Direct health care costs of managing perianal Crohn's Disease in a population based cohort.

BACKGROUND: Crohn's disease is a chronic condition that places a high health care cost burden. Perianal Crohn's disease (pCD) is a difficult phenotype to treat due to poorer response to medical and surgical therapies. No study has assessed if this translates to higher healthcare costs. The aim is to assess the cost of treating pCD and compare to the cost of non-perianal Crohn's disease (CD). METHODS: This is a retrospective case-control cohort study in a population-based setting. The direct healthcare costs for patients with pCD were calculated over 12 months. Data was compared to the control group of non-perianal CD patients on biologic treatment, with the use of the Mann-Whitney rank test to assess significance. RESULTS: 187 Crohn's patients were included (39 pCD, 148 CD). Per patient, annual cost was €17,779.19 and €17,576.86 respectively (p = .9391). Medications were responsible for the majority of cost at 78% and 92% of total cost in pCD and CD, respectively (€13,886.04 in pCD, and €16,007.10 in CD), of which biologics were the main driver. Surgical costs were higher in the pCD group due to a higher cost of luminal surgery (€2633.88 in pCD vs €209.79 in CD, p = .0270). CONCLUSION: This is the first study to assess the cost of treating perianal Crohn's disease in a real-world population. Although the costs were similar overall to non-perianal Crohn's patients, the perianal cohort had higher surgical costs from luminal surgery. This demonstrates the potential to apply early intensive treatment to reduce future surgical cost.

Crohn's disease is a lifelong disease where high-cost drugs are required to achieve optimal outcomes. There is minimal data regarding the cost of managing perianal fistulising Crohn's disease and whether the clinical complexity of these patients translates to higher healthcare costs. Costs were similar between luminal Crohn's disease patients treated with a biologic and those with perianal disease, though the distribution of costs varied. Knowing this distribution will allow for more effective allocation of resources.

Review article: consensus statements on therapeutic drug monitoring of anti-tumour necrosis factor therapy in inflammatory bowel diseases.

BACKGROUND: Therapeutic drug monitoring (TDM) in inflammatory bowel disease (IBD) patients receiving anti-tumour necrosis factor (TNF) agents can help optimise outcomes. Consensus statements based on current evidence will help the development of treatment guidelines. AIM: To develop evidence-based consensus statements for TDM-guided anti-TNF therapy in IBD. METHODS: A committee of 25 Australian and international experts was assembled. The initial draft statements were produced following a systematic literature search. A modified Delphi technique was used with 3 iterations. Statements were modified according to anonymous voting and feedback at each iteration. Statements with 80% agreement without or with minor reservation were accepted. RESULTS: 22/24 statements met criteria for consensus. For anti-TNF agents, TDM should be performed upon treatment failure, following successful induction, when contemplating a drug holiday and periodically in clinical remission only when results would change management. To achieve clinical remission in luminal IBD, infliximab and adalimumab trough concentrations in the range of 3-8 and 5-12 µg/mL, respectively, were deemed appropriate. The range may differ for different disease phenotypes or treatment endpoints-such as fistulising disease or to achieve mucosal healing. In treatment failure, TDM may identify mechanisms to guide subsequent decision-making. In stable clinical response, TDM-guided dosing may avoid future relapse. Data indicate drug-tolerant anti-drug antibody assays do not offer an advantage over drug-sensitive assays. Further data are required prior to recommending TDM for non-anti-TNF biological agents. CONCLUSION: Consensus statements support the role of TDM in optimising anti-TNF agents to treat IBD, especially in situations of treatment failure.

Intra-patient variability in adalimumab drug levels within and between cycles in Crohn's disease.

BACKGROUND: Whether therapeutic drug monitoring for adalimumab needs to be performed at trough has not been defined. AIM: To determine intra-patient adalimumab drug-level variation and to identify modulating patient and disease factors. METHODS: In this prospective observational study, adult patients with Crohn's disease established on maintenance adalimumab had drug levels measured repeatedly according to pre-defined schedules (visit 1: day 4-6, visit 2: day 7-9, trough: day 13-14) across two consecutive fortnightly cycles. Disease activity was assessed using Harvey-Bradshaw Index, C-reactive protein and faecal calprotectin. For this analysis, trough levels ≥4.9 µg/mL were considered therapeutic. RESULTS: Nineteen patients underwent 111 evaluations. Mean intra-patient drug levels from paired visits between cycles did not differ (visit1 cycle1: 4.81, cycle2: 5.21 µg/mL, P = 0.24, visit2 cycle1: 4.86, cycle2: 4.82, P = 0.91 and trough cycle1: 3.95, cycle2: 3.95, P = 0.99), irrespective of disease activity. Drug levels were stable over the first 9 days (visit 1-2), but declined to trough by a mean 1.06 and 0.89 µg/mL between visit 1 or 2, respectively (P < 0.001). Models using nontemporal factors (smoking, syringe delivery device) and levels at earlier visits accounted for 66-80% of the variance in trough levels. On receiver-operating curve analysis, thresholds identified in the first 9 days that predicted a therapeutic trough level were similar to the trough threshold itself, with high sensitivity but modest specificity. CONCLUSION: While therapeutic drug monitoring should be performed at trough, a drug level ≥4.9 µg/mL obtained during the first 9 days predicts a therapeutic trough drug level with reasonable confidence.

Changing face of care for patients with moderate to severe inflammatory bowel disease: the role of specialist nurses in the governance of anti-TNF prescribing.

BACKGROUND: Anti-tumour necrosis factor (TNF) therapy is highly effective for inflammatory bowel disease (IBD), but expensive and potentially toxic. Meticulous supervision prior to and during anti-TNF treatment is required to screen and monitor patients for adverse clinical events. In addition, a systematic administrative process is necessary to comply with Australian Medicare requirements and ensure ongoing therapy is uninterrupted. IBD nurses are essential components of multidisciplinary IBD services, but their role in facilitating the safe and timely delivery of anti-TNF drugs is unacknowledged. AIM: The aim of the study was to calculate time spent by IBD nurses on anti-TNF drug governance and its indirect cost. METHODS: Time spent on activities related to anti-TNF governance was retrospectively assessed by questionnaire among IBD nurses employed at Melbourne hospitals. The capacity of IBD clinics at these hospitals was separately evaluated by surveying medical heads of clinics. RESULTS: On average, each Melbourne IBD service handled 150 existing and 40 new anti-TNF referrals in 2013. The average annual time spent by nurses supervising an existing and newly referred anti-TNF patient was 3.5 and 5.25 h respectively, or a minimum of two full working days per week. If clinicians undertook this activity during normal clinic time, the organisational opportunity cost was at least 58%. CONCLUSIONS: Anti-TNF therapy governance is an essential quality component of IBD care that is associated with a definite, indirect cost for every patient treated. IBD nurses are best positioned to undertake this role, but an activity-based funding model is urgently required to resource this element of their work.

Sleep and physical activity measured by accelerometry in Crohn's disease.

BACKGROUND: Sleep and physical activity are inherent to human living, yet appear affected by Crohn's disease (CD), resulting in fatigue and disability. AIM: To objectively assess sleep quality and physical activity and their associations using accelerometers, comparing CD vs. matched healthy control (HC) subjects. METHODS: Exactly 49 CD and 30 HC subjects completed surveys encompassing self-reported fatigue and sleep quality, pathology testing and wore an accelerometer for 7 days, measuring physical activity and sleep. In this cross-sectional observational study, per-group comparisons were performed and in CD, factors associated with reduced activity and/or sleep quality were assessed via multivariate analyses. RESULTS: Regarding physical activity, CD subjects overall performed less total accelerometer counts (median 1.3 × 10(6) vs. 2.0 × 10(6) ), were more sedentary (97.7% vs. 96.2%) and completed fewer bouts of moderate-vigorous intensity exercise (1.0 vs. 5.0, each P < 0.01 (Mann-Whitney) than HC over 7 days. Factors associated with poor physical activity in CD included elevated serum CRP (OR = 22.6), lower vitamin D3 (OR = 13.1) and longer disease duration (OR = 1.2 per year, each P < 0.05). Regarding sleep, the CD group had similar total sleep time (median 458 vs. 447 min, P = 0.56), but more awakenings post-sleep onset (22 vs. 11, P = 0.01). Factors associated with severe sleep dysfunction in CD included lower haemoglobin (OR = 6.7) concurrent anti-TNF (OR = 6.5, each P < 0.05) and opioid therapy (OR = 6.6, P = 0.09). CONCLUSION: Utilising objective measurement in a habitual context over 7 days, patients with Crohn's disease exhibited poorer sleep quality and less physical activity than well-matched healthy controls.

Dietary sorbitol and mannitol: food content and distinct absorption patterns between healthy individuals and patients with irritable bowel syndrome.

BACKGROUND: Sorbitol and mannitol are naturally-occurring polyol isomers. Although poor absorption and induction of gastrointestinal symptoms by sorbitol are known, the properties of mannitol are poorly described. We aimed to expand data on food composition of these polyols, and to compare their absorptive capacities and symptom induction in patients with irritable bowel syndrome (IBS) and healthy individuals. METHODS: Food samples were analysed for sorbitol and mannitol content. The degree of absorption measured by breath hydrogen production and gastrointestinal symptoms (visual analogue scales) was evaluated in a randomised, double-blinded, placebo-controlled study in 21 healthy and 20 IBS subjects after challenges with 10 g of sorbitol, mannitol or glucose. RESULTS: Certain fruits and sugar-free gum contained sorbitol, whereas mannitol content was higher in certain vegetables. Similar proportions of patients with IBS (40%) and healthy subjects (33%) completely absorbed sorbitol, although more so with IBS absorbed mannitol (80% versus 43%; P = 0.02). Breath hydrogen production was similar in both groups after lactulose but was reduced in patients with IBS after both polyols. No difference in mean (SEM) hydrogen production was found in healthy controls after sorbitol [area-under-the-curve: 2766 (591) ppm 4 h(-1) ] or mannitol [2062 (468) ppm 4 h(-1) ] but, in patients with IBS, this was greater after sorbitol [1136 (204) ppm 4 h(-1) ] than mannitol [404 (154) ppm 4 h(-1) ; P = 0.002]. Overall gastrointestinal symptoms increased significantly after both polyols in patients with IBS only, although they were independent of malabsorption of either of the polyols. CONCLUSIONS: Increased and discordant absorption of mannitol and sorbitol occurs in patients with IBS compared to that in healthy controls. Polyols induced gastrointestinal symptoms in patients with IBS independently of their absorptive patterns, suggesting that the dietary restriction of polyols may be efficacious.

Objectively measured muscle fatigue in Crohn's disease: correlation with self-reported fatigue and associated factors for clinical application.

BACKGROUND & AIMS: The association of fatigue with decreased physical performance and underlying mechanisms are poorly understood in Crohn's disease (CD). We aimed to measure and compare self-reported fatigue with skeletal muscle fatigue in CD subjects and healthy controls, and to identify associated factors that may be amenable to change. METHODS: Demographic and clinical data were collected and fatigue assessed using the Fatigue Impact Scale (FIS) in 27 consecutive CD patients and 22 matched healthy controls. Circulating cytokines and growth factors were measured. The rate of quadriceps muscle fatigue was assessed using an isokinetic dynamometer as the decrement of force with 30 contractions performed over a 5-minute period. RESULTS: Compared with healthy controls, CD patients reported greater levels of fatigue (mean global FIS score 45.3 vs 10.5, physical dimension score 12.3 vs 2.7 respectively; each p<0.01) and muscle fatigue (-5.2 vs -1.3 Nm min(-1); p<0.05). The two indices were correlated (r = -0.52 in CD; p<0.01). Patients with CD had lower mean serum IGF-1 levels (16.1 vs 25.4 pmol/L, p<0.01) and higher oxidative stress (TBARS assay 4.3 vs 3.9 µM, p<0.05). On multivariate analysis, low serum vitamin D, IGF-1 and magnesium, and higher IL-6 levels were associated with increased muscle fatigue (all p ≤ 0.05). CONCLUSION: Subjects with CD had more muscle fatigue than matched healthy controls and this correlated well with self-reported fatigue. Of circulating factors that were independently associated with increased muscle fatigue, vitamin D, magnesium and IGF-1 could be targeted in future studies to reduce fatigue and improve physical performance.

Delving into disability in Crohn's disease: dysregulation of molecular pathways may explain skeletal muscle loss in Crohn's disease.

BACKGROUND/AIMS: In Crohn's disease (CD), skeletal muscle mass and function are reduced compared to healthy controls, potentially resulting in disability. Mechanisms contributing to muscle impairment, and thus potential therapeutic targets, are poorly understood. This study aimed to measure and compare skeletal muscle size and molecular targets involved in skeletal muscle growth, in CD subjects and healthy controls. METHODS: CD (n=27) and healthy (n=22) subjects were recruited from the IBD outpatient clinic and via local advertisement respectively. Demographics and clinical data were collected via survey and interview. Quadriceps muscle cross-sectional area was measured using peripheral quantitative CT scanning. Levels of muscle hypertrophy and atrophy signalling targets using quantitative PCR and western blotting were measured in muscle biopsies. RESULTS: Muscle size was 14% lower (p=0.055) and a 54% lower phosphorylated:total (p:t) Akt ratio was measured in the muscle samples (p<0.05), indicating an attenuated muscle hypertrophy pathway in CD compared with controls. In those with CD, a lower p:t Akt ratio (<0.97) was associated with lower serum vitamin D3, lower physical activity indices (49 vs 64 mmol/L, 1.7 vs 2.2×10(6) accelerometer counts respectively, each p<0.05) and a trend towards lower serum ferritin levels (128 vs 322mg/L, p=0.07), compared with CD subjects with normal/high p:t Akt ratios. CONCLUSION: The reduced muscle mass in CD may be explained, in part, by impaired activation of muscle protein synthesis pathways, notably the IGF1-Akt pathway. Normal vitamin D levels and regular exercise may be protective in CD against this trend, though confirmatory longitudinal studies are needed.

Chronic pain in inflammatory bowel disease: characteristics and associations of a hospital-based cohort.

BACKGROUND: Chronic pain (CP) is a common symptom in patients with inflammatory bowel disease. This study aimed to examine its prevalence, severity, clinical associations, and impact on psychological well-being and to identify patient factors that independently predict the presence of severe/disabling pain. METHODS: One hundred and twenty consecutive patients with inflammatory bowel disease attending a hospital-based clinic provided information through questionnaires on quality of life, mood disturbance, and functional gut symptoms. Those who had CP (pain occurring every day for 3 months within the past 6 months) provided additional information on the pain's intensity and associated disability and management and coping strategies. RESULTS: Forty-six patients (38%) had CP, most commonly in the abdomen (91%), and they had higher disease activity, reduced quality of life, and more depression and anxiety and took more paracetamol and opiates than those without. These indices were worse in the subgroup of 23 with moderate-severe pain/disability. Criteria for irritable bowel syndrome were met in 70% of those with pain irrespective of its severity. Multivariate analysis identified 4 independent associations with moderate-severe pain/disability: active disease (odds ratio, 49 [95% confidence intervals, 1.6-1455]), catastrophizing tendency (35 [3-228]), medication belief score (0.05 [0.005-0.55], and depression score (1.80 [1.02-3.17]). CONCLUSIONS: CP has major effects on quality of life and functional and social outcomes. Active disease and maladaptive coping strategies and negative attitudes and beliefs toward symptoms are independently associated with more severe pain. Management strategies should move the focus away from analgesic dependence toward psychosocial intervention and nonpharmacologic therapy.

A chronic care model significantly decreases costs and healthcare utilisation in patients with inflammatory bowel disease.

INTRODUCTION: Inflammatory bowel disease (IBD) is a chronic condition, yet the model of care is often reactive. We sought to examine whether a formal IBD service (IBDS) reduced inpatient healthcare utilisation or lowered costs for inpatient care. MATERIAL AND METHODS: With protocols, routine nurse phone follow-up a help-line, more proactive care was delivered, with many symptoms and concerns dealt with prior to routine presentation. Over two five month periods before (2007/8) and after (2009/10) introducing a formal IBDS two discrete cohorts of admitted IBD patients were identified at a single centre. Each patient was assigned five contemporaneously admitted, age and gender matched controls. Inpatient healthcare utilisation was compared between patients and controls and disease-specific factors amongst the two IBD cohorts. RESULTS: The initial audit captured 102 admitted IBD patients (510 controls, median age 44 years, 57% female); the second audit 95 patients (475 controls, median age 46 years, 45.3% female). In 2009/10, the number of admissions was lower in IBD patients than in controls (mean 1.53+/-1.03 vs. 2.54+/-2.35; p<0.0001). This contrasts with the first audit, where IBD patients had more admissions than controls. Following IBDS introduction, the mean total cost of inpatient care was lower for IBD patients than controls (US$12,857.48 (US$15,236.79) vs. US$ 30,467.78 (US$ 53,760.20), p=0.005). In addition, patients known to a specialist gastroenterologist (GE) and the IBD Service tended to have the lowest mean number of admissions (GE and IBDS 1.14 (+/-0.36) vs. no GE/IBDS 1.64 (+/-1.25)). CONCLUSIONS: Healthcare utilisation and disease burden in IBD decreased significantly since introducing an IBDS. These data suggest that proactive management improved outcomes. Contact with a gastroenterologist and IBDS seemed to give best results.

Potentially avoidable surgery in inflammatory bowel disease: what proportion of patients come to resection without optimal preoperative therapy? A guidelines-based audit.

BACKGROUND: Recently, promulgated inflammatory bowel disease (IBD) guidelines seek to decrease the need for surgery by improving disease control. However, resection rates remain static. AIMS: We therefore sought to determine the proportion of patients coming to surgery where preoperative management was not optimal according to guidelines. METHODS: Case notes of all patients with resection surgery for IBD from January 2007 to March 2008 at a metropolitan teaching hospital were retrospectively reviewed. Judgement was made as to whether preoperative management was optimal or suboptimal depending on whether it met guidelines. RESULTS: A total of 22 subjects with IBD-related resections were identified (15 males and seven females). In total, 17 had Crohn's disease (CD) (11 males) and five ulcerative colitis (UC) (four males). There were 10 smokers (nine CD and one UC). The two most common indications for surgery were inflammatory mass/abscess (n= 8) and refractory to medical therapy (n= 7). While all patients with known IBD (20/22) had seen a gastroenterologist in the past, five known IBD patients had resections undertaken without preoperative gastroenterologist input. Overall preoperative management was judged as optimal in only (9/22) 41%. Of those whose therapy did not meet guidelines (n= 13), five had azathioprine at doses <2 mg/kg, one declined therapy and nine with CD were current smokers. CONCLUSIONS: Over 50% of IBD resection patients had suboptimal preoperative management, with sub-therapeutic thiopurine dosing and smoking in CD the main problems. Thus, there are significant gains to be made with better use of standard therapies, as it appears that ∼50% of resection surgery was 'potentially avoidable'.

Systematic review: fatigue in inflammatory bowel disease.

BACKGROUND: Fatigue is common, disabling yet underappreciated, in patients with chronic diseases, including inflammatory bowel disease (IBD). AIMS: To examine the literature and determine the prevalence and patterns of fatigue in IBD patients, to identify opportunities and directions for future research in this area. METHODS: A systematic review using PubMed and Ovid Medline databases was conducted using search terms 'fatigue', 'Crohn', 'colitis' and 'inflammatory bowel disease'. A review of fatigue in other similar chronic diseases was also performed. RESULTS: Ten studies were found to include data on fatigue in IBD patients; all were conducted between 1999 and 2009. However, only one study (in children) measured fatigue in IBD patients as a primary outcome. In patients in remission, the prevalence of fatigue in IBD patients ranges from 41 to 48%. Data are sparse and conflicting on whether fatigue severity is proportional to disease severity/activity. CONCLUSIONS: Despite the clinical reality of fatigue, there are few published studies examining fatigue in IBD as a primary outcome. More data are needed on the prevalence, correlation between disease activity and fatigue severity, and putative pathogenic pathways involved in fatigue pathogenesis, before ultimately elucidating targeted therapies for fatigue in IBD patients.

Un-promoted issues in inflammatory bowel disease: opportunities to optimize care.

Inflammatory bowel diseases (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), are chronic inflammatory disorders of the gut, which lead to significant morbidity and impaired quality of life (QoL) in sufferers, without generally affecting mortality. Despite CD and UC being chronic, life-long illnesses, most medical management is directed at acute flares of disease. Moreover, with more intensive medical therapy and the development of biological therapy, there is a risk that management will become even more narrowly focused on acute care, and be directed only at those with more severe disease, rather than encompassing all sufferers and addressing important non-acute issues. This imbalance of concentration of medical attention on 'high-end' care is in part driven by the need to perform and publish randomized clinical trials of newer therapies to obtain registration and licensing for these agents, which thus occupy a large proportion of the recent IBD treatment literature. This leads to less attention on relatively 'low-technology' issues including: (i) the psychosocial burden of chronic disease, QoL and specific psychological comorbidities; (ii) comorbidity with functional gastrointestinal disorders (FGIDs); (iii) maintenance therapy, monitoring and compliance; (iv) smoking (with regard to CD); (v) sexuality, fertility, family planning and pregnancy; and (vi) iron deficiency and anaemia. We propose these to be the 'Un-promoted Issues' in IBD and review the importance and treatment of each of these in the current management of IBD.

The potential value of faecal lactoferrin as a screening test in hospitalized patients with diarrhoea.

BACKGROUND: Nosocomial diarrhoea is common and its investigation carries a significant healthcare cost. This study aimed to determine the utility of faecal lactoferrin (FL), a readily measurable marker of intestinal inflammation, in hospitalized patients with diarrhoea. METHODS: FL was quantified in consecutive faecal samples submitted to a hospital pathology laboratory. Patient data were extracted from hospital records. Receiver-operator curve (ROC) analysis was performed in a subset of patients where a decision about low or high likelihood of inflammation could be confidently made. Multivariate analyses were performed to identify associations with an elevated FL. Cost analyses were also performed. RESULTS: A total of 511 faecal samples from 433 patients (48% male, median age 67 years) was studied. Median FL concentration was 3.4 µg/mL (range 0-288). ROC analysis indicated an optimal cut-off value of 1.25 µg/mL (sensitivity 92%, specificity 97%, negative predictive value 97%) compared with the manufacturer's cut-off of 7.25 µg/mL (60%, 66% and 85% respectively). Multivariate analysis at the lower cut-off minimized potentially confounding variables. Proton pump inhibitor use independently increased (OR 2.3, 95% CI 1.5-3.8) and current smoking reduced (0.61, 0.38-0.99) the likelihood of an elevated FL. Only one out of 32 bacteriological positive samples would have been missed if FL was instituted as a screening test prior to microbiological assessment, which could have reduced laboratory-related costs by up to 56%. CONCLUSION: In hospitalized patients, a normal FL effectively excludes inflammatory diarrhoea and is proposed as a screening test prior to microbiological assessment of faeces. Prospective evaluation of this approach is warranted.