By Russell H. Greenfield, MD
Clinical Professor of Medicine, UNC-Chapel Hill School of Medicine
Dr. Greenfield reports no financial relationships relevant to this field of study.
Synopsis: Disappointing results from this double-blind, time-/attention-controlled study would cast doubt on the potential benefits of mindfulness-based stress reduction for people with moderately severe ulcerative colitis were it not for the presence of significant shortcomings in study methodology.
Source: Jedel S, et al. A randomized controlled trial of mindfulness-based stress reduction to prevent flare-up in patients with inactive ulcerative colitis. Digestion 2014;89:142-155.
Summary Points
- Ulcerative colitis (UC) is a chronic inflammatory disorder primarily affecting the mucosal lining of the colon and rectum. Clinical experience suggests that psychosocial stress may induce disease flare-ups.
- Mindfulness-based stress reduction (MBSR) is an effective stress management technique that often enhances a person's ability to cope with difficulties.
- This small, randomized, controlled trial largely failed to show meaningful clinical improvement in subjects with moderately severe UC in remission who practiced MBSR as opposed to controls. Methodological shortcomings were significant.
Ulcerative colitis (UC) is a chronic inflammatory disorder primarily affecting the mucosal lining of the colon and rectum. The disease course of UC is marked by variable periods of remission and flare-up with symptoms including abdominal pain, diarrhea, and rectal bleeding. An underlying cause for the disease has yet to be determined, and there is presently no cure. As such, clinical management is focused on reducing frequency and severity of flare-ups and associated complications, with heavy reliance on prescription medication such as prednisone, immunosuppressants, and biologics.
However, research strongly suggests that psychosocial stress can initiate the body’s pro-inflammatory cascade and potentially induce UC flare-ups. By extension, there has been growing interest in the use of stress-reduction techniques to help modulate disease activity in disorders having an inflammatory component. One of the most promising approaches is mindfulness-based stress reduction (MBSR), originally championed by Jon Kabat-Zinn and now offered in clinics around the globe.1 Mindfulness defines a state of focused attention that can be described as awareness of experience without evaluation or judgment.2 Data suggest that MBSR may offer therapeutic benefit in a variety of clinical settings, including mood disorders, chronic pain, cancer, post-traumatic stress disorder, and conditions characterized by inflammation. The aim of this randomized (concealed), double-blind, time-/attention-controlled study was to investigate the effects of MBSR on disease course (flare frequency), quality of life (QOL), markers of inflammation, and psychological parameters in people with moderately severe UC in remission over a 12-month period.
Patients aged 18-70 years were recruited from the Rush University Medical Center Inflammatory Bowel Disease (IBD) Clinic and the Greater Chicago area. Inclusion criteria included moderately severe but inactive UC (confirmed in all subjects through physical examination and sigmoidoscopy), at least one flare-up within the past 6 months, and taking no IBD medication or on a stable dose for at least 3 weeks prior to enrollment. Exclusion criteria included use of antibiotics within the prior month or anti-diarrheal medications within the previous week, unresolved history of physical or sexual abuse, current or past dissociative disorder, history of psychosis or prior hospitalization for self-harm/suicidal ideation, and prior mind/body therapy training. A clinical psychologist screened prospective subjects for psychiatric eligibility.
Participants were advised that they would be randomized to one of two courses of mind/body therapy, neither of which had been rigorously tested in people with UC but that were associated with health benefits in other settings. Baseline data (including self-report questionnaires, serum samples, 24-hour urine and stool collection) were collected at the first study visit, and subjects were assigned to either MBSR or a time-/attention-control group. The MBSR program followed the 8-week curriculum developed by Kabat-Zinn,3 including weekly 2.0-2.5 hour sessions of instruction in formal exercises such as sitting meditation, body scans, and yoga postures as well as more informal practices aimed at promoting mindfulness in everyday life. Homework assignments involved 45 min/day of CD-guided MBSR 6 days per week. A physician or psychologist with significant personal MBSR experience taught the courses. The control group was assigned eight sessions of slightly shorter duration in which information on stress and its physical effects was shared via lecture or video (program intended to control for time, support, and attention). Subjects started their programs within 1 month of baseline assessment. For both courses, compliance was defined as attendance at a minimum of five classes.
Assessments occurred at baseline (visit 1, pretreatment visit), post 8-week course (visit 2, weeks 9-12), and at 6- and 12-month follow-ups (visits 3 and 4). Data analysis was initiated only after all subjects had completed the study. If a UC flare-up developed at any point, the subjects completed their assessments and were then removed from the study. Primary outcome of interest was disease status defined as Mayo UC-DAI > 2 (a commonly employed composite measure of UC disease activity that accounts for stool consistency, rectal bleeding, findings on endoscopy, and physician global assessment), plus a rectal bleeding score > 2 and sigmoidoscopy score of > 2. Secondary outcomes of interest included changes in markers of inflammation and disease activity (calprotectin levels, cytokines [IL-6, IL-8, IL-10], CRP, the Inflammatory Bowel Disease Quality-of-Life (QOL) Questionnaire [IBD-Q]), as well as markers of stress and psychological assessments (serum ACTH, the Perceived Stress Questionnaire [PSQ], the Beck Depression Inventory [BDI], the State-Trait Anxiety Inventory (STAI), the Mindful Attention Awareness Scale [MAAS], and the Perceived Health Competence Scale [PHCS]). Intention-to-treat analysis was performed; participants who flared during the intervention were included in the analysis.
A total of 55 subjects met inclusion criteria and underwent randomization. Subjects in the MBSR group were about 7 years older than those in the control group at the time of UC diagnosis, had less severe symptoms, and were significantly older at time of participation in the study. Patients in both groups had moderately severe UC, with more than 40% being prednisone-dependent and averaging two flare-ups during the year prior to enrolling in the study. Two participants (one in each group) dropped out during their 8-week courses, while two patients randomized to MBSR and one in the control group attended fewer than five classes.
At the end of the study, no statistically significant difference existed between the two groups with respect to disease activity, the primary outcome of interest (number of flare-ups 13/27 = 48% MBSR group, 14/26 = 54% controls). Regarding secondary measures, no differences between the two groups were detected for calprotectin levels associated with flare-ups, or for time to and severity of flare-up. Serum levels of the anti-inflammatory cytokine IL-10 increased in patients in the MBSR group who flared, whereas IL-10 levels decreased in control group members who experienced a flare-up. Mixed-model analysis revealed significantly better QOL among subjects with UC flare-ups in the MBSR group compared to flared control group members as measured by the IBD-Q Total Scale (P = 0.001) and the bowel (P = 0.01) and emotion (P = 0.01) subscales, respectively. Among patients who experienced flare-ups, those in the MBSR group demonstrated significantly lower PSQ total (55.17 ± 8.66) and index scores (0.29 ± 0.10) at last visit. There were, however, no differences between members of the two groups, with flare-ups on measures of depression, anxiety, mindfulness, or perceived health competence (BDI: P = 0.64; STAI: P = 0.12; MAAS: P = 0.91; PHCS: P = 0.30). Likewise, there were no differences between MBSR and control groups on measures of depression (BDI: P = 0.75), anxiety (STAI: P = 0.92), mindfulness (MAAS: P = 0.43), or perceived health competence (PHCS: P = 0.33) at last visit among participants who did not experience a flare.
Post-hoc analysis showed that MBSR group subjects with the most severe symptoms at baseline (upper tertile of the IBD-Q Bowel Subscale) demonstrated a positive effect of MBSR as compared to those exhibiting less severe symptoms (upper tertile vs lower tertile, P < 0.001), something not observed in the control group. In addition, MBSR subjects within the highest tertile of baseline PSQ scores experienced a reduced flare-up rate compared to controls in the highest tertile. Flare rate among MBSR group subjects in the top tertile of baseline cortisol levels was reduced compared to controls with comparable baseline cortisol.
The authors conclude that MBSR did not affect the rate or severity of flare-ups in UC patients with moderately severe disease in remission, but that MBSR might be effective for those with high levels of perceived stress and urinary cortisol measures during remission. MBSR might improve QOL in similar UC patients who experience disease flare-ups by encouraging non-judgmental acceptance of their circumstances, thereby reducing any negative impact on QOL.
Commentary
It is, of course, far easier to sit in judgment of published research than to identify a problem that needs a solution, develop a research protocol, perform the study, assess the results, and finally share one’s findings in peer-reviewed literature. The research team behind the present work authentically deserve praise for their efforts, yet bear responsibility for significant methodological flaws (which they accept in the paper) that would have relegated any findings to a footnote worthy of interest at best and, at worst, to an opportunity lost. Unfortunately, the paper in question reads more like the latter.
The seed of the study makes good sense — MBSR has shown promise in numerous clinical scenarios. Since UC flare-ups and psychosocial stress seem intimately related, one could reasonably assume that MBSR would offer potential benefit in the setting of moderately severe disease. Positive findings from the trial are few and far between, although the importance of a positive effect on QOL measures should not be minimized. The results do not, however, suggest a meaningful clinical impact of MBSR on disease course or measures of inflammation in subjects with moderately severe UC. On the surface, this may be surprising, but the results were doomed from the outset due to factors including small sample size, significant baseline differences between the two groups, and a control group well-matched for time but not for attention and support. In addition, while the MBSR course was taught by practitioners with lengthy personal experience, it is unknown if the instructors were actually certified as MBSR trainers. A person long-committed to a practice is not necessarily an effective instructor in that practice, and individual response to training often varies based on the trainer’s skill, and, perhaps, their interpersonal skills.
In the end, and in the face of disappointing results, the research team offered that MBSR is a low-risk intervention that may still be of benefit to select patients with UC who respond poorly to psychosocial stress, even if it does not significantly impact disease course. That conclusion existed in the minds of many practitioners before the study began, and is neither burnished nor dulled by its publication due to the aforementioned shortcomings. Many prior studies suggest that MBSR can be a valuable tool in helping people cope with life’s challenges and uncertainties, even in the absence of an impact on clinical symptoms. A future paper by the researchers will address relevant findings of the interventions on stool microbiota, but their methodology will remain a weakness. MBSR is a promising intervention in various clinical settings, including UC. The research efforts behind this paper, though laudable, have unfortunately not borne clinically useful fruit.
References
- Kabat-Zinn J. Mindfulness-based interventions in context: Past, present, and future. Clin Psychol Sci Pract 2003;10:144-156.
- Selfridge N. Mindfulness based stress reduction: Non-doing for well-being. Altern Med Alert 2011;14:56-60.
- Kabat-Zinn J. Full Catastrophe Living: Using the Wisdom of Your Body and Mind to Face Stress, Pain and Illness. New York, Delacorte Press; 1990.
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