P. John Hamlin

Poor Correlation Between Clinical Disease Activity and Mucosal Inflammation, and the Role of Psychological Comorbidity, in Inflammatory Bowel Disease

OBJECTIVES:There is a move toward patient-reported outcome measures as end points in clinical trials of novel therapies for inflammatory bowel disease (IBD). However, the association between patient-reported symptoms and mucosal inflammation, and the influence of psychological factors, remains unclear. We examined this in a secondary care population.METHODS:Validated patient-reported disease activity indices were used to define clinically active disease in a cohort of 356 patients with ulcerative colitis (UC) or Crohn’s disease (CD). A fecal calprotectin ≥250 μg/g was used to define active mucosal inflammation. The hospital anxiety and depression scale (HADS) and patient health questionnaire (PHQ)-15 were used to assess for anxiety, depression, or somatization, respectively. Logistic regression analysis was performed to determine the association between symptoms, mucosal inflammation, and psychological comorbidity.RESULTS:Clinical disease activity was associated with mucosal inflammation in UC (odds ratio (OR) 3.36; 95% confidence interval (CI) 1.34–8.47) but not in CD (OR 1.69; 95% CI 0.74–3.83). Depression in UC (OR 1.21 per 1-point increase in HADS; 95% CI 1.02–1.44) and somatization in UC (OR 1.17 per 1-point increase in PHQ-15; 95% CI 1.03–1.33) and CD (OR 1.31 per 1-point increase in PHQ-15; 95% CI 1.13–1.52) were associated with clinical disease activity. Overall, patient-reported symptoms yielded poor positive predictive values for mucosal inflammation in both CD and UC.CONCLUSIONS:Patient-reported symptoms and the Harvey–Bradshaw index were poor predictors of mucosal inflammation in CD. Psychological comorbidity was associated with gastrointestinal symptom-reporting. A shift in the focus of IBD management toward one addressing both psychological and physical well-being is required.

Negative Effects on Psychological Health and Quality of Life of Genuine Irritable Bowel Syndrome–type Symptoms in Patients With Inflammatory Bowel Disease

BACKGROUND & AIMS Symptoms compatible with irritable bowel syndrome (IBS) are common in patients with inflammatory bowel disease (IBD), but it is unclear whether this relates to occult IBD activity. We attempted to resolve this issue in a secondary care population by using a cross‐sectional study design. METHODS We analyzed Rome III IBS symptoms, disease activity indices, and psychological, somatization, and quality of life data from 378 consecutive, unselected adult patients with IBD seen in clinics at St Jamess University Hospital in Leeds, United Kingdom from November 2012 through June 2015. Participants provided a stool sample for fecal calprotectin (FC) analysis; levels ≥250 &mgr;g/g were used to define mucosal inflammation. By using symptom data and FC levels we identified 4 distinct groups of patients: those with true IBS‐type symptoms (IBS‐type symptoms with FC levels <250 &mgr;g/g, regardless of disease activity indices), quiescent IBD (no IBS‐type symptoms with FC levels <250 &mgr;g/g, regardless of disease activity indices), occult inflammation (normal disease activity indices and FC levels ≥250 &mgr;g/g, regardless of IBS symptom status), or active IBD (abnormal disease activity indices with FC levels ≥250 &mgr;g/g, regardless of IBS symptom status). We compared characteristics between these groups. RESULTS Fifty‐seven of 206 patients with Crohns disease (27.7%) and 34 of 172 patients with ulcerative colitis (19.8%) had true IBS‐type symptoms. Levels of psychological comorbidity and somatization were significantly higher among patients with true IBS‐type symptoms than patients with quiescent IBD or occult inflammation. Quality of life levels were also significantly reduced compared with patients with quiescent disease or occult inflammation and were similar to those of patients with active IBD. By using FC levels ≥100 &mgr;g/g to define mucosal inflammation, we found a similar effect of IBS‐type symptoms on psychological health and quality of life. CONCLUSIONS In a cross‐sectional study, we identified a distinct group of patients with IBD and genuine IBS‐type symptoms in the absence of mucosal inflammation. These symptoms had negative effects on psychological well‐being and quality of life to the same degree as active IBD. New management strategies are required for this patient group.

Effect of psychological therapy on disease activity, psychological comorbidity, and quality of life in inflammatory bowel disease: a systematic review and meta-analysis

BACKGROUND Inflammatory bowel disease is associated with psychological comorbidity and impaired quality of life. Psychological comorbidity could affect the natural history of inflammatory bowel disease. Psychological therapies might therefore have beneficial effects on disease activity, mood, and quality of life in patients with inflammatory bowel disease. We did a systematic review and meta-analysis examining these issues. METHODS In this systematic review and meta-analysis, we searched MEDLINE, Embase, Embase Classic, PsychINFO, and the Cochrane Central Register of Controlled Trials for articles published between 1947 and Sept 22, 2016. Randomised controlled trials (RCTs) recruiting patients with inflammatory bowel disease aged at least 16 years that compared psychological therapy with a control intervention or usual treatment were eligible. We pooled dichotomous data to obtain relative risks of induction of remission in active disease or prevention of relapse of quiescent disease, with 95% CIs. We pooled continuous data to estimate standardised mean differences in disease activity indices, anxiety, depression, perceived stress, and quality-of-life scores in patients dichotomised into those with clinically active or quiescent disease, with 95% CIs. We extracted data from published reports and contacted the original investigators of studies for which the required data were not available. We pooled all data using a random-effects model. FINDINGS The search identified 1824 studies, with 14 RCTs of 1196 patients eligible for inclusion. The relative risk of relapse of quiescent inflammatory bowel disease with psychological therapy versus control was 0·98 (95% CI 0·77-1·24; p=0·87; I2=50%; six trials; 518 patients). We observed a significant difference in depression scores (standardised mean difference -0·17 [-0·33 to -0·01]; p=0·04; I2=0%; seven trials; 605 patients) and quality of life (0·30 [0·07-0·52]; p=0·01; I2=42%; nine trials; 578 patients) with psychological therapy versus control at the end of therapy for patients with quiescent disease. However, these beneficial effects were lost at final point of follow-up (depression scores -0·11 [-0·27 to 0·05], p=0·17, I2=0%, eight trials, 593 patients; quality of life 0·15 [-0·05 to 0·34], p=0·14, I2=22%, ten trials, 577 patients). When we assessed the effect of individual physiological therapies on quality of life, only cognitive behavioural therapy had any significant beneficial effect (0·37 [0·02-0·72]). We noted no effect on disease activity indices or other psychological wellbeing scores when compared with control in patients with quiescent disease. Dichotomous data for induction of remission and continuous data for change in clinical disease activity indices, depression, anxiety, and perceived stress scores were only reported in one RCT of patients with active disease. Quality of life was assessed in two RCTs of patients with active disease, but was not significantly different between intervention and control groups (0·27 [-0·05 to 0·59]). INTERPRETATION Psychological therapies, and cognitive behavioural therapy in particular, might have small short-term beneficial effects on depression scores and quality of life in patients with inflammatory bowel disease. Further RCTs of these interventions in patients with coexistent psychological distress are required. FUNDING None.

Adalimumab as second line anti-tumour necrosis factor alpha therapy for Crohn's disease: A single centre experience

BACKGROUND AND AIMS Non-response, loss of response, or intolerance to anti-tumour necrosis factor alpha (anti-TNFα) therapy is well recognised in Crohns disease (CD) patients. Data concerning outcomes following the use of a second anti-TNFα therapy, particularly in patients who do not respond to a first anti-TNFα agent, are still emerging. The aim of this study was to assess response and tolerability to adalimumab following infliximab failure in a single centre cohort of CD patients. METHODS Data were collected prospectively on 44 patients who received adalimumab therapy following infliximab failure. Initial response to adalimumab therapy at 6weeks following induction was defined using a two point decrease in the Harvey-Bradshaw Index, with remission at this point defined using a Harvey Bradshaw index≤4. Sustained clinical benefit at the last point of follow up was determined using a physicians global assessment. Corticosteroid-free sustained clinical benefit was also assessed at this point. RESULTS Thirty-four (77%) patients had initial response to adalimumab therapy, with 28 (64%) having sustained clinical benefit. Corticosteroid-free sustained clinical benefit was achieved in nine (53%) of 17 patients requiring steroids at commencement of adalimumab. Four (44%) of the 9 patients who were primary non-responders to infliximab responded to adalimumab. The majority of CD patients who failed adalimumab therapy required surgery. CONCLUSIONS Second-line anti-TNFα therapy with adalimumab is effective at both inducing remission and maintaining response in CD patients who have failed infliximab, regardless of the reason for infliximab failure.

Bi-directionality of Brain–Gut Interactions in Patients With Inflammatory Bowel Disease

BACKGROUND & AIMS Inflammatory bowel diseases (IBD) are associated with mood disorders, such as anxiety or depression, but it is not clear whether one contributes to development of the other, or if the interaction is bi-directional (anxiety or depression contributes to the progression of IBD, and IBD affects psychological health). We performed a 2-year longitudinal prospective study of patients in secondary to care investigate the bi-directionality of IBD and mood disorders. METHODS We collected data from 405 adult patients with a diagnosis of Crohns disease (CD) or ulcerative colitis (UC) from November 2012 through June 2017. Demographic features, subtypes of IBD, treatments, symptoms, somatization, and fecal level of calprotectin were recorded at baseline. IBD activity was determined at baseline and after the follow-up period (2 years or more) using the Harvey-Bradshaw Index for CD and the Simple Clinical Colitis Activity Index for UC (scores ≥5 used to define disease activity). Anxiety and depression data were collected using the Hospital Anxiety and Depression Scale (HADS), at baseline and after the follow-up period. Objective markers of disease activity, including glucocorticosteroid prescription or flare of disease activity, escalation of therapy, hospitalization secondary to IBD activity, and intestinal resection during follow-up were assessed via case note review. A brain-gut direction of disease activity was defined as development of new IBD activity in patients with quiescent IBD and abnormal HADS scores at baseline. A gut-brain direction of disease activity was defined by subsequent development of abnormal HADS scores in patients with active IBD and normal HADS scores at baseline. We performed multivariate Cox regression controlling for patient characteristics and follow-up duration. RESULTS Baseline CD or UC disease activity were associated with an almost 6-fold increase in risk for a later abnormal anxiety score (hazard ratio [HR], 5.77; 95% CI, 1.89-17.7). In patients with quiescent IBD at baseline, baseline abnormal anxiety scores were associated with later need for glucocorticosteroid prescription or flare of IBD activity (HR, 2.08; 95% CI, 1.31-3.30) and escalation of therapy (HR, 1.82; 95% CI, 1.19-2.80). These associations persisted when normal IBD activity index scores and fecal level of calprotectin <250 μg/g were used to define quiescent disease at baseline. CONCLUSIONS In a 2-year study of patients with CD or UC, we found evidence for bi-directional effects of IBD activity and psychological disorders. Patients with IBD should be monitored for psychological well-being.

Costs of adalimumab versus infliximab as first-line biological therapy for luminal Crohn's disease.

BACKGROUND AND AIMS Randomised controlled trials demonstrate that the anti-tumour necrosis factor-α (anti-TNFα) therapies infliximab and adalimumab are effective in inducing remission and preventing relapse of Crohns disease (CD). As few studies have compared costs and efficacy of these two drugs directly, we examined this issue. METHODS Data were collected for patients receiving either drug as first-line anti-TNFα for CD. Patients were matched as closely as possible on age, gender, weight, height, and date of commencement of therapy. Response to induction therapy was assessed at 12weeks, and sustained clinical benefit at last point of follow-up. Resource data were collected for all patients until study end, with National Health Services reference costs applied to calculate the total cost per patient with adalimumab compared with infliximab. RESULTS Thirty-six patients had been treated with adalimumab as first-line anti-TNFα since 2010. We matched an identical number of infliximab patients. Demographic data were similar between the two groups. Costs were significantly lower with adalimumab (£6692.95 less per patient (95% confidence interval £1816.61-£11569.29)), which was largely driven by the drug costs and drug administration costs associated with infliximab. Twenty-nine (80.6%) patients responded to induction therapy with both drugs, and 22 (61.1%) achieved glucocorticosteroid-free sustained clinical benefit with either drug at last point of follow-up. CONCLUSIONS Costs of infliximab used as first-line anti-TNFα therapy are greater, which may have implications for selection. Clinical outcomes appeared comparable, although power to detect a statistically significant difference would be limited.

VSL#3 and remission in active ulcerative colitis: larger studies required.

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Utility of fecal calprotectin in differentiating active inflammatory bowel disease from coexistent irritable bowel syndrome.

Utility of Fecal Calprotectin in Differentiating Active Inflammatory Bowel Disease From Coexistent Irritable Bowel Syndrome

Longitudinal impact of IBS-type symptoms on disease activity, healthcare utilization, psychological health, and quality of life in inflammatory bowel disease

OBJECTIVES: The impact of irritable bowel syndrome (IBS)‐type symptoms on the natural history of inflammatory bowel disease (IBD) is uncertain. We aimed to address this in a longitudinal study of secondary care patients. METHODS: Longitudinal disease activity was defined by disease flare, escalation of medical therapy, hospitalization, or intestinal resection. The number of investigations performed and clinics attended determined healthcare utilization. Psychological well‐being and quality of life were assessed using validated questionnaires. These outcomes were compared over a minimum period of 2 years between patients reporting IBS‐type symptoms and patients with quiescent disease, occult inflammation, and active disease at baseline. RESULTS: In 360 IBD patients, there were no differences in longitudinal disease activity between patients with IBS‐type symptoms and patients with quiescent disease or occult inflammation. Disease flare and escalation of medical therapy was more common in patients with active disease than in patients with IBS‐type symptoms (hazard ratio (HR) = 3.16; 95% confidence interval (CI) 1.93–5.19 and HR = 3.24; 95% CI 1.98–5.31, respectively). A greater number of investigations were performed in patients with IBS‐type symptoms than quiescent disease (P = 0.008), but not compared with patients with occult inflammation or active disease. Anxiety, depression, and somatization scores at follow up were higher, and quality‐of‐life scores lower, in patients with IBS‐type symptoms when compared with patients with quiescent disease, but were similar to patients with active disease. CONCLUSIONS: IBS‐type symptoms in IBD were associated with increased healthcare utilization, psychological comorbidity, reduced quality of life, but not adverse disease activity outcomes during extended follow‐up.

Is the Benefit of Granulocyte Monocyte Adsorptive Apheresis in Ulcerative Colitis Overstated

To the Editor We read the recent meta-analysis of Habermalz and Sauerland concerning the role of granulocyte monocyte adsorptive (GMA) apheresis in ulcerative colitis (UC) with interest [1]. While we agree that GMA apheresis may have a useful role in patients with UC who are steroid-dependent and have failed other therapies, there are several limitations of their study that, we feel, caution against the wholesale application of the findings to clinical practice. Firstly, the quality of the included studies was generally poor. Less than half of the studies reported the method used to generate the randomization schedule, the method used to conceal allocation, or blinded evaluators to treatment allocation. Lack of reporting of, or adherence to, these features of trial design would have led to an exaggeration of the treatment effect of GMA apheresis [2]. Secondly, the authors stated that ‘‘the meta-analysis was restricted to randomized controlled trials’’ (RCTs), yet they acknowledged that one of the trials was not a true RCT [3], but rather a quasi-randomized study, with participants allocated alternately to active therapy, or control. This type of study design is liable to selection bias, which may also overestimate the efficacy of active therapy. Thirdly, they stated in the discussion that ‘‘most of the results were not heterogeneous across the trials’’. In their analysis of RCTs reporting outcomes at 6 weeks, the I value was 63%, representing a significant degree of heterogeneity between studies [4]. Among the RCTs reporting data at 12 weeks, the I value was 0%, but as there were only three studies contributing data to this analysis, there would be limited power to detect any heterogeneity. The authors should therefore have used a random effects model [5], to give a more conservative estimate of the efficacy of GMA apheresis. Fourthly, the largest RCT conducted in this area showed no significant effect of GMA apheresis on remission or response [6]. Bizarrely, the authors stated in their discussion that they did not consider the results of that study to be in conflict with the meta-analysis, quoting an exploratory analysis of data from this RCT to support this assertion. As this was a post hoc analysis, rather than a pre-specified secondary analysis of the RCT, it should not be extrapolated to the findings of their meta-analysis. Finally, response and remission rates were combined in the meta-analysis, despite the fact that most of the trials they identified reported these separately, because the authors believed ‘‘high remission rates would negatively impact response rates.’’ An analysis of remission rates alone, and of remission or response rates combined was entirely feasible. This would have failed to demonstrate any significant benefit of GMA apheresis on remission in UC. The author’s final conclusion is that ‘‘current data indicate, uniformly, that GMA apheresis is more successful than drug therapy in achieving response and remission in UC’’. We disagree, and believe that larger, more rigorously designed RCTs are required before the role of GMA apheresis in UC is clear.