Download Inflammatory Bowel Disease and Stress

Inflammatory Bowel Disease and Stress
Inflammatory Bowel Disease
Inflammatory Bowel Disease (IBD) is a chronic inflammatory disease that consists primarily of 2
disorders, ulcerative colitis (UC) and Crohn's disease (CD). Approximately 1.6 million Americans
have IBD with more than 70,000 new cases every year.1 A majority of patients are diagnosed
before turning 35 years old, so subsequent lifetime treatment and management of IBD is
necessary. Even with treatment for IBD, active disease or recurrences occur. For UC, in a
designated year, an estimated 51% of patients have active disease, while for CD, in a 5 year
period, approximately 50% of patients will have moderate or severe disease.2
Medication is the primary treatment option for IBD3 with the main objectives of reaching and
maintaining remission and improving the quality of life. Since this disease is comprised of 2 main
types, and CD can vary in location, no standard regimen exists. There are 5 general groups of
medications for IBD: aminosalicylates (primarily for UC, may not work as well for CD),
corticosteroids (not indicated for long-term use due to side effects), immunomodulators
(typically administered to patients who did not respond to other medications or that responded
only to steroids), antibiotics (may provide small improvement for infections or CD that occurs in
the colonic or anal region), and biologic therapies (for those with moderate to severe disease for
whom conventional therapy was not effective). If further complications occur, surgery is the
next treatment considered. After 3 decades, as much as 33% of UC patients will require surgery,
while over time, approximately 70% of patients with CD will require surgery.2 Although current
therapies are able to control symptoms in approximately half of IBD patients, disadvantages
such as side effects (especially with corticosteroids) or expense (particularly with biologics) exist.
Controlling stress, which may contribute to IBD recurrence, could allow maintenance therapies
to work more effectively, prolong remission4,5, and potentially decrease the amount of
medications required to treat flare ups or more severe disease.6
Stress
Stress can be defined as a circumstance that overcomes the patient’s coping ability. 7 In patients
with IBD, stress may be related to or independent of the disease. The effects of stress can be
bidirectional, stress inducing flares or vice versa.8 For the population with IBD, there are
medical, psychological, and social contributors to stress. Symptoms, such as IBD flares or
infections are often unpredictable and inconvenient; complications may require surgery. An
increased risk of developing other diseases such as colorectal cancer9 and blood clots10 is also a
concern for patients with IBD. A higher rate of anxiety and depression is present in these
patients as compared with non-IBD controls. 11 IBD symptoms have been shown to disrupt
responsibilities including work, school, parenting, and recreational and social activities.12-15
Furthermore, a financial burden may weigh on patients due to time away from work or the cost
of chronic care and medications.16
Association Between Stress and IBD
Increasing evidence in animals and man shows that stress can negatively impact the central and
autonomic nervous systems (CNS and ANS, respectively) and subsequently alter intestinal
permeability and proinflammatory cytokine production.17-19 Interactions between the CNS and
the gut (via the corticotropin-releasing factor system, the hypothalamic-pituitary axis, and the
prefrontal amygdaloid complex) and those between the ANS and the gut (via the vagus nerves
and the sympathetic nerves) likely mediate these changes in the intestines.17,18,20-24 The
microbiome can also play a role in feedback from the gut to the nervous system or vice
versa.25,26
Two key clinical studies showed evidence for stress triggering increased IBD-related activity. A
prospective 1-year study in 383 patients with IBD compared participants with at least 1 flare to
those who had none. In these patients, high perceived stress was significantly related to
increased risk of flare (adjusted odds ratio = 2.40 [1.35, 4.26]). Other factors significantly
associated with flares were negative disposition and crucial life events.27 Another clinical study
demonstrated that in quiescent UC, acute stress elevated inflammatory parameters in the
rectum and blood when compared with the control treatment parameters.19 Specifically,
significant changes in the rectal mucosa TNF-α (increased by 102% in the perimucosal fluid [P =
.03]), reactive oxygen metabolites (increased by 475% [P = .001]), and blood flow (decreased by
22% [P = .05]) were noted. These data suggest acute stress may elicit inflammation that causes
relapse in inactive UC.
In addition, other clinical trials have demonstrated a relationship between perceived stress and
IBD. Higher perceived stress was linked to worse psychological health in patients with IBD than
in controls28,29 while inversely, in quiescent CD, patients who had lower stress and healthier
social coping mechanisms had a lower rate of relapse than patients with CD who had higher
stress.30 Higher scores of anxiety and depression (associated with perceived stress) as measured
by the Hospital Anxiety and Depression Scale were noted in patients with UC (anxiety score: 8.5
± 4.1 [mean ± SD] and depression score: 4.1 ± 3.3) and CD (8.6 ± 3.9 and 4.7 ± 3.3) than those in
healthy controls (3.2 ± 1.8 and 1.7 ± 1.4, respectively, P<.001 for both comparisons). A growing
number of reviews of clinical data cite the contribution of stress and psychological factors to the
course of UC and CD.31-33
Treating IBD by Treating Stress
Using medication to treat to treat flares and surgery to treat complications are the conventional
approaches to reducing the stress arising from IBD symptoms.34 However, since multiple factors
can contribute to stress, there is potential to address other causes of stress through adjunctive,
non-pharmacologic means. Substantial evidence exists for the efficacy of adjunctive, nonmedicinal therapies, such as cognitive behavioral therapy (CBT), hypnosis, and stress
management education/relaxation, as well as multimodal therapies in the treatment of IBS.35-44
However, there is limited evidence for the impact of these types of intervention in IBD, as
described in the studies below. If stress remains after non-pharmacologic interventions are
implemented, medication for psychological disorders, eg AD or depression may be
adminstered.45
Two small clinical studies have exhibited promising results using hypnotherapy intervention in
patients with UC. The largest was the Ulcerative Colitis Relapse Prevention Trial, a randomized,
prospective study in patients (54) with inactive UC that demonstrated hypnotherapy
significantly extended remission by 78 days (F-test = 4.8 [1, 48], P = .03) compared with controls.
Furthermore, at 1 year, a significantly (Chi square [χ2] = 3.9, P = .04) increased proportion of the
hypnotherapy cohort (68%) remained in remission compared with the control cohort (40%;
NCT00798642).5 Gut-directed hypnotherapy was administered in 7 weekly sessions which
transitioned to recommended self-hypnosis audio therapy; control treatment was non-directive
conversation about UC and the mind-body connection. UC symptoms were self-reported for
both groups.
Another pilot study in 17 patients with active UC showed hypnotherapy significantly decreased
the rectal mucosal levels of substance P (by 81% [P= 0.001]), histamine (by 35% [P=0.002]) and
IL-13 by 53% [P=0.003]), as well as significantly decreasing rectal mucosal blood flow (by 18%
[P=0.0004]).46 The levels of these components of inflammation post-hypnosis in active UC were
similar to those in quiescent disease. Patients administered a control procedure did not show
changes in the parameters assessed. Samples were collected from participants before and after
either the single hypnosis or control treatment.
While there is little data currently to support CBT effectiveness in adult patients with IBD (many
of whom likely have mood disorders) 47, there is data to support CBT use for stress-related
disorders such as anxiety disorder (AD).48 There is also limited evidence that CBT may be
effective in adolescents with IBD and AD. A single-arm study with 9 teenagers with IBD and AD
reported after a CBT program, 88% of the participants responded to the therapy and 50% did
not have AD any longer. Self-reported reductions in anxiety, pain, and disease severity were
noted.4
Multimodal therapy for IBD has also been investigated in 2 studies. A recent, uncontrolled pilot
study (in 48 patients with either IBD or IBS) of relaxation response based mind-body group
intervention (RR-MBI), demonstrated significant improvements in disease symptoms, quality of
life, pain, and anxiety and decreased gene expression for genes associated with inflammation,
cellular growth and division, and oxidative stress pathways.49 Participants engaged in a 9-week
RR-MBI (which included learning and practicing relaxation techniques and cognitive skills) were
given validated questionnaires (at baseline and 3 additional time points) and sampled for blood
(at baseline and post-intervention). For patients with IBD, at post-treatment (Week 10) and
follow-up (Week 13), scores were significantly improved for quality of life and symptom impact
(P<.01), pain (P<.003), and anxiety (P<.012). Other changes in IBD included downregulation of
genes involved in cell cycle/proliferation and immunology (e.g. MAPK, UBC, APP, and P38 MAPK)
and inflammation (eg VEGF-C, NF-κB).
Additionally, another study exhibited positive effects in IBD after multimodal treatment. A
randomized pilot study of patients (28) with inactive CD demonstrated improvements in patientreported disease severity (F-test = 6.5, P = .02) and quality of life (F-test = 15.2, P = .001),
perceived stress (F-test = 8.4, P = .01), and self-efficacy (F-test = 12.2, P = .003) scores compared
with controls following project management therapy.50 The 6-week treatment was designed to
appeal to patients that may not seek CBT support and were not diagnosed with psychological
disorders. The treatment combined project management philosophy with CBT skills and
disease/lifestyle management.
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