Histologic healing and factors associated with complete remission following conventional treatment in ulcerative colitis.

Background: Endoscopic and histological activity scores in ulcerative colitis (UC) are associated with clinical outcomes and have become important targets of clinical trials. However, these endpoints have been scarcely investigated in patients receiving only conventional treatment. Objective: We aimed to assess the deep and complete remission rates after 3 months of conventional treatment in patients with newly diagnosed UC with moderate to severe endoscopic activity. We also aimed to investigate whether selected clinical and biochemical variables at baseline were associated with complete remission status after 3 months. Design: This was a prospective cohort study. Methods: Newly diagnosed patients with active UC commencing 5-aminosalicylate, corticosteroid, and/or azathioprine treatment were consecutively included. Clinical, biochemical, endoscopic, and histological data were collected at baseline and after 3 months. Rates of clinical remission (Partial Mayo Score ⩽ 2), mucosal healing (Mayo Endoscopic Score ⩽ 1), and histologic healing (Nancy Index ⩽ 1) were determined. Deep remission was assessed as clinical remission plus mucosal healing and complete remission as deep remission plus histologic healing. Predictors of complete remission were identified by logistic regression. Results: A total of 180 patients were included in the study. Deep remission and complete remission occurred in 62.8% and 42.2% of patients, respectively. Thus, of patients in deep remission one-third had persistent histologic activity. Histologic activity in mucosally healed patients was associated with higher symptom scores and faecal calprotectin levels. Of baseline variables, less endoscopic distribution and disease activity showed strongest association with achieving complete remission, and limited distribution in combination with moderate activity gave highest odds for complete remission (odds ratio: 4.1, 95% confidence interval: 7.69-2.18). Conclusion: In patients with mucosal healing, persistent histologic activity was a common finding and was associated with increased disease activity. Pancolitis and severe inflammatory activity at baseline were associated with lower complete remission rates.

The influence of disease activity on fatigue in patients with ulcerative colitis - a longitudinal study.

OBJECTIVE: The relationship between the disease activity of ulcerative colitis and fatigue is unclear. We investigated how reaching deep remission versus remaining in active disease influenced the severity of fatigue. MATERIALS AND METHODS: We included 149 consecutive patients in a longitudinal study. Patients were re-examined after 3 months of conventional treatment and dichotomized into A: Active disease or B: Deep remission. The Partial Mayo Score (PMS) was recorded in all patients. Fatigue was rated using the fatigue visual analog scale (fVAS), Fatigue Severity Scale (FSS), and Short Form-36 Vitality Subscale (SF-36vs). A control group of 22 age and sex-matched healthy subjects were included as controls for patients reaching deep remission. RESULTS: After 3 months there were no significant differences in fVAS, FSS and SF-36vs scores in patients with active disease compared to patients reaching deep remission, when adjusting for baseline fatigue scores. Patients in remission based on MES-UC scores had no significant reduction in fatigue scores, whereas patients in remission based on PMS had all three fatigue scores reduced. However, patients reaching deep remission still had higher fVAS and lower SF-36vs scores compared to healthy control subjects. CONCLUSIONS: After 3 months of conventional treatment there were no differences in fatigue severity in patients reaching deep remission compared with patients still having active disease. Fatigue was more pronounced in patients in deep remission than in healthy subjects, and was associated with subjective and not objective measures of disease activity. This indicates that other potent factors than inflammation influence fatigue in UC.

Determination of lower cut-off levels of adalimumab associated with biochemical remission in Crohn's disease.

BACKGROUND AND AIM: Adalimumab is administered and dosed using a standardized treatment regimen. Although therapeutic drug monitoring (TDM) may help optimize treatment efficacy, the lower cut-off concentration of adalimumab needed to retain disease remission has not been established. This cross-sectional study of patients with Crohn's disease on stable medication aimed to determine a lower therapeutic drug concentration threshold of adalimumab associated with biochemical disease remission. METHODS: C-reactive protein (CRP) and fecal calprotectin were used as established markers and albumin as an explorative marker of disease activity. Time since introduction, treatment interval, drug dosage, serum drug concentration and antidrug antibodies, disease duration, age, and sex were recorded. RESULTS: The study included 101 patients who were divided into "active disease" and "remission" groups for inflammatory markers based on cut-off levels of 5 mg/L for CRP and 50 mg/kg for fecal calprotectin. Cut-off levels for albumin of 36.5 and 41.5 g/L were also added as further indicatives of remission. Receiver operating characteristic analysis found optimal thresholds for adalimumab associated with remission at 6.8-7.0 mg/L for the combination of CRP and fecal calprotectin and when combining CRP, fecal calprotectin, and albumin. CONCLUSIONS: In patients with Crohn's disease, serum adalimumab of at least 6.8 mg/L was associated with biochemical disease remission based on CRP and fecal calprotectin, supporting the use of TDM to ensure disease control. Albumin should be further tested in this setting.

A case of Ménétriere´s disease treated with the monoclonal antibody cetuximab.

Ménétriere´s disease is a rare disorder of the body and fundus of the stomach, characterized by a massive proliferation of the foveolar cells and subsequent excess mucous secretion. This results in hypoproteinemia due to loss of serum proteins across the gastric mucosa. The cause of Ménétriere´s disease is unknown, and due to the irreversible and premalignant character of the disorder, the patients affected have been subdued to gastrectomy as the only curable treatment. Epidermial growth factor (EGF) has been implicated in the pathogenesis, a finding that makes the disorder receptive to monoclonal antibody treatment against the EGF receptor. In this case report, we present a 41-year-old woman referred to our emergency department due to dizziness, nausea, and vomiting. A thorough medical investigation, combining clinical history, laboratory investigations, an upper endoscopy with full-thickness snare biopsies, and a CT scan confirmed Ménétriere´s disease, and she was successfully treated with the monoclonal antibody cetuximab.

Subtherapeutic concentrations of infliximab and adalimumab are associated with increased disease activity in Crohn's disease.

BACKGROUND: Low anti-tumor necrosis factor α (TNFα) serum concentrations may result in lack of treatment response in patients with inflammatory bowel disease. We determined the anti-TNFα drug concentrations in patients with inflammatory bowel disease and investigated whether or not subtherapeutic drug concentrations were associated with increased levels of disease activity. METHODS: In a single-center cross-sectional study, we included patients with ulcerative colitis or Crohn's disease who were receiving infliximab or adalimumab maintenance therapy. Demographic data, disease activity symptom scores (Partial Mayo Score, Harvey Bradshaw Index), inflammatory markers [C-reactive protein (CRP), fecal calprotectin], antidrug antibodies and serum drug concentrations were recorded. Therapeutic drug concentrations were defined as 3-8 mg/liter for infliximab and 5-12 mg/liter for adalimumab. RESULTS: Of 210 patients included, 137 (65.2%) had Crohn's disease. In the adalimumab group, subtherapeutic drug concentrations were measured in 16.7% of patients with ulcerative colitis and in 27.7% of patients with Crohn's disease. In the infliximab group, subtherapeutic drug concentrations were found in 23% (ulcerative colitis) and 30.3% (Crohn's disease) of patients. In Crohn's disease, subtherapeutic adalimumab concentrations were associated with higher fecal calprotectin and CRP concentrations compared with therapeutic concentrations. Subtherapeutic infliximab concentrations in patients with Crohn's disease were also associated with higher CRP concentrations compared with therapeutic concentrations. CONCLUSIONS: The prevalence of subtherapeutic drug levels ranged from 17% to 30%. In patients with Crohn's disease, subtherapeutic serum drug concentrations were associated with significantly higher disease activity with both anti-TNFα agents. These findings were not observed in patients with ulcerative colitis. Clinicaltrials.gov identifier [NCT02134054].

Conventional treatment regimens for ulcerative colitis alleviate fatigue - an observational cohort study.

OBJECTIVE: The aim of the study was to investigate the course of fatigue in a conventional inflammatory bowel disease treatment setting. MATERIALS AND METHODS: Eighty-two patients with newly diagnosed ulcerative colitis were included in an observational cohort study and received conventional non-biological drug treatment for 3 months. Colonoscopy was performed at diagnosis and after 3 months, disease activity was assessed by Mayo score and measurements of serum C-reactive protein (CRP) and fecal calprotectin levels. Fatigue was evaluated using the fatigue visual analog scale (fVAS). Mood was assessed with the hospital anxiety and depression scale (HADS). Associations between fVAS scores and time; age; CRP, fecal calprotectin, hemoglobin, and ferritin levels; and Mayo scores, Mayo endoscopic scores, and HADS depression subscale (HADS-D) scores were explored. RESULTS: Median fVAS scores decreased, as did Mayo scores and CRP and fecal calprotectin concentrations. HADS-D scores remained unchanged, whereas hemoglobin levels increased after 3 months. Increased fVAS scores were associated with higher ferritin, Mayo and HADS-D scores. There were no associations between fVAS scores and CRP, fecal calprotectin, or Mayo endoscopic scores. Colonic disease distribution did not influence fatigue significantly. CONCLUSIONS: Disease activity and fatigue improved after 3 months of conventional ulcerative colitis treatment. Over time, more severe fatigue was associated with more ulcerative colitis symptoms, but not with objective disease activity markers or colonic disease distribution. A clinical setting of standard treatment regimens and medical attention may alleviate fatigue in IBD patients.

Fatigue in Newly Diagnosed Inflammatory Bowel Disease.

BACKGROUND AND AIMS: The present study investigated the prevalence and severity of fatigue in patients with newly diagnosed and untreated ulcerative colitis (UC) and Crohn's disease (CD) and examined relevant disease variables that may influence the severity of fatigue. METHODS: Eighty-one patients with inflammatory bowel disease (IBD) (60 with UC and 21 with CD) were assessed for fatigue using two fatigue instruments: the Fatigue Severity Scale (FSS) and a fatigue visual analogue scale (fVAS). Cut-off for fatigue was defined as ≥4 for FSS and ≥50 for fVAS. Results were compared with fatigue scores from age-and gender-matched healthy individuals. Disease activity was assessed by symptom scores using the Mayo score in UC patients and the Harvey-Bradshaw index for CD patients, as well as C-reactive protein (CRP) and faecal calprotectin. RESULTS: The prevalence of fatigue based on FSS and fVAS was 47 and 42%, respectively, in UC and 62 and 48% in CD. In multivariate regression models, disease activity markers were not associated with fatigue, while a significant relationship was found with age and depression for both fatigue measures. CONCLUSIONS: Close to 50% of patients with IBD reported fatigue at the time of diagnosis. In newly diagnosed patients with active disease, the severity of fatigue was not associated with measures of disease activity.

Molecular pathways and cellular metabolism in colorectal cancer.

Colorectal cancer (CRC) is, for sporadic forms, most strongly related to lifestyle factors. The epidemic of obesity and physical inactivity has great impact on disease patterns. Likewise, an altered metabolism has consequences at the cellular and molecular level with implications for cancer initiation and growth. Understanding the genetic hallmarks of cancers has improved over the years and now also includes cancer metabolic reprogramming. The initiation of cancer through genetic instability, including chromosomal instability, microsatellite instability and epigenetic silencing through the CpG island methylator phenotype follows pathways with distinct clinical, pathological, and genetic characteristics. These can potentially be used for molecular classification and comprehensive tumor profiling for improved diagnostics, prognosis and treatment in CRC. For one, epidermal growth factor receptor-directed treatment now considerably prolongs survival in metastatic disease, but defining the true responders from non-responders has emerged as complex. Further, the use of both non-steroidal anti-inflammatory drugs including cyclooxygenase-2 inhibitors is associated with a decreased incidence of adenoma and reduced mortality rate of CRC. This review gives a brief yet updated overview of the current understanding of CRC as a genetic and molecular disease with potential for clinical pathways of prevention, improved prediction and better prognosis in the future.