Two-year combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for Crohn's disease

Background & Aims: Mycobacterium avium subspecies paratuberculosis has been proposed as a cause of Crohn’s disease. We report a prospective, parallel, placebo-controlled, double-blind, randomized trial of 2 years of clarithromycin, rifabutin, and clofazimine in active Crohn’s disease, with a further year of follow-up. Methods: Two hundred thirteen patients were randomized to clarithromycin 750 mg/day, rifabutin 450 mg/day, clofazimine 50 mg/day or placebo, in addition to a 16-week tapering course of prednisolone. Those in remission (Crohn’s Disease Activity Index ≤150) at week 16 continued their study medications in the maintenance phase of the trial. Primary end points were the proportion of patients experiencing at least 1 relapse at 12, 24, and 36 months. Results: At week 16, there were significantly more subjects in remission in the antibiotic arm (66%) than the placebo arm (50%; P = .02). Of 122 subjects entering the maintenance phase, 39% taking antibiotics experienced at least 1 relapse between weeks 16 and 52, compared with 56% taking placebo (P = .054). At week 104, the figures were 26% and 43%, respectively (P = .14). During the following year, 59% of the antibiotic group and 50% of the placebo group relapsed (P = .54). Conclusions: Using combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for up to 2 years, we did not find evidence of a sustained benefit. This finding does not support a significant role for Mycobacterium avium subspecies paratuberculosis in the pathogenesis of Crohn’s disease in the majority of patients. Short-term improvement was seen when this combination was added to corticosteroids, most likely because of nonspecific antibacterial effects.

Comorbidity between depression and inflammatory bowel disease explained by immune-inflammatory, oxidative, and nitrosative stress; tryptophan catabolite; and gut–brain pathways

The nature of depression has recently been reconceptualized, being conceived as the clinical expression of activated immune-inflammatory, oxidative, and nitrosative stress (IO&NS) pathways, including tryptophan catabolite (TRYCAT), autoimmune, and gut–brain pathways. IO&NS pathways are similarly integral to the pathogenesis of inflammatory bowel disease (IBD). The increased depression prevalence in IBD associates with a lower quality of life and increased morbidity in IBD, highlighting the role of depression in modulating the pathophysiology of IBD.This review covers data within such a wider conceptualization that better explains the heightened co-occurrence of IBD and depression. Common IO&NS underpinning between both disorders is evidenced by increased pro-inflammatory cytokine levels, eg, interleukin-1 (IL-1) and tumor necrosis factor-α, IL-6 trans-signalling; Th-1- and Th-17-like responses; neopterin and soluble IL-2 receptor levels; positive acute phase reactants (haptoglobin and C-reactive protein); lowered levels of negative acute phase reactants (albumin, transferrin, zinc) and anti-inflammatory cytokines (IL-10 and transforming growth factor-β); increased O&NS with damage to lipids, proteinsm and DNA; increased production of nitric oxide (NO) and inducible NO synthase; lowered plasma tryptophan but increased TRYCAT levels; autoimmune responses; and increased bacterial translocation. As such, heightened IO&NS processes in depression overlap with the biological underpinnings of IBD, potentially explaining their increased co-occurrence. This supports the perspective that there is a spectrum of IO&NS disorders that includes depression, both as an emergent comorbidity and as a contributor to IO&NS processes. Such a frame of reference has treatment implications for IBD when “comorbid” with depression.

Fluoxetine for maintenance of remission and to improve quality of life in patients with Crohn's disease: a pilot randomized placebo-controlled trial.

BACKGROUND AND AIMS: Previous studies have shown that antidepressants reduce inflammation in animal models of colitis. The present trial aimed to examine whether fluoxetine added to standard therapy for Crohn's disease [CD] maintained remission, improved quality of life [QoL] and/or mental health in people with CD as compared to placebo. METHODS: A parallel randomized double-blind placebo controlled trial was conducted. Participants with clinically established CD, with quiescent or only mild disease, were randomly assigned to receive either fluoxetine 20 mg daily or placebo, and followed for 12 months. Participants provided blood and stool samples and completed mental health and QoL questionnaires. Immune functions were assessed by stimulated cytokine secretion [CD3/CD28 stimulation] and flow cytometry for cell type. Linear mixed-effects models were used to compare groups. RESULTS: Of the 26 participants, 14 were randomized to receive fluoxetine and 12 to placebo. Overall, 14 [54%] participants were male. The mean age was 37.4 [SD=13.2] years. Fluoxetine had no effect on inflammatory bowel disease activity measured using either the Crohn's Disease Activity Index [F(3, 27.5)=0.064, p=0.978] or faecal calprotectin [F(3, 32.5)=1.08, p=0.371], but did have modest effects on immune function. There was no effect of fluoxetine on physical, psychological, social or environmental QoL, anxiety or depressive symptoms as compared to placebo [all p>0.05]. CONCLUSIONS: In this small pilot clinical trial, fluoxetine was not superior to placebo in maintaining remission or improving QoL. [ID: ACTRN12612001067864.].

Physical activity habits, limitations, and predictors in people with inflammatory bowel disease: a large cross-sectional online survey

BACKGROUND: Limited evidence suggests that physical activity has beneficial effects in people with inflammatory bowel disease (IBD). This study aimed to determine the physical activity habits of adults with IBD, the limitations to physical activity they experience because of their disease, and the extent to which their physical activity is affected by various demographic, clinical, and psychological factors. METHODS: Data were collected on 859 adult participants (52% with Crohn's disease, 75% women) through an online survey conducted between May and June 2016. Measures included physical activity (International Physical Activity Questionnaire), psychological symptoms (Hospital Anxiety and Depression Scale), fatigue (subitems of IBD fatigue scale), exercise perceptions (Exercise Benefits/Barriers Scale), and disease activity. Regression analyses were used to identify predictors of physical activity. RESULTS: Only 17% of respondents were categorized as "high active." Self-reported physical activity levels decreased, and fatigue and psychological scores increased, with increasing disease activity. Walking was the most common activity performed (57% of respondents) and running/jogging the most commonly avoided (34%). Many participants (n = 677) reported that IBD limited their physical activity, for reasons including abdominal/joint pain (70%), fatigue/tiredness (69%), disease flare-up (63%), and increased toilet urgency (61%). Physical activity was independently associated with depression, disease activity, and perceived barriers to exercise in people with Crohn's disease, and depression and age in people with ulcerative or indeterminate colitis (all P ≤ 0.038). CONCLUSIONS: This survey highlights several important factors that should be considered by designers of future physical activity interventions for people with IBD.

Covert dose reduction is a distinct type of medication non-adherence observed across all care settings in inflammatory bowel disease.

BACKGROUND: Non-adherence by dose omission is common and deleterious to outcomes in Inflammatory Bowel Disease (IBD), but covert dose reduction (CDR) remains unexplored. AIMS: To determine frequency and attitudinal predictors of overall medication non-adherence and of covert dose reduction as separate entities. METHODS: A cross sectional questionnaire was undertaken involving IBD patients in three different geographical regions and care settings. Demographics, medication adherence by dose omission, and rate of patient initiated dose reduction of conventional meds without practitioner knowledge (CDR) were assessed, along with attitudes toward IBD medication. RESULTS: Of 473 respondents (mean age 50.3 years, 60.2% female) frequency of non-adherence was 21.9%, and CDR 26.9% (p<0.001). By logistic regression, significant independent predictors of non-adherence were dissatisfaction with the patient-doctor relationship (p<0.001), depression (p=0.001), anxiety (p=0.047), and negative views regarding medication efficacy (p<0.001) or safety (p=0.017). Independent predictors of covert dose reduction included regular complementary medicine (CAM) use (p<0.001), experiencing more informative (p<0.001) and comfortable (p=0.006) consultations with alternative practitioners, disbelieving doctor delivered information (p=0.021) and safety concerns regarding conventional medication (p<0.001). Neither the frequency of non-adherence (p=0.569) nor CDR (p=0.914) differed between cohorts by different treatment settings. CONCLUSIONS: Covert dose reduction of IBD medication is more common than omission of medication doses, predicted by different factors to usual non-adherence, and has not been previously reported in IBD. The strongest predictor of CDR is regular CAM use.

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.

Attitudes towards antidepressants among people living with inflammatory bowel disease: an online Australia-wide survey.

BACKGROUND AND AIMS: Little research has been conducted on antidepressants (ADs) in inflammatory bowel disease (IBD) despite their widespread use and evidence that they may improve immunoregulatory activity. The present study aimed 1) To explore the use and type(s) of ADs currently prescribed to people living with IBD and to collect evidence with respect to any observed effect of ADs on the course of IBD, and 2) To explore experiences and opinions regarding the effect of ADs on IBD course and attitudes towards future trials with ADs. METHODS: A cross-sectional exploratory Australia-wide online survey was conducted. Numerical results of the survey were summarised using descriptive statistics and open-ended questions using a simple content analysis. RESULTS: Overall, 98 IBD respondents participated in the survey, 50% with Crohn's disease, and 79% females. Sixty five (66%) participants reported current and 46 (47%) reported past AD use. Of the current AD users, 51 (79%) reported that the symptoms ADs were prescribed for improved. Psychological well-being improved in 87% of participants. The majority of respondents observed no change in IBD activity while on ADs, however, 16 (25%) believed that ADs improved their IBD. Most (84%) respondents would recommend ADs to other people living with IBD, and 81% reported willingness to participate in clinical trials with ADs. CONCLUSIONS: Future clinical trials on ADs are warranted and likely to be accepted by people living with IBD in need of mental health care; however, it is yet unknown whether ADs will have a specific impact on long-term IBD activity.

An improved model of care for inflammatory bowel disease (IBD).

Recommendations from the 3rd round of the Report of the results for the national clinical audit of adult inflammatory bowel disease (IBD) inpatient care in the UK published earlier this year by UK's Royal College of Physicians and mentioned in the Lancet in March 20121 report improvements in the quality of care (QoC) of patients with IBD since audits began in 2006 but also list improvements yet to be achieved. Importantly, optimising the quality of life (QoL) of sufferers was indicated as deserving greater attention as part of the global approach to improved QoC.

An integrated model of care for inflammatory bowel disease sufferers in Australia: development and the effects of its implementation.

BACKGROUND: Psychological comorbidities are associated with poor outcome and increased healthcare utilization in patients with inflammatory bowel disease (IBD). However, a model of care addressing the biopsychosocial dimension of disease is not routinely applied in IBD. This review describes the development of such a model and the effects of its implementation in a hospital-based cohort of patients with IBD. METHODS: Three different approaches were used: 1) collecting baseline epidemiological data on mental health comorbidities; 2) raising awareness of and targeting mental health problems; 3) examining the effects of the model implementation. RESULTS: High rates of anxiety and depressive symptoms (36% and 13%, respectively) that are maintained over time were identified in IBD patients presenting at a metropolitan teaching hospital. Patients with documented psychological comorbidities were more likely to be hospitalized than those without (odds ratio [OR] = 4.13, 95% confidence interval [CI]: 1.25, 13.61). Improvements in disease activity, anxiety, depression, quality of life, and coping have been noted when cognitive-behavioral therapy (CBT) was provided to patients. A drop in the use of opiates (P = 0.037) and hospitalization rates (from 48% to 30%) in IBD patients has been noted as a result of introduction of the changed model of care. In addition, 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). CONCLUSION: Our data to date suggest that an integrated model of care for patients with IBD may yield superior long-term outcomes in terms of medication use and hospitalization rates and reduce healthcare costs.