Lauran Vogelaar

The impact of biologics on health-related quality of life in patients with inflammatory bowel disease.

Background: Inflammatory bowel disease (IBD) is characterized by a chronic relapsing inflammation of the gastrointestinal tract. Adult IBD patients suffer from a disabling disease which greatly affects health-related quality of life (HRQoL). A worse HRQoL in these patients may result in a defensive and ineffective use of medical attention and thus higher medical costs. Because of its chronic nature, IBD may also cause psychological problems in many patients which may also influence HRQoL and care-seeking behavior. An important factor reducing HRQoL is disease activity. Induction of remission and long-term remission are important goals for improving HRQoL. Furthermore, remission is associated with a decreased need for hospitalization and surgery and increased employment, which in turn improve HRQoL. Treatment strategies available for many years are corticosteroids, 5-aminosalicylates and immunnosuppressants, but these treatments did not show significant long-term improvement on HRQoL. The biologics, which induce rapid and sustained remission, may improve HRQoL. Objective: To review and evaluate the current literature on the effect of biologics on HRQoL of IBD patients. Methods: We performed a MEDLINE search and reviewed the effect of different biologics on HRQoL. The following subjects and synonyms of these terms were used: inflammatory bowel disease, Crohn’s disease, ulcerative colitis, quality of life, health-related quality of life, fatigue, different anti-TNF medication, and biologicals/biologics (MESH). Studies included were limited to English-language, adult population, full-text, randomized, double-blind, placebo-controlled in which HRQoL was measured. Results: Out of 202 identified articles, 8 randomized controlled trials (RCT) met the inclusion criteria. Two RCTs on infliximab showed significant improvement of HRQoL compared to placebo which was sustained over the long term. One RCT on adalimumab showed a significant and sustained improvement of HRQoL compared to placebo. This study showed also significant decrease of fatigue in the adalimumab-treated patients. Three RCTs on certolizumab showed a significant improvement of HRQoL in the intervention group compared to placebo. Two RCTs of natalizumab treatment were found. One study showed significant and sustained improvement compared to placebo, and also scores of HRQoL comparable to that in the general population, but in the other no significant results were found. Conclusion: The biologics infliximab, adalimumab, certolizumab, and natalizumab demonstrated significant improvement of HRQoL of IBD patients compared with placebo. However, we found differences in improvement of HRQoL between the different biologics.

Fatigue management in patients with IBD: a randomised controlled trial

Objective To assess the effectiveness of solution-focused therapy (SFT) on fatigue and quality of life (QoL) in patients with fatigued inflammatory bowel disease (IBD). Design Randomised controlled trial in two Dutch hospitals. Patients with IBD with quiescent IBD and with a Checklist Individual Strength—Fatigue (CIS—fatigue) score of ≥35 were enrolled. Patients were 1:1 randomised to receive SFT or care as usual (CAU) for 3 months. Patients were followed for a further 6 months after the SFT. Primary endpoint was defined as changes in fatigue and QoL during follow-up. Secondary endpoints included change in anxiety and depression, medication use, side effects to medication, disease activity, laboratory parameters (C-reactive protein, leucocytes and haemoglobin) and sleep quality. Results Ninety-eight patients were included, of whom 63% were women, mean age was 40.1 years. After the SFT course, 17 (39%) patients in the SFT group had a CIS-fatigue score below 35 compared with eight (18%) of patients in the CAU group (p=0.03). The SFT group also showed a greater reduction in fatigue across the first 6 months compared with the CAU group (CIS-fatigue: p=<0.001 and CIS-total: p=0.001). SFT was associated with a significant higher mean IBD questionnaire change at 3 months (p=0.020). At 9 months, no significant differences between the two groups were observed. Conclusions SFT has a significant beneficial effect on the severity of fatigue and QoL in patients with quiescent IBD. However, this effect diminished during follow-up.

Solution focused therapy: A promising new tool in the management of fatigue in Crohn's disease patients: Psychological interventions for the management of fatigue in Crohn's disease

BACKGROUND Crohns disease patients have a decreased Quality of Life (QoL) which is in part due to extreme fatigue. In a pilot study we prospectively assessed the feasibility and effect of psychological interventions in the management of fatigue. METHODS Patients with quiescent Crohns disease and a high fatigue score according to the Checklist Individual Strength were randomized to Problem Solving Therapy (PST), Solution Focused Therapy (SFT) or to a control group (treatment as usual, TAU). Patients completed the Inflammatory Bowel Disease Questionnaire, the EuroQol-5D, and the Trimbos questionnaire for Costs. RESULTS Twenty-nine patients were included (12 TAU, 9 PST, 8 SFT), of these 72% were female, mean age was 31 years (range 20-50). The SFT group improved on the fatigue scale in 85.7% of the patients, in the PST group 60% showed improved fatigue scores and in the TAU group 45.5%. Although not significant, in both intervention groups the QoL increased. Medical costs lowered in 57.1% of the patients in the SFT group, in the TAU 45.5% and the in PST group 20%. The drop out rate was highest in the PST group (44%; SFT 12.5%; TAU 8.3%). CONCLUSIONS PST and SFT both positively affect the fatigue and QoL scores in patients with Crohns disease. SFT seems most feasible with fewer dropouts and is therefore a promising new tool in the management of fatigue in Crohns disease patients.

Suppression of p21Rac Signaling and Increased Innate Immunity Mediate Remission in Crohn’s Disease

Overactivation of p21Rac1 is a rate-limiting step for innate immune function in Crohn’s disease and prevents remission. Crohn’s Disease on the Rac Crohn’s disease is a type of inflammatory bowel disease (IBD), wherein the body’s immune system attacks the gastrointestinal tract. In patients with Crohn’s, there are areas of apparently healthy tissue right next to damaged intestine, but it remains unclear what differentiates healthy and inflamed regions. Now, Parikh et al. examine signal transduction differences in healthy and inflamed tissue to find targets that may be protective in Crohn’s. The authors performed a comparative kinome profile in healthy controls as well as healthy and inflamed tissues from Crohn’s patients. They found that p21Rac1 GTPase signaling is suppressed in noninflamed tissue. What’s more, blocking p21Rac1 correlated with clinical improvement of IBD, potentially by boosting innate immune responses. These data suggest that blocking p21Rac1 may be protective for IBD. In inflammatory bowel disease (IBD), large areas of apparently healthy mucosa lie adjacent to ulcerated intestine. Knowledge of the mechanisms that maintain remission in an otherwise inflamed intestine could provide important clues to the pathogenesis of this disease and provide rationale for clinical treatment strategies. We used kinome profiling to generate comprehensive descriptions of signal transduction pathways in inflamed and noninflamed colonic mucosa in a cohort of IBD patients, and compared the results to non-IBD controls. We observed that p21Rac1 guanosine triphosphatase (GTPase) signaling was strongly suppressed in noninflamed colonic mucosa in IBD. This suppression was due to both reduced guanine nucleotide exchange factor activity and increased intrinsic GTPase activity. Pharmacological p21Rac1 inhibition correlated with clinical improvement in IBD, and mechanistically unrelated pharmacological p21Rac1 inhibitors increased innate immune functions such as phagocytosis, bacterial killing, and interleukin-8 production in healthy controls and patients. Thus, suppression of p21Rac activity assists innate immunity in bactericidal activity and may induce remission in IBD.

Determinants of fatigue in Crohn's disease patients

Objective Crohn’s disease (CD) is often associated with severe fatigue. Little is known about patients who may be at the highest risk for fatigue. Therefore, we assessed the disease phenotype and factors related to fatigue in the presence of CD in two different populations. Methods Patients presenting at the clinic of a referral hospital and a general hospital were included in the study. They completed questionnaires including the Checklist Individual Strength, the Hospital Anxiety and Depression Scale, a questionnaire on disease activity, and one on medication use. The Montreal classification and sociodemographics were obtained from medical records. Hemoglobin and C-reactive protein levels were measured at baseline. Results In total, 425 patients were included (276 women, mean age: 42 years). Compared with patients from the general hospital, patients at the referral hospital had worse disease activity, worse disease behavior, more bowel resections, and a higher percentage of side-effects to medication and use of anti-tumor necrosis factor (TNF). The prevalence of fatigue was significantly higher in the referral patients compared with the general patients (65.7 vs. 52.5%, respectively; P=0.01). Similar results were found in patients in remission (53.3 vs. 40.5%; P=0.061). Factors related to fatigue were the use of anti-TNF at baseline, side-effects to 5-aminosalicylic acid, disease activity, female sex, and shorter disease duration. Furthermore, we found improvement in fatigue and a trend toward lower disease activity after 1 year of anti-TNF use. Conclusion A high percentage of CD patients suffer from fatigue. As a more aggressive phenotype seems to be associated with more severe fatigue and patients in remission still suffer from fatigue, a multidimensional approach for fatigue is warranted in these patients.

A short course of corticosteroids prior to surveillance colonoscopy to decrease mucosal inflammation in inflammatory bowel disease patients: Results from a randomized controlled trial

BACKGROUND Inflammation is a known pitfall of surveillance colonoscopy for inflammatory bowel disease (IBD) as it is difficult to differentiate between inflammation and true dysplasia. This randomized controlled trial assessed the effectiveness of a low dose of corticosteroids prior to surveillance colonoscopy to decrease mucosal inflammation. METHODS IBD-patients scheduled for surveillance colonoscopy between July 2008-January 2010 were eligible to participate. Patients were randomized to either two weeks daily 20mg prednisone and calcium plus vitamin D prior to surveillance colonoscopy or no treatment. All biopsies were reviewed by an expert gastrointestinal pathologist who was blinded for medication-use. Statistics were performed using chi-square tests, non-parametric tests and binary logistic regression. RESULTS Sixty patients (M/F 30/30, UC/CD 31/29) participated: 31 (52%) in the treatment arm and 29 (48%) in the control group. In the treatment arm, 247 biopsies were scored against 262 in the control group. In the treatment arm 27 out of 247 biopsies (10.9%) had a score >1 on the Geboes scale, against 50 out of 262 biopsies (19.1%) in the control group, p=0.013. In total, 58% of the treatment arm against 66% of the control group had endoscopic or histological mucosal inflammation (p=0.6). There was a trend for patients in the treatment arm to have less severe inflammation compared with the control group, however this was not significant (p=0.12). CONCLUSIONS In our cohort, a short course of corticosteroids decreases the overall histological disease activity in individual biopsies without major side-effects. Moreover, there is a trend for corticosteroids to decrease the maximum severity of both endoscopic and histological disease activity per patient.

Physical fitness and physical activity in fatigued and non-fatigued inflammatory bowel disease patients

Abstract Objective. To assess physical fitness and physical activity in inflammatory bowel disease (IBD) patients and whether fatigue is associated with impaired physical fitness and impaired physical activity. Materials and methods. Ten patients with quiescent IBD and fatigue (fatigue group [FG]) based on the Checklist Individual Strength-Fatigue score of ≥35 were matched for age (±5 years) and sex with a non-fatigue group (NFG) with IBD. Physical fitness was measured with a cyclo-ergometric-based maximal exercise test, a submaximal 6-min walk test, and a dynamometer test to quantify the isokinetic muscle strength of the knee extensors and flexors. Level of physical activity was measured with an accelerometer-based activity monitor. Results. The patients in both groups did not differ in regard to medication use, clinical characteristics, and body composition. However, medium-to-large effect sizes for impaired physical fitness (both cardiorespiratory fitness and muscle strength) and physical activity were seen between the patients in the FG and the NFG. Especially, intensity of physical activity was significantly lower in the FG patients compared with the NFG patients (effect size: 1.02; p = 0.037). Similar results were seen when outcomes of the FG and NFG were compared with reference values of the normal population. Conclusion. Fatigued IBD patients show an impaired physical fitness and physical activity compared with non-fatigued IBD patients. This gives directions for a physical component in fatigue in IBD patients. Therefore, these new insights into fatigue indicate that these patients might benefit from an exercise program to improve physical fitness and physical activity.

Sex-dimorphic adverse drug reactions to immune suppressive agents in inflammatory bowel disease

AIM To analyze sex differences in adverse drug reactions (ADR) to the immune suppressive medication in inflammatory bowel disease (IBD) patients. METHODS All IBD patients attending the IBD outpatient clinic of a referral hospital were identified through the electronic diagnosis registration system. The electronic medical records of IBD patients were reviewed and the files of those patients who have used immune suppressive therapy for IBD, i.e., thiopurines, methotrexate, cyclosporine, tacrolimus and anti-tumor necrosis factor agents (anti-TNF); infliximab (IFX), adalimumab (ADA) and/or certolizumab, were further analyzed. The reported ADR to immune suppressive drugs were noted. The general definition of ADR used in clinical practice comprised the occurrence of the ADR in the temporal relationship with its disappearance upon discontinuation of the medication. Patients for whom the required information on drug use and ADR was not available in the electronic medical record and patients with only one registered contact and no further follow-up at the outpatient clinic were excluded. The difference in the incidence and type of ADR between male and female IBD patients were analyzed statistically by χ(2) test. RESULTS In total, 1009 IBD patients were identified in the electronic diagnosis registration system. Out of these 1009 patients, 843 patients were eligible for further analysis. There were 386 males (46%), mean age 42 years (range: 16-87 years) with a mean duration of the disease of 14 years (range: 0-54 years); 578 patients with Crohns disease, 244 with ulcerative colitis and 21 with unclassified colitis. Seventy percent (586 pts) of patients used any kind of immune suppressive agents at a certain point of the disease course, the majority of the patients (546 pts, 65%) used thiopurines, 176 pts (21%) methotrexate, 46 pts (5%) cyclosporine and one patient tacrolimus. One third (240 pts, 28%) of patients were treated with anti-TNF, the majority of patients (227 pts, 27%) used IFX, 99 (12%) used ADA and five patients certolizumab. There were no differences between male and female patients in the use of immune suppressive agents. With regards to ADR, no differences between males and females were observed in the incidence of ADR to thiopurines, methotrexate and cyclosporine. Among 77 pts who developed ADR to one or more anti-TNF agents, significantly more females (54 pts, 39% of all anti-TNF treated women) than males (23 pts, 23% of all anti-TNF treated men) experienced ADR to an anti-TNF agent [P = 0.011; odds ratio (OR) 2.2, 95%CI 1.2-3.8]. The most frequent ADR to both anti-TNF agents, IFX and ADA, were allergic reactions (15% of all IFX users and 7% of all patients treated with ADA) and for both agents a significantly higher rate of allergic reactions in females compared with males was observed. As a result of ADR, 36 patients (15% of all patients using anti-TNF) stopped the treatment, with significantly higher stopping rate among females (27 females, 19% vs 9 males, 9%, P = 0.024). CONCLUSION Treatment with anti-TNF antibodies is accompanied by sexual dimorphic profile of ADR with female patients being more at risk for allergic reactions and subsequent discontinuation of the treatment.

Analysis of SHIP1 expression and activity in Crohn’s disease patients

Background SH2 domain containing inositol-5-phosphatase (SHIP1) is an important modulator of innate and adaptive immunity. In mice, loss of SHIP1 provokes severe ileitis resembling Crohn’s disease (CD), as a result of deregulated immune responses, altered cytokine production and intestinal fibrosis. Recently, SHIP1 activity was shown to be correlated to the presence of a CD-associated single nucleotide polymorphism in ATG16L1. Here, we studied SHIP1 activity and expression in an adult cohort of CD patients. Methods SHIP1 activity, protein and mRNA expression in peripheral blood mononuclear cells from CD patients in clinical remission were determined by Malachite green assay, Western blotting and qRT-PCR respectively. Genomic DNA was genotyped for ATG16L1 rs2241880. Results SHIP1 protein levels are profoundly diminished in a subset of patients; however, SHIP1 activity and expression are not correlated to ATG16L1 SNP status in this adult cohort. Conclusions Aberrant SHIP1 activity can contribute to disease in a subset of adult CD patients, and warrants further investigation.

Practical Guideline for Fatigue Management in Inflammatory Bowel Disease.

During active inflammatory bowel disease (IBD) fatigue is a common symptom, which seems related to active gut inflammation. However, even in remission many patients suffer from fatigue that negatively affects quality of life and work productivity. Currently, robust knowledge on the pathogenesis and treatment of IBD-related fatigue is lacking. In order to alleviate the burden of IBD-related fatigue, a systematic approach is mandatory. We propose a fatigue attention cycle to enhance identification, evaluation and management of fatigued IBD patients. The benefits of the cycle are twofold. Firstly, it allows the systematic and uniform identification of patients with severe fatigue, in turn allowing tailored non-pharmacological and pharmacological interventions. Secondly, uniform identification of such patients creates a well-defined patient base to investigate the underlying pathogenesis of fatigue, resulting in a greater understanding of this debilitating phenomenon and possibly resulting in the discovery of predictive factors and new treatment interventions.