Understanding and managing psychological disorders in patients with inflammatory bowel disease: a practical guide.

Mood disturbances such as anxiety and depression are common in patients with inflammatory bowel disease (IBD), and impact negatively on their quality of life and disease course. An integrated multidisciplinary IBD team, which includes access to psychology and psychiatry opinion, makes possible the prompt recognition and management of psychological disturbance in patients with IBD. Based on our experience and existing literature, including systematic reviews of the effectiveness of available treatment modalities, a stepwise approach to the maintenance and restoration of psychological well-being is recommended, evolving upwards from lifestyle advice, through behavioural therapies to pharmacotherapy.

Use of intravenous iron and risk of anaphylaxis: A multinational observational post-authorisation safety study in Europe.

PURPOSE: This post-authorisation safety study estimated the risk of anaphylaxis in patients receiving intravenous (IV) iron in Europe, with interest in iron dextran and iron non-dextrans. Studies conducted in the United States have reported risk of anaphylaxis to IV iron ranging from 2.0 to 6.8 per 10 000 first treatments. METHODS: Cohort study of IV iron new users, captured mostly through pharmacy ambulatory dispensing, from populations covered by health and administrative data sources in five European countries from 1999 to 2017. Anaphylaxis events were identified through an algorithm that used parenteral penicillin as a positive control. RESULTS: A total of 304 210 patients with a first IV iron treatment (6367 iron dextran), among whom 13-16 anaphylaxis cases were identified and reported as a range to comply with data protection regulations. The pooled unadjusted incidence proportion (IP) ranged from 0.4 (95% confidence interval [CI], 0.2-0.9) to 0.5 (95% CI, 0.3-1.0) per 10 000 first treatments. No events were identified at first dextran treatments. There were 231 294 first penicillin treatments with 30 potential cases of anaphylaxis (IP = 1.2; 95% CI, 0.8-1.7 per 10 000 treatments). CONCLUSION: We found an IP of anaphylaxis from 0.4 to 0.5 per 10 000 first IV iron treatments. The study captured only a fraction of IV iron treatments administered in hospitals, where most first treatments are likely to happen. Due to this limitation, the study could not exclude a differential risk of anaphylaxis between iron dextran and iron non-dextrans. The IP of anaphylaxis in users of penicillin was consistent with incidences reported in the literature.

Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease.

Importance: Use of thiopurines may be limited by myelosuppression. TPMT pharmacogenetic testing identifies only 25% of at-risk patients of European ancestry. Among patients of East Asian ancestry, NUDT15 variants are associated with thiopurine-induced myelosuppression (TIM). Objective: To identify genetic variants associated with TIM among patients of European ancestry with inflammatory bowel disease (IBD). Design, Setting, and Participants: Case-control study of 491 patients affected by TIM and 679 thiopurine-tolerant unaffected patients who were recruited from 89 international sites between March 2012 and November 2015. Genome-wide association studies (GWAS) and exome-wide association studies (EWAS) were conducted in patients of European ancestry. The replication cohort comprised 73 patients affected by TIM and 840 thiopurine-tolerant unaffected patients. Exposures: Genetic variants associated with TIM. Main Outcomes and Measures: Thiopurine-induced myelosuppression, defined as a decline in absolute white blood cell count to 2.5 × 109/L or less or a decline in absolute neutrophil cell count to 1.0 × 109/L or less leading to a dose reduction or drug withdrawal. Results: Among 1077 patients (398 affected and 679 unaffected; median age at IBD diagnosis, 31.0 years [interquartile range, 21.2 to 44.1 years]; 540 [50%] women; 602 [56%] diagnosed as having Crohn disease), 919 (311 affected and 608 unaffected) were included in the GWAS analysis and 961 (328 affected and 633 unaffected) in the EWAS analysis. The GWAS analysis confirmed association of TPMT (chromosome 6, rs11969064) with TIM (30.5% [95/311] affected vs 16.4% [100/608] unaffected patients; odds ratio [OR], 2.3 [95% CI, 1.7 to 3.1], P = 5.2 × 10-9). The EWAS analysis demonstrated an association with an in-frame deletion in NUDT15 (chromosome 13, rs746071566) and TIM (5.8% [19/328] affected vs 0.2% [1/633] unaffected patients; OR, 38.2 [95% CI, 5.1 to 286.1], P = 1.3 × 10-8), which was replicated in a different cohort (2.7% [2/73] affected vs 0.2% [2/840] unaffected patients; OR, 11.8 [95% CI, 1.6 to 85.0], P = .03). Carriage of any of 3 coding NUDT15 variants was associated with an increased risk (OR, 27.3 [95% CI, 9.3 to 116.7], P = 1.1 × 10-7) of TIM, independent of TPMT genotype and thiopurine dose. Conclusions and Relevance: Among patients of European ancestry with IBD, variants in NUDT15 were associated with increased risk of TIM. These findings suggest that NUDT15 genotyping may be considered prior to initiation of thiopurine therapy; however, further study including additional validation in independent cohorts is required.

Herbs and Inflammatory Bowel Disease.

Although herbal preparations are widely used by patients with inflammatory bowel disease (IBD), evidence for their efficacy is limited and they may not always be safe. Mainly small studies of varying quality have suggested that several herbal preparations could be of benefit in IBD, but larger better-designed trials are needed to establish their place in inducing and maintaining remission. Patients and health care workers need to be made more aware of the limitations and risks of using herbal products for IBD.

Incidence and Outcome of Clostridium difficile Infection in Hospitalized Patients with Inflammatory Bowel Disease in the UK.

BACKGROUND AND AIMS: Previous studies have reported that Clostridium difficile infection [CDI] is more common, and has a worse outcome, in patients with inflammatory bowel disease [IBD] than in those without. We have now reassessed the incidence and outcome of CDI in in-patients with and without IBD, and the outcomes of admissions for IBD patients with and without CDI. METHODS: In-patients who had stool samples submitted for C. difficile testing [2007-2013] were collated. Two matched pools were generated: patients with IBD and CDI vs non-IBD patients with CDI [matched for age, sex and date] and patients with IBD and CDI vs IBD patients without CDI [matched for age and IBD type]. For each group, admission details, pre-admission and outcome data were compared. RESULTS: Four per cent [1079/21035] of samples were positive for CDI; 5% [49] of these were from IBD in-patients. The incidence of CDI in IBD patients decreased from 8.7% in 2007/08 to 0.4% in 2012/13 [p < 0.0001]. Length of stay was shorter in IBD patients with CDI than in non-IBD CDI patients (hazard ratio [HR] 0.335 [0.218-0.513]) and was no different between IBD patients with and without CDI (HR 0.661 [0.413-1.06]). IBD patients were diagnosed with CDI earlier in their admission than non-IBD patients (HR 0.182 [0.093-0.246]). No differences in mortality were found. CONCLUSIONS: The incidence of CDI complicating IBD has fallen since 2007. CDI is no longer associated with worse short-term outcomes in patients with IBD than in those without. Patients with CDI and IBD have similar outcomes to those with IBD alone.

Oral Iron Treatment Response and Predictors in Anaemic Adolescents and Adults with IBD: A Prospective Controlled Open-Label Trial.

BACKGROUND: Because of previous concerns about the efficacy and safety of oral iron for treating iron deficiency anaemia in inflammatory bowel disease [IBD], particularly in young people, we compared the effects of ferrous sulphate on haemoglobin response, disease activity and psychometric scores in adolescents and adults with IBD. We also assessed the relation of baseline serum hepcidin to haemoglobin response. METHODS: We undertook a prospective, open-label, 6-week non-inferiority trial of the effects of ferrous sulphate 200 mg twice daily on haemoglobin, iron status, hepcidin, disease activity (Harvey-Bradshaw Index, Simple Colitis Clinical Activity Index, C-reactive protein [CRP]), faecal calprotectin and psychometric scores in 45 adolescents [age 13-18 years] and 43 adults [>18 years]. RESULTS: On intention-to-treat analysis, ferrous sulphate produced similar rises in haemoglobin in adolescents {before treatment 10.3 g/dl [0.18] (mean [SEM]), after 11.7 [0.23]: p < 0.0001} and adults (10.9 g/dl [0.14], 11.9 [0.19]: p < 0.0001); transferrin saturation, ferritin [in adolescents] and hepcidin [in adults] also increased significantly. On per-protocol univariate analysis, the haemoglobin response was inversely related to baseline haemoglobin, CRP and hepcidin. Oral iron did not alter disease activity; it improved Short IBDQ and Perceived Stress Questionnaire scores in adults. CONCLUSION: Oral ferrous sulphate was no less effective or well-tolerated in adolescents than adults, and did not increase disease activity in this short-term study. The inverse relation between baseline CRP and hepcidin levels and the haemoglobin response suggests that CRP or hepcidin measurements could influence decisions on whether iron should be given orally or intravenously. [ClinTrials.gov registration number NCT01991314].

Treatment of iron deficiency anemia: practical considerations.

Iron deficiency anemia is a common problem worldwide, and doctors of all specialties need to be competent in its treatment. While most patients respond well to oral iron preparations, a substantial minority have side effects that make them adhere poorly to their treatment. For oral iron­intolerant patients, those responding poorly despite good adherence, and those with severe and/or symptomatic anemia, intravenous iron is an excellent alternative. It is, however, more expensive and carries a very small but potentially life­threatening risk of severe infusion­related hypersensitivity reactions. After outlining the main features of iron metabolism, in this review we compare the indications for therapy with oral and intravenous iron, and then focus on how to maximize the efficacy and safety of the two different routes.

Hypersensitivity reactions to intravenous iron: guidance for risk minimization and management.

Intravenous iron is widely used for the treatment of iron deficiency anemia when oral iron is inappropriate, ineffective or poorly tolerated. Acute hypersensitivity reactions during iron infusions are very rare but can be life-threatening. This paper reviews their frequency, pathogenesis and risk factors, and provides recommendations about their management and prevention. Complement activation-related pseudo-allergy triggered by iron nanoparticles is probably a more frequent pathogenetic mechanism in acute reactions to current formulations of intravenous iron than is an immunological IgE-mediated response. Major risk factors for hypersensitivity reactions include a previous reaction to an iron infusion, a fast iron infusion rate, multiple drug allergies, severe atopy, and possibly systemic inflammatory diseases. Early pregnancy is a contraindication to iron infusions, while old age and serious co-morbidity may worsen the impact of acute reactions if they occur. Management of iron infusions requires meticulous observation, and, in the event of an adverse reaction, prompt recognition and severity-related interventions by well-trained medical and nursing staff.

How can we improve models of care in inflammatory bowel disease? An international survey of IBD health professionals.

BACKGROUND AND AIMS: Few studies have specifically examined models of care in IBD. This survey was designed to help gather information from health professionals working in IBD services on current care models, and their views on how to best reshape existing models for IBD care worldwide. METHODS: An online mixed-methods survey was conducted with health professionals caring for IBD patients. Recruitment was conducted using the snowballing technique, where members of professional networks of the investigators were invited to participate. Results of the survey were summarised using descriptive statistics. RESULTS: Of the 135 included respondents, 76 (56%) were female, with a median age of 44 (range: 23-69) years, 50% were GI physicians, 34% nurses, 8% psychologists, 4% dieticians, 2% surgeons, 1% psychiatrists, and 1% physiotherapists. Overall, 73 (54%) respondents considered their IBD service to apply the integrated model of care, and only 5% reported that they worked exclusively using the biomedical care (no recognition of psychosocial factors). The majority of respondents reported including mental health assessment in their standard IBD care (65%), 51% believed that an ideal IBD service should be managed in specialist led clinics, and 64% wanted the service to be publicly funded. Respondents pictured an ideal IBD service as easy-access fully multi-disciplinary, with a significant role for IBD nurses and routine psychological and nutritional assessment and care. CONCLUSIONS: Health care professionals believe that an ideal IBD service should: be fully integrated, involve significant roles of nurses, psychologists and dieticians, run in specialist clinics, be easily accessible to patients and publicly funded.

Are maintenance strategies underused in Crohn's disease?

A key aim in the management of Crohn's disease is to maintain disease remission, whether this has been achieved by medical or surgical treatment. The reasons for doing this are to maintain quality of life, to avoid steroid dependence and to maintain mucosal healing with a view to preventing relapse, hospital admission and surgery, and improving disease natural history. Options for remission maintenance include smoking cessation, thiopurines, methotrexate, anti-TNF-α drugs and surgery. Evidence suggests that in some places now, and in most places in the past, too few patients are/were appropriately treated when in remission, and, in many instances, treatment regimens are/were insufficiently tailored to the patient's individual phenotype, prognosis and/or genotype.

Integrated models of care in managing inflammatory bowel disease: a discussion.

The World Health Organization has recommended the integrated model of care as the current best practice of care, and, in recent years, it has been gaining popularity worldwide in various settings. However, there have been very few reports on applications of this model to the care of patients with gastrointestinal problems and no reports in the case of inflammatory bowel disease (IBD). However, several IBD centres worldwide have been using the model as part of their standard care. This discussion paper aims to bring together these units' shared experiences with a range of integrated models of care in order to identify common features and provide recommendations on aspirational care for IBD patients.

Prevalence and management of anemia in children, adolescents, and adults with inflammatory bowel disease.

BACKGROUND: Children and adolescents with inflammatory bowel disease (IBD) are more likely to have Crohn's disease (CD) than ulcerative colitis (UC) and their disease tends to be more extensive and severe than in adults. We hypothesized that the prevalence of anemia would therefore be greater in children and adolescents than in adults attending IBD outpatient clinics. METHODS: Using the WHO age-adjusted definitions of anemia we assessed the prevalence, severity, type, and response to treatment of anemia in patients attending pediatric, adolescent, and adult IBD clinics at our hospital. RESULTS: The prevalence of anemia was 70% (41/59) in children, 42% (24/54) in adolescents, and 40% (49/124) in adults (P < 0.01). Overall, children (88% [36/41]) and adolescents (83% [20/24]) were more often iron-deficient than adults (55% [27/49]) (P < 0.01). Multivariate logistic regression showed that both active disease (odds ratio [OR], 4.7 95% confidence interval [CI], 2.5, 8.8) and attending the pediatric clinic (OR 3.7; 95% CI, 1.6, 8.4) but not the adolescent clinic predicted iron deficiency anemia. Fewer iron-deficient children (13% [5/36]) than adolescents (30% [6/20]) or adults (48% [13/27]) had been given oral iron (P < 0.05); none had received intravenous iron compared with 30% (6/20) adolescents and 41% (11/27) adults (P < 0.0001). CONCLUSIONS: Anemia is even more common in children than in older IBD patients. Oral iron was given to half of adolescents and adults but, despite similar tolerance and efficacy, only a quarter of children with iron-deficient anemia. Reasons for the apparent underutilization of iron therapy include a perceived lack of benefit and concerns about side effects, including worsening of IBD activity.

The influence of stress on the development and severity of immune-mediated diseases.

Evidence that psychological stress can increase inflammation and worsen the course of immune-mediated inflammatory disease (IMID) is steadily accumulating. The majority of data supporting this hypothesis come from studies in patients with inflammatory bowel disease (IBD). While there is no evidence to suggest that stress is a primary cause of IBD, many, although not all, studies have found that patients with IBD experience increased stress and stressful life events before disease exacerbations. Further, the disease itself can cause psychological stress, creating a vicious cycle. In addition to reviewing the epidemiological evidence supporting a stress-IMID relationship, this article also briefly discusses how stress-related changes in neural, endocrine, and immune functioning may contribute to the pathogenesis of immune diseases, IBD in particular. The effects of different pharmacological and nonpharmacological interventions, including stress management and behavioral therapy, on stress, mood, quality of life (QOL), and activity of the underlying IMID are also summarized.

Efficacy and tolerability of intravenous iron dextran and oral iron in inflammatory bowel disease: a case-matched study in clinical practice.

OBJECTIVES: Iron deficiency anaemia is common in inflammatory bowel disease (IBD); however, the optimum route of administration of iron replacement therapy is unclear. As inflammation may limit the absorption and efficacy of oral iron, we hypothesized that in routine clinical practice IV iron would be more effective than oral iron in patients with IBD matched for disease type, extent and activity. METHODS: Thirty-three IBD patients who had received IV iron dextran (Cosmofer) in 2008-2010 were identified and matched for age, sex, diagnosis and baseline disease activity, extent and behaviour to IBD patients given oral iron. RESULTS: Patients given IV iron dextran were more anaemic at baseline than those receiving oral iron. Although haemoglobin (Hb) concentrations were normalized in about a third of patients, and increased significantly in both groups, the mean increase in Hb after 8 weeks was greater in the iron dextran group [2.0 g/dl (0.3) vs. 0.6 g/dl (0.1), P<0.0001]. Response to oral or IV iron was unrelated to age, sex, ethnicity, disease duration, extent or activity. Fifteen percent (five out of 33) patients discontinued oral iron because of gastrointestinal side-effects and a further two out of 35 had anaphylactoid reactions to the IV iron dextran test doses. Neither of the iron formulations worsened disease activity. CONCLUSION: In routine clinical practice, in anaemic patients with IBD of similar type, extent and activity, IV Cosmofer is more efficacious in increasing Hb concentration than oral iron. Active disease does not impair the response to either IV or oral iron in patients with IBD, and neither product itself worsens disease activity.

Tobacco dependence and awareness of health risks of smoking in patients with inflammatory bowel disease.

BACKGROUND AND AIM: Smoking is a risk factor for developing Crohn's disease (CD) and worsens its outcome. Conversely, in ulcerative colitis (UC), the onset may be triggered by the smoking cessation and smoking may be beneficial. To help to ascertain whether patients with inflammatory bowel disease (IBD) would benefit from attending a smoking cessation clinic, we assessed: first, the prevalence of smoking; second, patients' awareness of the effects of smoking, and finally nicotine dependence in IBD patients compared with the healthy and disease-matched controls. METHODS: A total of 246 consecutive IBD outpatients (173 patients with CD, 73 patients with UC) completed a questionnaire on smoking habits and its effect on IBD. Smokers were assessed for dependence using the Fagerstrom test for nicotine dependence (FTND) score and their results were compared with those of age, sex, and ethnicity-matched healthy (five controls for each IBD patient) and asthma controls (one control for each IBD patient) attending a smoking cessation clinic. RESULTS: Thirty five out of 173 patients (20%) with CD and nine out of 73 patients (12%) with UC were current smokers, with 52 out of 173 patients (30%) with CD and 28 out of 73 patients (38%) with UC being ex-smokers. Ninety out of 173 patients (52%) with CD knew that smoking worsens CD, whereas only 15 out of 73 patients (21%) with UC knew of the beneficial effects of smoking on their disease (P=0.032). Knowledge was unrelated to smoking status. In patients with CD, the median (range) FTND score was 3 (0-8) compared with 7 (2-10) in healthy (P<0.001) and 6 (2-9) in asthma controls (P<0.0001). Only seven of the 35 (20%) smoking patients with CD were highly dependent (FTND score ≥6). Similarly, in the patients with UC, the FTND score was 1 (0-4), lower than in healthy, [6 (2-10)], and asthma controls, [7 (4-10); (P<0.004 for both groups)]. CONCLUSION: Patients with CD were better informed about the effects of smoking on their own disease than the patients with UC. Nicotine dependence in IBD patients is lower than in smokers' clinic clients and comparable with that of the general population. Their low nicotine dependence suggests that most IBD patients could be weaned off the smoking habit successfully in the IBD clinic and referral to a smoking cessation clinic was offered to the highly dependent minority and others expressing interest in attending.

Does psychological counseling alter the natural history of inflammatory bowel disease?

BACKGROUND: There is increasing evidence that psychological stress can increase mucosal inflammation and worsen the course of inflammatory bowel disease (IBD). We have now assessed whether psychotherapy by a counselor specially trained in the management of IBD can influence the course of disease. METHODS: Using retrospective case note review, we compared the course of IBD in 24 patients (13 ulcerative colitis; 11 Crohn's disease), during the year before (year 1) and the year after referral (year 2) for supportive outpatient psychotherapy to an IBD counselor, to that of 24 IBD controls who were matched to individual cases for age, sex, disease, duration of disease, medication at baseline, and for relapse rate in year 1. Counselor assessments were made using a visual analog scale 0-6 (0 denotes poor, 6 excellent response to counseling). The results are shown as median (range). RESULTS: Patients were referred for counseling because of disease-related stress (14 patients), work problems (3), concerns about surgery (5), and bereavement (2); they received 6 (1-13) 1-hour sessions in year 2. In the year after starting counseling (year 2), patients had fewer relapses (0 [0-2]) and outpatient attendances (3.5 [1-10]) than in the year before referral (year 1) (2 [0-5], P = 0.0008; and 6.5 [1-17], P = 0.0006, respectively; furthermore, steroid usage (1 course [0-4] before, 0 [0-2] after, P = 0.005) and relapse-related use of other IBD medications declined during psychotherapy (1 drug [0-5] before, 0 [0-2] after, P = 0.002). There were no differences in any of these measures between years 1 and 2 in the control group. Numbers of hospital admissions did not change between year 1 and 2 in either group. In the 20 patients who attended >1 session counseling helped solve stress-related difficulties (counselor's score 4 [3-5]), the counselor scored them 4 (3-6) overall in psychological well-being after the counseling sessions. CONCLUSIONS: IBD-focused counseling may improve not only psychological well-being, but also the course of IBD in individuals with psychosocial stress.

Management of stress in inflammatory bowel disease: a therapeutic option?

There is increasing evidence that psychological stress and associated mood disorders are linked with, and can adversely affect the course of, inflammatory bowel disease (IBD). Unfortunately, owing to methodological difficulties inherent in undertaking appropriately targeted and blinded trials, there are limited high-quality data regarding the effects on IBD of interventions aimed to ameliorate stress and mood disorders. Nevertheless, patients want psychological intervention as well as conventional medical strategies. Emerging trial evidence supports the suggestion that psychologically orientated therapy may ameliorate IBD-associated mood disorders, but there are no strong data as of yet to indicate that stress management has a beneficial effect on the activity or course of IBD. As yet, which, when and how interventions targeted at psychological stress and mood disturbances should be offered to individual patients with IBD is not clear.