic variations are proposed as potential biomarkers. AIM: We assessed a set of single nucleotide polymorphisms (SNPs) in genes related to the IFX mechanism of action and the presence of HLA-DQA1 * 05 allele on the primary response and long-term durability in CD patients. METHODS: A multi-centre cross-sectional study of IFX-exposed adult patients with CD was undertaken. Treatment persistence and time to failure were co-primary endpoints. DNA from the 131 patients was genotyped. Association between SNPs and clinical variables with IFX persistence was assessed. RESULTS: Failure to IFX was documented in 65 (49.6%) out of 131 patients. IFX persistence was associated either with carrying the TT genotype in ADAM17 rs10929587 (ORa=0.2; 95%CI=0.1-0.8; p = 0.021), or the CC genotype in SLCO1C1 rs3794271 (ORa=0.2; 95%CI=0.1-0.7; p = 0.008), according to multivariate logistic regression. In contrast, previous bowel resection increased the risk of IFX failure (ORa=2.8; 95%CI=1.1-7.3; p = 0.025). Cox regression analysis confirmed these findings and also identified IL23R rs10489629-TT (HRa 0.41; 95%CI=0.22-0.75; p = 0.004) and concomitant immunosuppressants (HRa 0.46; 95%CI=0.27-0.77; p = 0.003) as protection from IFX failure. However, no association between HLA-DQA1 * 05 allele and persistence of IFX therapy was found, with similar failure rates among carriers and non-carriers (52.8% vs. 47.4%, respectively; p = 0.544). CONCLUSIONS: SNPs rs10929587-TT in ADAM17, rs10489629-TT in IL23R and rs3794271-CC in SLCO1C1, together with no previous bowel surgery and concomitant immunosuppression, were identified as protection from failure to IFX.

Pathogenesis: common pathways between hidradenitis suppurativa and Crohn disease. / Etiopatogenia: nexos en común entre la hidradenitis supurativa y la enfermedad de Crohn.

Both hidradenitis suppurativa and Crohn disease are considered chronic inflammatory diseases due to immune dysregulation. The high prevalence of Crohn disease patients diagnosed with hidradenitis suppurativa suggests the existence of common pathogenic links. The present literature review analyses the similarities and differences in the pathogenesis of the two diseases, in the search for new research and knowledge targets.

Comparison of the effectiveness of two protocols for vaccination (standard and double dosage) against hepatitis B virus in patients with inflammatory bowel disease.

BACKGROUND: The response rate to hepatitis B virus (HBV) vaccination in patients with inflammatory bowel disease (IBD) is low. AIM: To compare two vaccination protocols-the standard dose and the double dose-in IBD patients. METHODS: Patients diagnosed with IBD from three tertiary hospitals were vaccinated against HBV with two different protocols: the standard protocol (Engerix-B single dose at 0, 1 and 6 months) and the new faster protocol based on a double dose (Engerix B double dose at 0, 1 and 2 months). Anti-HBs titres were measured 1-3 months after the last dose. A multivariate analysis was performed to identify factors that were predictive of response to the vaccine. RESULTS: The study sample comprised 148 patients (mean age 40 years, 69% Crohn's disease), 70% of whom were receiving immunosuppressive therapy (22% thiopurines, 23% anti-TNF and 25% both). The standard protocol was followed in 46% of patients and the double dose protocol in 54%. Considering anti-HBs >10 IU/L as a successful response to vaccination, the seroconversion rate was higher among patients vaccinated with the double dose than with the standard dose: 75% (95% CI, 65-85%) vs. 41% (95% CI, 29-54%) (P < 0.001). In the multivariate analysis, vaccination with the double dose was the only factor associated with a better response to the vaccine (OR, 4; 95% CI, 2-8; P < 0.001). CONCLUSIONS: The response rate to the HBV vaccination in IBD patients is low. Administration of a double dose was associated with a higher response rate. Therefore, the double dose protocol could be a suitable option in patients with IBD.

Efficacy of infliximab rescue therapy in patients with chronic refractory pouchitis: a multicenter study.

BACKGROUND: Despite medical therapy, 30% of patients with ulcerative colitis (UC) need to undergo surgery. Around 50% of patients with proctocolectomy with ileal pouch-anal anastomosis (IPAA) develop complications of the pouch. Clinical evidence for the use of infliximab (IFX) in refractory pouchitis is limited. The aim of this study was to report efficacy of IFX in these patients. METHODS: A retrospective, multicenter study was designed. Patients older than 18 years with chronic refractory pouchitis treated with IFX (5 mg/kg) were included. Short-term IFX efficacy was evaluated at week 8 and mid-term efficacy at weeks 26 and 52. Complete response was defined as cessation of diarrhea and urgency and partial response as marked clinical improvement but persisting symptoms. The modified Pouchitis Disease Activity Index (mPDAI) without endoscopy was calculated when available. RESULTS: Thirty-three consecutive UC patients with chronic refractory pouchitis were included (18 male, mean age 45 years, range 21-67). At week 8, 21% patients achieved complete response and 63% showed partial clinical response. At weeks 26 and 52, 33% and 27% achieved complete response and 33% and 18% showed partial clinical response, respectively. Thirteen patients (39%) withdrew treatment (four for lack of efficacy, four for loss of response and five for adverse events). None of the potential factors analyzed had an influence on response to IFX. CONCLUSIONS: IFX was effective in the short- and mid-term in patients with chronic refractory pouchitis. However, medication had to be discontinued in a high number of patients.

Matrix metalloproteinase 9 is involved in Crohn's disease-associated platelet hyperactivation through the release of soluble CD40 ligand.

BACKGROUND: Patients with Crohn's disease have an increased risk for systemic thromboembolism. Their platelets are hyperactive and possess an elevated endogenous content of CD40 ligand (CD40L), a tumour necrosis factor alpha family protein member. Under basal conditions and after stimulation, these platelets express more CD40L on their surface and release higher amounts of soluble (s)CD40L than control platelets, through a mechanism that might be mediated by matrix metalloproteinases (MMPs). OBJECTIVE: The aim of this work is to study whether enhanced sCD40L release secondary to changes in the platelet content of MMPs contributes to the higher state of activation of platelets from patients with Crohn's disease. METHODS: State of activation, CD40L and metalloproteinases content of platelets isolated from patients with Crohn's disease and age- and sex-matched control individuals were analysed, respectively, by flow cytometry, western blot and gelatin zymography. RESULTS: The hyperactive state of platelets from patients with Crohn's disease might rely on their enhanced release of sCD40L, since its inhibition by a broad-range inhibitor of MMPs (GM6001) reduced fibrinogen binding induced by platelet stimulation. Analysis of the content of MMPs in platelets from patients with Crohn's disease showed an exclusive increase in MMP-9 activity. Moreover, MMP-9 inhibition diminished sCD40L release and fibrinogen binding to activated platelets. CONCLUSIONS: The results suggest that platelets from patients with Crohn's disease release more sCD40L than controls as a consequence of their higher endogenous content of CD40L and of MMP-9, which is involved in CD40L shedding. The increased levels of released sCD40L might be responsible, at least in part, for the high state of activation of platelets from patients with Crohn's disease.

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. AIM: To describe the incidence, main causes and possible predictive factors of acute pancreatitis in inflammatory bowel disease. METHODS: Information was retrospectively extracted from the clinical records of patients followed in the IBD Units of nine hospitals in Madrid (n = 5073). RESULTS: A total of 82 acute pancreatitis episodes were diagnosed (cumulative incidence, 1.6%); 98% of them were mild. Recurrent acute pancreatitis developed in 13% of patients. Most cases of acute pancreatitis (63.4%) were attributed to drug exposure [azathioprine/mercaptopurine (AZA/MP) n = 46, mesalazine (mesalamine) n = 6]; 20.7% were idiopathic, and 12.2% were biliary. Incidence of acute pancreatitis in patients treated with AZA/MP was 3.1%. In patients with acute pancreatitis, female gender (OR 3.4 95% CI: 1.3-9.3; P = 0.012) and Crohn's disease (CD) (OR 5.8 95% CI: 1.6-20.6; P = 0.007) were risk factors for AZA/MP-associated acute pancreatitis, the latter also when analysed only in patients treated with AZA/MP (n = 1477) (OR 5.2 95% CI: 1.8-14; P = 0.002). CONCLUSIONS: The incidence of acute pancreatitis in our IBD patients (1.6%) is similar to that previously described. Drugs, mainly AZA/MP, are the leading cause. AZA-induced acute pancreatitis is always mild. Patients with CD are at a higher risk for AZA/MP-associated acute pancreatitis. The frequency of idiopathic acute pancreatitis is higher than expected, suggesting that part of these cases could be extraintestinal manifestations of IBD.

Corticosterone as a marker of susceptibility to oxidative/nitrosative cerebral damage after stress exposure in rats.

There are important individual differences in susceptibility to stress-induced diseases, most of them associated to the hypothalamic-pituitary and sympatho-medullo-adrenal axis functioning. Characterization of individual differences in animals may help to find the origin of this susceptibility. In order to study differences in oxidative and neuroinflammatory consequences in brain after stress exposure, we used an adult, male, outbred (Wistar:Hannover) population of 60 rats. Animals were subjected to 6h of immobilisation stress. Basal (1 week before stress) and post-stress (immediately after stress) plasma corticosterone (CC) was measured for each animal from the tail vein (basal: 239.74+/-19.44 ng/ml at 1500 h). Group H was assigned to animals with 33% higher levels of CC (>279.53 ng/ml) and group L to animals with 33% lower levels of CC (<199.09 ng/ml). After stress, animals with higher plasma CC levels in basal conditions showed higher adrenal response (higher post-stress CC levels) than rats with lower levels of basal CC. Furthermore, rats from H group are more vulnerable to accumulation of oxidative/nitrosative mediators in brain (higher calcium-independent nitric oxide activity and higher lipid peroxidation, by malondialdehyde determination, MDA) and also to the accumulation of proinflammatory mediators (higher PGE(2) levels) whereas showing less antiinflammatory protection (less 15-deoxy-PGJ(2) levels). Statistical analysis, by using ROC curves revealed cut-off values of basal plasma CC predicting animals with higher post-stress MDA and PGE(2) and lower PGJ(2) levels in brain. These data indicate that plasma basal levels of CC are an easily detectable and reproducible parameter for predicting the response of the individuals after an acute stress, providing further support for studies on individual differences.

[Liver damage and celiac disease]. / Daño hepático y enfermedad celíaca.

Celiac disease (CD) is an important cause of serum aminotransferase elevation: between 5 and 10% of patients with persistent and cryptogenetic transaminase elevation may have CD. In fact, a wide spectrum of liver injuries in children and adults may be related to CD, particularly: a) mild parenchymal damage characterized by absence of any clinical signs or symptoms suggesting chronic liver disease, and by non-specific histological changes reversible on a gluten-free diet; b) chronic liver damage with autoimmune etiology, including autoimmune hepatitis, primary sclerosing cholangitis, and primary biliary cirrhosis, which may be associated with CD but are generally unaffected by gluten withdrawal; and c) severe liver failure and decompensated cryptogenetic liver cirrhosis, potentially treatable with a gluten-free diet. Such different types of liver injuries may represent one same disorder where individual factors, such as genetic predisposition, precocity, and duration of exposure to gluten may influence reversibility of liver damage. A rigorous cross-checking for asymptomatic liver damage in CD individuals and, conversely, for CD in any cryptogenic liver disorder, including end-stage liver failure, is recommended.

[Osteoporosis and inflammatory bowel disease]. / Osteoporosis y enfermedad inflamatoria intestinal.

Inflammatory bowel disease is a chronic disease with an unknown ethiology although multiple factors intervene such as individual, genetic and immunologic susceptibility, as well as different environmental factors. Like other multisystemic diseases, its clinical manifestations are diverse and it may affect other organs besides the gastrointestinal tract. In the last few years there is a growing interest for one of these extraintestinal manifestations, osteoporosis and osteopenia that may affect up to 42% of patients and can condition an important increase in morbility. Inactivity, prolonged corticosteroid treatment, nutritional deficiencies and the disease per se have an important role in the development of this complication. This article reviews clinical and ethiological aspects of inflammatory bowel disease associated osteoporosis and offers a strategy for diagnosis and treatment.

Safety and efficacy of argon plasma coagulator ablation therapy for flat colorectal adenomas.

INTRODUCTION: argon-plasma coagulation (APC) has been used safely and efficaciously in multiple settings including colon polyp treatment. The aim of this study was to evaluate APC efficacy and safety in the treatment of flat colorectal adenomas. MATERIALS AND METHODS: APC ablation was prospectively performed and evaluated in 22 consecutive patients with colorectal adenomas, 11 of which had large sessile adenomas that were treated with piecemeal polypectomy and APC ablation of residual adenomatous tissue, whereas the remaining eleven patients with flat or carpet-like adenomas were only treated with APC. The mean initial longitudinal extension of adenomas to be treated with APC was 22 mm (range, 20 to 40 mm). RESULTS: the mean age of patients was 70 years. Adenomas were found most frequently in the rectum (50%) and cecum (23%). Complete ablation was achieved in 90.9% of adenomas. Recurrence was observed in 20% of patients, all of them in the rectum, after a mean follow-up period of 16.3 months (range, 8 to 35). All recurrences were managed satisfactorily. No major complications were seen. CONCLUSIONS: argon plasma coagulator ablation of flat colorectal adenomas is an efficacious and safe technique, specially in the right colon, but results must be confirmed in controlled trials with a higher number of patients.

[Liver failure due to mushroom poisoning: clinical course and new treatment perspectives]. / Toxicidad hepática por ingesta de setas: curso clínico y nuevas perspectivas de tratamiento.

Mushroom poisoning, mainly due to the Amanita genus, is an infrequent cause of liver failure in our environment. However, because of its high morbidity and mortality, it constitutes a medical emergency. The characteristic initial symptoms of vomiting, abdominal pain, and diarrhea are nonspecific and may be confused with gastroenteritis. If correct and early treatment is not given, renal and hepatic failure can develop, sometimes requiring liver transplantation. We present three cases of mushroom poisoning, which presented a different clinical course ranging from complete recovery with traditional medical treatment to severe acute liver failure requiring transplantation in one patient and albumin dialysis (molecular absorbent recycling system [MARS]) in another with favorable outcome. Although controlled clinical studies of the treatment of mushroom poisoning are lacking, recommendations based on the experience of various authors have been established. Penicillin G and silymarin seem to be useful. The development of new techniques of extracorporeal detoxification, mainly MARS, may represent an important support system in the treatment of these patients.

[Variability of the clinical expression of Ecstasy-induced hepatotoxicity]. / Variabilidad de la expresión clínica de la toxicidad hepática por éxtasis.

3,4-methylenedioxymethamphetamine (MDMA) is an amphetamine derivative, known as ecstasy. Because of its euphoric effects, the use of this substance as a drug of abuse is becoming increasingly widespread. The development of hyperthermia, disseminated intravascular coagulation, rhabdomyolysis, acute renal failure, cardiac arrhythmia and neurotoxicity have been described in association with the use of this drug. Moreover, in the last few years, cases of liver involvement, associated or not with the above-mentioned entities, have been described, ranging from mild acute hepatitis to fulminant hepatic failure and death. We present four cases of ecstasy-induced hepatotoxicity. Outcome was favorable in three patients while the fourth required liver transplantation. Consequently, ecstasy ingestion should be ruled out as a cause of acute non-viral hepat

N-(3-(aminomethyl)benzyl)acetamidine, an inducible nitric oxide synthase inhibitor, decreases colonic inflammation induced by trinitrobenzene sulphonic acid in rats.

Gastrointestinal inflammation has been associated with an increased generation of nitric oxide (NO) and the expression of the inducible NO synthase (iNOS). Using an experimental model of colitis induced by trinitrobenzene sulphonic acid (TNBS), we sought to determine whether the administration of N-(3-(Aminomethyl)benzyl)acetamidine (1400W), a specific inhibitor of iNOS, has a beneficial action on the colonic injury. 1400W (0.4 and 2 mg/kg/day) was administered intraperitoneally from day 5 to 10 after intrarectal instillation of TNBS. TNBS led to colonic ulceration and inflammation, an increase of colonic myeloperoxidase activity and the expression of the calcium-independent NOS from days 1 to 15. 1400W reduced the macroscopic damage and the histological changes induced by TNBS as well as the calcium-independent NOS activity and myeloperoxidase activity determined over 30 min after sacrifice. These findings indicate that the expression of iNOS accounts for most of the damage caused by TNBS and that the administration of 1400W after the onset of colitis has a beneficial action on the colonic injury.

Implication of TNF-alpha convertase (TACE/ADAM17) in inducible nitric oxide synthase expression and inflammation in an experimental model of colitis.

Tumour necrosis factor-alpha (TNF-alpha) is a pro-inflammatory cytokine which is shed in its soluble form by a disintegrin and metalloproteinase (ADAM) called TNF-alpha convertase (TACE; ADAM17). TNF-alpha plays a role in inflammatory bowel disease (IBD) and is involved in the expression of inducible nitric oxide synthase (iNOS) which has also been implicated in IBD. The study was designed to investigate whether colitis induced by trinitrobenzene sulphonic acid (TNBS) in rats produces an increase in TACE activity and/or expression and whether its pharmacological inhibition reduces TNF-alpha levels, iNOS expression and colonic damage in this model. TNBS (30 mg in 0.4 ml of 50% ethanol) was instilled into the colon of female Wistar rats. Saline or TACE inhibitor BB1101 (10 mg/kg/day) was administered intraperitoneally 5 days after TNBS instillation. On day 10, colons were removed and assessed for pathological score, myeloperoxidase (MPO), NO synthase (NOS), TACE enzymatic activity and protein levels, colonic TNF-alpha and NOx- levels. Instillation of TNBS caused an increase in TACE activity and expression and the release of TNF-alpha. TNBS also resulted in iNOS expression and colonic damage. BB1101 blocked TNBS-induced increase in TACE activity, TNF-alpha release and iNOS expression. Concomitantly, BB1101 ameliorated TNBS-induced colonic damage and inflammation. TNBS causes TNF-alpha release by an increase in TACE activity and expression and this results in the expression of iNOS and subsequent inflammation, suggesting that TACE inhibition may prove useful as a therapeutic means in IBD.