Factores ambientales en el desarrollo y evolución de la enfermedad inflamatoria intestinal / Environmental risk factors in the development and evolution of inflammatory bowel disease

Environmental factors may influence the development of Inflammatory Bowel Disease and modify its natural history. The objective of this review is to evaluate current evidence about environmental factors associated with the disease. A better knowledge about the pathogenesis of the disease can lead to better treatment strategies and suggestions to prevent the disease.

Utilidad de la monitorización terapéutica de infliximab en el manejo de la enfermedad inflamatoria intestinal / Usefulness of therapeutic monitoring of infliximab in the treatment of inflammatory bowel disease

Background: Primary non-response and secondary loss of response (LOR) are significant problems of biological therapy for inflammatory bowel disease (IBD). Therapeutic drug monitoring (TDM) in IBD patients receiving these drugs can improve outcomes. Aim: To measure serum infliximab levels and anti-infliximab antibodies (ATI) in patients with IBD post-induction phase and during maintenance therapy assessing the clinical course of IBD. Patients and Methods: Prospective study of IBD patients receiving infliximab between July 2016-May 2017. Group-A included patients who received induction therapy while Group-B included patients who were in maintenance therapy. TDM was performed in serum samples collected at weeks-14 and 30 in Group-A and before the infliximab maintenance dose in Group-B. Clinical scores, fecal calprotectin and endoscopic score were also evaluated. Results: Of 14 patients in Group-A, 57% achieved endoscopic response. Median serum infliximab concentrations at week-14 and 30 were 2.65 AU/mL (0.23-32.58) and 2.3 AU/mL (0.3-16.8), respectively. Patients with mucosal healing had non-significantly higher median infliximab concentrations at week- 14, as compared to week 30 (median 3.2 vs 2.2 AU/ml, respectively, p 0.6). ATI >10 ug/mL were found in one and seven patients at week-14 and 30, respectively. At 52 weeks of follow-up, four patients (31%) had LOR. Group-B included 36 patients, 33% had LOR. Median serum concentrations of infliximab were 1.4 AU/mL (0.27-7.03). No significant differences in serum infliximab concentration were observed between patients in remission and those with inflammatory activity. Seventeen patients had ATI >10 ug/mL. Conclusions: Clinical algorithms using TDM might help to optimize the pharmacological therapy of IBD.

Terapia de inducción acelerada con infliximab en paciente con colitis ulcerosa grave refractaria a corticoides: caso clínico / Acute severe ulcerative colitis treated with accelerated infliximab induction: case report

Acute severe ulcerative colitis (ASUC) is a potentially life-threatening condition that requires early recognition, hospitalization and adequate treatment. Currently, the use of infliximab in ulcerative colitis (UC) is recommended in the case of severe disease refractory to corticosteroids, once that superimposed bacterial or viral infections (such as cytomegalovirus or Clostridium difficile) have been excluded. However, conventional weight-based regimens of infliximab might be insufficient for patients with ASUC. Accelerated infliximab induction regimen may increase its serum concentration levels and efficacy by reducing early colectomy rates in these patients. We report a 34 year old female presenting with an ASUC. She was initially treated with hydrocortisone 300 mg/day and mesalazine enemas 4 g/day with an unfavorable clinical response. At the fifth day of therapy, an accelerated induction therapy with infliximab was started in doses of 10 mg/kg at weeks 0, 1 and 4. After the second dose, there was a favorable response with reduction of abdominal pain, stool frequency and hematochezia. She was discharged with prednisone and azathioprine. After a year of starting infliximab, the patient remains in clinical remission.

Experiencia local con natalizumab en pacientes con enfermedad de Crohn refractaria a anti-TNF: casos clínicos / Natalizumab for the treatment of Crohns disease: report of three cases

Anti-tumor necrosis factor-α (TNF) agents have dramatically changed the management of Crohn’s Disease (CD). However, a significant number of these patients do not respond at all or cease to respond to antibodies against TNF. In this clinical situation, the options include intensification of anti-TNF therapy by either increasing the dose or by shortening the administration interval, the use of a second anti-TNF or medications with a different mechanism of action. Among the later, Natalizumab, a humanized IgG4 monoclonal antibody against α4β1 and α4β7 integrins, is safe and effective in inducing and maintaining remission in active CD patient’s refractory to anti-TNF. In spite of this, Natalizumab use has been limited because of an increased risk of progressive multifocal leukoencephalophaty which results from reactivation of the John Cunningham (JC) virus. However, the presence of antibodies against JC virus in serum can be used to reduce the risk for this complication. We report three patients with Crohn’s disease refractory to treatment with infliximab, who responded successfully to the use of Natalizumab.

Mesotelioma benigno como causa de dolor abdominal inespecífico en un paciente con Enfermedad de Crohn / Benign multicystic peritoneal mesothelioma in a patient with Crohn disease

Benign multicystic peritoneal mesothelioma is an uncommon lesion arising from the peritoneal mesothelium. It is asymptomatic or presents with unspecific symptoms. Imaging techniques may reveal it, however the final diagnosis can only be made by histopathology. Surgery is the only effective treatment considering its high recurrence rate. We report a 19 years old male with Crohn’s disease. Due to persistent abdominal pain, an abdominal magnetic resonance imaging was performed, showing a complex cystic mass in the lower abdomen. The patient underwent surgery and the lesion was completely resected. The pathological study reported a benign multicystic peritoneal mesothelioma.

Consenso chileno de prevención, diagnóstico y tratamiento de la diarrea asociada a Clostridium difficile / Chilean consensus of prevention, diagnosis and treatment of Clostridium difficile-associated diarrhea

Background: Clostridium dijfficile-associated diarrhea (CDAD) has become very important due to the increase in its incidence, severity, recurrence and the associated economic burden. Having a national consensus guideline is essential to improve its management. Objective: To build a multidisciplinary and evidence-based consensus in prevention, diagnosis and treatment of CDAD. Methods: We convened a panel of experts in the field of infectious diseases, gastroenterology, evidence-based medicine and consensus methodology. The panel conducted a structured review of published literature in CDAD evaluating evidence levels and recommendation degree according to the methodology proposed by the GRADE working-group. A modified three-round Delphi technique was used to reach a consensus among the experts. Results: A group of 16 experts was established, 12 of them answered 18 clinically relevant questions. The levels of agreement achieved by the panel of 16 experts were 79% in the first round and 100% in the second and third round. The main consensus recommendations in prevention are: restricting the use of proton-pump inhibitors, primary prophylaxis with probiotics in antibiotics users, education of health personnel, isolation for patients hospitalized with CDAD, and cleaning the rooms exposed to C. difficile with products based in chlorine or hydrogen peroxide. In the diagnosis: use of biology molecular-based techniques is preferred and if not available, glutamate dehydrogenase-based algorithms may be recommended. With regard to treatment: the use of oral metronidazole in mild-moderate CDAD and oral vancomycin in severe CDAD are recommended. Treat the first recurrence with the same antibiotics according to severity. In the case of second and subsequent recurrences consider prolonged therapy with vancomycin, rifaximin or fecal microbiota transplant. Conclusion: The first Chilean consensus on prevention, diagnosis and treatment of CDAD is presented, which is a major step in improving national standards in the management of this disease.

Introducción: La diarrea asociada a Clostridium difficile (DACD) ha adquirido gran relevancia debido al aumento en su incidencia, gravedad, capacidad de recurrencia y carga económica asociada. Contar con una guía de consenso local es fundamental para mejorar su manejo. Objetivo: Elaborar un consenso multidisciplinara y basado en la evidencia en la prevención, diagnóstico y tratamiento de la DACD. Métodos: Se convocó a un panel de expertos en el área de enfermedades infecciosas, gastroenterología, medicina basada en la evidencia y metodología de consenso. El panel realizó una revisión estructurada de la literatura científica publicada en DACD evaluando el nivel de la evidencia y recomendación utilizando el sistema GRADE. Una técnica de Delfi modificada de tres rondas fue utilizada para alcanzar un consenso entre los expertos. Resultados: Se estableció un grupo de 16 expertos, 12 de ellos respondieron 18 preguntas de relevancia clínica. Los niveles de acuerdo alcanzados por el panel de 16 expertos fueron de 79% en la primera ronda y 100% en la segunda y tercera ronda. Las principales recomendaciones en prevención son: restricción del uso de inhibidores de la bomba de protones, profilaxis primaria con probióticos en usuarios de antimicrobianos de corto plazo, educación del personal de salud, aislamiento de contacto en pacientes hospitalizados con DACD y aseo de las habitaciones expuestas a C. difficile con productos en base a cloro o peróxido de hidrógeno. En el diagnóstico se recomienda: el uso de técnicas basadas en biología molecular y como alternativa algoritmos en base a glutamato deshidrogenasa. Con respecto al tratamiento, se recomienda el uso de metronidazol oral en DACD leve-moderada y vancomicina oral en DACD grave. El tratamiento de la primera recurrencia es con los mismos antimicrobianos de acuerdo a la gravedad, considerando en la segunda recurrencia y posteriores terapia prolongada con vancomicina, rifaximina o trasplante de microbiota fecal. Conclusión: Se presenta el primer consenso chileno en prevención, diagnóstico y tratamiento de DACD, paso trascendental en mejorar los estándares locales en el manejo de esta enfermedad.

Desarrollo de neoplasia en pacientes con enfermedad inflamatoria intestinal / Development of malignant tumors in patients with inflammatory bowel disease

Background: The chronic inflammation of the intestinal mucosa, the extra-intestinal manifestations of the disease and the immunosuppressive treatment of inflammatory bowel disease may increase cancer risk. Aim: To report the demographic and clinical features of patients with IBD who developed a malignant tumor. Material and Methods: Retrospective analysis of an IBD patient registry of a private clinic, diagnosed between 1976 and 2014. Results: 437 subjects were included, aged 15-88 years (58% women). Seventy two percent of patients had ulcerative colitis. The median time of follow up was 6 years. Ten patients (2.3%) developed a malignant tumor. In four, the tumor could be related to IBD (two colorectal cancers, one cholangiocarcinoma and one chronic myeloid leukemia (CML)). Two of 45 patients treated with biological therapy developed a tumor (CML and hypernephroma). Three of 170 patients on immunosuppressive treatment developed tumors. Only one had a tumor possibly related with the use of azathioprine (non-melanoma skin cancer). In only two patients, the treatment was changed at the time of their cancer diagnosis, from immunosuppressive medications to mesalamine. Conclusions: Only a small proportion of these patients with IBD developed a malignant tumor. The treatment of IBD has to be determined by the severity of the disease and not by the fear of developing a neoplasia. Following recommendations is fundamental to decrease the possibility of developing this complication.

Enfermedad inflamatoria intestinal en pacientes mayores de 60 años: ¿es una enfermedad diferente? / Differences by age in clinical features of inflammatory bowel disease

Background: Approximately, 15% of patients with Inflammatory Bowel Disease (IBD) are diagnosed at 60 years of age or more. Aim: To characterize and compare clinical variables between patients with IBD aged 60 years or more and their younger counterparts. Material and Methods: Retrospective study based on a registry of IBD patients diagnosed between the years 1976 and 2014. Results: Four hundred and nine IBD patients were included. Among them, 294 had Ulcerative Colitis (UC), 104 had Crohn s Disease (CD) and eleven had an indeterminate IBD. Forty-six patients (11.2%) were older than 60 years and 16 (3.9%) had been diagnosed after this age. When comparing patients by age, those aged 60 years or more had a higher frequency of CD and indeterminate IBD (p < 0.01) and a lower ileocolic location in CD (p = 0.02). Both groups were similar in terms of hospitalization due to IBD flare, surgery, use of steroids, immunosuppressive or biological therapies and drug-related adverse events. When analyzing age at diagnosis of IBD, patients diagnosed at ages of 60 years or more had a lower frequency of UC (p < 0.01), a higher frequency of exclusive colonic involvement (p = 0.01), and lower use of mesalamine (p < 0.01). There were no differences in drug-related adverse events, hospitalizations due to IBD flares and surgery according to age at diagnosis. Conclusions: In this population, clinical features of IBD in older patients were similar to those in younger patients.

Eventos adversos en la terapia farmacológica de la enfermedad inflamatoria intestinal / Adverse events associated with the treatment of inflammatory bowel disease

Background: The purpose of inflammatory bowel disease (IBD) treatment is to achieve resolution of symptoms and remission of disease with a minimum of adverse events (AE). Aim: To report AE of different prescriptions used for the treatment of IBD. Material and Methods: Analysis of a registry of patients with IBD held at a private clinic from 1976 to 2013. All used medications, the occurrence and severity of AE were recorded. Results: The records of 346 patients aged 16 to 86 years, 74% with ulcerative colitis, were analyzed. The most commonly type of medications prescribed were 5-aminosalicylates (5-ASAs) in 329 patients (92%), followed by adrenal steroids in 218 (61%). Forty nine AE were recorded in the same number of patents (14%). These were more common in patients with Crohn disease (n = 19, 21%). An univariate analysis, demonstrated that extra-intestinal manifestations, hospitalizations secondary to IBD crisis, requirement of surgery and treatment with steroids, immunosuppressants or biologic agents were significantly associated with the presence of AE. AEs were more common with immunosuppressants, followed by 5-ASAs and steroids. Discontinuation of therapy was required in 79, 100 and 43% of patients taking these medications, respectively. Twenty percent of AEs were severe. Leukopenia and pancytopenia along with alopecia were the most common AEs attributable to azathioprine. Conclusions: The occurrence of AEs in patients with IBD is uncommon. Even inmunosuppressants or biologic agents have a low rate of AE and most of them mild.

Enfermedad inflamatoria intestinal a partir de una experiencia local / Inflammatory bowel disease. Experience in 316 patients

Background: The incidence and prevalence of Inflammatory Bowel Disease (IBD) has increased. Aim: To determine demographic and clinical characteristics of patients with IBD in a Chilean private hospital. Patients and Methods: Review of a prospective registry of patients with IBD, started on 2012. It includes clinical, imaging, endoscopical and pathological information of patients. Results: Data of 316 patients with IBD, aged 16 to 86 years (56% females), were analyzed. Ulcerative Colitis (UC), Crohn´s and non-classifiable IBD were diagnosed in 230, 77 and 9 patients, respectively. The disease was diagnosed in 82% of patients in the period between 2002 and 2012. There was a peak in the diagnosis of both UC and CD between 20 and 39 years of age, without gender differences. The disease switched from UC to CD in six patients. In four, there was a change in disease behavior. Thirty eight patients were treated with biological therapy. The median lapse between the diagnosis and the use of biological therapy was 1 year in patients diagnosed after 2007, compared with 5.5 years among those patients diagnosed before 2007 (p = 0.001). There was a trend towards a higher requirement of surgery until 2006. Subsequently there was a stabilization of the requirement, concomitant with the incorporation of biological therapy. Conclusions: An adequate registry of IBD patients is necessary to improve demographic and clinical characteristics. A national registry is needed to assess the epidemiological changes of IBD in Chile.

Rol de infliximab en enfermedad inflamatoria intestinal: Experiencia local / Treatment of inflammatory bowel disease with infliximab: Experience in 25 patients

Background: Biological therapy has an important role in the treatment of Inflammatory Bowel Disease (IBD). However, the use of these drugs is resisted due to fears about their side effects. Aim: To report the experience with the use of Infliximab in patients with IBD. Material and Methods: Descriptive study of a historical cohort of patients with IBD treated between 2007 and 2012 with Infliximab. A favorable clinical response was considered when general, intestinal and extra-intestinal symptoms subsided after the second or third dose of the drug. Endoscopic or imaging response was evaluated between three and six months of treatment. Results: Twenty five patients aged 18 to 61 years (12 women) were included. Sixteen had Cohn’s Disease and 9 had Ulcerative Colitis. Treatment was indicated due to refractory disease in 13 patients, perianal involvement in nine, stenosis in two and pyoderma gangrenosum in one. Ten patients initiated Infliximab within less than two years of diagnosis. Twenty-two patients received combined treatment with immunosuppressive medications and the other three patients were treated exclusively with Infliximab. A favorable clinical response was observed in 88% after the second dose and 64% had endoscopic or imaging remission after 3-6 months. Twelve patients discontinued Infliximab, due to bad response to treatment in three patients, economic cost in three patients, and patient/doctor decision in six. Only three patients had side effects (herpes zoster and sinusitis). None of these motivated the discontinuation of treatment. Conclusions: In this cohort of patients with IBD, the use of Infliximab was associated with endoscopic or imaging remission in 64% of cases after 3-6 months of treatment with no major side effects.

Programa de detección de neoplasias colorrectales en población mayor de 50 años / A screening program for colorectal cancer in Chilean subjects aged fifty years or more

Background: Mortality from colorectal cancer (CCR) in Chile has nearly doubled over the past 15 years. International studies have shown that CCR screening programs based on fecal occult blood test (FOBT) reduce CCR mortality. Aim: To analyze the results from a CCR screening model in people over 50 years. Material and Methods: Between 2007 and 2009, a prospective multicenter study was performed in seven major Chilean cities. FOBT using an immunological method, was measured in asymptomatic subjects aged 50 years or more, without risk factors. In patients with a positive FOBT, with symptoms or with family risk factors, a colonoscopy was indicated. Results: A total of 6348 subjects were assessed, FOBT was performed in 4938 of them, with a compliance of 77%. The result was positive in 9.6%. A total of 2359 colonoscopies were ordered, with an overall compliance of 50.1%. Of the 1184 colonoscopies performed, adenomas and high risk adenomas were found in 304 (26%) and 75 (6%) patients, respectively. Thirteen patients were diagnosed with stage I and IICCR. Three of these lesions were excised endoscopically and 10 surgically. The detection rate of polyps, high risk adenomas and cancer was 75, 12 and 2 per 1000 screened individuals, respectively. Conclusions: This program allowed the early detection of an important number of high risk colon lesions, and all patients with CCR were diagnosed at early stages.